Compounds and methods for modulating ras-PI3k

Abstract

Compounds and methods for modulating RAS-PI3K.

Description

COMPOUNDS AND METHODS FOR MODULATING RAS-PI3KCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit under 35 U. S. C. § 119(e) of the earlier filing date of U. S. Provisional Patent Application No. 63 / 776,656, filed March 24, 2025, the entire content of which is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The disclosure relates to compounds and methods for modulating RAS-PI3K.BACKGROUND OF THE DISCLOSURE

[0003] There is a need for improved cancer therapeutics and methods of treatment.SUMMARY

[0004] Disclosed herein in some aspects are modulators of RAS-PI3K. Some aspects relate to a RAS-PI3K inhibitor. Some such aspects relate to a RAS-PI3K antagonist or agonist. The RAS-PI3K modulators may include a compound described herein. The RAS-PI3K modulators may be useful in a method described herein.

[0005] In one aspect, described herein is a compound having the structure of Formula (I),Formula (I),wherein,X is CH, or N,X1is CH, CF, or N; wherein only one of X1and X may be N,X2is CH or N,R1is -H, -CH3, or -O-CH3,in whichn is 1 or 2,Ra is -H, -CH3, or -CH2-CH3,Rb is -CN, -S(O)2-CH3, -S(=O)(=NH)-CH3, -S(=O)(=N-CH3)-CH3, -S(=O)(=N-phenyl)-CH3, orR3is -H or -F,R4is -F, -Cl, or -CH3, andis a 5 or 6 membered monocyclic heterocycle comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, cyclopropyl, oxo,is a 6, 7, 8, 9, 10, or 11 membered fused bicyclic or spiro bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, 1, or 2 oxygen atoms substituted with 0, 1, 2, or 3 substituents independently selected from -CHs, -CN, -CH2-CN, -CH2-OH, -CH2F, -F, oxo, -C(O)-CH3, -C(O)-OCH3, -CH2-CHF2, -CH2-CF3, -CH2-O-CH3, -O-CH3, -CH2-O-CH(CH3)2, -CH2-CH2-OH, -CH2-CH2-O-CH3, -is an 8 or 9 membered bridged heterocyclic ring system comprising 1 nitrogen atom and 1 oxygen atom substituted with 0 or 2 -F,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0006] In another aspect, described herein is a compound having the structure of Formula (I -a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I-a),wherein,X is CH or N,X1is CH or N; wherein only one of X1and X may be N,X2is CH or N,R1is -H or -CH3,n is 1 or 2,Ra is -H,Rb is -H, -CH3, or -CH2-CH3,Rc is -H,wherein when Rd- is -S(O)2-CH3, Rc- and Rd’ are trans to each other, orRc-, Rd- together with the carbon atoms they are attached to formR3is -H or -F,R4is -F, -Cl, or -CH3, andis a 5 or 6 membered monocyclic heterocycle comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, cyclopropyl, or oxo, oris a 6, 7, 8 or 10 membered fused, bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, -CN, -CH2-CN, -CH2-OH, -CH2F, -F, or oxo.

[0007] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0008] In another aspect, provided herein is a method of inhibiting RAS PI3K, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0009] In another aspect, provided herein is a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0010] In another aspect, provided herein is use of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the treatment of cancer.

[0011] In another aspect, provided herein is use of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the preparation of a medicament for the therapeutic treatment of cancer.

[0012] In another aspect, provided herein is use of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the treatment of an immunological disease or condition.

[0013] In another aspect, provided herein is use of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the preparation of a medicament for the therapeutic treatment of an immunological disease or condition.

[0014] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0016] RAS proteins are small GTPases known for their involvement in oncogenesis. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate cellular functions such as cell proliferation, differentiation, apoptosis, and senescence.Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. It is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro. Mice with mutations in the PI3K catalytic subunit pl 10a that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRAS-induced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature.

[0017] Disclose herein are compounds and methods for modulating RAS-PI3K activity. Some embodiments relate to a compound or method of inhibiting RAS-PI3K activity. Some embodiments relate to a compound or method of activating RAS-PI3K activity. The modulating of RAS-PI3K activity may be in vitro or in vivo. The compound for modulating RAS-PI3K may be formulated for administration to a subject. The RAS-PI3K modulation may be performed in a subject.

[0018] The compounds disclosed herein may be useful for treatment of diseases where RAS-PI3K activity may be a concern. In some embodiments, the compound is used for treatment of cancer. In some embodiments, the compound is used for treatment of an immunological disease or condition. In some embodiments, the compound is used for wound healing.COMPOUNDS OF THE DISCLOSURE

[0019] Disclosed herein in some embodiments are modulators of RAS-PI3K, such as inhibitors of RAS-PI3K.

[0020] In one aspect, described herein is a compound having the structure of Formula (I),Formula (I),wherein,X is CH, or N,X1is CH, CF, or N; wherein only one of X1and X may be N,X2is CH or N,R1is -H, -CH3, or -O-CH3,is a 5 or 6 membered monocyclic heterocycle comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, cyclopropyl, oxo,is a 6, 7, 8, 9, 10, or 11 membered fused bicyclic or spiro bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, 1, or 2 oxygen atoms substituted with 0, 1, 2, or 3 substituents independently selected from -CH3, -CN, -CH2-CN, -CH2-OH, -CH2F, -F, oxo, -C(O)-CH3, -C(O)-OCH3-CH2-CHF2, -CH2-CF3, -CH2-O-CH3, -O-CH3, -CH2-O-CH(CH3)2, -CH2-CH2-OH, -CH2-CH2-O-CH3is an 8 or 9 membered bridged heterocyclic ring system comprising 1 nitrogen atom and 1 oxygen atom substituted with 0 or 2 -F,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0021] In another aspect, provided herein is a compound having the structure of Formula (I -a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I-a),wherein,X is CH or N,X1is CH or N; wherein only one of X1and X may be N,X2is CH or N,R1is -H or -CH3,S(O)2-CH3, Rc and Rd- are trans to each other, orRc-, Rd- together with the carbon atoms they are attached to formR3is -H or -F,R4is -F, -Cl, or -CH3, andis a 5 or 6 membered monocyclic heterocycle comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, cyclopropyl, or oxo, oris a 6, 7, 8 or 10 membered fused, bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, -CN, -CH2-CN, -CH2-OH, -CH2F, -F, or oxo.

[0022] In some embodiments,wherein indicates attachment to the nitrogen atom of

[0023] In some embodiments,

[0024] In some embodiments,

[0025] In some embodiments,

[0026] In some embodiments,

[0027] Further embodiments include:The compound of Formula (I), whereinXis N, X1is CH, X2is CH; orXis CH, X1is N, X2is CH.or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0028] The compound of Formula (I), wherein is 6, 7, 8, 9, or 10 membered fused bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, 1, or 2 oxygen atoms substituted with 0, 1, 2, or 3 substituents independently selected from -CH3, -CN, -CH2-CN, - CH2-OH, -CH2F, -F,-oxo, -C(O)-CH3, -C(O)-OCH3, -CH2-CHF2, -CH2-CF3, -CH2-O-CH3, -O-or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0029] The compound of Formula (I), wherein X is N.

[0030] The compound of Formula (I), wherein X1is CH.

[0031] The compound of Formula (I), wherein X1is CF.

[0032] The compound of Formula (I), wherein X1is N.

[0033] The compound of Formula (I), wherein only one of X1and X is N.

[0034] The compound of Formula (I), wherein X2is CH.

[0035] The compound of Formula (I), wherein X2is N.

[0036] The compound of Formula (I), wherein R1is -H.

[0037] The compound of Formula (I), wherein R1is -CH3.

[0038] The compound of Formula (I), wherein R1is -O-CH3.

[0039] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rais -H.

[0040] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rais -CH3.

[0041] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rais -CH2-CH3.

[0042] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rb is - CN,

[0043] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rb is - S(O)2-CH3.

[0044] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rb is - S(=O)(=NH)-CH3.

[0045] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rb is - S(=O)(=N-CH3)-CH3.

[0046] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rb is - S(=O)(=N-phenyl)-CH3.

[0047] The compound of Formula (I), wherein R2is *-NH-CH(Ra)-CH=CH(Rb) and in which Rb is

[0048] The compound of Formula (I), wherein

[0049] The compound of Formula (I), wherein R2is

[0050] The compound of Formula (I), wherein R2is

[0051] The compound of Formula (I), wherein R3is -H.

[0052] The compound of Formula (I), wherein R3is -F.

[0053] The compound of Formula (I), wherein R4is -F.

[0054] The compound of Formula (I), wherein R4is -Cl

[0055] The compound of Formula (I), wherein R4is -CH3.

[0056] The compound of Formula (I), wherein is a 5 or 6 membered monocyclic heterocycle comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or2 substituents independently selected from -CH3, cyclopropyl, oxo, or -C(O)- OCH3.

[0057] The compound of Formula (I), wherein is a 6, 7, 8, 9, 10, or 11 membered fused bicyclic or spiro bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, 1, or 2 oxygen atoms substituted with 0, 1, 2, or 3 substituents independently selected from - CH3, -CN, -CH2-CN, -CH2-OH, -CH2F, -F, oxo, -C(O)-CH3, -C(O)-OCH3, -CH2-CHF2, -CH2-CF3, -CH2-O-CH3, -O-CH3, -CH2-O-CH(CH3)2, -CH2-CH2-OH, -CH2-CH2-O-CH3, -C≡CH, -

[0058] The compound of Formula (I), wherein is an 8 or 9 membered bridged heterocyclic ring system comprising 1 nitrogen atom and 1 oxygen atom substituted with 0 or 2 -F.

[0059] The compound of claim 1, wherein X is N, X1is CH, X2is CH.

[0060] The compound of claim 1, wherein X is CH, X1is N, X2is CH.

[0061] The compound of Formula (I), wherein R2is

[0062] The compound of Formula (I), wherein

[0063] The compound of Formula (I), wherein R2is

[0064] The compound of Formula (I), wherein

[0065] The compound of Formula (I), wherein

[0066] The compound of Formula (I), wherein

[0067] The compound of Formula (I), wherein

[0068] The compound of Formula (I), wherein

[0069] The compound of Formula (I), wherein R2isNC

[0070] The compound of Formula (I), wherein R2is

[0071] The compound of Formula (I), wherein R2is

[0072] The compound of Formula (I), wherein R2is

[0073] The compound of Formula (I), wherein

[0074] The compound of Formula (I), wherein

[0075] The compound of Formula (I), wherein

[0076] The compound of Formula (I), wherein

[0077] The compound of Formula (I), wherein

[0078] The compound of Formula

[0079] The compound of Formula (I), wherein

[0080] The compound of Formula (I), wherein

[0081] The compound of Formula (I), wherein

[0082] The compound of Formula (I), wherein

[0083] The compound of Formula (I), whereinis

[0084] The compound of Formula (I), whereins

[0085] The compound of Formula (I), whereins

[0086] The compound of Formula (I), wherein

[0087] The compound of Formula (I), whereins[

[0090] The compound of Formula (I), wherein

[0091] The compound of Formula (I), wherein

[0092] The compound of Formula (I), wherein is,

[0095] The compound of Formula (I), wherein

[0096] The compound of Formula (I), wherein

[0097] The compound of Formula (I), wherein

[0098] The compound of Formula (I), wherein

[0099] The compound of Formula (I), wherein

[0100] The compound of Formula (I), wherein

[0101] The compound of Formula (I), wherein

[0102] The compound of Formula (I), wherein

[0103] The compound of Formula (I), whereins

[0104] The compound of Formula (I), wherein

[0105] The compound of Formula (I), wherein

[0106] The compound of Formula (I), wherein is

[0107] The compound of Formula (I), wherein is

[0108] The compound of Formula (I), whereinis

[0109] The compound of Formula (I), wherein is

[0110] The compound of Formula (I), whereins

[0111] The compound of Formula (I), whereinis

[0112] The compound of Formula (I), wherein is

[0113] The compound of Formula (I), wherein is

[0114] The compound of Formula (I), whereins

[0115] The compound of Formula (I), wherein

[0116] The compound of Formula (I), wherein

[0117] The compound of Formula (I), wherein is

[0118] The compound of Formula (I), wherein

[0119] The compound of Formula (I), wherein

[0120]

[0121]

[0122] The compound of Formula (I), wherein

[0123] The compound of Formula (I), wherein

[0124] The compound of Formula (I), wherein

[0125] The compound of Formula (I), wherein

[0126] The compound of Formula (I), wherein

[0127] The compound of Formula (I), wherein

[0128] The compound of Formula (I), wherein

[0129] The compound of Formula (I), wherein

[0130] The compound of Formula (I), wherein

[0131] The compound of Formula (I), wherein is

[0132] The compound of Formula (I), wherein,

[0135] The compound of Formula (I), wherein is

[0136] The compound of Formula (I), wherein

[0137] The compound of Formula (I), wherein

[0138] The compound of Formula (I), wherein

[0139] The compound of Formula (I), wherein

[0140] The compound of Formula (I), wherein

[0141] The compound of Formula (I), wherein

[0142] The compound of Formula (I), wherein

[0143] The compound of Formula (I), wherein

[0144] The compound of Formula (I), wherein

[0145] The compounds of Formula (I) or Formula (I-a) can be present in chiral or achiral form. The form may either be racemic or R or S configuration. The compounds of Formula (I) or Formula (I -a) may be stereoisomers. The compounds may be atropisomers or pharmaceutically acceptable salts of an atropisomer.

[0146] Compounds of the disclosure include, but are not limited to, the compounds of Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compounds of the disclosure include, but are not limited to, the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the compounds of the disclosure include, but are not limited to, the compounds of Table 1.

[0148] All stereocenters labeled with (*S) or (R) are known, absolute stereochemistry. In cases where the stereochemistry is pure but unknown, the stereocenter is drawn and defined as (*S) or (*R).Stereochemistry that is drawn but not labeled is in the correct cis or trans configuration but are racemic and designated as “rac” or RS.Table 1. Compounds of the Disclosure.Further Forms of Compounds

[0149] In some aspects, a compound disclosed herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Furthermore, the compounds may exist as atropisomers. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments,separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0150] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0151] In one aspect, prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug, or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacokinetic, pharmacodynamic processes, and drug metabolism in vivo, once a pharmaceutically active compound is known, the design of prodrugs of the compound is possible. (See, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series).

[0152] In some embodiments, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0153] In some embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.

[0154] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0155] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0156] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0157] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,160,170,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0158] In some embodiments of a compound disclosed herein, one or more of R1, R2, R3, R4, Ra, Rb, Rc, and Rd groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

[0159] In some embodiments of a compound disclosed herein, one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R1, R2, R3, R4, Ra, Rb, Rc, and Rd.

[0160] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R1, R2, R3, R4, Ra, Rb, Rc, and Rd is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.

[0161] In certain embodiments, the compounds disclosed herein have some or all of the ’H atoms replaced with2H atoms. The methods of synthesis for deuterium -containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0162] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0163] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium -containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0164] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0165] “Pharmaceutically acceptable” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0166] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound disclosed herein with a base to form a salt.

[0167] Compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1 -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0168] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Pharmaceutical Compositions

[0169] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the manufacture of a medicament.

[0170] In one aspect, the compounds described herein (e.g., compound of Formula (I) or Formula (I-a), or pharmaceutically acceptable salt, solvate, or stereoisomer thereof) are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0171] A pharmaceutical composition, as used herein, refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fdling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[0172] Pharmaceutical formulations described herein are administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermaladministration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0173] In some embodiments, the compounds disclosed herein are administered orally.

[0174] In some embodiments, the compounds disclosed herein are administered topically. In such embodiments, the compound disclosed herein is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. In one aspect, the compounds disclosed herein are administered topically to the skin.

[0175] In another aspect, the compounds disclosed herein are administered by inhalation.

[0176] In another aspect, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0177] In another aspect, the compounds disclosed herein are formulated as eye drops.

[0178] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound disclosed herein is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by inhalation to the mammal; and / or (e) administered by nasal administration to the mammal; or and / or (f) administered by injection to the mammal; and / or (g) administered topically to the mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to the mammal; and / or (j) administered non-systemically or locally to the mammal.

[0179] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) the compound is administered continually; or (iv) the compound is administered continuously.

[0180] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound disclosed herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0181] In certain embodiments, the compound disclosed herein is administered in a local rather than systemic manner.

[0182] In some embodiments, the compound disclosed herein is administered topically. In some embodiments, the compound disclosed herein is administered systemically.

[0183] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds disclosed herein are in the form of a capsule.

[0184] In one aspect, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0185] For administration by inhalation, a compound disclosed herein is formulated for use as an aerosol, a mist, or a powder.

[0186] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0187] In some embodiments, compounds disclosed herein are prepared as transdermal dosage forms.

[0188] In one aspect, a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.

[0189] In some embodiments, the compound disclosed herein is be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0190] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.Methods of Treatment

[0191] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of modulating RAS-PI3K. In some embodiments, the method comprises inhibiting RAS-PI3K. In some embodiments, the method comprises activating RAS-PI3K.

[0192] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of treating a disease or condition. In some embodiments, provided herein is a method of treating a disease or condition, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease or condition is mediated by RAS-PI3K. In some embodiments, the disease or condition is mediated by the inhibition of RAS-PI3K. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidneycancer, and pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the disease or condition is an immunological disorder or condition. In some embodiments, the immunological disease or condition is promotion of wound healing.

[0193] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the manufacture of a medicament for modulating RAS-PI3K.

[0194] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating cancer in a subject in need thereof.

[0195] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the manufacture of a medicament for treating a cancer in a subject in need thereof.

[0196] In some embodiments, the disease mediated by RAS-PI3K is a cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer. In some embodiments, the cancer is a solid tumor.

[0197] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of treating an immunological disease or condition.

[0198] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the manufacture of a medicament for treating an immunological disease or condition in a subject in need thereof.

[0199] In some embodiments, the immunological disease or condition is selected from Psoriasis, Psoriatic Arthritis, Crohn’s disease, Ulcerative colitis, Lupus (including Systemic Lupus Erythematous, Cutaneous lupus, Lupus nephritis), Rheumatoid arthritis, Juvenile Idiopathic arthritis, Still’s disease, Spondyloarthritis, and Scleroderma, acute cytokine release syndrome associated with viral infections such as COVID, with cell therapies such as CAR-T and with gene therapy.

[0200] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of treating a disease or condition.

[0201] In some embodiments, administration of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, promotes wound healing.

[0202] In another aspect, provided herein is a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use as a therapeutically active substance.

[0203] In another aspect, provided herein is a use of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the treatment of an immunological disease or condition or cancer.

[0204] In another aspect, provided herein is a use of a compound of Formula (I) or Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the preparation of a medicament for the therapeutic treatment of an immunological disease or condition or cancer.Dosing and Treatment Regimens

[0205] In one aspect, the compounds disclosed herein are used in the preparation of medicaments for the treatment of diseases or conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, solvate, or stereoisomer thereof, in therapeutically effective amounts to said subject.

[0206] In some embodiments, the compositions containing the compound disclosed herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient or subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

[0207] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0208] In some embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). Doses employed for adult human treatment are typically in the range of 0.01mg-5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.Combination Treatments

[0209] In certain instances, it is appropriate to administer at least one compound disclosed herein in combination with another therapeutic agent.

[0210] In one specific embodiment, a compound disclosed herein is co-administered with a second therapeutic agent, wherein the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0211] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or moreother therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0212] If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.DEFINITIONS

[0213] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0214] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0215] ‘ ‘Oxo” refers to the =0 substituent.

[0216] “Alkyl” refers to a saturated linear or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a Ci-Cio alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, Ci-Cio alkyl, C1-C9 alkyl, Ci-C8alkyl, C1-C7 alkyl, Ci-C6alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, w-propyl, 1 -methylethyl (z -propyl), w-butyl, i -butyl, s-butyl. w-pentyl, 1,1 -dimethylethyl ( / -butyl), 3 -methylhexyl, 2-methylhexyl, 1 -ethyl -propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below.

[0217] “Alkylene” refers to a saturated linear or branched divalent hydrocarbon chain radical, having from one to twelve carbon atoms. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0218] “Alkoxy” refers to a radical of the formula -OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0219] “Heteroalkyl” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N (i.e., NH, N-alkyl) or S atom. “Heteroalkylene” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to -0CH20Me, -OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. Representative heteroalkylene groupsinclude, but are not limited to -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0220] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0221] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0222] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.

[0223] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to:,, an e e.

[0224] “Cycloalkyl” refers to a monocyclic or polycyclic, non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may have saturated, or partially unsaturated rings. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. In some embodiments, a cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, bicyclic or polycyclic. In some embodiments, cycloalkyl groups are selectedfrom among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo [1.1. l]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbomyl, decalinyl and adamantyl. In some embodiments, the cycloalkyl is monocyclic. Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the cycloalkyl is bicyclic. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups. In some embodiments, cycloalkyl groups are selected from among spiro[2.2]pentyl, bicyclo [1.1. l]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbomyl, 3,4-dihydronaphthalen-l(2H)-one and decalinyl. In some embodiments, the cycloalkyl is polycyclic. Polycyclic radicals include, for example, adamantyl. In some embodiments, the polycyclic cycloalkyl is adamantyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0225] ‘ ‘Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

[0226] ‘ ‘Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

[0227] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2.2.2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0228] “Haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy,1.2-dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0229] “Heterocycle,” “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and refer to a stable 3- to 14-membered saturated or partially unsaturated ring radical comprising 2 to 10 carbon atoms and from one to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be monocyclic, bicyclic (which may include a fused bicyclic heterocyclyl (when fused with an aryl or a heteroaryl ring, the heterocyclyl is bonded through a non-aromatic ring atom), bridged heterocyclyl or spiro heterocyclyl), or polycyclic. In some embodiments, the heterocyclyl is monocyclic or bicyclic. In some embodiments, the heterocyclyl is monocyclic. In some embodiments, the heterocyclyl is bicyclic. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogenatom may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocyclyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocyclyls have from 2 to 10 carbons in the ring. In some embodiments, heterocyclyls have from 2 to 8 carbons in the ring. In some embodiments, heterocyclyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocyclyls have from 2 to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, heterocyclyls have from 2 to 10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocyclyl, the number of carbon atoms in the heterocyclyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocyclyl (i.e., skeletal atoms of the heterocyclyl ring). Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.

[0230] “Heteroaryl” refers to an aryl radical that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl is monocyclic or bicyclic. Illustrative examples of heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9heteroaryl.

[0231] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-Cealkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2alkyl, nitro, and amino, including mono- and di-substituted amino groups (e.g., -NH2, -NHR, -NR2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0232] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:

[0233] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0234] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of asymptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0235] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0236] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0237] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.EXPERIMENTAL SECTION

[0238] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

[0239] The ’H-NMR data of selected compounds are listed in the form of ’H-NMR peaklists.Therein, for each signal peak the 5 value in ppm is given, followed by the signal intensity, reported in round brackets. The 5 value-signal intensity pairs from different peaks are separated by commas.Therefore, a peaklist is described by the general form: δ1(intensity1), δ2(intensity2),..., δi(intensityi),..., δn(intensityn).

[0240] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A ’H-NMR peaklist is similar to a classical ’H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical ’H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities,13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical ’H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication " Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter " MinimumHeight" can be adjusted between 1% and 4%.However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter " MinimumHeight" <1%.

[0241] Chemical names were generated using the ACD / Name software from ACD / Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD / Name generated names.

[0242] The following table lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.Table 2. Abbreviations.

[0243] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[0244] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.EXPERIMENTAL SECTION - GENERAL PART

[0245] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0246] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane / ethyl acetate or DCM / methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0247] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.EXPERIMENTAL SECTION - GENERAL PROCEDURES, SYNTHESIS OF INTERMEDIATESScheme 1: Synthesis of ( / ?)-3-(l-aminoethyl)-2 / / -thiete 1,1-dioxide.Intermediate 1: (7?)-3-(l-Aminoethyl)-2 / f-thiete 1,1-dioxide.

[0248] Step A: 3-Ethylthietan-3-ol. To a solution ofthietan-3-one (20 g, 227 mmol, 1.0 eq) in THF (150 mL) was added EtMgBr (76 mL, 227 mmol, 1.0 eq) dropwise at 0 °C under N2. The reaction was stirred at 25 °C for 2 h before being quenched by sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 1:0 - 5:1) to give 3-ethylthietan-3-ol (7.0 g, 26% yield) as a colorless oil.

[0249] Step B: 3-Ethyl-l,l-dioxo-thietan-3-ol. To a solution of 3-ethylthietan-3-ol (7.0 g, 59.2 mmol, 1.0 eq) in EtOAc (140 mL) at 0 °C was added m-CPBA (28 g, 130 mmol, 2.2 eq) portionwise under N2. The reaction was stirred at 25 °C for 2 h before being filtered. The filtrate was washed with sat. aq. Na2SO3and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 9:1 - 7:3) to provide 3-ethyl-l,l-dioxo-thietan-3-ol (3.2 g, 36% yield) as ayellow oil.

[0250] Step C: 3-Ethyl-2H-thiete 1,1-dioxide. To a solution of 3-ethyl-l,l-dioxo-thietan-3-ol (3.5 g, 23.3 mmol, 1.0 eq) in DCM (25 mL) at 0 °C was added Et3N (14 g, 140 mmol, 6.0 eq) followed by a solution of methanesulfonyl chloride (4.9 g, 43.3 mmol, 1.9 eq) in DCM (5 mL) dropwise under N2. The reaction was stirred at 25 °C for 2 h before being washed with sat. aq. NaHC’CF and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 1: 1) to give 3-ethyl-2H-thiete 1, 1-dioxide (2.7 g, 89% yield) as a colorless oil.

[0251] Step D: 3-(l-Bromoethyl)-2H-thiete 1,1-dioxide. To a solution of 3-ethyl-2H-thiete 1,1-dioxide (2.7 g, 20.8 mmol, 1.0 eq) in ACN (20 mL, IM) was added a solution of NBS (3.7 g, 20.8 mmol, 1.0 eq) and 2, 2'-azobis(2 -methylpropionitrile) (1.0 g, 6.24 mmol, 0.3 eq) in ACN (20 mL, IM). The reaction was stirred at 70 °C for 2 h. After cooling to rt, the mixture was concentrated under reducedpressure and the residue was purified by FCC (PE: EtOAc = 20: 1 to 5: 1) to give 3-( 1 -bromoethyl)-2H-thiete 1,1-dioxide (4.3 g, 98% yield) as a colorless oil.

[0252] Step E: 3-(1-Azidoethyl)-2H-thiete 1,1-dioxide. A solution of 3-(l-bromoethyl)-2H-thiete 1,1-dioxide (4.3 g, 20.4 mmol, 1.0 eq) in THF (40 mL, 0.5M) was cooled to 0 °C and a solution of sodium azide (1.7 g, 25.7 mmol, 1.3 eq) in water (40 mL, 0.5M) was added dropwise under N2. The mixture was stirred at 0 °C for 2 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 3-(1-azidoethyl)-2H-thiete 1,1-dioxide (2.0 g, 57% yield) as a yellow oil. ’H NMR (400 MHz, CDCh) 56.71 (d, J= 1.5 Hz, 1H), 4.53 - 4.44 (m, 2H), 4.41 (q, J = 6.9 Hz, 1H), 1.52 (d, J= 6.9 Hz, 3H).

[0253] Step F: 1-(1,1-Dioxo-2H-thiet-3-yl)ethanamine. To 3 -(1 -azidoethyl) -2H-thiete 1,1-dioxide (1.0 g, 5.77 mmol, 1.0 eq) in ethanol (25 mL, 0.2M) was added zinc, granular (1.1 g, 17.3 mmol, 3.0 eq) and NH4CI (1.5 g, 28.9 mmol, 1.3 eq) under N2. The reaction was stirred at 20 °C for 20 h before being filtered and concentrated under reduced pressure to provide 1-(1,1-dioxo-2H-thiet-3-yl)ethanamine (1.0 g, quant, yield) as a yellow oil, which was used in the next step directly.

[0254] Step G: tert-Butyl (R)-(1-(1,1-dioxido-2H-thiet-3-yl)ethyl)carbamate. To a solution of 1-(1, 1-dioxo-2H-thiet-3-yl)ethanamine (800 mg, 5.43 mmol, 1.0 eq) and DIPEA (1.4 g, 10.9 mmol, 2.0 eq) in DCM (2 mL, 2.7M) was added di-tert-butyl dicarbonate (1.4 g, 6.52 mmol, 1.2 eq). The reaction was stirred at 18 °C for 6 h before being concentrated and purified by FCC (PE: EtOAc = 5:1 to 1:2). The resulting product was separated via SFC to give tert-butyl (R)-(1-(1,1-dioxido-2H-thiet-3-yl)ethyl)carbamate (50 mg, 4% yield) as a white solid. ’H NMR (400 MHz, CDCh) 56.58 (s, 1H), 4.61 -4.60 (m, 1H), 4.46 (s, 2H), 1.46 (s, 9H), 1.42 - 1.39 (m, 3H).

[0255] Step H: (R)-3-(1-Aminoethyl)-2H-thiete 1,1-dioxide. A solution of tert-butyl (R)-(1-(1,1-dioxido-2H-thiet-3-yl)ethyl)carbamate (50 mg, 0.200 mmol, 1.0 eq) and TsOH monohydrate (77 mg, 0.400 mmol, 2.0 eq) in EtOAc (2.0 mL, 0.1M) was stirred at 80 °C for 24 h. After cooling to rt, the mixture was concentrated under reduced pressure to provide (R)-3-( 1 -aminoethyl) -2H-thiete 1,1-dioxide (TsOH salt, 90 mg, quant, yield) as a white solid, which was used in the next step directly. ’H NMR (400 MHz, DMSO-d6) 57.47 (d, J= 8.1 Hz, 2H), 7.15 (d, J= 1.5 Hz, 1H), 7.11 (d, J= 7.7 Hz, 2H), 4.74 -4.56 (m, 1H), 3.84 - 3.66 (m, 3H), 2.29 (s, 3H), 1.39 - 1.31 (m, 3H).Scheme 2: Synthesis of (27?)-4-(methylsulfinyl)but-3-en-2-amine.Intermediate 2: (27?)-4-(Methylsulfinyl)but-3-en-2-amine.

[0256] Step A: tert-Butyl ((2R)-4-(methylsulfinyl)but-3-en-2-yl)carbamate. A solution of diethyl ((methylsulfmyl)methyl)phosphonate (5.8 g, 27.0 mmol, 1.2 eq) in THF (80 mL, 0.2M) was placed under N2 and cooled to 0 °C. NaH (1.2 g, 29.3 mmol, 1.3 eq, 60% in mineral oil) was added in portions and the mixture was stirred at 0 °C for 0.5 h. tert-Butyl (R)-(l-oxopropan-2-yl)carbamate (3.9 g, 22.5 mmol, 1.0 eq) in THF (27 mL, 0.2M) was added dropwise and the reaction was stirred at 0 °C for 2 h. The mixture was poured into sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-5% MeOH in EtOAc) to give tert-butyl ((2R)-4-(methylsulfinyl)but-3-en-2-yl)carbamate (3.3 g, 63% yield, Z / E mixture) as a colorless oil. MS (ESI): mass calcd. for C10H19NO3S, 233.1; m / z found, 178.1 [M+2H-tBu]+.

[0257] Step B: (2R)-4-(Methylsulfmyl)but-3-en-2-amine. To a solution of tert-butyl ((2 / ?)-4-(methylsulfmyl)but-3-en-2-yl)carbamate (500 mg, 2.14 mmol, 1.0 eq, Z / E mixture) in DCM (6.0 mL, 0.36M) was added TFA (2.0 mL). The reaction was stirred at 25 °C for 0.5 h before being concentrated in vacuo to give (2R)-4-(methylsulfinyl)but-3-en-2-amine (TFA salt, 529 mg, quant, yield, Z / E mixture) as a yellow oil, which was used in the next step directly. MS (ESI): mass calcd. for C5H11NOS, 133.1; m / z found, 134.1 [M+H]+.Scheme 3: Synthesis of (?, Z)-4-methylsulfonyl)but-3-en-2-amine.Intermediate 3: (7?, Z)-4-Methylsulfonyl)but-3-en-2-amine.

[0258] Step A:. S-Methyl 4-methylbenzenesulfonothioate. To a solution of sodium 4-methylbenzenesulfonothioate (30 g, 143 mmol, 1.0 eq) in DMF (100 mL, 1.4M) was added iodomethane (8.9 mL, 143 mmol, 1.0 eq). The reaction was stirred for 24 h at 25 °C under N2 before being quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 50: 1) to give S-methyl 4-methylbenzenesulfonothioate (27 g, 94% yield) as a white solid. ’HNMR (400 MHz, CDCL) 57.81 (d, J= 8.4 Hz, 2H), 7.35 (d, J= 8.4 Hz, 2H), 2.50 (s, 3H), 2.46 (s, 3H).

[0259] Step B: tert-Butyl (R)-(4-(methylthio)but-3-yn-2-yl)carbamate. w-Butyllithium (40 mL, 99.3 mmol, 2.1 eq) was added dropwise to a stirred solution of tert-butyl (R)-but-3-yn-2-ylcarbamate (8.0 g,47.3 mmol, 1.0 eq) and TMEDA (5.5 g, 47.3 mmol, 1.0 eq) in THF (30 mL, 0.24M) at 0 °C under N2. After 30 minutes, S-methyl 4-methylbenzenesulfonothioate (10 g, 49.6 mmol, 1.1 eq) in THF (80 mL, 0.6M) was added. The reaction was stirred at 0 °C for 2 h before being quenched by sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 5: 1) to afford tert-butyl (R)-(4-(methylthio)but-3-yn-2-yl)carbamate (9.0 g, 88% yield) as a white solid.1H NMR (400 MHz, CDC13) 54.65 - 4.76 (m, 1H), 4.50 - 4.63 (m, 1H), 2.37 (s, 3H), 1.46 (s, 9H), 1.39 (d, J= 6.9 Hz, 3H).

[0260] Step C: tert-Butyl (R,Z)-(4-(methylthio)but-3-en-2-yl)carbamate. tert-Butyl (R)-(4-(methylthio)but-3-yn-2-yl)carbamate (3.0 g, 13.9 mmol, 1.0 eq), Lindlar catalyst (900 mg), and hexene (6 mL) were taken up in methanol (30 mL, 0.5M). The reaction was stirred under H2 (30 psi) at 25 °C for 3 h before being filtered and concentrated under vacuum. The resulting residue was purified by FCC (PE: EtOAc = 3: 1) to afford tert-butyl (R,Z)-(4-(methylthio)but-3-en-2-yl)carbamate (2.6 g, 86% yield) as a white solid. ’H NMR (400 MHz, DMSO-r / 6) 55.96 (d, J= 9.6 Hz, 1H), 5.43 (dd, J= 9.5, 8.0 Hz, 1H), 4.63 - 4.34 (m, 2H), 2.28 (s, 3H), 1.45 (s, 9H), 1.22 (d, J= 6.4 Hz, 3H).

[0261] Step D: tert-Butyl (R,Z)-(4-(methylsulfonyl)but-3-en-2-yl)carbamate. To a solution of tert-butyl (R,Z)-(4-(methylthio)but-3-en-2-yl)carbamate (2.6 g, 12.0 mmol, 1.0 eq) in DCM (10 mL, 1.2M) was added m-CPBA (6.2 g, 35.9 mmol, 3.0 eq) in portions over 5 min. The reaction was stirred at 25 °C for 2 h before being diluted with sat. aq. Na2SO3 and extracted with DCM. The extract was washed with sat. aq. NaHCO3and brine then dried over Na2SO4. filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 1: 1) to afford tert-butyl ( / ?, Z)-(4-(methylsulfonyl)but-3-en-2-yl)carbamate (2.4 g, 79% yield) as a white solid. ’H NMR (400 MHz, CDC13) 56.31 - 6.22 (m, 1H), 6.21 - 6.11 (m, 1H), 4.63 (s, 1H), 3.19 (s, 3H), 1.42 (s, 9H), 1.31 (d, J= 6.8 Hz, 3H).

[0262] Step E: (R,Z)-4-(Methylsulfonyl)but-3-en-2-amine. tert-Butyl (R,Z)-(4-(methylsulfonyl)but-3-en-2-yl)carbamate (2.4 g, 9.47 mmol, 1.0 eq) and TsOH monohydrate (1.8 g, 9.47 mmol, 1.0 eq) were taken up in ACN (30 mL, 0.3M). The reaction was stirred at 40 °C for 16 h before being concentrated under vacuum to afford (R,Z)-4-(methylsulfonyl)but-3-en-2-amine (TsOH salt, 3.0 g, quant, yield) as a white solid. This was used in the next step directly. ’H NMR (400 MHz, CDC13) 58.13 (br s, 1H), 7.51 (d, J= 8.0 Hz, 2H), 7.14 (d, J= 8.0 Hz, 2H), 6.75 (d, J= 11.2 Hz, 1H), 6.37 (dd, J= 11.2, 9.6 Hz, 1H), 5.09 (br s, 2H), 4.95 - 4.75 (m, 1H), 3.12 (s, 3H), 2.29 (s, 3H), 1.31 (d, J= 6.8 Hz, 3H).Scheme 4: Synthesis of (?^)-4-aminopent-2-enenitrile.Intermediate 4: (7?, E)-4-Aminopent-2-enenitrile.

[0263] Step A: tert-Butyl (R,E)-(4-cyanobut-3-en-2-yl)carbamate. A solution of diethyl (cyanomethyl)phosphonate (10 g, 57.0 mmol, 1.0 eq) in THF (200 mL, 0.3M) was placed under N2and cooled to 0 °C. Sodium hydride (2.3 g, 57.0 mmol, 1.0 eq, 60% in mineral oil) was added slowly over 0.5 h followed by tert-butyl (R)-(l-oxopropan-2-yl)carbamate (9.9 g, 57.0 mmol, 1.0 eq). The reaction was stirred at 0 °C for 2 h before being quenched with sat. aq. NH4CI and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (0-8% EtOAc in PE) to give two products: tert-butyl (R,E)-(4-cyanobut-3-en-2-yl)carbamate (4.2 g, 37% yield) ’H NMR (400 MHz, CDCh) 56.65 (dd, J= 16.4, 5.0 Hz, 1H), 5.47 (dd, J= 16.3, 1.8 Hz, 1H), 4.56 (br s, 1H), 4.35 (br s, 1H), 1.44 (s, 9H), 1.27 (d, J= 7.1 Hz, 3H) and tertbutyl (R, Z)-(4-cyanobut-3-en-2-yl)carbamate (2.0 g, 17% yield) ’HNMR (400 MHz, CDCh) 56.40 (br s, 1H), 5.36 (d, J = 11.3 Hz, 1H), 4.79 - 4.49 (m, 2H), 1.46 (s, 9H), 1.33 (br d, J= 6.8 Hz, 3H).

[0264] Step B: (R, E)-4-Aminopent-2-enenitrile. To a solution of tert-butyl (R,E)-(4-cyanobut-3-en-2-yl)carbamate (130 mg, 0.662 mmol, 1.0 eq) in ACN (3.0 mL, 0.2M) was added TsOH monohydrate (151 mg, 0.795 mmol, 1.2 eq). The reaction was stirred at 60 °C for 4 h before being concentrated under reduced pressure to give (R,E)-4-aminopent-2-enenitrile (TsOH salt, 63 mg, 98% yield) as a white solid. ’H NMR (400 MHz, DMSO-d6) 56.83 (dd, J= 16.6, 6.3 Hz, 1H), 5.99 (dd, J= 16.6, 1.4 Hz, 1H), 4.04 (br d, J= 5.4 Hz, 1H), 3.58 (br s, 2H), 1.29 (d, J= 6.8 Hz, 3H).Intermediate 5: (7?, Z)-4-Aminopent-2-enenitrile.

[0265] tert-Butyl (R,Z)-(4-cyanobut-3-en-2-yl)carbamate (Intermediate 4, Step A) was elaborated to the title compound in a manner analogous to Intermediate 4, Step B. ’H NMR (400 MHz, DMSO-t / e) 5 8.13 (s, 3H), 7.48 (d, J= 8.0 Hz, 2H), 7.12 (d, J= 8.0 Hz, 2H), 6.60 (dd, J= 10.8, 9.2 Hz, 1H), 6.11 -5.89 (m, 1H), 4.20 - 4.04 (m, 1H), 2.29 (s, 3H), 1.34 (d, J= 6.8 Hz, 3H).Intermediate 6: (7?,£)-4-Aminohex-2-enenitrile.

[0266] The title compound was prepared in a manner analogous to Intermediate 4 using tert-butyl (R)-(l-oxobutan-2-yl)carbamate instead of tert-butyl (R)-(1-oxopropan-2-yl)carbamate in Step A. ’H NMR (400 MHz, DMSO-d6) 58.14 (br s, 3H), 7.49 (d, J= 7.9 Hz, 2H), 7.13 (d, J= 7.9 Hz, 2H), 6.75 (dd, J = 16.5, 7.6 Hz, 1H), 6.03 (d, J= 16.5 Hz, 1H), 3.87 - 3.83 (m, 1H), 2.29 (s, 3H), 1.72 - 1.56 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).Intermediate 7: (Z)-3-(Azetidin-3-yl)acrylonitrile.

[0267] The title compound was prepared in a manner analogous to Intermediate 4 using tert-butyl 3-formylazetidine-1 -carboxylate instead of tert-butyl (R)-(1-oxopropan-2-yl)carbamate in Step A.Separation of tert-butyl 3-(2-cyanovinyl)azetidine-l-carboxylate (Step A) via SFC (Stationary Phase: OD (5x25cm); Mobile Phase: 15% ACN / EtOH; Rt = 1.23 min, first eluting product) provided tert-butyl 3-((Z)-2-cyanovinyl)azetidine-l -carboxylate, which was elaborated to the title compound in a manner analogous to Intermediate 4, Step B. 'HNMR (400 MHz, DMSO-t / e) 58.88 - 8.41 (m, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.12 (d, J= 8.0 Hz, 2H), 6.91 (dd, J= 10.8, 9.2 Hz, 1H), 5.83 (dd, J= 10.8, 0.8 Hz, 1H), 4.22 - 4.10 (m, 2H), 4.01 - 3.92 (m, 2H), 3.91 - 3.79 (m, 1H), 2.29 (s, 3H).Scheme 5: Synthesis of (£)-3-(azetidin-3-yl)acrylonitrile.Intermediate 8: (E)-3-(Azetidin-3-yl)acrylonitrile.

[0268] Step A: tert-Butyl 3 -((A')-3 -oxoprop- l-enyl)azetidine-l -carboxylate. To a solution of tert-butyl 3-formylazetidine-1-carboxylate (10 g, 54.0 mmol, 1.0 eq) in ACN (100 mL, 0.5M) was added 2-(triphenyl-λ5-phosphaneylidene)acetaldehyde (16 g, 51.3 mmol, 0.95 eq). The reaction was stirred for 16 h at 25 °C then concentrated in vacuo. The resulting residue was slurried with MTBE at 0 °C and filtered. The filtrate was concentrated in vacuo and purified by FCC (10-20% EtOAc in PE) to afford tert-butyl 3-((E)-3-oxoprop-1-enyl)azetidine-1-carboxylate (8.0 g, 70% yield) as a yellow oil. ’H NMR (400 MHz, CDCls) 59.50 (d, J= 7.6 Hz, 1H), 6.89 (dd, J= 15.7, 7.9 Hz, 1H), 6.09 (ddd, J= 15.7, 7.7, 1.0 Hz, 1H), 4.14 (t, J= 8.6 Hz, 2H), 3.78 (dd, J= 8.6, 5.8 Hz, 2H), 3.46 - 3.34 (m, 1H), 1.38 (s, 9H).

[0269] Step B: tert-Butyl 3-((E)-2-cyanovinyl)azetidine- 1 -carboxylate. To the solution of tert-butyl 3-((E)-3-oxoprop-l-enyl)azetidine-l-carboxylate (8.0 g, 37.9 mmol, 1.0 eq) in ACN (20 mL, 0.5M) was added sodium dodecyl sulfate (2.2 g, 7.57 mmol, 0.2 eq), ammonium acetate (15 g, 189 mmol, 5.0 eq) in water (60 mL, 0.5M), and diacetoxyiodo benzene (15 g, 45.4 mmol, 1.2 eq). The reaction was stirred at 25 °C for 2 h before being quenched with sat. aq. NaHCO3and filtered. The filtrate was extracted with EtOAc and the organic layers were washed with sat. aq. Na2S2O4 and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by FCC (10-20% EtOAc in PE) to afford tert-butyl 3-((E)-2-cyanovinyl)azetidine-1-carboxylate (6.0 g, 76% yield) as a yellow oil. ’H NMR (400 MHz, CDC13) 56.87 (dd, J= 16.3, 8.3 Hz, 1H), 5.42 (dd, J= 16.3, 1.1 Hz, 1H), 4.19 -4.14 (m, 2H), 3.79 (dd, J= 8.8, 5.6 Hz, 2H), 3.42 - 3.25 (m, 1H), 1.44 (s, 9H).

[0270] Step C: (£)-3-(Azetidin-3-yl)acrylonitrile. To a solution of tert-butyl 3-((E)-2-cyanovinyl)azetidine-1-carboxylate (50 mg, 0.240 mmol, 1.0 eq) in ACN (0.30 mL, 0.8M) was added TsOH monohydrate (55 mg, 0.288 mmol, 1.2 eq). The reaction was stirred at 60 °C for 1 h. After cooling to rt, the mixture was concentrated under reduced pressure, diluted with MTBE (1.0 mL), and recrystallized to give (£)-3-(azetidin-3-yl)acrylonitrile (TsOH salt, 21 mg, 78% yield) as a yellow oil. ’H NMR (400 MHz, DMSO-tL) 58.87 - 8.35 (m, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.13 (d, J= 8.0 Hz, 2H), 7.00 (dd, J= 16.4, 7.6 Hz, 1H), 5.90 (dd, J= 16.4, 1.2 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.99 - 3.89 (m, 2H), 3.75 - 3.68 (m, 1H), 2.29 (s, 3H).Scheme 6: Synthesis of (?,£)-4-amino-l-(3,3-difluoroazetidin-l-yl)pent-2-en-l-one.Intermediate 9: (7?,£)-4-Amino-l-(3,3-difluoroazetidin-l-yl)pent-2-en-l-one.

[0271] Step A: Methyl ( / ?. A')-4-( / c77-biitoxycarbonylamino)pcnt-2-cnoatc. To a solution of trimethyl phosphonoacetate (19 g, 104 mmol, 1.2 eq) in THF (40 mL, 2M) at -70 °C was added LiHMDS (40 mL, 1.4 eq, IM in THF) and this was stirred at -70 °C for 1 h. tert-Butyl (R)-(1-oxopropan-2-yl)carbamate (15 g, 86.6 mmol, 1.0 eq) in THF (20 mL) was added and the reaction was stirred at -70 °C for 1 h. The mixture was quenched with sat. aq. NH4CI and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to provide methyl (R,E)-4-(tert-butoxycarbonylamino)pent-2-enoate (2.5 g, 13% yield). ’HNMR (400 MHz, CDCh) 56.88 (dd, J= 15.7, 5.0 Hz, 1H), 5.91 (dd, J = 15.7, 1.6 Hz, 1H), 4.61 - 4.33 (m, 2H), 3.74 (s, 3H), 1.44 (s, 9H), 1.27 (d, J= 7.0 Hz, 3H).

[0272] Step B: ( / ?. A')-4-( / -Butoxycarbonylamino)pcnt-2-cnoic acid. To a solution of methyl (R,E)-4-(tert-butoxycarbonylamino)pent-2-enoate (200 mg, 0.87 mmol, 1.0 eq) in THF / water (v / v 3:1, 4.0 mL, 0.2M) was added LiOH hydrate (110 mg, 2.62 mmol, 3.0 eq) and the reaction was stirred at 25 °C for 12 h. The solution was adjusted to pH ~4 with HC1 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (R,E)-4-(tert-butoxycarbonylamino)pent-2-enoic acid (190 mg, quant, yield) as a colorless oil, which was used in the next step without purification. ’H NMR (400 MHz, CDCI3) 56.98 (br dd, J= 15.8, 4.4 Hz, 1H), 5.92 (dd, J= 15.7, 1.4 Hz, 1H), 4.64 - 4.37 (m, 1H), 1.46 (s, 9H), 1.29 (d, J = 6.9 Hz, 3H).

[0273] Step C: tert-Butyl (R,E)-(5-(3,3-difluoroazetidin-1-yl)-5-oxopent-3-en-2-yl)carbamate. To a solution of (R,E)-4-(tert-butoxycarbonylamino)pent-2-enoic acid (1.5 g, 6.97 mmol, 1.0 eq), 3,3-difluoroazetidine HC1 (1.1 g, 8.36 mmol, 1.2 eq), and T3P® (3.3 g, 10.4 mmol, 1.5 eq) in DCM (5.0 mL, 1.4M) was added DIPEA (2.3 g, 17.4 mmol, 2.5 eq). The reaction was stirred at 25 °C for 2 h. The mixture was purified by FCC (PE: EtOAc = 5: 1) to give tert-butyl (R,E)-(5-(3,3-difluoroazetidin-1-yl)-5-oxopent-3-en-2-yl)carbamate (1.4 g, 69% yield) as a white solid. MS (ESI): mass calcd. for C13H20F2N2O3, 290; m / z found, 291 [M+H]+. 'H NMR (400 MHz, CDC13) 56.82 (br dd, J= 15.1, 5.4 Hz, 1H), 5.93 (dd, J= 15.3, 1.2 Hz, 1H), 4.59 - 4.30 (m, 6H), 1.45 (s, 9H), 1.28 (d, J= 6.9Hz, 3H).

[0274] Step D: (R, E)-4-Amino-l-(3,3-difluoroazetidin-l-yl)pent-2-en-l-one. To a solution of tertbutyl (R, E)-(5 -(3, 3 -difluoroazetidin-l-yl)-5 -oxopent-3 -en-2-yl)carbamate (300 mg, 1.03 mmol, 1.0 eq) in ACN (5.0 mL, 0.2M) was added TsOH (890 mg, 5.17 mmol, 5.0 eq). The reaction was stirred at 65 °C for 12 h before being concentrated to give (R,E)-4-amino-1-(3,3-difluoroazetidin-1-yl)pent-2-en-1-one (TsOH salt, 300 mg, 80% yield) as a white solid.Intermediate 10: (E)-4-Amino-l-(3,3-difluoroazetidin-l-yl)but-2-en-l-one.

[0275] The title compound was prepared in a manner analogous to Intermediate 9 using tert-butyl (2-oxoethyl)carbamate instead of tert-butyl (R)-(1-oxopropan-2-yl)carbamate in Step A.Scheme 7: Synthesis of (3-chloro-4-fluoropyridin-2-yl)magnesium bromide.Intermediate 11: (3-Chloro-4-fluoropyridin-2-yl)magnesium bromide.

[0276] Step A: 2-Bromo-3-chloro-4-fluoropyridine. 2-Bromo-4-fluoropyridine (5.0 g, 28.4 mmol, 1.0 eq) in THF (100 mL), LDA (43 mL, IM in THF, 42.6 mmol, 1.5 eq), and perchloroethane (8.7 g, 36.9 mmol, 1.3 eq) in THF (100 mL) were reacted in a flow system at 20 °C. The resulting mixture was poured into sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by FCC (0-10% EtOAc in PE) to give 2-bromo-3-chloro-4-fluoropyridine (2.3 g, 39% yield) as a yellow oil. ’H NMR (400 MHz, CDCI3) 58.29 (dd, J= 7.1, 5.4 Hz, 1H), 7.13 (dd, J= 7.6, 5.4 Hz, 1H).

[0277] Step B: (3 -Chloro-4-fluoropyridin-2-yl)magnesium bromide. A solution of 2-bromo-3-chloro-4-fluoropyridine (2.4 g, 11.4 mmol, 1.0 eq) in THF (6.0 mL, 2M) was placed under N2 and cooled to 0 °C. iPrMgCl. LiCl (12.5 mL, 12.5 mmol, 1.1 eq, IM in THF) was added dropwise and the reaction wasstirred at 20 °C for 0.5 h. The solution of (3-chloro-4-fluoropyridin-2-yl)magnesium bromide (-0.6M in THF, 18.5 mL) was used in the next step as is.Scheme 8: Synthesis of rac-(l*7?,2*5,5*iS)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo [3.1.0] hexane.Intermediate 12: rac-(l *7?,2*5,5*iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo [3.1.0] hexane.

[0278] Step A: / -Butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of NaIO4(741 mg, 3.47 mmol, 3.8 eq) in H2O (2.0 mL, 0.2M) was added RuCL (9.5 mg, 0.046 mmol, 0.05 eq). The mixture was stirred for 5 min before a solution of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.912 mmol, 1.0 eq) in EtOAc (2.0 mL, 0.2M) was added. The reaction was stirred at 25 °C for 16 h before being filtered then poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-25% EtOAc in PE) to give tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 94% yield) as a colorless oil. MS (ESI): mass calcd. for C10H13F2NO3, 233.1; m / z found, 178.2 [M+2H-tBu]+. 'H NMR (400 MHz, CDC13) 53.91 - 4.10 (m, 2H), 2.76 - 2.91 (m, 1H), 2.52 (td, J= 8.6, 7.1 Hz, 1H), 1.53 (s, 9H).

[0279] Step B: tert-Butyl ((( I *. S'.3* / ?)-3-(2-chloro-3-fluorobcnzoyl)-2.2-difluorocyclopropyl)methyl)carbamate. A solution of tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.5 g, 6.43 mmol, 1.0 eq) in THF (15 mL, 0.4M) was placed under N2 and cooled to 0 °C. (2-Chloro-3-fhiorophenyl)magnesium bromide (9.6 mL, 9.65 mmol, 1.5 eq, IM in THF) was added and the reaction was stirred at 0 °C for 2 h before being quenched with sat. aq. NFLC1. The mixture was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl (((l*S,3*R)-3-(2-chloro-3-fluorobenzoyl)-2,2-difhrorocyclopropyl)methyl)carbamate (1.8 g, 77% yield) as a yellow oil. ’HNMR (400 MHz, CDCI3) 5 7.33 - 7.40 (m, IH), 7.09 - 7.22 (m, 2H), 5.34 (s, IH), 3.79 - 4.21 (m, IH), 2.37 - 2.71 (m, 2H), 2.21 - 2.33 (m, IH), 1.45 (s, 9H).

[0280] Step C: (( l*. S'.3* / ?)-3-(Aminomcthyl)-2.2-difluorocyclopropyl)(2-chloro-3-fhrorophenyl)methanone. tert-Butyl ((( 1 *S,3*R)-3-(2-chloro-3-fluorobenzoyl)-2,2-difhrorocyclopropyl)methyl)carbamate (1.8 g, 4.95 mmol, 1.0 eq) was taken up in DCM / TFA (v / v 3:1, 24 mL, 0.2M). The reaction was stirred at 20 °C for 2 h before being concentrated under vacuum to give ((l*S,3*R)-3-(aminomethyl)-2,2-difIuorocyclopropyl)(2-chloro-3-fluorophenyl)methanone (TFA salt, 1.8 g, 96% yield) as a yellow oil, which was used directly in the next step.

[0281] Step D: rac-(l * / ?.2*S'.5*S)-2-(2-Chloro-3-fluorophcnyl)-6.6-difliioro-3-azabicyclo[3.1.0]hexane. To a solution of ((l*. S'.3* / ?)-3-(aminomcthyl)-2.2-difluorocyclopropyl)(2-chloro-3-fhrorophenyl)methanone (TFA salt, 1.8 g, 4.77 mmol, 1.0 eq) in ethanol (20 mL, 0.23M) was added acetic acid (0.5 mL, 0.23M) and sodium cyanoborohydride (509 mg, 8.10 mmol, 1.7 eq). The reaction was stirred at 20 °C for 2 h before being diluted with sat. aq. NaHCOs and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (1.1 g, 93% yield) as a colorless oil. ’HNMR (400 MHz, DMSO-t / e) 57.47 -7.55 (m, IH), 7.31 - 7.42 (m, 2H), 4.76 - 4.89 (m, IH), 3.36 - 3.45 (m, 2H), 2.58 - 2.64 (m, IH), 2.36 -2.43 (m, IH).Intermediate 13: (17?,2iS,5A)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane.

[0282] The title compound was prepared in a manner analogous to Intermediate 12, Steps B-D, using tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step B. Separation of rac-(1*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Step D) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 35% zPrOH / CCh with 0.1% NH4OH; Rt = 4.70 min, second eluting product) provided the title compound. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for CnHnClFN, 211.0; m / z found, 212.1 [M+H]+.Intermediate 14: rac-(l* / ?,2*iS,5*iS)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptane.

[0283] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl 3-azabicyclo[3.2.0]heptane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C12H13CIFN, 225.1; m / z found, 226.0 [M+H]+.Intermediate 15: (3a* / ?,4*iS,6a*A)-4-(2-Chloro-3-fluorophenyl)hexahydro-LH-furo[3,4-c]pyrrole.

[0284] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*R,6a*S)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. Separation of rac-(3a*R,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Step D) via SFC (Stationary phase: WHELK-01 (5x25 cm); Mobile phase: 25% iPrOH / CO2 with 0.1% NH4OH; Rt = 7.90 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.0 [M+H]+. ’HNMR (400 MHz, CDCI3) 57.47 (d, J= 7.8 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.07 (t, J= 8.5 Hz, 1H), 4.47 (d, J= 6.6 Hz, 1H), 4.02 (t, J= 8.2 Hz, 1H), 3.58 (dd, J= 8.7, 5.4 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.36 -3.25 (m, 1H), 3.17 - 3.07 (m, 3H), 2.99 - 2.89 (m, 1H).Scheme 9: Synthesis of (liS,45,57?)-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one.Intermediate 16: (liS,4iS,57?)-4-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one.

[0285] Step A: tert-Butyl (1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of (1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 13, 500 mg, 2.36 mmol, 1.0 eq) and sodium bicarbonate (595 mg, 7.09 mmol, 3.0 eq) in THF / water (v / v 1:1, 10 mb, 0.24M) was added BOC2O (567 mg, 2.60 mmol, 1.1 eq). The reaction was stirred at 25 °C for 2 h then poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give tert-butyl (1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (730 mg, quant, yield) as a yellow oil. MS (ESI): mass calcd. for C16H19CIFNO2, 311.1; m / z found, 256.1 [M+2H-tBu]+.

[0286] Step B: tert-Butyl ( l / .2. S'.5. S')-2-(2-chloro-3-tluorophcnyl)-4-oxo-3-azabicyclo|3.1,0|hcxanc-3-carboxylate. To a solution ofNalC (1.5 g, 7.02 mmol, 3.0 eq) in water (7.0 mL, 0.17M) was added RuCh (97 mg, 0.468 mmol, 0.2 eq). The mixture was stirred at 25 °C for 5 min before addition of tertbutyl ( l / ?.2. S'.5, S)-2-(2-chloro-3-fliiorophcnyl)-3-azabicyclo|3.1.0|hcxanc-3-carboxylatc (730 mg, 2.34 mmol, 1.0 eq) in EtOAc (7.0 mL, 0.17M). The reaction was stirred at 25 °C for 2 h before being quenched with sat. aq. Na2S2O3 and filtered. The filtrate was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl ( l / ?.2. S'.5, S')-2-(2-chloro-3-tluorophcn l)-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (700 mg, 92% yield) as a pale yellow oil. MS (ESI): mass calcd. for C16H17ClFNO3, 325.1; m / z found, 270.0 [M+2H-tBu]+. ’H NMR (400 MHz, CDC13) 57.26 - 7.21 (m, 1H), 7.13 (dt, J= 8.4, 1.3 Hz, 1H), 6.82 (d, J= 7.8 Hz, 1H), 5.69 (d, J= 6.3 Hz, 1H), 2.45 (dtd, J= 7.7, 6.1, 4.4 Hz, 1H), 2.21 (ddd, J= 9.0, 5.9, 3.4 Hz, 1H), 1.25 (s, 9H), 1.00 - 0.91 (m, 1H), 0.89 - 0.83 (m, 1H).

[0287] Step C: (15,45,5R)-4-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one. A solution of tert-butyl ( l / .2. S'.5. S)-2-(2-chloro-3-fliiorophcnyl)-4-oxo-3-azabicyclo|3.1,0]hexane-3 -carboxylate (700 mg, 2.15 mmol, 1.0 eq) was taken up in HC1 (10 mL, 4M in EtOAc). The reaction was stirred at 25 °C for 2 h before being adjusted to pH 8-9 with sat. aq. NaHCOs and extracted with EtOAc. The combined extracts were washed with brine, dried overNa2SO4, and filtered. The filtrate was concentrated under vacuum to give (15,45,5R)-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1,0]hexan-2-one (470 mg, 97% yield) as a pale yellow solid.Scheme 10: Synthesis of rac-(l* / ?,4*5,5* / ?)-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile.Intermediate 17: rac-(l* / ?,4*5,5* / ?)-4-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-l-carbonitrile.

[0288] To a solution of rac-3-azabicyclo[3.1.0]hexane-l-carbonitrile (500 mg, 2.64 mmol, 1.0 eq) and BOC2O (693 mg, 3.17 mmol, 1.2 eq) in MeOH (5.0 mL, 0.5M) was added sodium carbonate (841 mg, 7.93 mmol, 3.0 eq). The reaction was stirred at rt for 16 h before being quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give crude tert-butyl rac-(l*R,5*R)-l-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate (550 mg, quant, yield) as a colorless oil.

[0289] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(l*R,5*R)-l-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. 'HNMR (400 MHz, CDCI3) 57.36 (d, J= 7.7 Hz, 1H), 7.23 (td, J= 8.0, 5.4 Hz, 1H), 7.11 (td, J= 8.4, 1.5 Hz, 1H), 4.82 (d, J= 3.5 Hz, 1H), 3.50 - 3.36 (m, 2H), 2.53 (ddd, J= 8.4, 5.0, 3.6 Hz, 1H), 1.43 (t, J = 5.3 Hz, 1H), 1.16 (dd, J= 8.3, 5.4 Hz, 1H).Scheme 11: Synthesis of rac-(l*7?,2*iS,5*iS,6*iS)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane.Intermediate 18: rac-(l* / ?,2*iS,5*iS,6*A)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo [3.1.0] hexane.

[0290] Step A: tert-Butyl exo-6-(methylsulfonyloxymethyl)-3 -azab icy clo [3.1.0]hexane-3 -carboxylate. To a solution of tert-butyl exo-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 14.1 mmol, 1.0 eq) in DCM (20 mL, 0.7M) was added methanesulfonic anhydride (3.7 g, 21.1 mmol, 1.5 eq) and TEA (4.3 g, 42.2 mmol, 3.0 eq) at 0 °C. The reaction was stirred at 20 °C for 6 h before being quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-50% EtOAc in PE) to give tert-butyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.3 g, 81% yield) as acolorless oil. ’HNMR (400 MHz, CDCh) 54.24 - 3.97 (m, 2H), 3.71 - 3.54 (m, 2H), 3.42 - 3.30 (m, 2H), 3.03 (s, 3H), 1.60 (s, 1H), 1.46 - 1.42 (m, 10H), 1.16 - 1.07 (m, 1H).

[0291] Step B: tert-Butyl exo-6-methyl-3 -azabicyclo [3.1,0]hexane-3-carboxylate. A solution of tertbutyl exo-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.3 g, 11.3 mmol, 1.0 eq) in THF (30 mL, 0.4M) was placed under N2. Lithium aluminum hydride (9.1 mL, 22.7 mmol, 2.0 eq, 2.5M in THF) was added dropwise to the solution at 0 °C. The reaction was stirred at 20 °C for 0.5 h before being quenched with water and 15% aq. NaOH dropwise at 0 °C. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (0-10% EtOAc in PE) to give tert-butyl exo-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (700 mg, 31% yield) as a colorless oil. 'HNMR (400 MHz, CDCh) 53.52 (br s, 2H), 3.31 (brd, J= 10.6 Hz, 2H), 1.44 (s, 9H), 1.18 (br s, 2H), 1.02 (d, J= 6.1 Hz, 3H), 0.57 - 0.46 (m, 1H).

[0292] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl exo-6-methyl-3 -azab icy clo [3.1.0]hexane-3 -carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and (2,3-difhiorophenyl)magnesium bromide instead of (2-chloro-3-fhrorophenyl)magnesium bromide in Step B. MS (ESI): mass calcd. for C12H15F2N, 209.1; m / z found, 210.2 [M+H]+.Intermediate 19: rac-(l*iS,2*iS,5* / ?,6*iS)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo [3.1.0] hexane

[0293] The title compound was prepared in a manner analogous to Intermediate 18 using (2-chloro-3-fluorophenyl)magnesium bromide instead of (2,3-difluorophenyl)magnesium bromide in Step D. MS (ESI): mass calcd. for C12H13CIFN, 225.1; m / z found, 226.1 [M+H]+. 'HNMR (400 MHz, CDC13) 57.44 (d, J= 7.8 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.12 - 7.06 (m, 1H), 4.69 (d, J= 3.6 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.85 - 2.76 (m, 1H), 1.52 (td, J = 6.7, 3.3 Hz, 1H), 1.32 (td, J = 6.5, 3.0 Hz, 1H), 1.09 - 1.01 (m, 4H).Intermediate 20: rac-(l*iS,2*iS,5* / ?,6*iS)-2-(3-Fluoro-2-methylphenyl)-6-methyl-3-azabicyclo [3.1.0] hexane.

[0294] The title compound was prepared in a manner analogous to Intermediate 18 using (3-fluoro-2-methylphenyl)magnesium bromide instead of (2,3-difluorophenyl)magnesium bromide in Step D. MS (ESI): mass calcd. for C13H16FN, 205.1; m / z found, 206.1 [M+H]+. ’HNMR (400 MHz, CDCh) 57.38 (d, J= 7.8 Hz, 1H), 7.18 - 7.09 (m, 1H), 6.95 (t, J= 8.8 Hz, 1H), 4.38 (d, J= 3.3 Hz, 1H), 3.17 - 3.02 (m,2H), 2.35 (d, J = 2.3 Hz, 3H), 1.58 - 1.40 (m, 1H), 1.35 - 1.29 (m, 1H), 1.25 (td, J = 6.4, 3.3 Hz, 1H), 1.11 (d, J= 6.0 Hz, 3H), 0.90 (dt, J= 6.1, 3.0 Hz, 1H).Intermediate 21: rac-(l* / ?,2*iS,5*iS,6*A)-2-(3-Chloro-4-fluoropyridin-2-yl)-6-methyl-3-azabicyclo [3.1.0] hexane.

[0295] The title compound was prepared in a manner analogous to Intermediate 18 using (3-chloro-4-fluoropyridin-2-yl)magnesium bromide (Intermediate 11) instead of (2,3-difluorophenyl)magnesium bromide in Step D. MS (ESI): mass calcd. for C11H12CIFN2, 226.1; m / z found, 227.1 [M+H]+.Scheme 12: Synthesis of rac-(l*iS,2*iS,5*7?,6*iS)-2-(2,3-difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane.Intermediate 22: rac-(l*5,2*iS,5*7?,6*iS)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo [3.1.0] hexane.

[0296] To tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 4.69 mmol, 1.0 eq) in DCM (20 mL, 0.23M) was added DAST (1.5 g, 9.37 mmol, 2.0 eq) at 0 °C. The reaction was stirred at 0 °C for 1 h before being poured into sat. aq. NaHCOs and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-20% EtOAc in PE) to give tert-butyl rac-(l*A,5*S,6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (450 mg, 45% yield) as a yellow oil. 'HNMR (400 MHz, CDC13) 54.48 - 4.08 (m, 2H), 3.61 (br s, 2H), 3.37 (br d, J= 10.3 Hz, 2H), 1.54 (br s, 2H), 1.44 (s, 9H), 1.15 - 1.03 (m, 1H).

[0297] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(l*A,5*S,6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step B. 'H NMR (400 MHz, CDCh) 57.43 - 7.33 (m, 1H), 7.14 - 7.06 (m, 2H), 4.73 - 4.63 (m, 1H), 4.39 - 4.13 (m, 2H), 3.31 - 3.25 (m, 2H), 1.83 (dt, J= 6.8, 3.4 Hz, 1H), 1.65 (br dd, J= 6.3, 2.7 Hz, 1H), 1.59 - 1.52 (m, 1H).Intermediate 23: rac-(l*iS,2*iS,5* / ?,6*iS)-2-(3-Fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo [3.1.0] hexane.

[0298] The title compound was prepared in a manner analogous to Intermediate 22 using (3-fluoro-2-methylphenyl)magnesium bromide instead of (2,3-difluorophenyl)magnesium bromide in Step C. MS (ESI): mass calcd. for C13H15F2N, 223.1; m / z found, 224.1 [M+H]+. ’H NMR (400 MHz, CDCh) 57.45 (d, J= 7.8 Hz, 1H), 7.20 - 7.13 (m, 1H), 7.00 (t, J= 8.9 Hz, 1H), 4.62 (t, J= 2.4 Hz, 1H), 4.35 (br dd, J = 9.6, 7.5 Hz, 2H), 3.32 - 3.25 (m, 2H), 2.32 (d, J= 2.1 Hz, 3H), 1.83 - 1.76 (m, 1H), 1.70 - 1.65 (m, 1H), 1.60 (br dd, J= 7.0, 3.5 Hz, 1H).Intermediate 24: rac-(l*iS,2*iS,5* / ?,6*iS)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo [3.1.0] hexane.

[0299] The title compound was prepared in a manner analogous to Intermediate 22 using (2-chloro-3-fluorophenyl)magnesium bromide instead of (2,3-difluorophenyl)magnesium bromide in Step C. MS (ESI): mass calcd. for C12H12CIF2N, 243.1; m / z found, 244.0 [M+H]+. 'H NMR (400 MHz, CDCh) 5 7.52 (br d, J= 7.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.12 - 7.04 (m, 1H), 4.70 (br s, 1H), 4.45 - 4.17 (m, 2H), 3.26 (s, 2H), 1.84 (br d, J= 3.8 Hz, 1H), 1.61 (br d, J= 4.6 Hz, 2H).Scheme 13: Synthesis of rac-((l*iS,2*iS,5*7?,6*iS)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol.Intermediate 25: rac-((l *S,2 *S,5 *R,6 *A)-2-(2-Chlor o-3-fluorophenyl)-3-azabicyclo [3.1.0] hexan-6-yl)methanol.

[0300] To a solution of tert-butyl rac-( 1 *R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1,0]hexane-3-carboxylate (500 mg, 2.34 mmol, 1.0 eq) in DCM (10 mL, 0.2M) was added imidazole (319 mg, 4.69 mmol, 2.0 eq) and tert-butyl chlorodimethylsilane (707 mg, 4.69 mmol, 2.0 eq). The reaction was stirred at 25 °C for 5 h before being diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 1:9) to give tert-butyl rac-(l*R,5*S,6r)-6-(((tert-butyldimethylsilyl)oxy)methyl)-3 -azabicyclo [3.1.0]hexane-3 -carboxylate (760 mg, quant, yield) as a colorless oil. ’H NMR (400 MHz, CDC13) 53.56 (br d, J= 6.9 Hz, 4H), 3.34 (br d, J= 10.5 Hz, 2H), 1.44 (s, 9H), 1.43 - 1.40 (m, 2H), 0.89 (s, 9H), 0.87 - 0.81 (m, 1H), 0.05 (s, 6H).

[0301] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(l*R,5*S,6r)-6-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3 -azabicyclo [3.1,0]hexane-3-carboxylate in Step A. ’H NMR (400 MHz, CDCh) 57.54 (d, J= 7.8 Hz, 1H), 7.36 - 7.22 (m, 2H), 4.45 - 4.35 (m, 2H), 3.19 - 3.13 (m, 2H), 3.02 - 2.96 (m, 2H), 1.56 (td, J= 6.8, 3.4 Hz, 1H), 1.37 - 1.31 (m, 1H), 1.18 - 1.14 (m, 1H).Scheme 14: Synthesis of 5-(2-chloro-3-fluorophenyl)-l-methylpiperazin-2-one.

[0302] Step A: 5-(2-Chloro-3-fluorophenyl)-l-methylpyrazin-2(H7)-one. To a mixture of 5-bromo-l-methylpyrazin-2(127)-one (6.4 g, 33.9 mmol, 1.0 eq), 2-(2-chloro-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.5 g, 37.2 mmol, 1.1 eq), and Pd(dppf)C12 (2.4 g, 3.39 mmol, 0.1 eq) in 1,4-dioxane (160 mL, 0.18M) was added potassium carbonate (9.4 g, 67.7 mmol, 2.0 eq) in water (32 mL, 0.18M). The reaction was placed under N2 and stirred at 100 °C for 13 h. After cooling to rt, the mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (50-67% EtOAc in PE) to give 5 -(2-chloro-3 -fluorophenyl)- l-methylpyrazin-2(127)-one (5.8 g, 72% yield) as a light yellow solid. 'HNMR (400 MHz, CDC13) 58.26 (d, J= 1.1 Hz, 1H), 7.66 (d, J= 1.0 Hz, 1H), 7.45 (td, J= 7.8, 1.3 Hz, 1H), 7.33 (dt, J= 8.0, 5.3 Hz, 1H), 7.18 (dt, J= 8.4, 1.5 Hz, 1H), 3.63 (s, 3H).

[0303] Step B: 5-(2-Chloro-3-fluorophenyl)-l-methylpiperazin-2-one. To a solution of platinum dioxide (500 mg, 2.20 mmol, 0.1 eq) in EtOAc (50 mL, 0.4M) was added 5 -(2-chloro-3 -fluorophenyl)- 1-methylpyrazin-2(H7)-one (5.0 g, 21.0 mmol, 1.0 eq). The reaction was placed under H2(15 psi) and stirred at 25 °C for 4 h. The mixture was filtered and concentrated under reduced pressure to give 5-(2-chloro-3 -fluorophenyl)- l-methylpiperazin-2 -one (5.1 g, quant, yield) as a white solid, which was used in the next step directly. MS (ESI): mass calcd. for C11H12CIFN2O, 242.1; m / z found, 243.0 [M+H]+. ’H NMR (400 MHz, DMSO-6) 57.91 (d, J= 7.4 Hz, 1H), 7.62 - 7.54 (m, 2H), 5.19 (dd, J= 11.4, 4.3 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.94 - 3.68 (m, 2H), 3.61 (dd, J= 13.0, 4.4 Hz, 1H), 2.90 (s, 3H).Scheme 15: Synthesis of rac-((l*iS,2*iS,5* / ?,6*A)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile.Intermediate 27: rac-((l *S,2 *S,5 *R,6 *5)-2-(2-Chlor o-3-fluorophenyl)-3-azabicyclo [3.1.0] hexane-6-carbonitrile.

[0304] Step A: tert-Butyl rac-( 1 *S,5*S,6*S)-6-cyano-2-oxo-3-azabicyclo[3.1,0]hexane-3-carboxylate. To a solution of sodium periodate (13 g, 62.0 mmol, 3.8 eq) in water (50 mL, 0.16M) was added R11CI3 (169 mg, 0.816 mmol, 0.05 eq) and the mixture was stirred for 5 min. To the solution was added tertbutyl rac-(l*S,5*S,6*S)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.4 g, 16.3 mmol, 1.0 eq) in EtOAc (50 mL, 0.16M). The reaction was stirred at 20 °C for 1 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with sat. aq. Na2S2O3 and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl rac-(l*S,5*S,6*5)-6-cyano-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.5 g, 97% yield) as a white solid. ’HNMR (400 MHz, CDCh) 53.99 - 3.79 (m, 2H), 2.65 (ddd, J= 6.6, 2.8, 1.1 Hz, 1H), 2.53 (br d, J= 3.6 Hz, 1H), 1.73 (t, J= 3.2 Hz, 1H), 1.50 (s, 9H).

[0305] Step B: tert-Butyl rac-( 1 *. S'.5*. S'.6*. S)-2-(2-chloro-3-fluorophcnyl)-6-cyano-2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate. A solution of tert-butyl rac-( I *. S'.5*. S'.6*. S)-6-cyano-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.5 g, 6.75 mmol, 1.0 eq) in THF (10 mL, 0.7M) was placed under N2 and cooled to 0 °C. To the solution was added (2-chloro-3-fluorophenyl)magnesium bromide (7.4 mL, 7.42 mmol, 1.1 eq, IM in THF) and the reaction was stirred at 0 °C for 1 h. The mixture was quenched with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (30-50% EtOAc in PE) to give tert-butyl rac-(l*S,5*S,6*5)-2-(2-chloro-3-fluorophenyl)-6-cyano-2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.2 g, 92% yield) as a yellow oil. MS (ESI): mass calcd. for C17H18CIFN2O3, 352.1; m / z found, 235.1 [M-BocTEO].

[0306] Step C: rac-(l*. S'.5* / ?.6*. S)-2-(2-Chloro-3-fliiorophcnyl)-3-azabicyclo|3. l.0|hcx-2-cnc-6-carbonitrile. To a solution of tert-butyl (rac-l *. S'.5*. S'.6*. S)-2-(2-chloro-3-fluorophcnyl)-6-cyano-2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.8 g, 5.10 mmol, 1.0 eq) in ACN (20 mL, 0.26M) was added TsOH monohydrate (970 mg, 5.10 mmol, 1.0 eq). The reaction was stirred at 50 °C for 1 h before being concentrated under reduced pressure to give rac-( I *. S'.5* / ?.6*. S')-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hex-2-ene-6-carbonitrile (TsOH salt, 2.0 g, 96% yield) as a white solid. MS (ESI): mass calcd. for CI2H8C1FN2, 234.0; m / z found, 235.2 [M+H]+.

[0307] Step D: rac-((l*S,2*S,5*A,6*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile. To a solution of rac-( I *. S'.5* / ?.6*. S)-2-(2-chloro-3-fliiorophcnyl)-3-azabicyclo|3.1,0|hcx-2-ene-6-carbonitrile (TsOH salt, 2.0 g, 4.92 mmol, 1.0 eq) in MeOH (20 mL, 0.24M) was added sodium cyanoborohydride (618 mg, 9.83 mmol, 2.0 eq) and AcOH (3.0 mL). The reaction was stirred at 20 °C for 1 h before being quenched with sat. aq. NaHCOs and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford rac-((l*S,2*S,5*A,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (1.0 g, 86% yield) as a yellow oil. MS (ESI): mass calcd. for C12H10CIFN2, 236.1; m / z found, 237.1 [M+H]+. ’HNMR (400 MHz, CDC13) 57.39 (d, J= 7.8 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.12 (brd, J= 1.1 Hz, 1H), 4.72 (d, J= 3.3 Hz, 1H), 3.37 - 3.22 (m, 2H), 2.52 (td, J= 6.8, 3.4 Hz, 1H), 2.21 (td, J= 6.8, 3.3 Hz, 1H), 1.74 (brt, J= 3.3 Hz, 1H).Intermediate 28: rac-((l *S,2 *S,5 *R,6 *iS)-2-(2,3-Difluorophenyl)-3-azabicyclo [3.1.0] hexane-6-carbonitrile

[0308] The title compound was prepared in a manner analogous to Intermediate 27 using (2,3-difluorophenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step B. MS (ESI): mass calcd. for C12H10F2N2, 220.1; m / z found, 221.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 57.26 - 7.21 (m, 1H), 7.15 - 7.07 (m, 2H), 4.67 (d, J= 3.0 Hz, 1H), 3.33 - 3.28 (m, 1H), 3.28 - 3.23 (m, 1H), 2.43 (dq, J= 3.4, 2.5 Hz, 1H), 2.22 (td, J= 6.8, 3.3 Hz, 1H), 1.92 (s, 1H), 1.73 (t, J= 3.3 Hz, 1H).Intermediate 29: rac-((l *S,2 *S,5 * / ?,6 *5)-2-(3-Fluor o-2-methylphenyl)-3-azabicyclo [3.1.0] hexane-6-carbonitrile.

[0309] The title compound was prepared in a manner analogous to Intermediate 27 using (3-fluoro-2-methylphenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step B. MS (ESI): mass calcd. for C13H13FN2, 216.1; m / z found, 217.1 [M+H]+. ’HNMR (400 MHz, DMSO-6) 57.36 - 7.29 (m, 1H), 7.28 - 7.19 (m, 1H), 7.14 - 7.02 (m, 1H), 4.33 (br s, 1H), 3.13 - 3.02 (m, 1H), 3.00 - 2.88 (m, 1H), 2.44 (br d, J= 2.0 Hz, 1H), 2.39 (td, J= 6.6, 3.3 Hz, 1H), 2.29 (d, J= 2.1 Hz, 3H), 2.21 (td, J= 6.6, 3.2 Hz, 1H), 1.84 (t, J= 3.4 Hz, 1H).Scheme 16: Synthesis of 2-(rac-(l* / ?, 2*5, 5*5,6 *5)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetonitrile.Intermediate 30: 2-(rac-(l*7?,2*5,5*5,6*5)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetonitrile.

[0310] To a solution of tert-butyl rac-( 1 *R,5*5,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1,0]hexane-3-carboxylate (2.0 g, 9.38 mmol, 1.0 eq) in DMF (80 mL, 0.12M) under N2 was added 1,2-diiodoethane (3.2 g, 11.2 mmol, 1.2 eq) and triphenylphosphine (2.9 g, 11.2 mmol, 1.2 eq). When the solid was dissolved completely, potassium carbonate (3.9 g, 28.1 mmol, 3.0 eq) and trimethylsilyl cyanide (3.7 g, 37.5 mmol, 4.0 eq) were added. The reaction was stirred at 15 °C under N2 for 12 h before being quenched with sat. aq. NaHCO3and extracted with EtOAc. The combined organic layers were washedwith water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE: EtOAc = 2:1) to give tert-butyl exo-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.8 g, 85%yield) as alight yellow oil. ’HNMR (400 MHz, CDCh) 53.70 - 3.55 (m, 2H), 3.40 - 3.29 (m, 2H), 2.59 - 2.30 (m, 2H), 1.53 (t, J= 2.8 Hz, 2H), 1.44 (s, 9H), 0.97 - 0.89 (m, 1H).

[0311] The title compound was prepared in a manner analogous to Intermediate 27 using tert-butyl exo-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl rac-( l*. S',5*. S'.6*. S')-6-cyano-3 -azabicyclo [3.1,0]hexane-3-carboxylate in Step A. 'H NMR (400 MHz, CDCh) 57.54 (d, J = 7.8 Hz, 1H), 7.36 - 7.22 (m, 2H), 4.45 - 4.35 (m, 2H), 3.19 - 3.13 (m, 2H), 3.02 - 2.96 (m, 2H), 1.56 (td, J = 6.8, 3.4 Hz, 1H), 1.37 - 1.31 (m, 1H), 1.18 - 1.14 (m, 1H).Intermediate 31: (5, E)-3-(Pyrrolidin-3-yl)acrylonitrile.

[0312] The title compound was prepared in a manner analogous to Intermediate 8 using tert-butyl (R)-3 -formylpyrrolidine-1 -carboxylate instead of tert-butyl 3 -formylazetidine- 1 -carboxylate in Step A. Intermediate 32: (17?,25,55)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane.

[0313] Separation of Intermediate 12 via SFC (Stationary phase: AD (5x25 cm); Mobile phase: 11% MeOH / CO₂ with 0.1% NH₄OH; Rt = 3.83 min, first eluting product) provided the title compound.Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C11H9CIF3N, 247.1; m / z found, 247.9 [M+H]+.Intermediate 33: rac-(l * / ?, 2*5,5 *5)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane.

[0314] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and using ZnBr2 instead of TFA in Step C. MS (ESI): mass calcd. for C13H15CIFN, 239.1; m / z found, 240.1 [M+H]+. ’H NMR (400 MHz, DMSO-th) 57.54 (d, J= 7.6 Hz, 1H), 7.36 - 7.21 (m, 2H), 4.68 (d, J= 4.1 Hz, 1H), 3.26 (dd, J= 9.4, 5.1 Hz, 1H), 3.04 (d,J= 9.4 Hz, 1H), 2.68 (br d, J= 9.3 Hz, 1H), 1.68 (dd, J= 7.4, 4.5 Hz, 1H), 1.29 (dd, J = 7.4, 5.0 Hz, 1H), 1.11 (s, 3H), 0.90 (s, 3H).Intermediate 34: 3-(2-Chloro-3-fluorophenyl)-8-oxa-2-azaspiro[4.5]decane.

[0315] The title compound was prepared in a manner analogous to Intermediate 12, Steps B-D, using tert-butyl 3-oxo-8-oxa-2-azaspiro[4.5]decane-2 -carboxylate instead of tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step B. MS (ESI): mass calcd. for C14H17ClFNO, 269.1; m / z found, 270.1 [M+H]+. ’HNMR (400 MHz, CDCh) 57.51 (d, J = 7.8 Hz, 1H), 7.23 (dt, J= 8.0, 5.5 Hz, 1H), 7.03 (dt, J= 8.5, 1.3 Hz, 1H), 4.65 (t, J= 8.3 Hz, 1H), 3.72 (t, J= 5.4 Hz, 2H), 3.69 - 3.57 (m, 2H), 3.12 - 3.05 (m, 1H), 3.02 - 2.94 (m, 1H), 2.37 (dd, J= 12.8, 7.7 Hz, 1H), 1.71 - 1.60 (m, 4H), 1.39 (dd, J = 12.9, 8.9 Hz, 1H).Scheme 22: Synthesis of tert-butyl rac-(3a*iS,7a*?)-hexahydropyrano[3,4-c]pyrrole-2(3 / 7)-carboxylate.Intermediate 35: tert-Butyl rac-(3a*iS,7a*?)-hexahydropyrano[3,4-c]pyrrole-2(3 / 7)-carboxylate.

[0316] Step A: 2-Bcnzylhcxahydropyrano|3.4-c|pyrrol-4(IH)-onc. To a solution of 5.6-dihydro-2H-pyran-2-one (25 g, 255 mmol, 1.0 eq) in DCM (600 mL, 0.4M) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (91 g, 382 mmol, 1.5 eq). The solution was degassed and purged with N2 before addition of 2,2,2-trifluoroacetic acid (44 g, 382 mmol, 1.5 eq) in DCM (45 mL, 0.4M) dropwise at 0 °C. The reaction was stirred at 15 °C for 16 h before being diluted with sat. aq. NaHCO3and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (45-55% EtOAc in hexanes) to give 2-benzylhexahydropyrano[3,4-c]pyrrol-4(1H)-one (50 g, 85% yield)as a yellow oil. ’HNMR (400 MHz, CDC13) 57.36 - 7.24 (m, 5H), 4.38 (ddd, J= 11.1, 5.7, 3.1 Hz, 1H), 4.19 (ddd, J= 11.3, 9.3, 2.3 Hz, 1H), 3.64 - 3.57 (m, 1H), 3.55 - 3.48 (m, 1H), 3.17 - 3.02 (m, 1H), 2.96 -2.84 (m, 2H), 2.78 (dd, J= 9.1, 7.7 Hz, 1H), 2.74 - 2.60 (m, 1H), 2.27 (dd, J= 9.2, 5.7 Hz, 1H), 2.06 -1.92 (m, 1H), 1.72 - 1.55 (m, 1H).

[0317] Step B: 2-(l-Benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)ethan-l-ol. A solution of 2-benzylhexahydropyrano[3,4-c]pyrrol-4(1H)-one (20 g, 86.5 mmol, 1.0 eq) in THF (400 mL, 0.2M) was degassed and purged with N2. To the solution was added lithium borohydride (2M in THF, 65 mL, 130 mmol, 1.5 eq) dropwise at 0 °C. The reaction was stirred at 15 °C under N2 for 16 h before being quenched with sat. aq. NH4CI at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was poured into methanol (400 mL, 0.27M) and stirred at 80 °C for 16 h. After cooling to rt, the mixture was concentrated under reduced pressure to give 2-(l-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)ethan-l-ol (20 g, 80% yield) as a pale yellow oil. ’H NMR (400 MHz, CDCh) 57.37 - 7.23 (m, 5H), 3.82 - 3.55 (m, 6H), 2.83 (dd, J= 9.2, 2.4 Hz, 1H), 2.73 (dd, J= 8.4, 6.1 Hz, 1H), 2.62 (d, J= 8.0 Hz, 2H), 2.48 (br dd, J = 13.9, 7.9 Hz, 1H), 2.29 - 2.20 (m, 1H), 1.89 (td, J= 13.2, 6.8 Hz, 1H), 1.82 - 1.70 (m, 1H).

[0318] Step C: 2-(l -Benzyl -4-(hydroxymethyl)pyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate. To a solution of 2-(l -benzyl -4-(hydroxymethyl)pyrrolidin-3-yl)ethan-l-ol (5.0 g, 21.2 mmol, 1.0 eq) in toluene (300 mL, 0.07M) was added DIPEA (8.9 mL, 63.7 mmol, 3.0 eq),p-toluenesulfonyl chloride (5.3 g, 27.6 mmol, 1.3 eq), and 4-(dimethylamino)pyridine (130 mg, 1.06 mmol, 0.05 eq). The reaction was stirred at 15 °C for 16 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (5-10% MeOH in DCM) to give 2-(l-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate (2.3 g, 28% yield) as a yellow oil. MS (ESI): mass calcd. for C21H27NO4S, 389.1; m / z found, 390.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.81 - 7.76 (m, 2H), 7.58 - 7.50 (m, 2H), 7.45 - 7.36 (m, 5H), 4.25 - 4.07 (m, 4H), 3.80 - 3.48 (m, 4H), 3.05 - 2.71 (m, 4H), 2.48 (s, 3H), 1.68 - 1.59 (m, 1H), 1.58 - 1.46 (m, 1H).

[0319] Step D: 2-Benzyloctahydropyrano[3,4-c]pyrrole. To a solution of 2-(l -benzyl -4-(hydroxymethyl)pyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate (1.3 g, 3.34 mmol, 1.0 eq) in toluene (130 mL, 0.03M) was added DIPEA (1.4 mL, 10.0 mmol, 3.0 eq). The reaction was stirred at 120 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (7-10% MeOH in DCM) to give 2-benzyloctahydropyrano[3,4-c]pyrrole (1.1 g, 35% yield) as a yellow oil. MS (ESI): mass calcd. for C14H19NO, 217.1; m / z found, 218.1 [M+H]+. ’HNMR (400 MHz, CDCh) 57.38 - 7.28 (m, 4H), 7.26 -7.22 (m, 1H), 3.79 - 3.66 (m, 4H), 3.66 - 3.58 (m, 1H), 3.53 (ddd, J= 11.5, 7.7, 4.1 Hz, 1H), 2.86 (t, J = 7.8 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.69 - 2.57 (m, 2H), 2.40 - 2.21 (m, 2H), 1.80 - 1.60 (m, 2H).

[0320] Step E: Octahydropyrano[3,4-c]pyrrole. To a solution of Pd(OH)2 / C (980 mg, 5% Pd wetted with -55% water) in ethanol (50 mL, 0.14M) was added 2-benzyloctahydropyrano[3,4-c]pyrrole (1.5 g, 6.76 mmol, 1.0 eq). The reaction was degassed, purged with H2, and stirred at 30 °C under H2 (30 Psi) for 8 h. The mixture was filtered and concentrated under reduced pressure to give octahydropyrano[3,4-c]pyrrole (860 mg, quant, yield) as a colorless oil. ’HNMR (400 MHz, CDCh) 53.86 (d, J= 11.6 Hz, 1H), 3.81 - 3.66 (m, 3H), 3.44 (dd, J= 11.6, 7.0 Hz, 1H), 3.33 - 3.23 (m, 3H), 3.14 (dd, J= 11.3, 3.2 Hz, 1H), 2.41 (dd, J = 5.3, 2.3 Hz, 1H), 2.33 (d, J = 5.1 Hz, 1H), 1.75 - 1.64 (m, 2H).

[0321] Step F: tert-Butyl rac-(3a*S,7a*R)-hexahydropyrano[3,4-c]pyrrole-2(3H)-carboxylate. To a solution of octahydropyrano[3,4-c]pyrrole (860 mg, 6.76 mmol, 1.0 eq) in DCM (20 mL, 0.34M) was added di-tert-butyl dicarbonate (2.2 g, 10.1 mmol, 1.5 eq) and DIPEA (1.4 g, 13.5 mmol, 2.0 eq). The reaction was stirred at 15 °C for 2 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (20-25% EtOAc in hexanes) to give tert-butyl rac-(3a*S,7a*R)-hexahydropyrano[3,4-c]pyrrole-2(3H)-carboxylate (1.2 g, 80% yield) as a colorless oil. ’HNMR (400 MHz, CDCh) 53.89 - 3.75 (m, 1H), 3.73 - 3.60 (m, 2H), 3.55 - 3.17 (m, 5H), 2.39 - 2.18 (m, 2H), 1.75 - 1.63 (m, 1H), 1.62 - 1.57 (m, 1H), 1.47 (s, 9H).Intermediate 36: rac-(l*5,3a*iS,7a*7?)-l-(2-Chloro-3-fluorophenyl)octahydropyrano[3,4-c]pyrrole.

[0322] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*S,7a*R)-hexahydropyrano[3,4-c]pyrrole-2(3H)-carboxylate (Intermediate 35) instead of tertbutyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. tert-Butyl 1-oxohexahydropyrano[3,4-c]pyrrole-2(3H)-carboxylate was isolated from Step A via FCC on silica (20-25% EtOAc in hexanes, first eluting product) and elaborated to the title compound using Steps B-D. MS (ESI): mass calcd. for C13H15ClFNO, 255.1; m / z found, 256.2 [M+H]+.Intermediate 37: rac-(l*5,3a*iS,7a*?)-l-(2,3-Difluorophenyl)octahydropyrano[3,4-c]pyrrole.

[0323] The title compound was prepared in a manner analogous to Intermediate 36 using 2,3-difluorophenyl magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step B.Intermediate 38: rac-(l*5,3a*iS,7a*?)-l-(2-Chlorophenyl)octahydropyrano[3,4-c]pyrrole.

[0324] The title compound was prepared in a manner analogous to Intermediate 36 using 2-chlorophenyl magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step B. Intermediate 39: rac-(l*iS,3a*iS,7a*?)-l-(3-Fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole.

[0325] The title compound was prepared in a manner analogous to Intermediate 36 using (3-fluoro-2-methylphenyl)magnesium bromide instead of (2-chloro-3-fluorophenyl)magnesium bromide in Step B.Intermediate 40: rac-(3*iS,3a* / ?,7a*iS)-3-(2-Chloro-3-fluorophenyl)octahydropyrano[3,4-c]pyrrole.

[0326] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*S,7a*A)-hexahydropyrano[3,4-c]pyrrole-2(327)-carboxylate (Intermediate 35) instead of tertbutyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. tert-Butyl 3-oxohexahydropyrano[3,4-c]pyrrole-2(377)-carboxylate was isolated from Step A via FCC on silica (20-25% EtOAc in hexanes, second eluting product) and elaborated to the title compound using Steps B-D. MS (ESI): mass calcd. for C13H15ClFNO, 255.1; m / z found, 256.2 [M+H]+.Intermediate 41: rac-(4a*iS,5* / ?,7a* / ?)-5-(2-Chloro-3-fluorophenyl)hexahydro-5 / f-[l,4]dioxino[2,3-c] pyrrole.

[0327] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl (4a*R,7a*S)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrole-6-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and using ZnBr2 instead of TFA in Step C. MS (ESI): mass calcd. for C12H13ClFNO2, 257.1; m / z found, 258.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.16 -7.01 (m, 3H), 4.42 (dt, J= 7.8, 3.9 Hz, 1H), 3.93 - 3.88 (m, 2H), 3.77 - 3.63 (m, 4H), 3.52 - 3.45 (m, 3H).Intermediate 42: 7-(2-Chloro-3-fluorophenyl)-2-oxa-6-azaspiro[3.4] octane.

[0328] The title compound was prepared in a manner analogous to Intermediate 12, Steps B-D, using tert-butyl 6-oxo-2-oxa-7-azaspiro[3.4]octane-7-carboxylate instead of tert-butyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step B. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.0 [M+H]+.Intermediate 43: rac-(3a*?,6*7?,6a*?)-6-(2-Chloro-3-fluorophenyl)hexahydro-2 / f-furo[2,3-c] pyrrole.

[0329] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*5,6a*5)-hexahydro-5H-furo[2,3-c]pyrrole-5-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. tert-Butyl 6-oxohexahydro-5H-furo[2,3-c]pyrrole-5-carboxylate was isolated from Step A via FCC on silica (20-25% EtOAc in hexanes, second eluting product) and elaborated to the title compound using Steps B-D. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.3 [M+H]+.Intermediate 44: rac-(3a*5,4*5,6a*5)-4-(2-Chloro-3-fluorophenyl)hexahydro-2 / f-furo[2,3-c] pyrrole.

[0330] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*S,6a*5)-hexahydro-5H-furo[2,3-c]pyrrole-5-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. tert-Butyl 4-oxohexahydro-5H-furo[2,3-c]pyrrole-5-carboxylate was isolated from Step A via FCC on silica (20-25% EtOAc in hexanes, first eluting product) and elaborated to the title compound using Steps B-D. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.3 [M+H]+.Intermediate 45: rac-(l *5,2 *7?,5*7?)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.1] octane.

[0331] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl 6-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and using ZnBr2 instead of TFA in Step C. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.2 [M+H]+.Intermediate 46: rac-(l *S,2 *7?,5*7?)-2-(2-Chloro-3-fluorophenyl)-8-oxa-3-azabicyclo[3.2.1] octane.

[0332] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and using ZnBr2 instead of TFA in Step C. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.51 (d, J= 7.8 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.07 (dt, J= 8.5, 1.4 Hz, 1H), 4.58 (d, J= 1.6 Hz, 1H), 4.46 - 4.33 (m, 2H), 3.29 (dd, J= 11.0, 2.1 Hz, 1H), 2.85 (d, J= 10.9 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.95 - 1.82 (m, 2H), 1.59 - 1.55 (m, 1H), 1.53 - 1.47 (m, 1H).Intermediate 47: rac-(l*5,5*7?,6*iS)-6-(2-Chloro-3-fluorophenyl)-9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonane.

[0333] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl (l*R,5*5)-9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A.Intermediate 48: rac-(2*7?,3a*7?,6a*5)-2-(2-Chloro-3-fluorophenyl)hexahydro-l / 7-furo[3,4-Z>] pyrrole.

[0334] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*R,6a*S)-hexahydro-1H-furo[3,4-b]pyrrole-1-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and was isolated from Step D via RP-HPLC (1-30% ACN in 0.1% aq. TFA, first eluting product).Intermediate 49: rac-(2*iS,3a* / ?,6a*iS)-2-(2-Chloro-3-fluorophenyl)hexahydro-EH-furo[3,4-Z>] pyrrole.

[0335] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(3a*R,6a*S)-hexahydro-1H-furo[3,4-b]pyrrole-1-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and was isolated from Step D via RP-HPLC (1-30% ACN in 0.1% aq. TFA, second eluting product).Intermediate 50: 8-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[4.4]nonane.

[0336] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl 2- oxa-7-azaspiro[4.4]nonane-7-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3- carboxylate in Step A.Scheme 23: Synthesis of tert-butyl 7-oxo-2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-8- carboxylate.Intermediate 51: 7-(2-Chloro-3-fluorophenyl)-2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonane.

[0337] Step A: 5-Oxa-2,8-diazaspiro[3.5]nonan-7-one. tert-Butyl 7-oxo-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.13 mmol, 1.0 eq) was taken up in 4M HC1 in EtOAc and stirred at 15 °C for 1 h. The reaction was concentrated in vacuo to afford 5-oxa-2,8-diazaspiro[3.5]nonan-7-one (HC1 salt, 0.73 g, quant, yield) as a white solid.

[0338] Step B: 2-(2,2,2-Trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-7-one. To 5-oxa-2,8-diazaspiro[3.5]nonan-7-one (680 mg, 3.81 mmol, 1.0 eq) in toluene (6.0 mL, 0.6M) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.3 g, 5.71 mmol, 1.5 eq) and TEA (2.1 mL, 15.2 mmol, 4.0 eq). The reaction was stirred at 80 °C for 12 h. After cooling to rt, the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4,filtered, and concentrated in vacuo to give 2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-7-one (420 mg, 49% yield) as a white solid. ’H NMR (400 MHz, CDCh) 56.33 (br s, 1H), 4.19 (s, 2H), 3.66 (d, J= 2.5 Hz, 2H), 3.62 (d, J= 8.6 Hz, 2H), 3.29 (d, J= 8.6 Hz, 2H), 3.09 (q, J= 9.3 Hz, 2H).

[0339] Step C: tert-Butyl 7-oxo-2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3,5]nonane-8-carboxylate. To a solution of 2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-7-one (420 mg, 1.87 mmol, 1.0 eq) in DCM (3.0 mL, 0.6M) was added BOC2O (613 mg, 2.81 mmol, 1.5 eq), DMAP (114 mg, 0.937 mmol, 0.5 eq), and TEA (0.78 mb, 5.62 mmol, 3.0 eq). The reaction was stirred at 15 °C for 12 h before being quenched with water and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC on silica (10-30% EtOAc in hexanes) to afford tert-butyl 7-oxo-2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3,5]nonane-8-carboxylate (350 mg, 58% yield) as a yellow oil. ’H NMR (400 MHz, CDCh) 5 4.21 (s, 2H), 3.97 (s, 2H), 3.63 (d, J= 8.3 Hz, 2H), 3.28 (brd, J= 8.3 Hz, 2H), 3.14 - 3.04 (m, 2H), 1.57 (s, 9H).

[0340] The title compound was prepared in a manner analogous to Intermediate 12, Steps B-D, using tert-butyl 7-oxo-2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate instead of tertbutyl 6,6-difluoro-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step B. MS (ESI): mass calcd. for C14H15ClF4N2O, 338.1; m / z found, 339.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.45 (d, J= 7.8 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.08 (dt, J= 8.5, 1.3 Hz, 1H), 4.37 (dd, J= 9.8, 3.1 Hz, 1H), 3.90 (d, J= 7.5 Hz, 1H), 3.82 (dd, J= 11.2, 3.2 Hz, 1H), 3.50 (br d, J= 7.7 Hz, 1H), 3.41 (d, J= 11.5 Hz, 1H), 3.27 -3.16 (m, 3H), 3.11 (q, J = 9.3 Hz, 3H).Intermediate 52: rac-(l*iS,2*iS,5* / ?,6*iS)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo [3.1.0] hexane.

[0341] A solution of tert-butyl rac-( 1 *R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1,0]hexane-3-carboxylate (3.0 g, 14.1 mmol, 1.0 eq) in THF (30 mL, 0.47M) was degassed and purged withN2. NaH (1.1 g, 28.1 mmol, 2.0 eq, 60% in mineral oil) was added to the solution at 0 °C portionwise. The solution was stirred at 25 °C for 40 min before iodomethane (4.4 g, 30.9 mmol, 2.2 eq) was added. The reaction was stirred at 25 °C for 12 h before being quenched with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-20% EtOAc in PE) to give tert-butyl rac-(1*R,5*S,6r)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.0 g, 94% yield) as a yellow oil.

[0342] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(1*R,5*S,6r)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A.1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 7.15 (td, J= 8.0, 5.4 Hz, 1H), 6.99 (td, J= 8.5, 1.4 Hz, 1H), 4.60 (d, J= 3.6 Hz, 1H), 3.22 -3.15 (m, 7H), 1.98 (s, 1H), 1.64 (dt, J= 6.8, 3.5 Hz, 1H), 1.43 (dt, J= 6.7, 3.3 Hz, 1H), 1.33 (tt, J= 6.8, 3.4 Hz, 1H).Intermediate 53: rac-(l* / ?,4*iS,5* / ?)-4-(2-Chloro-3-fluorophenyl)-l-(methoxymethyl)-3-azabicyclo [3.1.0] hexane.

[0343] The title compound was prepared in a manner analogous to Intermediate 52 using tert-butyl rac-(1*R,5*R)-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. The desired regioisomer was recovered as the second eluting product from Step B, FCC on silica (25-50% EtOAc in PE). MS (ESI): mass calcd. for C13H15ClFNO, 255.1; m / z found, 256.1 [M+H]+. ’H NMR (400 MHz, CDCh) 57.48 (d, J= 7.8 Hz, 1H), 7.22 (dt, J= 8.0, 5.4 Hz, 1H), 7.10 - 7.03 (m, 1H), 4.75 (d, J= 3.4 Hz, 1H), 3.61 (d, J= 10.4 Hz, 1H), 3.48 (d, J= 10.4 Hz, 1H), 3.40 (s, 3H), 3.26 (s, 2H), 2.20 - 2.08 (m, 1H), 1.70 (td, J= 7.8, 3.8 Hz, 1H), 0.99 (t, J= 4.4 Hz, 1H), 0.56 (dd, J= 8.0, 5.0 Hz, 1H).Scheme 24: Synthesis of tert-butyl rac-(4a*iS,7a*A)-hexahydropyrano[2,3-c]pyrrole-6(2 / 7)-carboxylate.Intermediate 54: rac-(4a*5,5*iS,7a*iS)-5-(2-Chloro-3-fluorophenyl)octahydropyrano[2,3-c]pyrrole.

[0344] Step A: tert-Butyl rac-(3*S,4*5)-3-(allyloxy)-4-vinylpyrrolidine-l-carboxylate. tert-Butyl rac-(3*. S'.4*. S)-3-hydroxy-4-vinylpyrrolidinc- 1 -carboxylate (14 g, 65.6 mmol, 1.0 eq) was taken up in DMF (140 mL, 0.5M), placed under N2, and cooled to 0 °C. To the solution was added sodium hydride (4.0 g, 98.5 mmol, 1.5 eq) and this was stirred at 0 °C for 20 min. 3 -Bromoprop- 1-ene (16 g, 131 mmol, 2.0 eq) was added dropwise and the reaction was stirred at 0 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (10-15% EtOAc in hexanes) to give tert-butyl rac-(3*S,4*S)-3-(allyloxy)-4-vinylpyrrolidine-1-carboxylate (14 g, 84% yield) as a yellow oil. ’H NMR (400 MHz, CDC13) 56.04 - 5.78 (m, 2H), 5.33 -5.24 (m, 1H), 5.22 - 5.11 (m, 3H), 4.12 - 4.00 (m, 1H), 3.99 - 3.91 (m, 2H), 3.58 - 3.49 (m, 2H), 3.43 -3.29 (m, 2H), 2.80 (tdd, J= 13.1, 8.4, 4.3 Hz, 1H), 1.47 (s, 9H).

[0345] Step B: tert-Butyl rac-(4a*S,7a*S)-4a,5,7,7a-tetrahydropyrano[2,3-c]pyrrole-6(227)-carboxylate. To a mixture of tert-butyl rac-(3*S,4*S)-3-(allyloxy)-4-vinylpyrrolidine- 1 -carboxylate (14 g, 55.3 mmol, 1.0 eq) in DCM (140 mL, 0.4M) was added Grubbs catalyst, 2nd generation (4.7 g, 5.53 mmol, 0.1 eq) and Cui (530 mg, 2.76 mmol, 0.05 eq). The reaction was placed under N2 and stirred at 15 °C for 16 h. The mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (10-30% EtOAc in hexanes) to give tert-butyl rac-(4a*S,7a*S)-4a,5,7,7a-tetrahydropyrano[2,3-c]pyrrole-6(227)-carboxylate (10 g, 80% yield) as a yellow oil. ’H NMR (400 MHz, CDCh) 55.85 (br s, 2H), 4.19 (s, 2H), 4.05 (t, J= 4.2 Hz, 1H), 3.81 - 3.42 (m, 3H), 3.12 (dt, J= 10.3, 4.4 Hz, 1H), 2.52 (br s, 1H), 1.46 (s, 9H).

[0346] Step C: tert-Butyl rac-(4a*S,7a*S)-hexahydropyrano[2,3-c]pyrrole-6(227)-carboxylate. To a solution of Pd / C (100 mg, 5% Palladium on Carbon, wetted with ca. 55% water) in methanol (100 mL, 0.4M) was added tert-butyl rac-(4a*S,7a*S)-4a,5,7,7a-tetrahydropyrano[2,3-c]pyrrole-6(227)-carboxylate (10 g, 44.4 mmol, 1.0 eq). The reaction was purged with H2 and stirred at 30 °C under H2 (30 psi) for 2 h. The mixture was filtered and concentrated under reduced pressure to give tert-butyl rac-(4a*S,7a*S)-hexahydropyrano[2,3-c]pyrrole-6(2H)-carboxylate (10 g, quant, yield) as a yellow oil. ’H NMR (400 MHz, CDCh) 53.98 - 3.90 (m, 2H), 3.43 - 3.36 (m, 4H), 2.26 - 2.15 (m, 1H), 1.81 - 1.78 (m, 2H), 1.60 (s, 2H), 1.45 (s, 9H), 1.43 - 1.36 (m, 1H).

[0347] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(4a*S,7a*S)-hexahydropyrano[2,3-c]pyrrole-6(227)-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A and using trimethylsilyl trifluoromethanesulfonate instead of TFA in Step C. MS (ESI): mass calcd. for: C13H15ClFNO, 255.1; m / z found, 256.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.57 (d, J= 7.8 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.08 - 7.02 (m, 1H), 4.70 (d, J= 8.1 Hz, 1H), 4.24 (dt, J= 5.8, 3.2 Hz, 1H), 3.77 - 3.69 (m, 1H), 3.52 - 3.41 (m, 3H), 3.32 (dd, J= 11.1, 3.1 Hz, 1H), 3.17 (dd, J= 11.0, 5.9 Hz, 1H), 2.65 - 2.56 (m, 3H), 1.67 - 1.59 (m, 1H).Scheme 25: Synthesis of tert-butyl rac-(l*iS,5*7?)-6-oxa-3-azabicyclo[3.2.0]heptane-3-carboxylate.Intermediate 55: rac-(l *R,2 *S,5 *A)-2-(2-Chlor o-3-fluorophenyl)-6-oxa-3-azabicyclo [3.2.0] heptane.

[0348] Step A: tert-Butyl rac-(3*S,4*R)-3-hydroxy-4-((tosyloxy)methyl)pyrrolidine-l-carboxylate. To a solution of tert-butyl 3 -hydroxy-4-(hydroxymethyl)pyrrolidine-l -carboxylate (7.5 g, 34.5 mmol, 1.0eq) in toluene (150 mL, 0.2M) was added TEA (14 mL, 104 mmol, 3.0 eq), p-toluenesulfonyl chloride (6.6 g, 34.5 mmol, 1.0 eq), and 4-(dimethylamino)pyridine (211 mg, 1.73 mmol, 0.05 eq). The reaction was stirred at 25 °C for 2 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (35-65% ACN in 10 mM aq. NH4HCO3) to give tert-butyl rac-(3*S,4*R)-3-hydroxy-4-((tosyloxy)methyl)pyrrolidine- 1-carboxylate (900 mg, 7% yield) as a white solid. ’HNMR (400 MHz, CDC13) 57.88 - 7.77 (m, 2H), 7.38 (br d, J= 7.8 Hz, 2H), 4.41 (br s, 1H), 4.32 (br t, J= 9.7 Hz, 1H), 4.06 (br s, 1H), 3.64 - 3.39 (m, 3H), 3.07 (br d, J= 9.8 Hz, 1H), 2.59 - 2.39 (m, 4H), 1.48 - 1.42 (m, 9H).

[0349] Step B: tert-Butyl rac-(l*S,5*R)-6-oxa-3-azabicyclo[3.2.0]heptane-3-carboxylate. A solution of tert-butyl rac-(3*S,4*R)-3-hydroxy-4-((tosyloxy)methyl)pyrrolidine-l-carboxylate (500 mg, 1.35 mmol, 1.0 eq) in DMF (10 mL, 0. IM) was placed under N2 and cooled to 0 °C. To the solution was added sodium hydride (81 mg, 2.02 mmol, 1.5 eq, 60% in mineral oil) in portions. The reaction was stirred at 25 °C for 2 h under N2 before being poured into sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl rac-( 1 *S,5*R)-6-oxa-3-azabicyclo[3.2.0]heptane-3-carboxylate (200 mg, 75% yield) as a pale yellow oil. ’H NMR (400 MHz, CDCI3) 55.38 - 5.25 (m, 1H), 4.89 - 4.76 (m, 1H), 4.45 - 4.28 (m, 1H), 4.05 - 3.83 (m, 2H), 3.50 - 3.35 (m, 1H), 3.20 (br dd, J= 11.8, 6.3 Hz, 1H), 3.14 - 3.06 (m, 1H), 1.51 (s, 9H).

[0350] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(l*S,5*R)-6-oxa-3-azabicyclo[3.2.0]heptane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo [3.1.0]hexane-3 -carboxylate in Step A. MS (ESI): mass calcd. for CnHnClFNO, 227.1; m / z found, 228.2 [M+H]+.Scheme 26: Synthesis of tert-butyl 6-(isopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.Intermediate 56: rac-(l*7?,2*7?,5*iS,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-(isopropoxymethyl)-3-azabicyclo [3.1.0] hexane.

[0351] Step A: tert-Butyl 6-(((methylsulfonyl)oxy)methyl)-3 -azabicyclo [3.1.0]hexane-3 -carboxylate. A solution of tert-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, 9.38 mmol, 1.0 eq) in DCM (20 mL, 0.5M) was placed under N2 and cooled to 0 °C. DIPEA (2.8 g, 28.1 mmol, 3.0 eq) and methanesulfonic anhydride (2.4 g, 14.1 mmol, 1.5 eq) were added and the reaction was stirred at0 °C for 0.5 h. The mixture was poured into water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC on silica (20-40% EtOAc in hexanes) to give tert-butyl 6-(((methylsulfonyl)oxy)methyl)-3 -azabicyclo [3.1.0]hexane-3 -carboxylate (2.0 g, 73% yield) as a white solid. 'H NMR (400 MHz, CDC13) 54.25 - 4.03 (m, 2H), 3.71 - 3.51 (m, 2H), 3.37 (br s, 2H), 3.03 (s, 3H), 1.60 (br s, 2H), 1.44 (s, 9H), 1.16 - 1.07 (m, 1H).

[0352] Step B: tert-Butyl 6-(isopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. A solution of sodium hydride (900 mg, 22.5 mmol, 3.3 eq) in DMF (30 mL, 0.14M) was placed under N2 and cooled to 0 °C. Propan-2-ol (1.7 mL, 22.0 mmol, 3.2 eq) was added dropwise and the mixture was stirred at 0 °C for 0.5 h then at 25 °C for 0.5 h. tert-Butyl 6-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, 6.86 mmol, 1.0 eq) in DMF (20 mL, 0.14M) was added into the mixture dropwise at 25 °C. The reaction was stirred at 60 °C for 2 h then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC on silica (0-15% EtOAc in hexanes) to give tert-butyl 6-(isopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.2 g, 68% yield) as a pale yellow oil. 'HNMR (400 MHz, CDCh) 53.69 - 3.51 (m, 3H), 3.44 - 3.28 (m, 3H), 3.21 (br s, 1H), 1.46 - 1.39 (m, 11H), 1.15 (d, J = 6.0 Hz, 6H), 0.90 (tt, J= 6.7, 3.3 Hz, 1H).

[0353] The title compound was prepared in a manner analogous to Intermediate 12 using tert-butyl 6-(isopropoxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo [3.1.0]hexane-3 -carboxylate in Step A.Scheme 27: Synthesis of l-((rac-(l*iS,2*7?,5*7?,6*7?)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)cyclopropan-l-ol.Intermediate 57: l-((rac-(l*iS,2*7?,5*7?,6*7?)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)cyclopropan-l-ol.

[0354] Methyl 2-(rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate was prepared in a manner analogous to Intermediate 12 using tert-butyl rac-(l*R,5*S,6*s)-6-(2-methoxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl 6,6-difluoro-3-azabicyclo [3.1.0]hexane-3 -carboxylate in Step A.

[0355] Step E: tert-Butyl rac-( 1 *R,2*S,5*S,6*5)-2-(2-chloro-3-fluorophenyl)-6-(2-methoxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of methyl 2-(rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-3 -azabicyclo [3.1.0]hexan-6-yl)acetate (1.6 g, 5.23 mmol, 1.0 eq) in DCM(20 mL, 0.26M) was added DIPEA (1.0 g, 7.85 mmol, 1.5 eq) and BOC2O (1.4 g, 6.28 mmol, 1.2 eq). The reaction was stirred at 15 °C for 2 h before being quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (Hexane: EtOAc = 3: 1) to give tert-butyl rac-( I * / ?.2*. S'.5*. S'.6*. S)-2-(2-chloro-3-fluorophcnyl)-6-(2-mcthoxy-2-oxocth l)-3-azabicyclo[3.1,0]hexane-3-carboxylate (1.6 g, 82% yield) as a colorless oil. ’H NMR (400 MHz, CDCI3) 57.24 - 7.14 (m, 1H), 7.04 (br t, J= 8.2 Hz, 1H), 6.97 - 6.76 (m, 1H), 5.37 (br d, J= 4.7 Hz, 1H), 3.86 -3.64 (m, 2H), 3.47 (s, 3H), 2.24 - 2.11 (m, 1H), 2.09 - 1.94 (m, 2H), 1.61 (br s, 1H), 1.51 - 1.07 (m, 9H), 1.01 - 0.83 (m, 1H).

[0356] Step F: tert-Butyl rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((l-hydroxycyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of tert-butyl rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(2-methoxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 2.6 mmol, 1.0 eq) in THF (20 mL, 0.1M) was added titanium(IV) isopropoxide (740 mg, 2.6 mmol, 1.0 eq) at 0 °C under N2. To the mixture was added ethylmagnesium bromide (1.9 mL, 5.73 mmol, 3.0 mmol in Et20, 2.2 eq) dropwise at 0 °C. The resulting solution was stirred at 0-15 °C for 1 h. The reaction was quenched with sat. aq. NH4CI and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-50% EtOAc in hexanes) to give tert-butyl rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((l-hydroxycyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (850 mg, 85% yield) as a colorless oil. ’HNMR (400 MHz, CDCh) 57.22 (dt, J= 7.9, 5.4 Hz, 1H), 7.05 (brt, J= 8.1 Hz, 1H), 6.95 (br s, 1H), 5.38 (br d, J= 4.9 Hz, 1H), 3.87 - 3.60 (m, 2H), 2.16 - 2.05 (m, 1H), 1.77 (dd, J= 14.4, 5.1 Hz, 1H), 1.68 - 1.53 (m, 2H), 1.52 -1.35 (m, 3H), 1.31 (br s, 1H), 1.22 - 1.02 (m, 6H), 0.81 - 0.66 (m, 1H), 0.58 - 0.39 (m, 2H), 0.31 - 0.14 (m, 2H).

[0357] Step G: l-((rac-(l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)cyclopropan-l-ol. tert-Butyl rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-((l-hydroxycyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.31 mmol, 1.0 eq) was taken up in DCM / TFA (v / v 3:1, 8.0 mL, 0.2M) and stirred at 15 °C for 0.5 h. The mixture was concentrated then diluted with sat. aq. NaHC’Ch and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give a mixture of l-((rac-(l*S,2*R,5*R,6*R)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)cyclopropan-l-ol and tert-butyl rac-( I * / ?.2*. S'.5*. S'.6*. S)-2-(2-chloro-3-tluorophcnyl)-6-(2-oxobutyl)-3 -azabicyclo [3.1.0]hexane-3 -carboxylate (368 mg) which was used in the next step directly.Intermediate 58: 2-(rac-(l*iS,2*7?,5*7?,6*7?)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-l-ol.

[0358] The title compound was prepared in a manner analogous to Intermediate 25 using tert-butyl rac-(l*S,5*A)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A.Intermediate 59: rac-(l *S,2 *R,5 *R,6 *7?)-2-(2-Chlor o-3-fluorophenyl)-6-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane.

[0359] The title compound was prepared in a manner analogous to Intermediate 52 using tert-butyl rac-(l*S,5*A)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of tert-butyl rac-(1*R,5*S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A.Intermediate 60: rac-(l* / ?,4* / ?,5*iS,6*iS)-4-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one.

[0360] The title compound was prepared in a manner analogous to Intermediate 16 using rac-(l*S,2*S,5*A,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 19) instead of (l / .2. SA. S)-2-(2-chloro-3-fliiorophcnyl)-3-azabicyclo|3, 1,0|hcxanc in Step A.Intermediate 61: (15,4iS,57?)-4-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-2-one.

[0361] The title compound was prepared in a manner analogous to Intermediate 16 using (lR,2S,5S)-2- (2-chloro-3-fIuorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 32) instead of (lA,2S,5S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane in Step A.Intermediate 62: rac-(l*5,4*7?,5*7?,6*5)-4-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-2-one.

[0362] The title compound was prepared in a manner analogous to Intermediate 16 using rac-(l*5,2*5,5*A,6*5)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 24) instead of (l / ?.2. S'.5. S)-2-(2-chloro-3-fliiorophcnyl)-3-azabicyclo|3. 1,0|hcxanc in Step A.Intermediate 63: rac-(l* / ?, 4*5,5 *5)-4-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one.

[0363] The title compound was prepared in a manner analogous to Intermediate 16 using rac- (1 * / ?.2 *5,5 *S')-2-(2-chloro-3-fliiorophcnyl)-6.6-dimcthyl-3-azabicyclo| 3.1.0]hexane (Intermediate 33) instead of (lA,25,55)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane in Step A and using ZnBr2 instead of HC1 in Step C. MS (ESI): mass calcd. for C13H13CIFNO, 253.1; m / z found, 254.1 [M+H]+. Intermediate 64: rac-(3a*7?,4*5,6a*5)-4-(2-Chloro-3-fluorophenyl)hexahydro-l / f-furo[3,4-c] pyrrole.

[0364] The title compound was prepared in a manner analogous to Intermediate 12 using / c77-biityl rac-(3a* / ?.6a*5)-tctrahydro-IH-furo|3.4-c|pyrrolc-5(3 / / )-carboxylatc instead of tert-butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.0 [M+H]+.Scheme 28: Synthesis of methyl 5-((l*5,3a*?,6a*5)-l-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(EH)-yl)pyrazine-2-carboxylate.Intermediate 65: Methyl 5-((l*iS,3a*?,6a*A)-l-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c|pyrrol-2(l / / )-yl)pyrazine-2-carboxylate.

[0365] Step A: 5-((9H-Fluoren-9-yl)methyl) 2-( / c77-biityl) l-oxotetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,327)-dicarboxylate. To a solution of tert-butyl l-oxohcxahydropyrrolo|3.4-c|pyrrolc-2( lrt(-carboxylate (13 g, 57.5 mmol, 1.0 eq) in DCM (130 L, 0.44M) was added DIPEA (22 g, 172 mmol, 3.0 eq) and 9H-fluorcn-9-ylmcthyl chloroformate (22 g, 86.2 mmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h before being quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC on silica (0-50% EtOAc in PE) to give 5-((9H-fluorcn-9-yl)mcthyl) 2-(tert-butyl) l-oxotctrahydropyrrolo|3.4-c |pyrrolc-2.5(IH.3H)-dicarboxylatc (8.0 g, 31% yield) as a white solid. MS (ESI): mass calcd. for C26H28N2O5, 448.2; m / z found, 349.1 [M+2H-Boc]+. ’H NMR (400 MHz, CDCh) 57.78 (d, J= 7.5 Hz, 2H), 7.60 (br d, J= 7.4 Hz, 2H), 7.49 - 7.38 (m, 2H), 7.38 - 7.29 (m, 2H), 4.49 - 4.30 (m, 2H), 4.27 - 4.20 (m, 1H), 4.05 - 3.80 (m, 3H), 3.67 (brdd, J= 11.4, 8.3 Hz, 2H), 3.32 - 3.11 (m, 2H), 3.06 - 2.91 (m, 1H), 1.56 (s, 9H).

[0366] Step B: (9H-Fluorcn-9-y I (methyl 3-((( / c77-biitoxycarbonyl)amino)mcthyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-l -carboxylate. A solution of 5-((9H-fluorcn-9-yl)mcthyl) 2-( / c77-butyl) 1-oxotctrahydropyrrolo|3.4-c|pyrrolc-2.5(IH.3H)-dicarboxylatc (2.6 g, 5.80 mmol, 1.0 eq) in THF (30 mL, 0.2M) was placed under N2. (2-Chloro-3-fhrorophenyl)magnesium bromide (8.7 mL, 8.69 mmol, 1.5 eq, IM in THF) was added dropwise at 0 °C. The reaction was stirred at 0-25 °C for 16 h before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by FCC on silica (0-50% EtOAc in PE) to give (9H-fluorcn-9-y I (methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-l -carboxylate (2.7 g, 80% yield) as a colorless oil.

[0367] Step C: (9H-Fluoren-9-yl)methyl 3-(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-l-carboxylate. (9H-Fluoren-9-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-l -carboxylate (2.7 g, 4.66 mmol, 1.0 eq) was taken up in DCM / TFA (v / v 3:1, 28 mb, 0.2M) and stirred at 20 °C for 2 h. The mixture was concentrated in vacuo to give (9 / / -fluorcn-9-yl)methyl 3 -(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-l -carboxylate (TFA salt, 2.7 g, 98% yield) as a yellow oil.

[0368] Step D: rac-(9H-Fluoren-9-y 1 )methyl (3a*A,4*A,6a*A)-4-(2-chloro-3-fhiorophcnyl)hcxahydropyrrolo|3.4-c|pyrrolc-2( l / / )-carboxylatc. To a solution of (9H-fluoren-9-yl)methyl 3-(aminomethyl)-4-(2-chloro-3-fluorobenzoyl)pyrrolidine-l-carboxylate (TFA salt, 2.7 g, 4.55 mmol, 1.0 eq) in MeOH (50 mL, 0.1M) was added sodium cyanoborohydride (572 mg, 9.11 mmol, 2.0 eq). The reaction was stirred at 20 °C for 16 h before being poured into sat. aq. NaHCOs and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give rac-(9H-fluoren-9-yl)methyl (3a* / ?.4* / ?.6a* / ?)-4-(2-chloro-3-fluorophcnyl)hcxahydropyrrolo|3.4-c |pyrrolc-2( l / / )-carboxylatc (2.1 g, quant, yield) as a yellow oil. MS (ESI): mass calcd. for C27H24CIFN2O2, 462.2; m / z found, 463.2 [M+H]+.

[0369] Step E: rac-(9H-Fluoren-9-yl)methyl (3a* / ?.4* / ?.6a* / ?)-4-(2-chloro-3-fluorophcnyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(127)-carboxylate. To a solution of rac-(9 / / -fluorcn-9-yl)mcth l (3a* / ?.4* / ?.6a* / ?)-4-(2-chloro-3-fluorophcnyl)hcxahydropyrrolo|3.4-c]pyrrole-2(127)-carboxylate (2.1 g, 4.54 mmol, 1.0 eq) in DMF (25 mL, 0.2M) was added methyl 5-fluoro-2-pyrazinecarboxylate (850 mg, 5.44 mmol, 1.2 eq) and DIPEA (1.8 g, 13.6 mmol, 3.0 eq). The reaction was stirred at 25 °C for 16 h under N2 before being poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC on silica (0-100% EtOAc in PE) to give rac-(9H-fluoren-9-yl)methyl (3a* / .4* / .6a* / )-4-(2-chloro-3-fliiorophcnyl)-5-(5-(mcthoxycarbonyl)pyrazin-2-y I )hcxahydropyrrolo| 3.4-c |pyrrolc-2( I / / (-carboxylate (2.5 g, 92% yield) as a colorless oil. MS (ESI): mass calcd. for C33H28ClFN4O4, 598.2; m / z found, 599.2 [M+H]+.1H NMR (400 MHz, CDC13) 58.82 (br s, 1H), 7.85 - 7.56 (m, 4H), 7.50 - 7.31 (m, 4H), 7.28 - 7.23 (m, 1H), 7.21 - 7.01 (m, 2H), 6.89 - 6.71 (m, 1H), 5.63 (br d, J= 6.6 Hz, 1H), 4.43 - 4.06 (m, 4H), 3.95 (s, 3H), 3.84 - 3.60 (m, 3H), 3.59 - 3.44 (m, 1H), 3.39 - 3.06 (m, 3H).

[0370] Step F: Methyl 5-(rac-( l* / ?.3a*. S'.6a* / ?)-l-(2-chloro-3-fluorophcnyl)hcxahydropyrrolo|3.4-c|pyrrol-2( l / / )- l)pyrazinc-2-carbox latc. To a solution of rac-(9 / / -fluorcn-9-y I (meth l (3a* / ?.4* / ?.6a* / ?)-4-(2-chloro-3-fliiorophcnyl)-5-(5-(mcthoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(127)-carboxylate (500 mg, 0.835 mmol, 1.0 eq) in DCM (6.0 mL, 0.14M) was added piperidine (1.5 mL, 15.1 mmol, 18 eq). The reaction was stirred at 25 °C for 2 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give methyl 5-(rac-(I*R,3a*S,6a*R)-I-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(127)-yl)pyrazine-2-carboxylate (300 mg, 95% yield) as a yellow oil. MS (ESI): mass calcd. for C18H18ClFN4O2, 376.1; m / z found, 377.1 [M+H]+.

[0371] Step G: tert-Butyl (3a*. S'.4*. S'.6a*. S)-4-(2-chloro-3-fluorophcnyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2( I / / (-carboxylate. To a solution of methyl 5-(rac-(l*R,3a*S,6a*R)-l-(2-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(127)-yl)pyrazine-2 -carboxylate (300 mg, 0.796 mmol, 1.0 eq) in DCM (6.0 mL, 0.13M) was added BOC2O (209 mg, 0.955 mmol, 1.2 eq) and TEA (242 mg, 2.39 mmol, 3.0 eq). The reaction was stirred at 25 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by FCC on silica (50-100% EtOAc in PE) to give tert-butyl rac-(3a*R,4*R,6a*R)-4-(2-chloro-3-fluorophenyl)-5 -(5 -(methoxy carbonyl)pyrazin-2-yl)hexahydropyrrolo [3,4-c]pyrrole-2( 1H) -carboxylate. Separation via SFC (Stationary phase: WHELK-01 (25x5 cm); Mobile phase: 50% MeOH / CO2; Rt = 10.9 min, second eluting product) provided tert-butyl (3a*. S'.4*. S'.6a*. S)-4-(2-chloro-3-fluorophcnyl)-5-(5-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(127)-carboxylate. MS (ESI): mass calcd. for C23H26CIFN4O4, 476.2; m / z found, 477.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 58.56 (br s, 1H), 8.07 - 7.78 (m, 1H), 7.41 - 7.13 (m, 2H), 7.04 - 6.93 (m, 1H), 5.58 (d, J= 8.6 Hz, 1H), 4.16 - 3.98 (m, 1H), 3.96 - 3.82 (m, 1H), 3.77 (s, 3H), 3.54 - 3.41 (m, 2H), 3.30 -2.88 (m, 4H), 1.34 - 1.15 (m, 9H).

[0372] Step H: Methyl 5-(( I *. S',3a* / ?.6a*. S)- l-(2-chloro-3-fluorophcnyl)hcxahydropyrrolo|3.4-c|pyrrol-2( l / / )-yl)pyrazinc-2-carbox latc. tert-Butyl (3a*. S'.4*. S'.6a*. S)-4-(2-chloro-3-fluorophcnyl)-5-(5-(mcthoxycarbonyl)pyrazin-2-yl)hcxahydropyrrolo|3.4-c|pyrrolc-2( I / / (-carboxylate (500 mg, 1.05 mmol, 1.0 eq) was taken up in MeOH (5.2 mL, 0.2M). To this was added HCl (0.26 mL, 1.05 mmol, 1.0 eq, 4N in dioxane) and the reaction was allowed to stir at 60 °C for 1 hr. Upon cooling to rt, the mixture was concentrated under reduced pressure to provide methyl 5-((l*. S'.3a* / ?.6a*. S)-l-(2-chloro-3-fhiorophcnyl)hcxahydropyrrolo|3.4-c|pyrrol-2( l / / )-yl)pyrazinc-2-carboxylatc (395 mg, quant, yield) as a white solid. MS (ESI): mass calcd. for C18H18ClFN4O2, 376.1; m / z found, 377.0 [M+H]+.Scheme 29: Synthesis of rac-(3* / ?,10a* / ?)-3-(2-chloro-3-fluorophenyl)octahydro-2 / f-pyrazino[l,2-< / ][l,4]oxazepane.Intermediate 66: rac-(3* / ?,10a* / ?)-3-(2-Chloro-3-fluorophenyl)octahydro-2 / f-pyrazino[l,2-< / ][l,4]oxazepine.

[0373] Step A: 2-Amino-2-(2-chloro-3-fluorophenyl)acetonitrile. To a solution of 2-chloro-3-fluorobenzaldehyde (10 g, 63.1 mmol, 1.0 eq) in DCM (50 mL, 1.3M) was added trimethylsilyl cyanide (7.8 g, 78.8 mmol, 1.3 eq) and zinc iodide (2.0 g, 6.31 mmol, 0.1 eq) at 0 °C. The mixture was stirred at 25 °C for 15 mins before ammonia (7M in MeOH, 70 g, 631 mmol, 10 eq) was added at 0 °C. The reaction was stirred at 25 °C for 16 h before being poured into sat. aq. NaHCOs and stirred for 10 min then extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in MTBE (30 mL) and stirred at 25 °C for 0.5 h. The mixture was filtered to collect the precipitate 2-amino-2-(2-chloro-3-fhiorophenyl)acetonitrile (9.9 g, 85% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-t / e) 57.99 -7.94 (m, 1H), 7.93 - 7.81 (m, 2H), 5.61 (t, J= 8.4 Hz, 1H), 3.39 (br d, J= 8.3 Hz, 2H).

[0374] Step B: 2-Amino-2-(2-chloro-3-fluorophenyl)acetic acid. To a solution of 2-amino-2-(2-chloro-3-fhrorophenyl)acetonitrile (9.9 g, 53.6 mmol, 1.0 eq) was added HC1 (6N, 100 mL) and the reaction was stirred at 100 °C for 16 h. After cooling to rt, the mixture was concentrated in vacuo to give 2-amino-2-(2-chloro-3-fluorophenyl)acetic acid (HC1 salt, 10.9 g, quant, yield) as a yellow solid. MS (ESI): mass calcd. for C8H7ClFNO2, 203.0; m / z found, 204.0 [M+H]+.

[0375] Step C: Methyl 2-amino-2-(2-chloro-3-fluorophenyl)acetate. To the solution of 2-amino-2-(2-chloro-3-fluorophenyl)acetic acid (HC1 salt, 10.9 g, 45.4 mmol, 1.0 eq) in methanol (100 mL, 0.45M) was added SOC12(20 mL) slowly at 0 °C. The reaction was stirred at 80 °C for 16 h. After cooling to rt, the mixture was concentrated in vacuo and the resulting residue was adjusted to pH ~8 with sat. aq. NaHCCh and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 2-amino-2-(2-chloro-3-fluorophenyl)acetate (9.9 g, quant, yield) as a yellow oil. ’HNMR (400 MHz, CDCh) 57.26 (br s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 5.05 (s, 1H), 3.74 (s, 3H).

[0376] Step D: tert-Butyl 5-((l-(2-chloro-3-fluorophenyl)-2-methoxy-2-oxoethyl)carbamoyl)-l,4-oxazepane-4-carboxylate. To a solution of methyl 2-amino-2-(2-chloro-3-fluorophenyl)acetate (0.8 g, 3.67 mmol, 1.0 eq), 4-(tert-butoxy carbonyl)- l,4-oxazepane-5 -carboxylic acid (0.9 g, 3.67 mmol, 1.0 eq), and TEA (1.3 mL, 9.17 mmol, 2.5 eq) in DCM (10 mL, 0.4M) was added 2,4,6-tributyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (4.0 g, 5.50 mmol, 1.5 eq). The reaction was stirred at 20 °C for 2 h before being diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by ECC on silica (30-50% EtOAc in hexanes) to give tert-butyl 5-((l-(2-chloro-3-fluorophenyl)-2-methoxy-2-oxoethyl)carbamoyl)-l,4-oxazepane-4-carboxylate (1.3 g, 77% yield) as acolorless oil. ’HNMR (400 MHz, CDC13) 57.74 - 7.55 (m, 1H), 7.26 - 7.04 (m, 3H), 5.91 (d, J = 7.5 Hz, 1H), 4.72 - 4.35 (m, 1H), 4.07 - 3.79 (m, 3H), 3.79 - 3.67 (m, 3H), 3.62 - 3.08 (m, 3H), 2.48 - 2.08 (m, 2H), 1.59 - 1.37 (m, 9H).

[0377] Step E: Methyl 2-(2-chloro-3-fluorophenyl)-2-(l,4-oxazepane-5-carboxamido)acetate. A solution of tert-butyl 5-((l-(2-chloro-3-fluorophenyl)-2-methoxy-2-oxoethyl)carbamoyl)-l,4-oxazepane-4-carboxylate (1.3 g, 2.83 mmol, 1.0 eq) in HC1 (4N in EtOAc, 10 mL) was stirred at 20 °C for 2 h. The reaction was concentrated to give methyl 2-(2-chloro-3-fluorophenyl)-2-(l,4-oxazepane-5-carboxamido)acetate (HC1 salt, 1.1 g, quant, yield) as a yellow solid.

[0378] Step F: 3 -(2-Chloro-3-fluorophcn l)hcxahydro-4 / / -pyrazino| l.2-t / || 1,4] oxazepine- 1,4(927)-dione. To a solution of methyl 2-(2-chloro-3-fluorophenyl)-2-(l,4-oxazepane-5-carboxamido)acetate (HC1 salt, 1.1 g, 2.81 mmol, 1.0 eq) in methanol (12 mL, 0.2M) was added TEA (8.7 g, 86.3 mmol, 31 eq) and the reaction was stirred at 90 °C for 72 h. After cooling to rt, the mixture was concentrated in vacuo, diluted with water, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by RP-HPLC (10-40% ACN in 10 mM aq. NH4HCO3) to give 3-(2-chloro-3-fluorophcnyl)hcxahydro-4 / 7-pyrazino| 1,2-t / | [1,4] oxazepine- l,4(977)-dione (340 mg, 39% yield) as a white solid. ’H NMR (400 MHz, CDCh) 57.37 - 7.28 (m, 1H), 7.20 (t, J= 8.4 Hz, 1H), 7.11 (d, J= 7.6 Hz, 1H), 6.64 - 6.09 (m, 1H), 5.58 (s, 1H), 4.57 - 4.38 (m, 1H), 4.34 - 4.20 (m, 1H), 4.01 - 3.68 (m, 4H), 3.29 - 3.11 (m, 1H), 2.55 - 2.15 (m, 2H).

[0379] Step G: rac-( *R, IOa* / ?)-3-(2-Chloro-3-fluorophcnyl)octahydro-2 / 7-pyrazino| 1,2-t / || l.4|oxazcpinc. A solution of3-(2-chloro-3-fluorophcnyl)hcxahydro-4 / 7-pyrazino| l.2-<7][l,4]oxazepine-l,4(977)-dione (340 mg, 1.09 mmol, 1.0 eq) in THF (5.0 mL, 0.2M) was placed under N2 and cooled to 0 °C. To the solution was added borane tetrahydrofuran complex (IM, 7.6 mL, 7.61 mmol, 7.0 eq). The reaction was stirred at 80 °C for 24 h under N2. After cooling to 0 °C, the reaction was quenched by slow addition of MeOH (20 mL). The mixture was stirred at 15 °C for 0.5 h, and then 80 °C for 1 h. After cooling to rt, the mixture was concentrated in vacuo to afford rac-(3*7?,10a*7?)-3-(2-chloro-3-fliiorophcnyl)octahydro-2 / 7-pyrazino| l.2-t / || l,4]oxazepine (300 mg, 97% yield) as a white solid.Intermediate 67: rac-(7* / ?,9a*iS)-7-(2-Chloro-3-fluorophenyl)octahydropyrazino[2,l-c][l,4]oxazine.

[0380] The title compound was prepared in a manner analogous to Intermediate 66 using 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid instead of 4-(tert-butoxycarbonyl)-l,4-oxazepane-5-carboxylic acid in Step D. MS (ESI): mass calcd. for C13H16CIFN2O, 270.1; m / z found, 271.3 [M+H]+.Intermediate 68: rac-(7* / ?,9a*iS)-7-(3-Fluoro-2-methylphenyl)octahydropyrazino[2,l-c][l,4]oxazine.

[0381] The title compound was prepared in a manner analogous to Intermediate 66 using 3-fluoro-2-methylbenzaldehyde instead of 2-chloro-3 -fluorobenzaldehyde in Step A and using 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid instead of 4-(tert-butoxycarbonyl)-l,4-oxazepane-5-carboxylic acid in Step D.Intermediate 69: rac-(3* / ?,9a* / ?)-3-(2-Chloro-3-fluorophenyl)-8,8-difluorooctahydro-2 / f-pyrido [1,2-a] pyrazine.

[0382] The title compound was prepared in a manner analogous to Intermediate 66 using l-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2 -carboxylic acid instead of 4-(tert-butoxy carbonyl)- 1,4-oxazepane-5 -carboxylic acid in Step D. MS (ESI): mass calcd. for C14H16CIF3N2, 304.1; m / z found, 305.0 [M+H]+.Intermediate 70: rac-(3* / ?,8a* / ?)-3-(2-Chloro-3-fluorophenyl)-7,7-difluorooctahydropyrrolo[l,2-a] pyrazine.

[0383] The title compound was prepared in a manner analogous to Intermediate 66 using -(tertbutoxy carbonyl)-4,4-difluoropyrrolidine-2 -carboxylic acid instead of 4-(tert-butoxy carbonyl)- 1,4-oxazepane-5-carboxylic acid in Step D. MS (ESI): mass calcd. for C13H14CIF3N2, 290.1; m / z found, 291.2 [M+H]+.Scheme 30: Synthesis of (*S)-((7?, E)-3-aminobut-l-en-l-yl)(imino)(methyl)-X6-sulfanone.Intermediate 71: (*S)-((7?^)-3-Aminobut-l-en-l-yl)(imino)(methyl)-X6-sulfanone.

[0384] Step A: / -Butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-X6-sulfaneylidene)carbamate. To a solution of diethyl ((methylsulfmyl)methyl)phosphonate (2.0 g, 9.34 mmol, 1.0 eq) in DCM (26mL, 0.36M) was added tert-butyl carbamate (2.2 g, 18.7 mmol, 2.0 eq), MgO (1.5 g, 37.4 mmol, 4.0 eq), Rh2(OAc)4 (124 mg, 0.280 mmol, 0.03 eq), and PhI(0Ac)2 (4.5 g, 14.0 mmol, 1.5 eq). The reaction was stirred at 50 °C for 8 h under N2. After cooling to rt, the mixture was filtered and concentrated in vacuo. The resulting residue was purified by FCC on silica (10-40% EtOAc in hexanes) to afford tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-X6-sulfaneylidene)carbamate (2.4 g, 78% yield) as a pale yellow oil. ’H NMR (400 MHz, CDC13) 54.36 (t, J= 15.9 Hz, 1H), 4.31 - 4.17 (m, 4H), 3.95 (t, J= 15.4 Hz, 1H), 3.41 (s, 3H), 1.49 (s, 9H), 1.38 (t, J= 7.1 Hz, 6H).

[0385] Step B: tert-Butyl ((R, E)-4-((*S)-A-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)but-3-en-2-yl)carbamate. To a solution of tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-X6-sulfaneylidene)carbamate (2.1 g, 6.24 mmol, 1.2 eq) in THF (20 mL, 0.17M) was added potassium tert-butoxide (875 mg, 7.79 mmol, 1.5 eq) at 0 °C under N2. The mixture was stirred at 0.5 h at 20 °C before addition of tert-butyl ( / ?)-( I -oxopropan -2 -y I (carbamate (900 mg, 5.20 mmol, 1.0 eq) in THF (10 mL, 0.17M). The reaction was stirred at 0 °C for 2 h under N2 before being quenched with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC on silica (10-30% EtOAc in hexanes) to afford tert-butyl ((2R, E)-4-(A-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)but-3-en-2-yl)carbamate (500 mg, 28% yield) as a colorless oil. Separation via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 25% EtOH / CO2; Rt = 2.25 min) provided tert-butyl ((R, E)-4-((*S)-A-(tert-biitoxycarbonyl)-S'-mcthylsiilfonimidoyl)biit-3-cn-2-yl)carbamatc. 'HNMR (400 MHz, CDCL) 56.96 -6.85 (m, 1H), 6.57 - 6.45 (m, 1H), 4.64 - 4.40 (m, 2H), 3.25 - 3.21 (m, 3H), 1.47 (d, J= 13.8 Hz, 18H), 1.33 (d, J = 6.9 Hz, 3H)

[0386] Step C: (*S)-((R, E)-3-Aminobut-l-en-l-yl)(imino)(methyl)-X6-sulfanone. To a solution of tertbutyl (( / ?. A')-4-((*. S)-A-( / c77-biitoxycarbonyl)-S'-mcthylsiilfonimidoyl)biit-3-cn-2-yl)carbamatc (200 mg, 0.574 mmol, 1.0 eq) in ACN (3.0 mL, 0.2M) was added TsOH. H2O (218 mg, 1.15 mmol, 2.0 eq). The reaction was stirred at 60 °C for 2 h before being concentrated in vacuo to give (*. S)-(( / ?. A')-3-aminobut-l-en-l-yl)(imino)(methyl)-X6-sulfanone (TsOH salt, 180 mg, 98% yield) as a white solid. MS (ESI): mass calcd. for C5H12N2OS, 148.1; m / z found, 149.1 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.26 (br s, 2H), 7.43 (br s, 1H), 7.30 - 7.22 (m, 1H), 7.11 - 7.04 (m, 1H), 4.26 (br d, J= 5.8 Hz, 1H), 3.62 (br s, 3H), 1.39 - 1.36 (m, 3H).Intermediate 72: (* / ?)-((7?,f)-3-Aminobut-l-en-l-yl)(imino)(methyl)-X6-sulfanone.

[0387] Separation of tert-butyl ((2R, E)-4-(A-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)but-3-en-2-yl)carbamate (Intermediate 71, Step B) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 25% EtOH / CCL; Rt = 4.20 min) provided tert-butyl ((R, E)-4-((*R)-A-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)but-3-en-2-yl)carbamate. This was elaborated to the title compound in a manner analogous to Intermediate 71, Step C. MS (ESI): mass calcd. for C5H12N2OS, 148.1; m / z found, 149.1[M+H]+. 'HNMR (400 MHz, DMSO-6) 58.30 (br s, 2H), 7.46 - 7.38 (m, 1H), 7.35 - 7.26 (m, 1H), 7.18 (br d, J= 5.2 Hz, 1H), 4.34 - 4.23 (m, 1H), 3.71 (s, 3H), 1.39 (d, J= 6.8 Hz, 3H).Scheme 31: Synthesis of ((, )-3-aminobut-1-en-1-yl)(methyl)(methylimino)-λ6-sulfanone.Intermediate 73: ((7?^)-3-Aminobut-l-en-l-yl)(methyl)(methylimino)-X6-sulfanone.

[0388] Step A: / crt-Butyl ( / . A')-(4-iodobut-3-cn-2-yl)carbamatc. A solution of / c77-biityl ( / ?)-but-3-yn-2-ylcarbamate (5.0 g, 29.5 mmol, 1.0 eq) in THF (100 mb, 0.3M) was degassed and purged with N2. To the solution was added chloro(hydrido)zirconium bis(cyclopentane) (9.9 g, 38.4 mmol, 1.3 eq). The mixture was stirred at 25 °C for 40 min before addition of iodine (7.5 g, 29.5 mmol, 1.0 eq). After 10 min, the mixture was poured into sat. aq. Na2S2O3 at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (5-10% EtOAc in hexanes) to give tert-butyl ( / . A)-(4-iodobut-3-cn-2-yl)carbamatc (6.0 g, 68% yield) as a pale yellow oil. ’H NMR (400 MHz, CDCh) 56.50 (dd, J= 14.5, 5.6 Hz, 1H), 6.27 (d, J= 14.6 Hz, 1H), 4.48 (s, 1H), 4.31 - 4.15 (m, 1H), 1.45 (s, 9H), 1.22 (d, J= 6.9 Hz, 3H).

[0389] Step B: tert- Butyl ( / ?. A)-(4-(mcthy I th io)but-3-cn-2-y I (carbamate. To a solution of / c77-biityl ( / . A')-(4-iodobiit-3-cn-2-yl)carbamatc (6.0 g, 20.2 mmol, 1.0 eq) in toluene (160 mL, 0.1M) was added copper(I) iodide (1.9 g, 10.1 mmol, 0.5 eq), l,8-diazabicycloundec-7-ene (6.2 g, 40.4 mmol, 2.0 eq), and sodium methanethiolate (4.3 g, 60.6 mmol, 3.0 eq). The reaction was stirred at 80 °C for 4 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (10-15% EtOAc in hexanes) to give tert-butyl ( / ?. A)-(4-(methylthio)but-3-en-2-yl)carbamate (2.7 g, 62% yield) as a colorless oil. MS (ESI): mass calcd. for C10H19NO2S, 217.1; m / z found, 218.1 [M+H]+. ’HNMR (400 MHz, CDCI3) 56.20 (d, J= 15.1 Hz, 1H), 5.35 (dd, J= 15.1, 5.7 Hz, 1H), 4.44 (br d, J= 2.1 Hz, 1H), 4.28 (br s, 1H), 2.24 (s, 3H), 1.45 (s, 9H), 1.23 (d, J = 6.6 Hz, 3H).

[0390] Step C: tert- Butyl ((2 / ?. A')-4-(. S'-mcthylsulfommidoyl)biit-3-cn-2-y I (carbarn ate. To a solution of tert-butyl ( / . A')-(4-(mcthylthio)biit-3-cn-2-yl)carbamatc (1.0 g, 4.60 mmol, 1.0 eq) in methanol (20 mL, 0.2M) was added diacetoxyiodo benzene (8.9 g, 27.6 mmol, 6.0 eq) and ammonium carbamate (2.9 g, 36.8 mmol, 8.0 eq). The reaction was stirred at 25 °C for 2 h before being diluted with water andextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (70-80% EtOAc in hexanes) to give tert-butyl ((2 / ?. / '.')-4-(. S'-mcthylsulfonimidoyl)but-3-cn-2-yl)carbamate (660 mg, 58% yield) as a pale yellow solid. MS (ESI): mass calcd. for C10H20N2O3S, 248.1; m / z found, 249.2 [M+H]+. H NMR (400 MHz, CDCh) 56.79 (td, J= 14.9, 4.8 Hz, 1H), 6.57 (td, J= 14.9, 1.7 Hz, 1H), 4.57 (br s, 1H), 4.48 (br s, 1H), 3.01 (s, 3H),1.46 (s, 9H), 1.32 (d, J = 6.9 Hz, 3H).

[0391] Step D: tert-Butyl ((2 / ?. A')-4-(A.. S'-dimcthylsulfonimidoyl)biit-3-cn-2-yl)carbamatc. To a solution of tert-butyl ((2 / . A)-4-(. S'-mcthylsiilfonimidoyl)biit-3-cn-2-y I (carbamate (200 mg, 0.810 mmol, 1.0 eq) in DCM (4.0 mL, 0.2M) was added trimethyloxonium tetrafluoroborate (143 mg, 0.970 mmol, 1.2 eq). The mixture was stirred at 25 °C for 10 min before addition of potassium carbonate (223 mg, 1.61 mmol, 2.0 eq). The reaction was stirred at 25 °C for 16 h before being diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl ((2R, E)-4-(N, S-dimethylsulfonimidoyl)but-3-en-2-yl)carbamate (60 mg, 28% yield) as a pale yellow oil. MS (ESI): mass calcd. for C11H22N2O3S, 262.1; m / z found, 263.3 [M+H]+. ’HNMR (400 MHz, CDCh) 56.81 -6.70 (m, 1H), 6.32 - 6.24 (m, 1H), 4.64 - 4.37 (m, 2H), 2.97 (d, J= 1.8 Hz, 3H), 2.72 (d, J= 3.1 Hz, 3H), 1.46 (s, 9H), 1.33 (d, J= 6.9 Hz, 3H).

[0392] Step E: ((R, E)-3-Aminobut-l-en-l-yl)(methyl)(methylimino)-X6-sulfanone. To a solution of tert-butyl ((2 / ?. A')-4-(A.. S'-dimcthylsiilfonimidoyl)biit-3-cn-2-yl)carbamatc (60 mg, 0.230 mmol, 1.0 eq) in ACN (2.0 mL, 0.1M) was added TSOH. H2O (65 mg, 0.340 mmol, 1.5 eq). The reaction was stirred at 60 °C for 2 h then concentrated in vacuo to give (( / ?. / '.)-3-aminobut- 1 -en- 1 -yl)(methyl)(methylimino)-X6-sulfanone (TsOH salt, 70 mg, 92% yield) as a pale yellow solid.Scheme 32: Synthesis of ((7?,£)-3-aminobut-l-en-l-yl)(methyl)(phenylimino)-X6-sulfanone.Intermediate 74: ((7?,£)-3-Aminobut-l-en-l-yl)(methyl)(phenylimino)-X6-sulfanone.

[0393] To a solution of tert-butyl ((2 / ?. A')-4-(. S'-mcth lsulfonimido l)biit-3-cn-2- l)carbamatc (Intermediate 73, Step C, 300 mg, 1.21 mmol, 1.0 eq) in methanol (9.0 mL, 0.1M) was added phenylboronic acid (295 mg, 2.42 mmol, 2.0 eq) and copper diacetate (110 mg, 0.600 mmol, 0.5 eq). The reaction was degassed, purged with O2, and stirred at 25 °C under O2 (15 psi) for 16 h. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (20-25% EtOAc in hexanes) to give tert-butyl ((2 / ?. A)-4-(. S'-mcthyl-A-phenylsulfonimidoyl)but-3-en-2-yl)carbamate (300 mg, 77% yield) as a white solid. MS (ESI): masscalcd. for C16H24N2O3S, 324.1; m / z found, 325.2 [M+H]+. 'HNMR (400 MHz, CDCI3) 57.24 - 7.17 (m, 2H), 7.07 - 7.01 (m, 2H), 6.98 - 6.77 (m, 2H), 6.49 - 6.37 (m, 1H), 4.63 - 4.46 (m, 1H), 3.13 (d, J= 2.3 Hz, 3H), 1.46 - 1.40 (m, 9H), 1.30 - 1.25 (m, 3H).

[0394] / e / V-Butyl ((2 / ?. A')-4-(. S'-mcthyl-A-phcnylsulfonimidoyl)biit-3-cn-2-yl)carbamatc was elaborated to the title compound in a manner analogous to Intermediate 73, Step E.Scheme 33: Synthesis of 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane.Intermediate 75: 6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane.

[0395] Step A: / ert-Butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate. To a solution of sodium periodate (8.6 g, 39.6 mmol, 3.0 eq) in water (30 m, 0.2M) was added R11CI3 (274 mg, 1.32 mmol, 0.1 eq). The mixture was stirred at 25 °C for 15 min before tert-butyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (3.0 g, 13.2 mmol, 1.0 eq) in EtOAc (30 mb, 0.2M) was slowly added to the mixture at 0 °C.The reaction was stirred at 25 °C for 1 h then quenched with sat. aq. Na2S20s and filtered. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were washed with sat. aq. Na2S2O3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tertbutyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (2.5 g, 79% yield) as a pale yellow solid. ’H NMR (400 MHz, CDCI3) 54.54 - 4.46 (m, 4H), 3.65 (dd, J= 6.8, 5.6 Hz, 2H), 2.83 (s, 2H), 2.21 - 2.12 (m, 2H), 1.53 (s, 9H).

[0396] Step B: tert-Butyl 6-diphenoxyphosphoryloxy-2-oxa-7 -azaspiro [3.5]non-5 -ene-7 -carboxylate. A solution of tert-butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 4.14 mmol, 1.0 eq) in THF (15 mb, 0.3M) was placed under N2 and cooled to -78 °C. To this was added KHMDS (4.6 mb, 4.56 mmol, 1.1 eq, IM in THF) dropwise and the solution was stirred at -78 °C under N2 for 30 min. To the solution was added diphenyl phosphorochloridate (1.2 g, 4.35 mmol, 1.1 eq) and the reaction was stirred at -78 °C for 2 h. The mixture was poured into sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-35% EtOAc in hexanes) to give tert-butyl 6-diphenoxyphosphoryloxy-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (1.7 g, 87%yield) as a yellow oil. ’H NMR (400 MHz, CDC13) 57.40 - 7.32 (m, 4H), 7.27 - 7.19 (m, 6H), 5.35 (d, J = 2.8 Hz, 1H), 4.59 (d, J= 6.0 Hz, 2H), 4.35 (d, J= 6.0 Hz, 2H), 3.61 - 3.49 (m, 2H), 2.14 (td, J= 5.1, 2.8 Hz, 2H), 1.45 (s, 9H).

[0397] Step C: tert-Butyl 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate. To a solution of tert-butyl 6-diphenoxyphosphoryloxy-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (1.7 g, 3.59 mmol, 1.0 eq) in 1,4-dioxane / water (v / v 5:1, 24 mb, 0.15M) was added (2-chloro-3-fluorophenyl)boronic acid (939 mg, 5.39 mmol, 1.5 eq), potassium carbonate (1.5 g, 10.8 mmol, 3.0 eq), and Pd(PPhs)4 (415 mg, 0.360 mmol, 0.1 eq). The reaction was placed under N2 and stirred at 80 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (10-15% EtOAc in hexanes) to give tertbutyl 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (1.2 g, 95% yield) as a pale yellow oil. MS (ESI): mass calcd. for C18H21CIFNO3, 353.1; m / z found, 298.2 [M+2H-tBu]+. ’H NMR (400 MHz, CDCI3) 57.25 - 7.17 (m, 1H), 7.13 - 7.05 (m, 2H), 5.42 (s, 1H), 4.70 (d, J= 5.9 Hz, 2H), 4.46 (d, J= 5.9 Hz, 2H), 3.71(br s, 2H), 2.31 (t, J= 5.4 Hz, 2H), 1.10 (s, 9H).

[0398] Step D: 6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]non-6-ene. tert-Butyl 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (1.2 g, 3.39 mmol, 1.0 eq) was taken up in TFA / DCM (v / v 1:3, 16 mL, 0.2M) and stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]non-6-ene (TFA salt, 1.2 g, quant, yield) as a yellow oil, which was used directly.

[0399] Step E: 6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane. A solution of 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]non-6-ene (1.2 g, 3.37 mmol, 1.0 eq) in methanol (20 mL, 0.17M) was placed under N2 and cooled to 0 °C. Sodium cyanoborohydride (636 mg, 10.1 mmol, 3.0 eq) was added in portions and the reaction was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure then diluted with sat. aq. NaHCCF and stirred for 1 h at 25 °C. The solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 6-(2-chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonane (800 mg, 75% yield) as a pale yellow oil. MS (ESI): mass calcd. for C13H15ClFNO, 255.1; m / z found, 256.2 [M+H]+.Scheme 34: Synthesis of rac-(l * / ?, 4*5,5 *iS)-4-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo [3.2.1] octane.Intermediate 76: rac-(l* / ?,4*iS,5*iS)-4-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.1]octane.

[0400] Step A: tert-Butyl ((rac-(3*R,5*S)-5-(2-chloro-3-fluorobenzoyl)tetrahydrofuran-3-yl)methyl)carbamate. To a solution of tert-butyl rac-( 1 * / ?.5*. S)-4-oxo-6-oxa-3-azabicyclo|3,2. l]octane-3-carboxylate (640 mg, 2.82 mmol, 1.0 eq) in THF (10 mL, 0.3M) was added (2-chloro-3-fluorophenyl)magnesium bromide (3.2 mL, 3.24 mmol, 1.1 eq, IM in THF) at 0 °C under N2. The reaction was stirred at 15 °C for 1 h before being quenched with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC on silica (10-30% EtOAc in hexanes) to give tert-butyl ((rac-(3* / ?.5*. S)-5-(2-chloro-3-fluorobcnzoyl)tctrahydrofiiran-3-yl)mcthyl)carbamatc (570 mg, 57% yield) as a white solid. MS (ESI): mass calcd. for C17H21CIFNO4, 357.1; m / z found, 258.1 [M+2H-Boc]+. ’HNMR (400 MHz, CDCL) 57.26 - 6.99 (m, 2H), 6.83 - 6.34 (m, 1H), 5.15 - 4.51 (m, 1H), 4.08 - 3.91 (m, 3H), 3.78 - 3.58 (m, 1H), 3.51 - 3.02 (m, 1H), 2.76 - 2.29 (m, 1H), 1.97 - 1.74 (m, 2H), 1.44 (s, 9H).

[0401] Step B: tert-Butyl ((rac-(3*R,5*S)-5-((*S)-(2-chloro-3-fluorophenyl)(hydroxy)methyl)tetrahydrofuran-3-yl)methyl)carbamate. To a solution of tert-butyl ((rac-(3*R,5*S)-5-(2-chloro-3-fluorobenzoyl)tetrahydrofuran-3-yl)methyl)carbamate (500 mg, 1.40 mmol, 1.0 eq) in methanol (10 mL, 0.1M) was added NaBFL (106 mg, 2.80 mmol, 2.0 eq). The reaction was stirred at 15 °C for 2 h before being quenched with MeOH and concentrated in vacuo. The resulting residue was purified by prep-TLC (hexane: EtOAc = 2: 1, Rf(Pl) = 0.4) to afford tert-butyl ((rac-(3*R,5*5)-5-((*S)-(2-chloro-3-fluorophenyl)(hydroxy)methyl)tetrahydrofuran-3-yl)methyl)carbamate (180 mg, 36% yield) as a colorless oil. MS (ESI): mass calcd. for C17H23CIFNO4, 359.1; m / z found, 260.1 [M+2H-Boc]+. ’H NMR (400 MHz, CDCL) 57.43 (d, J = 8.0 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.15 - 7.04 (m, 1H), 5.40 (d, J= 3.1 Hz, 1H), 4.65 (d, J= 1.3 Hz, 1H), 4.35 - 4.24 (m, 1H), 3.93 (d, J= 0.9 Hz, 1H), 3.69 (dd, J= 8.6, 6.4 Hz, 1H), 3.18 (d, J = 6.5 Hz, 2H), 2.80 (dd, J= 4.6, 2.1 Hz, 1H), 2.52 - 2.36 (m, 1H), 1.63 - 1.58 (m, 2H), 1.45 (s, 9H).

[0402] Step C: rac-(*. S)-((2*. S'.4* / ?)-4-((( / c77-Biitoxycarbonyl)amino)mcthyl)tctrahydrofiiran-2-yl)(2-chloro-3-fluorophenyl)methyl methane sulfonate. To a solution of tert-butyl ((rac-(3*R,5*S)-5-((*S)-(2-chloro-3-fluorophenyl)(hydroxy)methyl)tetrahydrofuran-3-yl)methyl)carbamate (180 mg, 0.500 mmol, 1.0 eq) in DCM (3.0 mb, 0.2M) was added TEA (0.21 m, 1.50 mmol, 3.0 eq), MS2O (131 mg, 0.750 mmol, 1.5 eq), and DMAP (3.1 mg, 0.025 mmol, 0.05 eq). The reaction was stirred at 25 °C for 16 h before being diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (hexane: EtOAc = 2: 1, Rf(Pl) = 0.4) to afford rac-(*S)-((2*S,4*R)-4-(((tert-butoxycarbonyl)amino)methyl)tetrahydrofuran-2-yl)(2-chloro-3-fluorophenyl)methyl methanesulfonate (180 mg, 82% yield) as a colorless oil. MS (ESI): mass calcd. for C18H25ClFNO6S, 437.1; m / z found, 460.0 [M+Na]+. ’HNMR (400 MHz, CDCI3) 57.43 - 7.37 (m, 1H), 7.34 (dd, J= 8.0, 5.1 Hz, 1H), 7.17 (dt, J= 8.4, 1.5 Hz, 1H), 6.08 (d, J= 3.9 Hz, 1H), 4.65 (s, 1H), 4.31 (ddd, J = 9.0, 6.6, 4.0 Hz, 1H), 3.93 (t, J= 7.9 Hz, 1H), 3.60 (t, J= 7.9 Hz, 1H), 3.27 - 3.17 (m, 1H), 3.15 - 3.08 (m, 1H), 3.02 (s, 3H), 2.57 -2.44 (m, 1H), 2.00 - 1.86 (m, 1H), 1.66 (td, J= 12.5, 8.9 Hz, 1H), 1.45 (s, 9H).

[0403] Step D: rac-(*. S)-((2*. S'.4* / ?)-4-(Aminomcthyl)tctrahydrofuran-2-yl)(2-chloro-3-fluorophenyl)methyl methanesulfonate. To a solution of rac-(*S)-((2*S,4*R)-4-(((tert-butoxycarbonyl)amino)methyl)tetrahydrofuran-2-yl)(2-chloro-3-fluorophenyl)methyl methanesulfonate (180 mg, 0.411 mmol, 1.0 eq) in DCM (1.0 mb, 0.4M) was added p-toluenesulfonic acid (196 mg, 1.03 mmol, 2.5 eq). The reaction was stirred at 25 °C for 16 h then concentrated under reduced pressure to give rac-(*S)-((2*S,4*R)-4-(aminomethyl)tetrahydrofuran-2-yl)(2-chloro-3-fluorophenyl)methyl methanesulfonate (TsOH salt, 200 mg, 95% yield) as a yellow oil. MS (ESI): mass calcd. for C13H17ClFNO4S, 337.1; m / z found, 338.0 [M+H]+.

[0404] Step E: rac-(l*R,4*S,5*S)-4-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.1]octane. To a solution of rac-(*S)-((2*S,4*R)-4-(aminomethyl)tetrahydrofuran-2-yl)(2-chloro-3-fluorophenyl)methyl methanesulfonate (TsOH salt, 200 mg, 0.392 mmol, 1.0 eq) in DCM (2.0 mb, 0.2M) was added TEA (317 mg, 3.14 mmol, 8.0 eq). The reaction was stirred at 35 °C for 24 h then concentrated under reduced pressure to give rac-(l*R,4*S,5*S)-4-(2-chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.1]octane (90 mg, 95% yield) as a yellow oil. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.1 [M+H]+.Scheme 35: Synthesis of rac-(l* / ?, 4*5,5 *5)-4-(2-chloro-3-fluorophenyl)-l-methoxy-3-azabicyclo[3.1.0]hexane.Intermediate 77: rac-(l* / ?, 4*5,5 *5)-4-(2-Chloro-3-fluorophenyl)-l-methoxy-3-azabicyclo[3.1.0]hexane.

[0405] Step A: A-Benzyl-l-(2-chloro-3-fluorophenyl)methanimine. To a solution of 2-chloro-3-fluorobenzaldehyde (13 g, 81.9 mmol, 1.0 eq) in DCM (130 mL, 0.6M) was added phenylmethanamine (8.8 g, 81.9 mmol, 1.0 eq) and 4A molecular sieves (20 g). The mixture was stirred at 40 °C for 4 h then filtered and concentrated to give A-bcnzyl- 1 -(2-chloro-3-fluorophcn l)mcthaniminc (20 g, 98% yield).

[0406] Step B: A-Bcnzyl-l-(2-chloro-3-fluorophcnyl)prop-2-cn-l-aminc. To a solution of A-bcnzyl- 1 -(2-chloro-3-fhiorophenyl)methanimine (15 g, 60.6 mmol, 1.0 eq) in toluene (150 mL, 0.4M) was added boron trifluoride diethyl etherate (36 mL, 303 mmol, 5.0 eq) at -78 °C under N2. After 10 min at -78 °C, vinylmagnesium bromide (484 mL, 484 mmol, 8.0 eq, IM in THF) was added dropwise. The reaction was stirred at 20 °C for 2 h under N2 then diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to provide N-benzyl-l-(2-chloro-3-fluorophenyl)prop-2-en-l -amine (24 g, 86% yield) as a white solid. 'H NMR (400 MHz, CDCh) 57.79 (br d, J= 7.8 Hz, 1H), 7.55 - 7.29 (m, 6H), 7.21 - 7.09 (m, 1H), 6.23 (ddd, J= 17.2, 10.0, 7.5 Hz, 1H), 5.50 - 5.27 (m, 2H), 5.02 (brd, J= 7.4 Hz, 1H), 4.07 - 3.88 (m, 2H).

[0407] Step C: Methyl A-benzyl-A-(l-(2-chloro-3-fluorophenyl)allyl)glycinate. To a solution of A-benzyl-l-(2-chloro-3-fluorophenyl)prop-2-en-l -amine (20 g, 72.5 mmol, 1.0 eq) in DMSO (200 mL, 0.36M) was added DIPEA (37 g, 290 mmol, 4.0 eq) and methyl 2-bromoacetate (22 g, 145 mmol, 2.0 eq). The reaction was stirred at 100 °C for 12 h. After cooling to rt, the mixture was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to give methyl A-bcnzy I -A-( I -(2-ch loro-3 -fluorophcny I )ally I (glycinate (11 g, 42% yield) as a white solid. ’H NMR (400 MHz, CDCL) 57.60 (d, J= 7.9 Hz, 1H), 7.33 - 7.28 (m, 5H), 7.26 - 7.23 (m, 1H), 7.09 - 7.01 (m, 1H), 5.81 (td, J= 16.9, 9.5 Hz, 1H), 5.47 - 5.39 (m, 1H), 5.22 (d, J= 9.1 Hz, 1H), 5.13 (dd, J= 10.0, 1.3 Hz, 1H), 3.91 (d, J= 13.8 Hz, 1H), 3.75 - 3.69 (m, 1H), 3.64 (s, 3H), 3.47 - 3.41 (m, 1H), 3.32 - 3.25 (m, 1H).

[0408] Step D: rac-(l*R,4*5,5*5)-3-Benzyl-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-l-ol. To a solution of methyl A-bcnzyl-A-( l-(2-chloro-3-fluorophcnyl)allyl)glycinatc (7.6 g, 21.9 mmol, 1.0 eq) in anhydrous THF (760 mL, 0.03M) under N2 was added chlorotriisopropoxytitanium(IV) (6.8 g, 26.2 mmol, 1.2 eq) followed by cyclopentylmagnesium chloride (49 mL, 98.3 mmol, 4.5 eq, 2M in THF) dropwise over 4 h. The solution was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) followed by RP-HPLC (20-50% ACN in 0.1% aq. TFA) to give rac-(l*A,4*S,5*S)-3-benzyl-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-l-ol (620 mg, second eluting product). MS (ESI): mass calcd. for CisHnClFNO, 317.1; m / z found, 318.1 [M+H]+. ’HNMR (400 MHz, CDC13) 87.45 (d, J = 7.9 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.28 (br s, 2H), 7.25 (br s, 2H), 7.11 - 7.03 (m, 1H), 4.41 (d, J = 3.8 Hz, 1H), 3.75 (d, J= 13.4 Hz, 1H), 3.45 - 3.12 (m, 2H), 2.76 (d, J= 8.5 Hz, 1H), 2.01 - 1.93 (m, 1H), 1.27 (t, J= 7.1 Hz, 1H), 1.14 (t, J = 4.7 Hz, 1H), 0.75 (dd, J= 9.1, 5.4 Hz, 1H).

[0409] Step E: rac-(l* / ?.4*. S'.5*, S)-3-Bcnzyl-4-(2-chloro-3-fliiorophcn l)-l-mcthoxy-3-azabicyclo[3.1.0]hexane. To a solution of rac-(l*A,4*S,5*S)-3-benzyl-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-l-ol (570 mg, 1.79 mmol, 1.0 eq) in THF (5.0 mL, 0.36M) was added NaH (108 mg, 2.69 mmol, 1.5 eq) and iodomethane (382 mg, 2.69 mmol, 1.5 eq). The reaction was stirred at 20 °C for 2 h under N2 before being diluted with sat. aq. NH4CI and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-25% EtOAc in PE) to give rac-( 1 * A,4*S,5 *5)-3 -benzyl-4-(2-chloro-3 -fluorophenyl)- 1 -methoxy-3 -azabicyclo [3.1.0]hexane (370 mg, 62% yield) as a white solid. ’HNMR (400 MHz, CDCI3) 87.46 (d, J= 7.8 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.29 (s, 2H), 7.26 - 7.22 (m, 1H), 7.15 - 7.02 (m, 1H), 4.39 (d, J= 3.6 Hz, 1H), 3.76 (d, J= 13.3 Hz, 1H), 3.36 - 3.30 (m, 4H), 3.23 (d, J= 13.3 Hz, 1H), 2.74 (d, J= 8.4 Hz, 1H), 2.05 (td, J= 8.7, 4.2 Hz, 1H), 1.06 (t, J= 4.7 Hz, 1H), 0.68 (dd, J= 8.9, 5.3 Hz, 1H).

[0410] Step F: rac-(l*A,4*S,5*S)-4-(2-Chloro-3-fluorophenyl)-l-methoxy-3-azabicyclo[3.1.0]hexane. rac-(l*A,4*S,5*S)-3-Benzyl-4-(2-chloro-3-fluorophenyl)-l-methoxy-3-azabicyclo[3.1.0]hexane (0.18 g, 1.0 eq) was dissolved in THF (9.0 mL) and pumped through a flow reactor at a rate of 0.30 mL / min. H2 was introduced via a mass flow controller at 20.9 seem (50 eq) and the system was maintained at 0.5 MPa. rac-(l*A,4*S,5*S)-4-(2-Chloro-3-fluorophenyl)-l-methoxy-3-azabicyclo[3.1.0]hexane (0.15 g, 17% yield) was obtained as a yellow solid and used in the next step without further purification. MS (ESI): mass calcd. for C12H13ClFNO, 241.1; m / z found, 242.2 [M+H]+.Scheme 36: Synthesis of rac-(l*7?,2*5,5*iS,6*iS)-2-(2-chloro-3-fluorophenyl)-6-(prop-l-yn-l-yl)-3-azabicyclo [3.1.0] hexane.Intermediate 78: rac-(l*7?,2*iS,5*iS,6*A)-2-(2-Chloro-3-fluorophenyl)-6-(prop-l-yn-l-yl)-3-azabicyclo [3.1.0] hexane.

[0411] Step A: / crt-Butyl rac-( 1 *. S'.2*. S'.5* / ?.6*. S')-2-(2-chloro-3-fluorophcnyl)-6-(hydroxymcthyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of (rac-(l*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (Intermediate 25, 1.8 g, 8.28 mmol, 1.0 eq) in DCM (40 mL, 0.2M) was added Boc₂O (2.7 g, 12.4 mmol, 1.5 eq) and TEA (3.5 mL, 24.8 mmol, 3.0 eq) at 0 °C. The reaction was stirred at 15 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-35% EtOAc in hexane) to give tert-butyl rac-(l*. S'.2*. S'.5* / ?.6*. S)-2-(2-chloro-3-fliiorophcnyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, 71% yield) as a pale yellow oil. ’H NMR (400 MHz, CDCh) 57.23 - 7.15 (m, 1H), 7.04 (brt, J= 8.3 Hz, 1H), 6.97 - 6.85 (m, 1H), 5.39 (d, J = 5.1 Hz, 1H), 3.90 - 3.70 (m, 2H), 3.47 - 3.36 (m, 1H), 3.30 (br d, J= 7.4 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.74 - 1.62 (m, 1H), 1.42 (br dd, J= 13.4, 6.4 Hz, 1H), 1.27 - 0.87 (m, 9H).

[0412] Step B: tert-Butyl rac-( l*. S'.2*. S'.5* / ?.6*. S)-2-(2-chloro-3-fliiorophcnyl)-6-formyl-3-azabicyclo [3.1.0]hexane-3 -carboxylate. To a solution of tert-butyl rac-(l*. S'.2*. S'.5* / ?.6*. S)-2-(2-chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.3 g, 6.73 mmol, 1.0 eq) in DCM (40 mL, 0.2M) was added Dess-Martin periodinane (4.3 g, 10.1 mmol, 1.5 eq). The reaction was stirred at 20 °C for 5 h then filtered and poured into sat. aq. NaHCO3and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-30% EtOAc in hexane) to give tert-butyl rac-(l*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.5 g, 66% yield) as a colorless oil. MS (ESI): mass calcd. for C17H19CIFNO3, 339.1; m / z found, 284.3 [M+2H-tBu]+. ’HNMR (400 MHz, CDCh) 59.27 (d, J= 3.8 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.11 - 7.03 (m, 1H), 6.93 (br d, J= 6.5 Hz, 1H), 5.49 (d, J = 4.8 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.85 - 3.76 (m, 1H), 2.80 (br s, 1H), 2.46 - 2.33 (m, 1H), 1.89 (br s, 1H), 1.31 - 0.98 (m, 9H).

[0413] Step C: tert-Butyl rac-( l* / ?.2*. S'.5*. S'.6*. S)-2-(2-chloro-3-fliiorophcnyl)-6-cthynyl-3-azab icy clo [3.1.0]hexane-3 -carboxylate. To a solution of tert-butyl rac-( l*. S'.2*. S'.5* / ?.6*. S)-2-(2-chloro-3-fluorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.47 mmol, 1.0 eq) and potassium carbonate (407 mg, 2.94 mmol, 2.0 eq) in methanol (15 mL, 0.1M) was added 1-diazo-l-dimethoxyphosphoryl-propan-2-one (311 mg, 1.62 mmol, 1.1 eq) dropwise. The reaction was stirred at 25 °C for 2 h before being concentrated under reduced pressure then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl rac-( I * / ?.2*. S'.5*, S'.6*. S)-2-(2-chloro-3-fluorophenyl)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (260 mg, 53% yield) as a white solid.IllMS (ESI): mass calcd. for C18H19ClFNO2, 335.1; m / z found, 280.3 [M+2H-tBu]+. 'HNMR (400 MHz, CDCh) 57.21 (dt, J= 7.9, 5.4 Hz, 1H), 7.07 (br t, J= 8.2 Hz, 1H), 6.86 (br d, J= 5.6 Hz, 1H), 5.40 (d, J = 5.0 Hz, 1H), 3.84 - 3.72 (m, 2H), 2.44 (br s, 1H), 2.04 (td, J= 7.1, 3.8 Hz, 1H), 1.79 (d, J= 2.0 Hz, 1H), 1.41 - 0.99 (m, 10H).

[0414] Step D: tert-Butyl rac-(l* / ?.2*. S'.5*. S'.6*. S')-2-(2-chloro-3-fluorophcnyl)-6-prop-l-ynyl-3-azabicyclo [3.1.0]hexane-3 -carboxylate. tert-Butyl rac-( I * / ?.2*. S'.5*, S'.6*. S)-2-(2-chloro-3-fluorophcn l)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (260 mg, 0.774 mmol, 1.0 eq) was taken up in THF (5.0 mL, 0.15M), placed under N2, and cooled to -78 °C. To the solution was added n-BuLi (0.5 mL, 1.16 mmol, 1.5 eq, 2.5M in hexane) and the solution was stirred for 30 min. lodomethane (165 mg, 1.16 mmol, 1.5 eq) was added at -78 °C and the reaction was allowed to warm to 25 °C and stirred for 1 h.The reaction was quenched with sat. aq. NFUC1 at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (Hexane: EtOAc = 5: 1) to give tert-butyl rac-(l*A,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-prop-l-ynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (180 mg, 66% yield) as a colorless oil. MS (ESI): mass calcd. for C19H21ClFNO2, 349.1; m / z found, 294.2 [M+2H-tBu]+. 'HNMR (400 MHz, CDC13) 57.24 - 7.18 (m, 1H), 7.10 - 6.98 (m, 1H), 6.86 (br d, J= 2.5 Hz, 1H), 5.38 (d, J= 5.0 Hz, 1H), 3.82 - 3.69 (m, 2H), 2.34 (br s, 1H), 1.97 - 1.88 (m, 1H), 1.69 (d, J = 2.0 Hz, 3H), 1.43 - 1.35 (m, 1H), 1.25 - 0.90 (m, 9H).

[0415] Step E: rac-(l*A,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(prop-l-yn-l-yl)-3-azabicyclo[3.1.0]hexane. A solution of tert-butyl rac-( l* / ?.2*. S'.5*. S'.6*. S)-2-(2-chloro-3-fliiorophcnyl)-6-prop- l-ynyl-3 -azabicyclo [3.1.0]hexane-3 -carboxylate (180 mg, 0.515 mmol, 1.0 eq) in DCM / TFA (v / v 3:1, 4.0 mL, 0.1M) was stirred at 20 °C for 3 h. The mixture was poured into sat. aq. NaHC’CF and extracted with DCM. The combined organic layers were dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give rac-(l*A,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-6-(prop- l-yn-l-yl)-3 -azabicyclo [3.1.0]hexane (100 mg, 78% yield) as ayellow solid. MS (ESI): mass calcd. for C14H13CIFN, 249.1; m / z found, 250.3 [M+H]+. ’H NMR (400 MHz, CDC13) 57.48 (d, J= 7.9 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.08 (dt, J= 8.5, 1.4 Hz, 1H), 4.70 (d, J= 3.4 Hz, 1H), 3.35 - 3.15 (m, 2H), 2.05 (td, J= 6.7, 3.4 Hz, 1H), 1.80 (td, J= 6.8, 3.5 Hz, 1H), 1.75 (d, J= 2.1 Hz, 3H), 1.61 (br s, 1H).Scheme 37: Synthesis of 3-(2-chloro-3-fhiorophenyl)-2,3-dihydro-l / 7-pyrrolo[3,4-c]pyridine.Intermediate 79: 3-(2-Chloro-3-fhiorophenyl)-2,3-dihydro-l / 7-pyrrolo[3,4-c]pyridine.

[0416] Step A: tert-Butyl ((3-(2-chloro-3-fluorobenzoyl)pyridin-4-yl)methyl)carbamate. A solution of tert-butyl 3-oxo-l.3-dihydro-2H-pyrrolo|3.4-c|pyridinc-2-carboxylatc (1.5 g, 6.40 mmol, 1.0 eq) in THF (30 mL, 0.2M) was purged with N2 and cooled to 0 °C. To the solution was added (2-chloro-3-fluorophenyl)magnesium bromide (9.6 mL, 9.61 mmol, 1.5 eq, IM in THF). The reaction was allowed to warm to rt and stirred for 5 h. The mixture was quenched with sat. aq. NH4CI at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried overNa2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (35-45% EtOAc in hexane) to give tert-butyl ((3-(2-chloro-3-fluorobenzoyl)pyridin-4-yl)methyl)carbamate (1.2 g, 51% yield) as a yellow solid. MS (ESI): mass calcd. for C18H18ClFN2O3, 364.1; m / z found, 365.3 [M+H]+.

[0417] Step B: tert-Butyl ((3-((2-chloro-3-fluorophenyl)(hydroxy)methyl)pyridin-4-yl)methyl)carbamate. To a solution of tert-butyl ((3-(2-chloro-3-fluorobenzoyl)pyridin-4-yl)methyl)carbamate (2.0 g, 5.48 mmol, 1.0 eq) in methanol (40 mL, 0.1M) was added sodium borohydride (415 mg, 11.0 mmol, 2.0 eq) at 0 °C under N2. The reaction was stirred at 25 °C for 16 h before being poured into water and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (45-55% EtOAc in hexane) to give tert-butyl ((3-((2-chloro-3-fluorophenyl)(hydroxy)methyl)pyridin-4-yl)methyl)carbamate (900 mg, 45% yield) as a white solid. MS (ESI): mass calcd. for CI8H2OC1FN203, 366.1; m / z found, 367.3 [M+H]+. 'HNMR (400 MHz, CDCh) 5 8.49 (d, J= 5.0 Hz, 1H), 8.21 (br s, 1H), 7.57 (br d, J= 5.4 Hz, 1H), 7.37 (dt, J= 8.0, 5.4 Hz, 1H), 7.20 -7.11 (m, 1H), 6.44 (s, 1H), 5.24 (br s, 1H), 4.65 (br d, J= 11.6 Hz, 1H), 4.27 (dd, J= 15.8, 6.5 Hz, 1H), 1.43 (s, 9H).

[0418] Step C: tert-Butyl 3 -(2-chloro-3 -fluorophenyl)- l.3-dihydro-2H-pyrrolo|3.4-c|pyridinc-2-carboxylate. To the solution of tert-butyl ((3-((2-chloro-3-fluorophenyl)(hydroxy)methyl)pyridin-4-yl)methyl)carbamate (900 mg, 2.45 mmol, 1.0 eq) in toluene (18 mL, 0.1M) was added cyanomethylenetributylphosphorane (1.8 g, 7.36 mmol, 3.0 eq) and the reaction stirred at 110 °C for 16 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-35% EtOAc in hexane) to give tert-butyl 3-(2-chloro-3-fluorophcnyl)-l.3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (420 mg, 49% yield) as a pale yellow solid. MS (ESI): mass calcd. for C18H18ClFN2O2, 348.1; m / z found, 349.3 [M+H]+. ’H NMR (400 MHz, CDCh) 58.55 (br d, J= 4.6 Hz, 1H), 8.44 (s, 1H), 7.35 (br d, J= 4.8 Hz, 1H), 7.23 - 7.15 (m, 1H), 7.14 - 7.07 (m, 1H),6.94 (brd, J = 8.0 Hz, 1H), 6.61 - 6.51 (m, 1H), 5.03 - 4.88 (m, 2H), 1.33 - 1.18 (m, 9H).

[0419] Step D: 3-(2-Chloro-3-fluorophcnyl)-2.3-dihydro-l / / -pyrrolo|3.4-c|pyridinc. A solution of tert-butyl 3-(2-chloro-3-fluorophenyl)-l,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2 -carboxylate (420 mg, 1.20 mmol, 1.0 eq) in DCM / TFA (v / v 3:1, 8.0 mL, 0.15M) was stirred at 20 °C for 1 h. The mixture was poured into sat. aq. NaHCO3and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-(2-chloro-3-fluorophenyl)-2,3-dihydro- lH-pyrrolo[3,4-c]pyridine (220 mg, 73% yield) as a yellow solid. MS (ESI): mass calcd. for C13H10CIFN2, 248.0; m / z found, 249.1 [M+H]+.Scheme 38: Synthesis of l-(2-chloro-3-fluorophenyl)-2,3-dihydro-l / / -pyrrolo[3,4-c|pyridine.Intermediate 80: l-(2-Chloro-3-fluorophenyl)-2,3-dihydro-l / / -pyrrolo [3, 4-c] pyridine.

[0420] Step A: tert-Butyl ((4-((2-chloro-3-fluorophenyl)(hydroxy)methyl)pyridin-3-yl)methyl)carbamate. / C77-Biityl A-(3-pyridylmcthyl)carbamatc (2.0 g, 9.60 mmol, 1.0 eq) was dissolved in anhydrous THF (20 mL, 0.5M) and cooled to -78 °C under N2. To the mixture was added tert-butyllithium (24 mL, 31.7 mmol, 3.3 eq, 1.3M in THF) dropwise over 10 min. The mixture was stirred at -78 °C for 2 h. To the reaction was added 2-chloro-3 -fluorobenzaldehyde (3.3 g, 21.1 mmol, 2.2 eq) in THF (20 mL, 0.5M) dropwise over 10 min and the reaction was stirred at -78 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-50% EtOAc in hexane) to give tert-butyl ((4-((2 -chloro-3 -fhiorophenyl)(hydroxy)methyl)pyridin-3-yl)methyl)carbamate (1.5 g, 17% yield) as a white solid. MS (ESI): mass calcd. for C18H20CIFN2O3, 366.1; m / z found, 367.2 [M+H]+.

[0421] Step B: tert-Butyl l-(2-chloro-3 -fluorophenyl)- l.3-dihydro-2H-pyrrolo|3.4-c|pyridinc-2-carboxylate. To a solution of tert-butyl ((4-((2-chloro-3-fluorophenyl)(hydroxy)methyl)pyridin-3-yl)methyl)carbamate (1.3 g, 1.59 mmol, 1.0 eq) in DCM (13 mL, 0.1M) was added TEA (0.66 mb, 4.78 mmol, 3.0 eq), methanesulfonic anhydride (417 mg, 2.39 mmol, 1.5 eq), and DMAP (9.7 mg, 0.079 mmol, 0.05 eq). The reaction was stirred at 25 °C for 16 h before being diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried overlS^SCE, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (25-50% EtOAc in hexane) to afford tert-butyl 1 -(2 -chloro-3 -fluorophenyl)- 1,3 -dihydro-2H-pyrrolo [3,4-c]pyridine-2 -carboxylate (200 mg, 36% yield) as a colorless oil. ’H NMR (400 MHz, CDCI3) 58.67 (s, 1H), 8.48 (d, J= 5.4 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.12 - 7.06 (m, 1H), 6.98 - 6.89 (m, 1H), 6.58 - 6.48 (m, 1H), 5.01 -4.93 (m, 2H), 1.33 - 1.17 (m, 9H).

[0422] Step C: l-(2-Chloro-3-fhiorophcnyl)-2.3-dihydro-IH-pyrrolo|3.4-c|pyridinc. A solution of te / - b 11 ty 1 1 -(2 -chloro-3 -fluorophenyl)- 1,3 -dihydro-2H-py rrolo [3,4-c]pyridine-2 -carboxylate (200 mg, 0.573 mmol, 1.0 eq) in DCM / TFA (v / v 2:1, 3.0 mL, 0.2M) was stirred at 20 °C for 2 h. The mixture waspoured into sat. aq. NaHCO3and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give l-(2-chloro-3-fluorophenyl)-2,3-dihydro- I H-pyrrolo| 3.4-c (pyridine (130 mg, 91% yield) as a yellow oil. MS (ESI): mass calcd. for C13H10CIFN2, 248.0; m / z found, 249.1 [M+H]+.EXPERIMENTAL SECTION - EXAMPLESScheme 17: Synthesis of 5-(fS’)-2-(2-chlorophenyl)pyrrolidin-l-yl)- / V-(( / ?)-l-(l,l-dioxido-2 / / -thiet-3-yl)ethyl)pyrazine-2-carboxamide.Example 1: 5-((X)-2-(2-Chlorophenyl)pyrrolidin-l-yl)- / V-(( / ?)-l-(l,l-dioxido-2 / / -thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0423] Step A: Methyl (S)-5-(2-(2-chlorophenyl)pyrrolidin-l-yl)pyrazine-2-carboxylate. (S)-2-(2-Chlorophenyl)pyrrolidine (150 mg, 0.653 mmol, 1.0 eq) and methyl 5 -chloropyrazine-2 -carboxylate (115 mg, 0.653 mmol, 1.0 eq) were taken up in 1,4-dioxane (2.2 mL, 0.3M). To this was added DIPEA (0.24 mL, 1.37 mmol, 2.1 eq) and the reaction was heated to 100 °C for 12 h. After cooling to rt, the reaction was quenched with water and brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-50% EtOAc in heptanes) provided methyl (S)-5-(2-(2-chlorophenyl)pyrrolidin-l-yl)pyrazine-2-carboxylate (213 mg, quant, yield). MS (ESI): mass calcd. for C16H16CIN3O2, 317.1; m / z found, 318.0 [M+H]+.

[0424] Step B: (5)-5-(2-(2-Chlorophenyl)pyrrolidin-l-yl)pyrazine-2-carboxylic acid. Methyl (S)-5-(2-(2 -chlorophenyl)pyrrolidin-l-yl)pyrazine-2 -carboxylate (213 mg, 0.670 mmol, 1.0 eq) was taken up in MeOH (2.7 mL, 0.25M). To this was added LiOH (2.7 mL, 5.36 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60 °C for 2 h. After cooling to rt, the reaction was adjusted to pH ~2 with IN HC1. The precipitate was collected by filtration to provide (*S)-5-(2-(2-chlorophcnyl)pyrrolidin- 1 -yljpyrazinc-2-carboxylic acid (188 mg, 92% yield) as a white solid. MS (ESI): mass calcd. for C15H14CIN3O2, 303.1; m / z found, 304.0 [M+H]+.

[0425] Step C: 5-((*S)-2-(2-Chlorophcnyl)pyrrolidin-l- l)- '-(( / ?)-l-(l. l-dioxido-2 / / -thict-3-yl)ethyl)pyrazine-2-carboxamide. (S)-5-(2-(2-Chlorophenyl)pyrrolidin-l-yl)pyrazine-2-carboxylic acid (40 mg, 0.132 mmol, 1.0 eq) and HATU (58 mg, 0.145 mmol, 1.1 eq) were taken up in DMF (0.66 mL,0.2M). To this was added DIPEA (0.11 mL, 0.658 mmol, 5.0 eq) and the reaction was stirred at rt for 10 min. Then, ( / ?)-3-(l-aminocth l)-2 / / -thictc 1,1-dioxide, TsOH (Intermediate 1, 44 mg, 0.138 mmol, 1.05 eq) was added and the reaction was stirred at rt for 2 h. The crude material was purified by RP-HPLC (5-95%ACN in 0.1%HCOOH water) to provide 5-((. S)-2-(2-chlorophcn l)pyrrolidin-l- l)-A-(( / ?)-l-( l.l-dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide (45 mg, 79% yield) as a white solid. MS (ESI): mass calcd. for C20H21CIN4O3S, 432.1; m / z found, 433.2 [M+H]+. ’H NMR (400 MHz, CDC13) 58.81 (s, 1H), 7.55 - 7.37 (m, 3H), 7.21 (td, J= 7.6, 1.7 Hz, 1H), 7.15 (td, J= 7.6, 1.4 Hz, 1H), 6.94 (dd, J= 7.7, 1.7 Hz, 1H), 6.57 (d, J= 1.7 Hz, 1H), 5.39 (s, 1H), 5.09 - 4.98 (m, 1H), 4.45 (t, J= 1.3 Hz, 2H), 4.05 -3.96 (m, 1H), 3.87 - 3.71 (m, 1H), 2.54 (t, J= 9.7 Hz, 1H), 2.13 - 2.00 (m, 3H), 1.45 (d, J= 7.1 Hz, 3H).Example 2: 5-((5)-2-(2-Chloro-3-fluorophenyl)pyrrolidin-l-yl)-A-((7?)- l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0426] The title compound was prepared in a manner analogous to Example 1 using (. S)-2-(2-ch loro-3 -fluorophenyl)pyrrolidine (SFC separation of 2-(2-chloro-3-fluorophenyl)pyrrolidine: Stationary phase: WHELK-01 (25x5 cm); Mobile phase: 25% EtOH / CO2with 0.1% NH₄OH; Rt = 4.52 min, second eluting product) instead of (. S)-2-(2-chlorophcnyl)pyrrolidinc in Step A. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C20H20CIFN4O3S, 450.1; m / z found, 451.0 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.75 (br d, J= 8.5 Hz, 1H), 8.53 (br s, 1H), 7.98 - 7.67 (m, 1H), 7.36 - 7.21 (m, 2H), 6.99 - 6.88 (m, 2H), 5.47 (br d, J= 7.9 Hz, 1H), 4.93 (quin, J= 7.3 Hz, 1H), 4.50 (s, 2H), 4.08 - 3.96 (m, 1H), 3.69 (q, J= 8.5 Hz, 1H), 2.46 (br s, 1H), 2.14 - 2.02 (m, 1H), 1.99 - 1.82 (m, 2H), 1.36 (d, J= 7.1 Hz, 3H).Example 3: (5,£)-3-(l-(5-(2-(2-Chlorophenyl)pyrrolidin-l-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0427] The title compound was prepared in a manner analogous to Example 1 using (E)-3-(azetidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?)-3-( l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C21H20CIN5O, 393.1; m / z found, 394.2 [M+H]+. 'HNMR (400 MHz, CDCI3) 5 8.82 (s, 1H), 7.43 (dd, J= 7.8, 1.4 Hz, 2H), 7.19 (dtd, J= 25.7, 7.4, 1.5 Hz, 2H), 7.01 - 6.78 (m, 2H),5.49 - 5.26 (m, 2H), 4.79 (t, J= 9.5 Hz, 1H), 4.40 (qd, J= 8.2, 4.3 Hz, 2H), 4.08 - 3.94 (m, 2H), 3.84 -3.71 (m, 1H), 3.48 - 3.38 (m, 1H), 2.58 - 2.45 (m, 1H), 2.14 - 2.00 (m, 3H).Example 4: 5-((17?,25,5iS)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0428] The title compound was prepared in a manner analogous to Example 1 using (1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 13) instead of (S)-2-(2-chlorophenyl)pyrrolidine and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H20CIFN4O3S, 462.1; m / z found, 463.1 [M+H]+. ’HNMR (400 MHz, DMSO-6) 58.78 (d, J= 8.4 Hz, 1H), 8.50 (d, J= 0.8 Hz, 1H), 7.69 (br s, 1H), 7.35 - 7.17 (m, 2H), 6.92 (d, J= 1.8 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.55 (d, J= 5.3 Hz, 1H), 4.92 (quin, J= 7.2 Hz, 1H), 4.50 (s, 2H), 4.08 (d, J= 10.4 Hz, 1H), 3.88 (dd, J= 10.4, 5.1 Hz, 1H), 2.34 - 2.26 (m, 1H), 2.04 - 1.92 (m, 1H), 1.35 (d, J = 7.2 Hz, 3H), 0.65 (dt, J= 7.9, 5.4 Hz, 1H), 0.30 (q, J= 4.4 Hz, 1H).Example 5: 5-((17?,25,5iS)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrimidine-2-carboxamide.

[0429] The title compound was prepared in a manner analogous to Example 1 using (1R,2S,5S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (Intermediate 13) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5 -fluoropyrimidine-2 -carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C21H20CIFN4O3S, 462.1; m / z found, 463.1 [M+H]+. ’HNMR (400 MHz, DMSO-6) 58.91 (d, J= 8.4 Hz, 1H), 7.86 (s, 2H), 7.41 - 7.34 (m, 1H), 7.29 (dt, J= 7.9, 5.8 Hz, 1H), 6.92 (d, J= 1.6 Hz, 1H), 6.85 (br d, J= 7.6 Hz, 1H), 5.34 (d, J = 4.9 Hz, 1H), 4.90 (brt, J= 7.1 Hz, 1H), 4.50 (s, 2H), 4.09 (d, J= 9.5 Hz, 1H), 3.65 (dd, J= 9.4, 4.9 Hz, 1H), 2.35 - 2.25 (m, 1H), 2.04 - 1.94 (m, 1H), 1.34 (d, J= 7.0 Hz, 3H), 0.62 (dt, J= 7.8, 5.3 Hz, 1H), 0.36 (br d, J= 4.3 Hz, 1H).Example 6: (E)-3-(l-(5-((17?,2iS,5A)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0430] The title compound was prepared in a manner analogous to Example 5 using (A')-3-(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?)-3-( l-aminocth l)-2 / / -thictc 1,1 -dioxide in Step C. MS (ESI): mass calcd. for C22H19CIFN5O, 423.1; m / z found, 424.0 [M+H]+. 'H NMR (400 MHz, DMSO-6) 57.85 (s, 2H), 7.39 - 7.22 (m, 2H), 7.10 (br dd, J= 16.4, 7.7 Hz, 1H), 6.82 (br d, J= 7.3 Hz, 1H), 5.83 (br d, J= 16.0 Hz, 1H), 5.31 (br d, J= 4.6 Hz, 1H), 4.58 (brt, J= 9.1 Hz, 1H), 4.32 - 4.25 (m, 1H), 4.18 (br t, J= 9.4 Hz, 1H), 4.07 (br d, J= 9.4 Hz, 1H), 3.89 (br dd, J= 9.6, 4.4 Hz, 1H), 3.63 (br dd, J= 9.0, 4.6 Hz, 1H), 3.51 - 3.47 (m, 1H), 2.30 (br s, 1H), 1.97 (br s, 1H), 0.66 - 0.56 (m, 1H), 0.31 (br d, J = 3.3 Hz, 1H).Example 7: 5-((3a*?,4*iS,6a*A)-4-(2-Chloro-3-fluorophenyl)tetrahydro-l / 7-furo[3,4-c]pyrrol-5(3 / 7)-yl)-JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0431] The title compound was prepared in a manner analogous to Example 1 using (3a*R,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)hexahydro-1H-furo[3,4-c]pyrrole (Intermediate 15) instead of (S)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. MS (ESI): mass calcd. for C22H22CIFN4O4S, 492.1; m / z found, 493.0 [M+H]+. 'HNMR (400 MHz, CDCh) 58.80 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.40 (s, 1H), 7.18 - 7.04 (m, 2H), 6.78 (dt, J= 7.5, 1.3 Hz, 1H), 6.57 (d, J= 1.6 Hz, 1H), 5.62 (d, J= 9.1 Hz, 1H), 5.03 (p, J= 6.9 Hz, 1H), 4.46 - 4.35 (m, 3H), 3.89 (dd, J= 9.2, 2.7 Hz, 1H), 3.82 (dd, J= 9.2, 6.0 Hz, 1H), 3.74 - 3.62 (m, 2H), 3.51 (dd, J= 10.0, 7.5 Hz, 1H), 3.32 - 3.22 (m, 2H), 1.45 (d, J= 7.0 Hz, 3H).Example 8: 5-((3a*?,4*iS,6a*A)-4-(2-Chloro-3-fluorophenyl)tetrahydro-l / 7-furo[3,4-c]pyrrol-5(3 / 7)-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0432] The title compound was prepared in a manner analogous to Example 7 using (R,E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C.MS (ESI): mass calcd. for C22H21ClFN5O2, 441.1; m / z found, 442.0 [M+H]+. 'H NMR (400 MHz, CDCh) 58.81 (d, J= 1.4 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.18 - 7.06 (m, 2H), 6.79 (dt, J= 7.5, 1.5 Hz, 1H), 6.70 (dd, J= 16.3, 5.0 Hz, 1H), 5.61 (d, J= 9.0 Hz, 1H), 5.46 (dd, J= 16.4, 1.8 Hz, 1H), 4.89 - 4.76 (m, 1H), 4.42 (dd, J= 11.7, 9.0 Hz, 1H), 3.89 (dd, J = 9.2, 2.7 Hz, 1H), 3.83 (dd, J = 9.2, 6.0 Hz, 1H), 3.75 - 3.63 (m, 2H), 3.51 (dd, J= 9.9, 7.4 Hz, 1H), 3.33 - 3.20 (m, 2H), 1.35 (d, J= 7.1 Hz, 3H).Example 9: (E)-3-(l-(5-((3a*7?,4*5,6a*iS)-4-(2-Chloro-3-fluorophenyl)tetrahydro-l / 7-furo[3,4-c]pyrrol-5(3 / 7)-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0433] The title compound was prepared in a manner analogous to Example 7 using (E)-3-(azetidin-3-yl)acrylonitrile (Intermediate 8) instead of (R)-3-(1-aminoethyl)-2H-thiete 1,1-dioxide in Step C. MS (ESI): mass calcd. for C23H21CIFN5O2, 453.1; m / z found, 454.0 [M+H]+. 'HNMR (400 MHz, CDCh) 5 8.82 (d, J= 1.3 Hz, 1H), 7.41 (s, 1H), 7.23 - 7.02 (m, 2H), 6.96 - 6.84 (m, 1H), 6.81 (dt, J= 7.4, 1.3 Hz, 1H), 5.60 (d, J= 9.0 Hz, 1H), 5.44 (dd, J= 16.4, 1.1 Hz, 1H), 4.81 (t, J= 9.5 Hz, 1H), 4.48 - 4.36 (m, 3H), 4.08 - 3.99 (m, 1H), 3.95 - 3.79 (m, 2H), 3.75 - 3.63 (m, 2H), 3.59 - 3.38 (m, 2H), 3.35 - 3.18 (m, 2H).Example 10: 5-((17?, 2S,5S, 6S)-2-(2, 3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0434] The title compound was prepared in a manner analogous to Example 1 using rac-(l*A,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 18) instead of (. S)-2-(2-chlorophcny I (pyrrolidine. methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5-chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of methyl 5-(rac-(l*A,2*S,5*S,6*S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (Step A) via SFC (Stationary phase: WHELK-01 (25x5 cm); Mobile phase: 45% Me0H / C02; Rt = 8.30 min, second eluting product) afforded methyl 5-((lA,2S,5S,6S)-2-(2,3-difluorophenyl)-6-methyl-3 -azabicyclo [3.1,0]hexan-3-yl)pyrazine-2 -carboxylate, which was elaborated to the title compound in a manner analogous to Example 1, Steps B-C. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C22H22F2N4O3S, 460.1; m / z found, 461.0 [M+H]+. ’H NMR (400 MHz, CDCh) 58.76 (d, J= 1.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.07 (dtd, J= 9.7, 8.0, 1.6 Hz, 1H), 6.93 (tdd, J= 8.2, 4.9, 1.6 Hz, 1H), 6.60 - 6.51 (m, 2H), 5.45 (d, J= 5.5 Hz, 1H), 5.09 - 4.97 (m, 1H), 4.48 - 4.38 (m, 2H), 4.00 (d, J= 10.9 Hz, 1H), 3.90 (dd, J = 10.9, 5.5 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.71 - 1.63 (m, 1H), 1.46 (d, J= 7.0 Hz, 3H), 0.93 (d, J= 6.0 Hz, 3H), 0.75 - 0.68 (m, 1H).Example 11: N-((R, £)-4-Cyanobut-3-en-2-yl)-5-((17?, 2S,5S, 6S)-2-(2, 3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxamide.

[0435] The title compound was prepared in a manner analogous to Example 10 using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of (A)-3-(l-aminoethyl)-2H-thiete 1,1-dioxide in Step C. MS (ESI): mass calcd. for C22H21F2N5O, 409.2; m / z found, 410.0 [M+H]+.1H NMR (400 MHz, CDCh) 58.78 (d, J= 1.4 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.39 (d, J= 8.3 Hz, 1H), 7.07 (dtd, J= 9.7, 7.9, 1.6 Hz, 1H), 6.93 (tdd, J= 8.1, 4.8, 1.5 Hz, 1H), 6.70 (dd, J= 16.3, 4.9 Hz, 1H), 6.57 (ddt, J= 7.8, 6.2, 1.6 Hz, 1H), 5.49 - 5.40 (m, 2H), 4.88 - 4.76 (m, 1H), 4.00 (d, J= 10.9 Hz, 1H), 3.90 (dd, J= 10.9, 5.5 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.71 - 1.62 (m, 1H), 1.35 (d, J= 7.1 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H), 0.72 (tq, J = 6.2, 3.1 Hz, 1H).Example 12: (£)-3-(l-(5-((17?, 2S,5S, 6S)-2-(2, 3-Difhiorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0436] The title compound was prepared in a manner analogous to Example 10 using (A')-3-(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?)-3-(l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C23H21F2N5O, 421.2; m / z found, 422.0 [M+H]+. 'HNMR (400 MHz, CDCh) 5 8.76 (d, J= 1.7 Hz, 1H), 7.45 (d, J= 4.6 Hz, 1H), 7.07 (q, J= 8.5 Hz, 1H), 6.99 - 6.82 (m, 2H), 6.64 -6.49 (m, 1H), 5.50 - 5.32 (m, 2H), 4.87 - 4.68 (m, 1H), 4.46 - 4.34 (m, 2H), 4.10 - 3.94 (m, 2H), 3.88 (dd, J= 10.9, 5.5 Hz, 1H), 3.52 - 3.37 (m, 1H), 2.06 - 1.97 (m, 1H), 1.68 - 1.61 (m, 1H), 0.93 (d, J= 6.0 Hz, 3H), 0.75 - 0.65 (m, 1H).Example 13: 5-((l*iS,2*7?,5*7?,6*7?)-2-(3-Chloro-4-fluoropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0437] The title compound was prepared in a manner analogous to Example 1 using rac-(l*A,2*S,5*S,6*S)-2-(3-chloro-4-fluoropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 21) instead of (. S)-2-(2-chlorophcny I (pyrrolidine. methyl 5 -fluoropyrazine-2 -carboxylate instead of methyl 5 -chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of 5-(rac-( I *. S'.2* / ?.5* / ?.6* / ?)-2-(3-chloro-4-fliioropyridin-2-yl)-6-mcthyl-3-azabicyclo|3. 1,0|hcxan-3-yl)- '-(( / ?)-l-(l. l-dioxido-2 / / -thict-3- l)cth l)pyrazinc-2 -carboxamide (Step C) via SFC (Stationary phase: IM (3x25 cm); Mobile phase: 50% iPrOH / CCE: Rt = 10.8 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C21H21CIFN5O3S, 477.1; m / z found, 478.2 [M+H]+. ’HNMR (400 MHz, DMSO-r / ,) 58.70 (d, J= 8.5 Hz, 1H), 8.41 - 8.24 (m, 2H), 7.88 - 7.53 (m, 1H), 7.41 (dd, J= 8.8, 5.5 Hz, 1H), 6.92 (d, J= 1.8 Hz, 1H), 5.72 (d, J = 5.6 Hz, 1H), 4.91 (q, J = 7.0 Hz, 1H), 4.49 (s, 2H), 4.00 - 3.83 (m, 2H), 2.13 - 2.04 (m, 1H), 1.81 - 1.70 (m, 1H), 1.35 (d, J= 7.1 Hz, 3H), 1.07 - 0.93 (m, 1H), 0.86 (d, J= 6.1 Hz, 3H).Example 14: JV-((7?, E)-4-Cyanobut-3-en-2-yl)-5-((l*iS,2*iS,5* / ?,6*iS)-2-(3-fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide.

[0438] The title compound was prepared in a manner analogous to Example 1 using rac-(l*S,2*S,5*7?,6*S)-2-(3-fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 20) instead of (. S)-2-(2-chlorophcny I (pyrrolidine. methyl 5 -fluoropyrimidine-2 -carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A and using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-(l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. Separation of A-((7?, E)-4-cyanobut-3-en-2-yl)-5-(rac-(l*S,2*S,5*7?,6*S)-2-(3-fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2 -carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 40% EtOH / CCE; Rt = 7.07 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H24FN5O, 405.2; m / z found, 406.2 [M+H]+. ’H NMR (400 MHz, DMSO-r / ,,) 58.61 (d, J= 8.4 Hz, 1H), 7.83 (s, 2H), 7.13 - 7.03 (m, 2H), 6.90 (dd, J= 16.5, 5.4 Hz, 1H), 6.66 (br d, J= 7.1 Hz, 1H), 5.67 (dd, J= 16.5, 1.5 Hz, 1H), 5.21 (d, J= 5.1 Hz, 1H), 4.66 (sxt, J= 6.9 Hz, 1H), 4.05 (d, J = 9.8 Hz, 1H), 3.61 (dd, J = 9.7, 5.2 Hz, 1H), 2.42 (s, 3H), 2.06 - 1.98 (m, 1H), 1.75 - 1.66 (m, 1H), 1.24 (d, J= 7.0 Hz, 3H), 0.86 (d, J= 5.9 Hz, 3H), 0.75 (td, J= 6.0, 3.1 Hz, 1H). Example 15: 5-((15, 25,57?, 65)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-W-((7?)-l-(l,l-dioxido-277-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0439] The title compound was prepared in a manner analogous to Example 1 using rac-(l*5,2*5,5*7?,6*5)-2-(2,3-difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 22) instead of (. S)-2-(2-chlorophcnyl)pyrrolidinc. methyl 5 -fluoropyrazine -2 -carboxylate instead of methyl 5-chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of methyl 5-(rac-(l*R,2*5,5*5,6*5)-2-(2,3-difhiorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (Step A) via SFC (Stationary phase: WHELK-01 (25x5 cm); Mobile phase: 44% MeOH / CO2; Rt = 7.20 min, second eluting product) afforded methyl 5-((15,25,57?,65)-2-(2,3-difluorophenyl)-6-(fIuoromethyl)-3 -azabicyclo [3.1,0]hexan-3-yl)pyrazine-2 -carboxylate, which was elaborated to the title compound in a manner analogous to Example 1, Steps B-C. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. forC22H21F3N4O3S, 478.1; m / z found, 479.0 [M+H]+. ’H NMR (400 MHz, CDCh) 58.77 (d, J= 1.4 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.09 (dtd, J= 9.7, 8.0, 1.6 Hz, 1H), 6.96 (tdd, J= 8.2, 4.8, 1.5 Hz, 1H), 6.61 (ddd, J = 7.7, 4.5, 3.0 Hz, 1H), 6.57 (d, J= 1.7 Hz, 1H), 5.51 (dd, J = 5.5, 2.2 Hz, 1H), 5.09 - 4.98 (m, 1H), 4.44 (dd, J= 2.1, 1.1 Hz, 2H), 4.35 - 3.99 (m, 3H), 3.95 (ddd, J= 10.9, 5.4, 1.9 Hz, 1H), 2.37 -2.30 (m, 1H), 2.08 - 2.00 (m, 1H), 1.46 (d, J= 7.1 Hz, 3H), 1.30 - 1.18 (m, 1H).Example 16: JV-((7?,7T)-4-Cyanobut-3-en-2-yl)-5-((15,25,57?,65)-2-(2,3-difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxamide.

[0440] The title compound was prepared in a manner analogous to Example 15 using ( / ?. / '.')-4-aminopent-2-enenitrile (Intermediate 4) instead of (7?)-3-(l-aminoethyl)-277-thiete 1,1-dioxide in Step C. MS (ESI): mass calcd. for C22H20F3N5O, 427.2; m / z found, 428.0 [M+H]+.1H NMR (400 MHz, CDCh) 58.79 (d, J= 1.4 Hz, 1H), 7.50 (d, J = 1.4 Hz, 1H), 7.40 (d, J= 8.2 Hz, 1H), 7.09 (dtd, J= 9.7, 8.0, 1.6 Hz, 1H), 6.96 (tdd, J= 8.1, 4.8, 1.5 Hz, 1H), 6.70 (dd, J= 16.3, 4.9 Hz, 1H), 6.65 - 6.58 (m, 1H), 5.50 (dd, J = 5.6, 2.2 Hz, 1H), 5.45 (dd, J= 16.4, 1.8 Hz, 1H), 4.89 - 4.76 (m, 1H), 4.35 - 4.00 (m, 3H), 3.95 (ddd, J= 11.0, 5.3, 1.9 Hz, 1H), 2.37 - 2.30 (m, 1H), 2.04 (ddd, J = 7.6, 5.2, 3.5 Hz, 1H), 1.36 (d, J = 7.1 Hz, 3H), 1.30 - 1.19 (m, 1H).Example 17: (E)-3-(l-(5-((15,25,57?,65)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0441] The title compound was prepared in a manner analogous to Example 15 using ( ’)-3 -(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of (7?)-3-(l-aminoethyl)-277-thiete 1,1-dioxide in Step C. MS (ESI): mass calcd. for C23H20F3N5O, 439.2; m / z found, 440.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.53 (d, J= 4.2 Hz, 1H), 7.12 (q, J= 8.5 Hz, 1H), 7.03 - 6.87 (m, 2H), 6.69 - 6.55 (m, 1H), 5.57 - 5.36 (m, 2H), 4.82 (t, J= 9.5 Hz, 1H), 4.52 - 4.00 (m, 6H), 4.00 - 3.92 (m, 1H), 3.55 - 3.40 (m, 1H), 2.40 - 2.30 (m, 1H), 2.11 - 1.99 (m, 1H), 1.30 - 1.19 (m, 1H).Example 18: V-(( / ?)-l-( 1,l-l)ioxido-2 / / -thiet-3-yl)ethyl)-5-(( F7?,27?,5 5,67?)-2-(3-fhioro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxamide.

[0442] The title compound was prepared in a manner analogous to Example 1 using rac-(l*S,2*S,5*J?,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 23) instead of (. S)-2-(2-chlorophcnyl)pyrrolidinc. methyl 5-fluoropyrazine-2-carboxylate instead of methyl 5 -chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A.Separation of methyl 5-(rac-(l*R,2*R,5*S,6*R)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2 -carboxylate (Step A) via SFC (Stationary phase: IM (25x5 cm); Mobile phase: 55% McOH / CCf: Rt = 9.50 min, second eluting product) afforded methyl 5-((l*R,2*R,5*S,6*R)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2 -carboxylate, which was elaborated to the title compound in a manner analogous to Example 1, Steps B-C. MS (ESI): mass calcd. for C23H24F2N4O3S, 474.1; m / z found, 475.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 58.74 (d, J= 8.4 Hz, 1H), 8.56 (s, 1H), 7.45 (br s, 1H), 7.14 - 7.01 (m, 2H), 6.90 (d, J= 1.8 Hz, 1H), 6.66 (d, J= 7.4 Hz, 1H), 5.52 (br d, J= 3.6 Hz, 1H), 4.91 (brt, J= 7. I Hz, 1H), 4.49 (s, 2H), 4.30 - 4.01 (m, 3H), 3.92 (ddd, J= 11.1, 5.2, 1.9 Hz, 1H), 2.43 - 2.36 (m, 4H), 2.07 - 2.00 (m, 1H), 1.33 (d, J= 7.0 Hz, 3H), 1.24 - 1.17 (m, 1H).Example 19: 5-((*7?)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-l-yl)-A-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0443] The title compound was prepared in a manner analogous to Example 1 using 5-(2-chloro-3-fluorophenyl)-l-methylpiperazin-2-one (Intermediate 26) instead of (. S)-2-(2-chlorophcny I (pyrrolidine, methyl 5 -fluoropyrazine-2 -carboxylate instead of methyl 5-chloropyrazine-2-carboxylate, and DMSO instead of 1,4-dioxane in Step A. Separation of methyl 5-(2-(2-chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-l-yl)pyrazine-2-carboxylate (Step A) via SFC (Stationary phase: IH (25x3 cm); Mobile phase: 38% MeOH with 0.1% NH4OH / CO2; Rt = 6.60 min, second eluting product) afforded methyl (*R)-5-(2-(2-chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-l-yl)pyrazine-2 -carboxylate, which was elaborated to the title compound in a manner analogous to Example 1, Steps B-C. MS (ESI): mass calcd. for C21H21CIFN5O4S, 493.1; m / z found, 494.0 [M+H]+. ’H NMR (400 MHz, CDCI3) 58.05 (d, J= 1.4Hz, 1H), 6.89 (d, J= 1.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.44 - 6.32 (m, 2H), 6.07 - 6.01 (m, 1H), 5.80 (d, J= 1.7 Hz, 1H), 4.94 (t, J = 3.7 Hz, 1H), 4.33 - 4.22 (m, 1H), 3.90 (d, J= 17.0 Hz, 1H), 3.74 -3.61 (m, 3H), 3.35 (dd, J= 13.8, 4.3 Hz, 1H), 2.86 (dd, J= 13.8, 3.2 Hz, 1H), 2.10 (s, 3H), 0.69 (d, J = 7.1 Hz, 3H).Example 20: 5-((* / ?)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-l-yl)-JV-((7?,£)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0444] The title compound was prepared in a manner analogous to Example 19 using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C21H20CIFN6O2, 442.1; m / z found, 443.0 [M+H]+. 'H NMR (400 MHz, CDCh) 58.93 - 8.78 (m, 1H), 7.67 (t, J= 1.6 Hz, 1H), 7.46 (d, J= 8.3 Hz, 1H), 7.25 - 7.10 (m, 2H), 6.84 (dt, J= 7.2, 1.5 Hz, 1H), 6.77 - 6.64 (m, 1H), 5.73 (q, J= 3.2 Hz, 1H), 5.48 (dt, J= 16.4, 2.0 Hz, 1H), 4.85 (dtt, J= 8.9, 5.6, 1.7 Hz, 1H), 4.70 (dd, J= 17.0, 2.7 Hz, 1H), 4.47 (dd, J= 16.9, 1.6 Hz, 1H), 4.15 (dd, J= 13.8, 4.2 Hz, 1H), 3.70 - 3.61 (m, 1H), 2.90 (d, J= 2.4 Hz, 3H), 1.38 (dd, J= 7.1, 1.9 Hz, 3H).Example 21: 5-((l*7?,2*7?,5*iS,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0445] The title compound was prepared in a manner analogous to Example 1 using rac- (( I *. S'.2*. S'.5* / ?.6*. S)-2-(2-chloro-3-fliiorophcnyl)-3-azabicyclo|3. 1.0|hcxanc-6-carbonitrilc (Intermediate 27) instead of (. S)-2-(2-chlorophcny I (pyrrolidine. methyl 5 -fluoropyrazine-2 -carboxylate instead of methyl 5 -chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A and using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. Separation 5-(rac-(l*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-A-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase:WHELK-01 (3x25 cm); Mobile phase: 50% iPrOH / CO2; Rt = 11.2 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H18CIFN6O, 436.1; m / z found, 437.2[M+H]+. 'HNMR (400 MHz, DMSO-6) 58.57 (d, J= 8.3 Hz, 1H), 8.49 (d, J= 0.9 Hz, 1H), 7.70 (s, 1H), 7.42 - 7.33 (m, 1H), 7.31 - 7.23 (m, 1H), 6.99 - 6.84 (m, 2H), 5.68 (dd, J= 16.4, 1.6 Hz, 1H), 5.62 (d, J= 4.8 Hz, 1H), 4.68 (br d, J= 6.6 Hz, 1H), 4.24 (d, J= 10.9 Hz, 1H), 3.89 (dd, J= 10.9, 4.9 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.82 - 2.75 (m, 1H), 1.81 (t, J= 3.4 Hz, 1H), 1.25 (d, J= 7.0 Hz, 3H).Example 22: 5-((l*7?,2*7?,5*iS,6*7?)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0446] The title compound was prepared in a manner analogous to Example 21 using rac-((l*S,2*S,5*7?,6*S)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 29) instead of rac-((l*S,2*S,5*7?,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile in Step A. Separation of 5-(rac-( l*. S'.2*. S'.5* / ?.6*. S)-6-cyano-2-(3-fliioro-2-mcthylphcnyl)-3-azabicyclo|3.1.0|hcxan-3-yl)- '-(( / ?. A')-4-cyanobiit-3-cn-2-yl)pyrazinc-2-carboxamidc (Step C) via SFC (Stationary phase: IK (3x25 cm); Mobile phase: 50% iPrOH / CO₂; Rt = 13.2 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H21FN6O, 416.2; m / z found, 417.2 [M+H]+. ’HNMR (400 MHz, DMSO-6) 58.57 (d, J= 1.1 Hz, 1H), 8.50 (d, J= 8.4 Hz, 1H), 7.41 (s, 1H), 7.18 -7.05 (m, 2H), 6.89 (dd, J= 16.4, 5.3 Hz, 1H), 6.80 - 6.71 (m, 1H), 5.65 (dd, J= 16.4, 1.7 Hz, 1H), 5.55 (d, J= 4.8 Hz, 1H), 4.76 - 4.61 (m, 1H), 4.22 (d, J= 11.5 Hz, 1H), 3.87 (dd, J= 11.4, 4.9 Hz, 1H), 3.11 (td, J= 7.9, 4.1 Hz, 1H), 2.77 - 2.69 (m, 1H), 2.44 (s, 3H), 1.81 (t, J= 3.5 Hz, 1H), 1.23 (d, J= 7.0 Hz, 3H).Example 23: 5-((l *S,2 *S,5 *R,6 *iS)-6-Cyano-2-(2,3-difluor ophenyl)-3-azabicyclo [3.1.0] hexan-3-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0447] The title compound was prepared in a manner analogous to Example 21 using rac-((l*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 28) instead of rac-((l*S,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile in Step A. Separation of 5-(rac-(l*S,2*S,5*R,6*S)-2-(2,3-difluorophenyl)-6-cyano-3-azabicyclo|3. 1.0|hcxan-3-yl)- '-(( / ?. A')-4-cyanobiit-3-cn-2-yl)pyrazinc-2-carboxamidc (Step C) via SFC(Stationary phase: IH (3x25 cm); Mobile phase: 35% MeOH / CCh with 0.1% NH4OH; Rt = 4.09 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H18F2N6O, 420.1; m / z found, 421.1 [M+H]+. ’HNMR(400 MHz, DMSO-6) 58.56 (d, J= 8.4 Hz, IH), 8.50 (d, J= 1.3 Hz, IH), 7.78 (s, IH), 7.44 - 7.30 (m, IH), 7.15 - 7.06 (m, IH), 6.91 (dd, J= 16.4, 5.4 Hz, IH), 6.83 (brt, J= 7.1 Hz, IH), 5.68 (dd, J= 16.4, 1.7 Hz, IH), 5.59 (d, J= 4.8 Hz, IH), 4.69 (dq, J=6.9, 1.6 Hz, IH), 4.21 (d, J= 10.9 Hz, IH), 3.86 (dd, J= 10.9, 4.9 Hz, IH), 3.02 (td, J= 7.8, 4.1 Hz, IH), 2.83 - 2.72 (m, IH), 1.81 (t, J= 3.6 Hz, IH), 1.25 (d, J = 7.0 Hz, 3H).Example 24: 5-((l*7?,2*7?,5*iS,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?,£)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0448] The title compound was prepared in a manner analogous to Example 1 using rac- (( I *. S'.2*. S'.5* / ?.6*. S)-2-(2-chloro-3-fliiorophcnyl)-3-azabicyclo|3.1,0|hcxan-6-yl)mcthanol (Intermediate 25) instead of (. S)-2-(2-chlorophcny I (pyrrolidine and DMSO instead of 1,4-dioxane in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of (R)-3-(l-aminoethyl)-2H-thiete 1,1 -dioxide in Step C. Separation of 5-(rac-( I * / ?.2* / ?.5*. S'.6* / ?)-2-(2-chloro-3-fluorophcnyl)-6-(hydroxymcthyl)-3-azabicyclo [3.1.0]hexan-3-yl)-A-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide (Step C) via SFC (Stationary phase: WHELK-01 (3x25 cm); Mobile phase: 50% iPrOH / CO2; Rt = 9.85 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H21ClFN5O2, 441.1; m / z found, 442.1 [M+H]+. ’HNMR(400 MHz, DMSO-6) 58.56 - 8.43 (m, 2H), 7.67 (br s, IH), 7.34 - 7.15 (m, 2H), 6.91 (dd, J= 16.4, 5.3 Hz, IH), 6.78 (br d, J= 7.6 Hz, IH), 5.67 (dd, J= 16.4, 1.6 Hz, IH), 5.55 (d, J= 5.4 Hz, IH), 4.76 - 4.60 (m, IH), 4.47 (t, J= 5.5 Hz, IH), 4.07 (d, J= 10.5 Hz, IH), 3.89 (dd, J = 10.6, 5.4 Hz, IH), 3.26 - 3.17 (m, IH), 3.15 - 3.07 (m, IH), 2.25 - 2.18 (m, IH), 1.93 - 1.87 (m, IH), 1.25 (d, J= 7.0 Hz, 3H), 0.92 (br s, IH).Example 25: 5-((l * / ?,2 S',5 S’)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0|heptan-3-yl)- / V-((?,£)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0449] The title compound was prepared in a manner analogous to Example 1 using rac-(l*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptane (Intermediate 14) instead of (.8)-2-(2-chlorophenyl)pyrrolidine, methyl 5-fluoropyrimidine-2-carboxylate instead of methyl 5-chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A and using ( / ?. A')-4-aminopcnt-2-enenitrile (Intermediate 4) instead of (R)-3-(l-aminoethyl)-2H-thiete 1,1 -dioxide in Step C. Separation of 5-(rac-(l*A,2*S,5*S)-2-(2-chloro-3-fhiorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-A-((A, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 45% iPrOH / CO2; Rt = 9.24 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H21CIFN5O, 425.2; m / z found, 426.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J= 8.3 Hz, 1H), 7.96 (s, 2H), 7.40 - 7.27 (m, 2H), 7.17 - 7.06 (m, 1H), 6.91 (dd, J = 16.5, 5.4 Hz, 1H), 5.69 (dd, J= 16.4, 1.7 Hz, 1H), 5.22 (d, J = 8.5 Hz, 1H), 4.76 - 4.60 (m, 1H), 3.97 (dd, J= 10.5, 2.8 Hz, 1H), 3.70 (dd, J= 10.3, 8.1 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.27 - 3.19 (m, 1H), 2.24 -2.06 (m, 1H), 1.86 - 1.75 (m, 1H), 1.75 - 1.65 (m, 1H), 1.28 - 1.15 (m, 4H).Example 26: 5-((l*iS,2*7?,5*7?,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0450] The title compound was prepared in a manner analogous to Example 1 using 2-(rac-(l*R,2*S,5*S,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetonitrile (Intermediate 30) instead of (. S)-2-(2-chlorophcny I (pyrrolidine. methyl 5-fluoropyrimidine-2-carboxylate instead of methyl 5 -chloropyrazine-2 -carboxylate, and DMSO instead of 1,4-dioxane in Step A and using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of (R)-3-( l-aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation of 5-(rac-(l*S,2*R,5*R,6*R)-2-(2-chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH / CO2; Rt = 12.8 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H20CIFN6O, 450.1; m / z found, 451.0 [M+H]+. ’HNMR (400 MHz, DMSO-6) 58.65 (d, J= 8.3 Hz, 1H), 7.86 (s, 2H), 7.41 - 7.34 (m, 1H), 7.30 (dt, J= 7.9, 5.7 Hz, 1H), 6.95 - 6.84 (m, 2H), 5.68 (dd, J= 16.4, 1.6 Hz, 1H), 5.36 (d, J= 5.1 Hz, 1H), 4.67 (dq, J= 6.9, 1.4 Hz, 1H), 4.14 (d, J= 9.8 Hz, 1H), 3.67 (dd, J= 9.8, 5.1 Hz, 1H), 2.57 -2.51 (m, 1H), 2.48 - 2.40 (m, 1H), 2.36 - 2.29 (m, 1H), 2.06 - 1.97 (m, 1H), 1.24 (d, J= 7.0 Hz, 3H), 1.12 - 1.01 (m, 1H).Scheme 18: Synthesis of 5-((iS)-2-(2-chlorophenyl)pyrrolidin-l-yl)-A-((7?, E)-4-((*iS)-iS-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2-carboxamide.Example 27: 5-((iS)-2-(2-Chlorophenyl)pyrrolidin-l-yl)-A-((7?^)-4-((*iS)-iS-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2-carboxamide.

[0451] 5-((S)-2-(2-Chlorophenyl)pyrrolidin-l-yl)-jV-((2J?, E)-4-(methylsulfinyl)but-3-en-2-yl)pyrazine-2-carboxamide was prepared in a manner analogous to Example 1 using (2 / ?)-4-(mcthy I sulfinyl )but-3-cn-2-amine (Intermediate 2) instead of ( / ?)-3-(l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C20H23CIN4O2S, 418.1; m / z found, 419.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.89 – 8.76 (m, 1H), 7.48 - 7.35 (m, 3H), 7.23 (br t, J= 7.0 Hz, 1H), 7.19 - 7.13 (m, 1H), 6.96 (br t, J= 6.3 Hz, 1H), 6.53 - 6.38 (m, 1H), 6.28 - 5.84 (m, 1H), 5.38 (br d, J= 6.0 Hz, 1H), 5.12 - 4.89 (m, 1H), 4.07 - 3.97 (m, 1H), 3.87 - 3.74 (m, 1H), 2.81 (s, 2H), 2.60 (d, J= 3.1 Hz, 1H), 2.58 - 2.50 (m, 1H), 2.08 (br dd, J= 6.3, 2.9 Hz, 3H), 1.39 (dd, J= 6.8, 3.9 Hz, 3H).

[0452] Step D: To a solution of 5-((. S)-2-(2-chlorophcnyl)pyrrolidin-l-yl)- '-((2 / ?. A')-4-(methylsulfmyl)but-3-en-2-yl)pyrazine-2 -carboxamide (250 mg, 0.597 mmol, 1.0 eq) in MeOH (6.0 mL, 0.1M) was added PhI(OAc)2 (577 mg, 1.79 mmol, 3.0 eq). The mixture was stirred at 25 °C for 5 min before ammonium carbamate (186 mg, 2.39 mmol, 4.0 eq) was added. The reaction was stirred at 25 °C for 1 h before being diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried overNa2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (30-80% EtOH in heptane) to give 5-((. S)-2-(2-chlorophcnyl)pyrrolidin-l-yl)-A-((2 / ?. A')-4-(rac-S'-mcthylsiilfonimidoyl)but-3-cn-2-yl)pyrazinc-2-carboxamidc (25 mg, 25% yield) as a white solid. Separation via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 20% MeOH / CCE; Rt = 10.9 min) provided the title compound. MS (ESI): mass calcd. for C20H24CIN5O2S, 433.1; m / z found, 434.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) δ 8.55 (br s, 1H), 8.48 (d, J= 8.7 Hz, IH), 7.96 - 7.58 (m, IH), 7.50 (d, J= 7.4 Hz, IH), 7.34 - 7.19 (m, 2H), 7.05 (d, J= 7.3 Hz, IH), 6.72 - 6.66 (m, IH), 6.62 (s, IH), 5.45 (br d, J= 7.5 Hz, IH), 4.81 - 4.73 (m, IH), 4.05 - 3.98 (m, IH), 3.79 (s, IH), 3.75 - 3.66 (m, IH), 2.88 (s, 3H), 2.44 (br s, IH), 2.13 - 2.01 (m, IH), 1.97 - 1.87 (m, 2H), 1.29 (d, J= 7.0 Hz, 3H).Example 28: 5-((iS)-2-(2-Chlorophenyl)pyrrolidin-l-yl)-A-((7?, E)-4-((*7?)-iS-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2-carboxamide.

[0453] The title compound was isolated from the separation of 5-((. S)-2-(2-chlorophcnyl)pyrrolidin-l-yl)- '-((2 / ? Ji)-4-(rac-S'-mcthylsiilfommidoyl)biit-3-cn-2-yl)pyrazinc-2-carboxamidc (Example 27, Step D) via SFC (Stationary phase: IH (3x25 cm); Mobile phase: 20% MeOH / CCE; Rt = 13.3 min). MS(ESI): mass calcd. for C20H24CIN5O2S, 433.1; m / z found, 434.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br s, 1H), 8.49 (br d, J= 8.5 Hz, IH), 7.93 - 7.56 (m, IH), 7.49 (d, J = 7.6 Hz, IH), 7.31 - 7.26 (m, IH), 7.25 - 7.20 (m, IH), 7.05 (d, J= 7.5 Hz, IH), 6.72 - 6.65 (m, IH), 6.63 - 6.58 (m, IH), 5.44 (br d, J= 7.5 Hz, IH), 4.83 - 4.74 (m, IH), 4.05 - 3.97 (m, IH), 3.81 (s, IH), 3.74 - 3.66 (m, IH), 2.88 (s, 3H), 2.43 (br s, IH), 2.11 -2.01 (m, IH), 1.97 - 1.84 (m, 2H), 1.29 (d, J= 6.9Hz, 3H).Scheme 19: Synthesis of 5-((17?,2iS,5A)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)- JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrimidine-2-carboxamide.Example 29: 5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrimidine-2-carboxamide.

[0454] Step A: Methyl 5-(( l / ?.2. S'.5. S)-2-(2-chloro-3-fluorophcnyl)-6.6-difliioro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate. To amixture ofrac-(l * / .2*S'.5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (Intermediate 12, 10 g, 40.4 mmol, 1.0 eq) in1,4-dioxane (200 mL, 0.2M) was added methyl 5-bromopyrimidine-2-carboxylate (13 g, 60.6 mmol, 1.5 eq), cesium carbonate (39 g, 121 mmol, 3.0 eq), and RuPhos Pd G4 (6.9 g, 8.08 mmol, 0.2 eq). The reaction was placed under N2 and stirred at 100 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (50-100%EtOAc in PE) to give methyl 5-(rac-(l*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate (9.8 g, 63% yield) as a yellow solid. Separation via SFC (Stationary phase: AD (25x5 cm); Mobile phase: 40% MeOH / CO₂; Rt = 3.82 min, first eluting product) afforded methyl 5-((l / ?.2. SA. S)-2-(2-chloro-3-fluorophcnyl)-6.6-difliioro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C17H13CIF3N3O2, 383.1; m / z found, 384.1 [M+H]+. 'HNMR (400 MHz, CDC13) 57.97 (s, 2H), 7.19 - 7.08 (m, 2H), 6.93 - 6.85 (m, 1H), 5.58 (dd, J= 5.9, 3.0 Hz, 1H), 4.34 (d, J = 9.9 Hz, 1H), 3.99 (s, 3H), 3.96 - 3.87 (m, 1H), 3.08 (ddd, J= 11.8, 9.8, 5.9 Hz, 1H), 2.62 (dt, J= 10.6, 6.3 Hz, 1H).

[0455] Step B: 5-((lA,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylic acid. Methyl 5-((l / ?.2. S'.5. S)-2-(2-chloro-3-fluorophcnyl)-6.6-difliioro-3-azabicyclo [3.1.0]hexan-3-yl)pyrimidine-2 -carboxylate (500 mg, 1.30 mmol, 1.0 eq) was taken up in MeOH (6.5 mL, 0.2M). To this was added LiOH (5.2 mL, 10.4 mmol, 8.0 eq, 2M in water) and the reaction was stirred at 60 °C for 3 h. After cooling to rt, the reaction was adjusted to pH~2 with IN HC1. The precipitated product was collected by filtration to provide 5-((l / ?.2. S'.5. S')-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2 -carboxylic acid (452 mg, 94% yield). MS (ESI): mass calcd. for C16H11CIF3N3O2, 369.1; m / z found, 370.0 [M+H]+.

[0456] Step C: 5-((lA,2S,55)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)- '-(( / ?)- 1-( 1.1 -dioxido-2 / / -thict-3- l)cth l)p rimidinc-2 -carboxamide. 5-((l / ?.2. S'.5. S')-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2 -carboxylic acid (20 mg, 0.054 mmol, 1.0 eq) and HATU (32 mg, 0.081 mmol, 1.5 eq) were taken up in DMF (0.14 mL, 0.2M). To this was added DIPEA (75 μL, 0.433 mmol, 8.0 eq) and the reaction was stirred at rt for 10 min. (R)-3-(l-Aminoethyl)-2H-thiete 1,1 -dioxide, TsOH (Intermediate 1, 19 mg, 0.060 mmol, 1.1 eq) was added and the reaction was stirred at rt for 2 h. The crude material was purified by RP-HPLC (5-95% ACN in 0.1% HCOOH water) to provide 5-((lA,2S,5S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicy clo [3.1,0|hcxan-3- l)- '-(( / ?)-l-( 1,1 -dioxido-2 / / -thict-3- l)cth l)pyri midinc-2 -carboxamide (25 mg, 91% yield) as a white solid. MS (ESI): mass calcd. for C21H18CIF3N4O3S, 498.1; m / z found, 499.0 [M+H]+. ’HNMR (400 MHz, CDCI3) 57.92 (s, 2H), 7.83 (d, J= 8.5 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.89 (td, J = 5.5, 2.2 Hz, 1H), 6.60 (d, J= 1.8 Hz, 1H), 5.58 (dd, J= 6.0, 2.9 Hz, 1H), 5.20 - 5.06 (m, 1H), 4.53 -4.41 (m, 2H), 4.35 (d, J= 9.9 Hz, 1H), 4.00 - 3.86 (m, 1H), 3.15 - 3.06 (m, 1H), 2.72 - 2.56 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H).Example 30: 5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?, Z)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2-carboxamide.

[0457] The title compound was prepared in a manner analogous to Example 29 using (R, Z)-4-methylsulfonyl)but-3-en-2 -amine (Intermediate 3) instead of ( / ?)-3-( l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C21H20CIF3N4O3S, 500.1; m / z found, 501.0 [M+H]+. 'HNMR (400 MHz, CDCh) 57.89 (s, 2H), 7.71 (d, J= 6.5 Hz, 1H), 7.18 - 7.06 (m, 2H), 6.91 - 6.83 (m, 1H), 6.29 (dd, J= 11.0, 1.0 Hz, 1H), 6.09 (dd, J= 11.0, 9.8 Hz, 1H), 5.59 - 5.49 (m, 2H), 4.32 (d, J= 9.8 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.32 (s, 3H), 3.14 - 3.03 (m, 1H), 2.66 - 2.55 (m, 1H), 1.42 (d, J= 6.8 Hz, 3H).Example 31: (E)-3-(l-(5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0458] The title compound was prepared in a manner analogous to Example 29 using (A')-3-(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?)-3-(l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C22H17ClF3N5O, 459.1; m / z found, 460.2 [M+H]+. 'HNMR (400 MHz, CDCh) 5 7.91 (s, 2H), 7.20 - 7.06 (m, 2H), 6.96 - 6.79 (m, 2H), 5.58 - 5.38 (m, 2H), 4.82 (dd, J= 10.6, 8.4 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.31 (d, J = 9.9Hz, 1H), 4.17 - 4.01 (m, 1H), 3.95 - 3.84 (m, 1H), 3.53 - 3.39 (m, 1H), 3.13 - 3.03 (m, 1H), 2.66 - 2.55 (m, 1H).Example 32: (Z)-3-(l-(5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0459] The title compound was prepared in a manner analogous to Example 29 using (Z)-3-(azetidin-3-yl)acrylonitrile (Intermediate 7) instead of ( / ?)-3-(l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. MS(ESI): mass calcd. for C22H17ClF3N5O, 459.1; m / z found, 460.0 [M+H]+. 'HNMR (400 MHz, CDC13) 5 7.90 (s, 2H), 7.16 - 7.08 (m, 2H), 6.86 (tt, J= 5.0, 2.2 Hz, 1H), 6.72 (ddd, J= 10.8, 9.8, 2.8 Hz, 1H), 5.51 (ddd, J= 5.1, 3.0, 1.6 Hz, 1H), 5.39 (ddd, J= 10.7, 2.1, 0.9 Hz, 1H), 4.88 (tdd, J= 8.5, 2.7, 1.4 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.43 (ddd, J= 9.9, 5.6, 3.9 Hz, 1H), 4.30 (d, J= 9.9 Hz, 1H), 4.09 - 4.01 (m, 1H), 3.92 - 3.77 (m, 2H), 3.07 (ddd, J= 11.9, 9.8, 5.9 Hz, 1H), 2.64 - 2.53 (m, 1H).Example 33: 5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0460] The title compound was prepared in a manner analogous to Example 29 using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C₂₁H₁₇ClF₃N₅O, 447.1; m / z found, 448.2 [M+H]+. 'H NMR (400 MHz, CDCh) 57.91 (s, 2H), 7.68 (d, J= 8.4 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.91 - 6.84 (m, 1H), 6.71 (dd, J = 16.4, 4.8 Hz, 1H), 5.55 (dd, J= 6.0, 3.0 Hz, 1H), 5.47 (dd, J= 16.4, 1.9 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.33 (d, J= 9.8 Hz, 1H), 3.96 - 3.86 (m, 1H), 3.13 - 3.03 (m, 1H), 2.67 - 2.55 (m, 1H), 1.37 (d, J= 7.1 Hz, 3H).Example 34: 5-((17?,25,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, E)-l-cyanopent-l-en-3-yl)pyrimidine-2-carboxamide.

[0461] The title compound was prepared in a manner analogous to Example 29 using (R, E)-4-aminohex-2-enenitrile (Intermediate 6) instead of ( / ?)-3-(l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C22H19CIF3N5O, 461.1; m / z found, 462.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 58.64 (d, J= 8.6 Hz, 1H), 7.93 (s, 2H), 7.49 - 7.22 (m, 2H), 6.96 - 6.83 (m, 2H), 5.78 - 5.53 (m, 2H), 4.49 (br dd, J= 7.9, 6.7 Hz, 1H), 4.36 (d, J= 10.3 Hz, 1H), 3.94 (br t, J= 7.7 Hz, 1H), 3.26 (ddd, J= 12.0, 10.5, 6.0 Hz, 1H), 2.92 (td, J= 11.3, 5.6 Hz, 1H), 1.69 - 1.53 (m, 2H), 0.83 (t, J= 7.4 Hz, 3H).Example 35: 5-((17?,25,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, Z)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0462] The title compound was prepared in a manner analogous to Example 29 using ( / ?. Z)-4-aminopent-2-enenitrile (Intermediate 5) instead of ( / ?)-3-( l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C.MS (ESI): mass calcd. for C₂₁H₁₇ClF₃N₅O, 447.1; m / z found, 448.0 [M+H]+. 'H NMR (400 MHz, CDCh) 57.90 (s, 3H), 7.19 - 7.06 (m, 2H), 6.88 (td, J= 5.5, 3.4 Hz, 1H), 6.52 (dd, J= 11.3, 7.1 Hz, 1H), 5.52 (dd, J = 5.9, 2.9 Hz, 1H), 5.37 (dd, J= 11.3, 1.2 Hz, 1H), 5.03 - 4.90 (m, 1H), 4.31 (d, J= 9.8 Hz, 1H), 3.96 - 3.84 (m, 1H), 3.13 - 3.02 (m, 1H), 2.66 - 2.53 (m, 1H), 1.45 (d, J= 7.0 Hz, 3H).Example 36: 5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, E)-5-(3,3-difluoroazetidin-l-yl)-5-oxopent-3-en-2-yl)pyrimidine-2-carboxamide.

[0463] The title compound was prepared in a manner analogous to Example 29 using ( / . A')-4-amino-l-(3,3-difluoroazetidin-l-yl)pent-2-en-l-one (Intermediate 9) instead of ( / ?)-3-( l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C24H21CIF5N5O2, 541.1; m / z found, 542.2 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 58.64 (d, J= 8.6 Hz, 1H), 7.92 (s, 2H), 7.44 - 7.36 (m, 1H), 7.29 (dt, J = 8.0, 5.6 Hz, 1H), 6.95 - 6.85 (m, 1H), 6.74 (dd, J= 15.4, 6.3 Hz, 1H), 6.03 (dd, J= 15.4, 1.3 Hz, 1H), 5.61 (dd, J= 5.8, 2.4 Hz, 1H), 4.78 - 4.53 (m, 3H), 4.41 - 4.20 (m, 3H), 4.02 - 3.89 (m, 1H), 3.25 (ddd, J = 12.0, 10.3, 6.0 Hz, 1H), 2.91 (dt, J= 11.1, 6.3 Hz, 1H), 1.25 (d, J= 6.9 Hz, 3H).Example 37: 5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((E)-4-(3,3-difluoroazetidin-l-yl)-4-oxobut-2-en-l-yl)pyrimidine-2-carboxamide.

[0464] The title compound was prepared in a manner analogous to Example 29 using (A')-4-amino- 1 -(3,3-difluoroazetidin-l-yl)but-2-en-l-one (Intermediate 10) instead of ( / ?)-3-( l-aminocth l)-2 / / -thictc 1,1-dioxide in Step C. MS (ESI): mass calcd. for C23H19CIF5N5O2, 527.1; m / z found, 528.0 [M+H]+. ’H NMR (400 MHz, CDCh) 57.91 (d, J= 3.4 Hz, 3H), 7.19 - 7.09 (m, 2H), 6.96 - 6.84 (m, 2H), 5.99 (dt, J = 15.3, 1.7 Hz, 1H), 5.54 (dd, J= 6.0, 3.0 Hz, 1H), 4.63 - 4.15 (m, 7H), 3.96 - 3.87 (m, 1H), 3.15 - 3.02 (m, 1H), 2.67 - 2.54 (m, 1H).Example 38: 5-((l*7?,2*7?,5*iS,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0465] The title compound was prepared in a manner analogous to Example 29 using rac-(l*5,2*S,5*R,6*S)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 24) instead of rac-(l * / ?.2*S 5*S)-2-(2-chloro-3-fliiorophcnyl)-6.6-difliioro-3-azabicyclo[3.1.0]hexane in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of ( / ?)-3-(l-aminocthyl)-2 / / -thictc 1,1-dioxide in Step C. Separation of 5-(rac-(l*R,2*R,5*S,6*R)-2-(2-chloro-3 -fhrorophenyl)-6-(fIuoromethyl)-3 -azabicyclo [3.1,0]hexan-3 -yl)-A-((R, E)-4-cyanobut-3 -en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 50% iPrOH / CO2; Rt = 8.90 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H20CIF2N5O, 443.1; m / z found, 444.0 [M+H]+. ’H NMR (400 MHz, DMSO-6) 58.66 (d, J= 8.4 Hz, 1H), 7.86 (s, 2H), 7.41 - 7.34 (m, 1H), 7.33 - 7.26 (m, 1H), 6.96 - 6.84 (m, 2H), 5.68 (dd, J= 16.4, 1.5 Hz, 1H), 5.37 (br d, J= 3.8 Hz, 1H), 4.73 - 4.61 (m, 1H), 4.35 - 4.02 (m, 3H), 3.72 - 3.64 (m, 1H), 2.41 - 2.35 (m, 1H), 2.08 (td, J= 7.6, 3.8 Hz, 1H), 1.24 (d, J= 6.9Hz, 4H).Example 39: (E)-3-(l-(5-((l*7?,2*7?,5*iS,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0466] The title compound was prepared in a manner analogous to Example 38 using (A')-3-(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?. A')-4-aminopcnt-2-cncnitrilc in Step C. Separation of methyl 5-(rac-(l*S,2*S,5*R,6*S)-2-(2-chloro-3-fhrorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate (Step A) via SFC (Stationary phase: OJ (3x25 cm); Mobile phase: 40% MeOH / CO₂; Rt = 6.22 min, second eluting product) provided methyl 5-((l*R,2*R,5*S,6*R)-2-(2-chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxylate, which was elaborated to the title compound in a manner analogous to Example 38, Steps B-C. MS (ESI): mass calcd. for C23H20CIF2N5O, 455.1; m / z found, 456.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 57.85 (s, 2H), 7.43 - 7.25 (m, 2H), 7.10 (dd, J= 16.4, 8.0 Hz, 1H), 6.88 (d, J= 7.6Hz, 1H), 5.83 (d, J= 16.3 Hz, 1H), 5.35 (br d, J= 4.4 Hz, 1H), 4.58 (t, J =9.3 Hz, 1H), 4.33 -4.02 (m, 5H), 3.90 (ddd, J = 9.9, 5.9, 3.8 Hz, 1H), 3.66 (ddd, J= 12, 5.0, 2.6 Hz, 1H), 3.56 - 3.43 (m, 1H), 2.42 - 2.35 (m, 1H), 2.11 - 2.03 (m, 1H), 1.21 (br dd, J= 7.3, 3.0 Hz, 1H).Example 40: A-((7?, E)-4-Cyanobut-3-en-2-yl)-5-((l*iS,2*iS,5* / ?,6*A)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carboxamide.

[0467] The title compound was prepared in a manner analogous to Example 38 using rac-(l*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (Intermediate 23) instead of rac-(l*R,2*S,5*S)-2-(2-chloro-3-fhiorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of (R)-3-(l-aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation ofA-(( / ?. A')-4-cyanobut-3-cn-2-yl)-5-(rac-(l*S,2*S,5*R,6*S)-2-(3-fhioro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2 -carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% MeOH / CO₂; Rt = 3.14 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H23F2N5O, 423.2; m / z found, 424.2 [M+H]+. ’H NMR (400 MHz, DMSO-6) 58.63 (br d, J= 8.4 Hz, 1H), 7.86 (s, 2H), 7.26 - 7.03 (m, 2H), 6.93 - 6.83 (m, 1H), 6.72 (br d, J = 7.3 Hz, 1H), 5.80 - 5.65 (m, 1H), 5.28 (br d, J= 2.9 Hz, 1H), 4.77 - 4.55 (m, 1H), 4.31 -4.01 (m, 3H), 3.65 (dt, J = 4.8, 3.0 Hz, 1H), 2.41 (s, 3H), 2.36 (br dd, J = 7.6, 4.1 Hz, 1H), 2.15 - 2.02 (m, 1H), 1.24 (br d, J = 7.0 Hz, 4H). Example 41: 5-((l*7?,2*7?,5*iS,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0468] The title compound was prepared in a manner analogous to Example 29 using rac-(l*S,2*S,5*J?,6*S)-2-(2-chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexane (Intermediate 19) instead of rac-(l*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane in Step A and using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of (R)-3-(l-aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation of 5-(rac-( l* / ?.2* / ?.5*. S'.6* / ?)-2-(2-chloro-3-fluorophcnyl)-6-mcthyl-3-azabicyclo[3.1.0]hexan-3-yl)-A-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 50% EtOH / CO₂; Rt = 8.32 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C22H21CIFN5O, 425.1; m / z found, 426.1 [M+H]+.1HNMR (400 MHz, DMSO-d6) 58.65 (d, J= 8.4 Hz, 1H), 7.83 (s, 2H), 7.41 - 7.21 (m, 2H), 6.95 - 6.78 (m, 2H), 5.68 (dd, J= 16.5, 1.4 Hz, 1H), 5.31 (d, J= 5.1 Hz, 1H), 4.75 - 4.58 (m, 1H), 4.08 (d, J= 9.6 Hz, 1H), 3.63 (dd, J = 9.6, 5.3 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.80 - 1.69 (m, 1H), 1.24 (d, J= 7.0 Hz, 3H), 0.87 (d, J= 5.9 Hz, 3H), 0.75 (br d, J= 2.9 Hz, 1H).Example 42: (£)-3-(l-(5-((l*7?,2*7?,5*5,6*7?)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile.

[0469] The title compound was prepared in a manner analogous to Example 41 using (A)-3-(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?. A)-4-aminopcnt-2-cncnitrilc in Step C. Separation of (E)-3-(l-(5-(rac-(l*R,2*R,5*S,6*R)-2-(2-chloro-3-fhrorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile (Step C) via SFC (Stationary phase: WHELK-01 (3x25 cm); Mobile phase: 65% iPrOH / ACN (1: 1) / CO2; Rt = 5.97 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H21CIFN5O, 437.1; m / z found, 438.0 [M+H]+. ’H NMR (400 MHz, DMSO-6) 57.82 (s, 2H), 7.39 - 7.33 (m, 1H), 7.28 (dt, J= 8.0, 5.6 Hz, 1H), 7.10 (ddd, J= 16.3, 8.0, 1.0 Hz, 1H), 6.81 (d, J= 7.7 Hz, 1H), 5.83 (dd, J= 16.3, 0.8 Hz, 1H), 5.28 (d, J= 5.3 Hz, 1H), 4.57 (t, J= 9.2 Hz, 1H), 4.28 (td, J= 10.0, 6.4 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.05 (d, J= 9.7 Hz, 1H), 3.89 (ddd, J= 10.0, 5.9, 3.7 Hz, 1H), 3.62 (dd, J= 9.6, 5.3 Hz, 1H), 3.54 - 3.43 (m, 1H), 2.05 (ddd, J= 7.3, 5.1, 3.5 Hz, 1H), 1.76 - 1.70 (m, 1H), 0.86 (d, J = 6.0 Hz, 3H), 0.75 - 0.66 (m, 1H).Example 43: 5-((15, 25,57?, 65)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-W-((7?,£)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0470] The title compound was prepared in a manner analogous to Example 29 using rac-((l*S,2*S,5*A,6*S)-2-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 27) instead of rac-( I * / ?.2*S\5*S')-2-(2-chloro-3-f'liiorophcnyl)-6.6-difliioro-3-azabicyclo|3. 1,0|hcxanc in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of (A)-3-( 1 -aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation of 5-(rac-(l*S,2*S,5*A,6*S)-2-(2-chloro-3-fluorophenyl)-6-cyano-3 -azabicyclo [3.1.0]hexan-3-yl)-A-((A, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide (Step C) via SFC (Stationary phase: OD (3x25 cm); Mobile phase: 50% iPrOH / CO₂; Rt = 13.2 min, second eluting product) provided the title compound. Absolute stereochemistry was determined by single crystal x-ray structure. MS (ESI): mass calcd. for C22H18CIFN6O, 436.1; m / z found, 437.2 [M+H]+. ’HNMR (400 MHz, DMSO-d6) 58.68 (d, J= 8.4 Hz, 1H), 7.88 (s, 2H), 7.47 - 7.40 (m, 1H), 7.33 (dt, J= 7.9, 5.8 Hz, 1H), 6.96 (d, J= 7.8 Hz, 1H), 6.90 (dd, J= 16.4, 5.3 Hz, 1H), 5.68 (dd, J= 16.4, 1.4 Hz, 1H), 5.44 (d, J= 4.5 Hz, 1H), 4.75 - 4.57 (m, 1H), 4.25 (d, J= 10.1 Hz, 1H), 3.67 (dd, J= 10.1, 4.7 Hz, 1H), 3.03 (td, J= 7.7, 4.0 Hz, 1H), 2.79 (td, J= 7.6, 3.9 Hz, 1H), 1.87 (t, J= 3.5 Hz, 1H), 1.24 (d, J= 6.9 Hz, 3H).Example 44: (l*5,2*iS,5*7?,6*iS)-2-(2-Chloro-3-fluorophenyl)-3-(2-(3-((E)-2-cyanovinyl)azetidine-l-carbonyl)pyrimidin-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile.

[0471] The title compound was prepared in a manner analogous to Example 29 using (A')-3-(azctidin-3-yl)acrylonitrile (Intermediate 8) instead of ( / ?. A')-4-aminopcnt-2-cncnitrilc in Step C. Separation of rac-(l*S,2*S,5*A,6*S)-2-(2-chloro-3-fluorophenyl)-3-(2-(3-((E)-2-cyanovinyl)azetidine-l-carbonyl)pyrimidin-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 55% iPrOH / CO₂ with 0.1% isopropylamine; Rt = 5.06 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H18CIFN6O, 448.1; m / z found, 449.0 [M+H]+. ’H NMR (400 MHz, DMSO-6) 57.87 (s, 2H), 7.47 - 7.40 (m, 1H), 7.37 - 7.29 (m, 1H), 7.10 (dd, J= 16.5, 8.3 Hz, 1H), 6.93 (br d, J= 7.9 Hz, 1H), 5.84 (d, J= 16.3 Hz, 1H), 5.42 (d, J = 4.5 Hz, 1H), 4.57 (br t, J= 9.0 Hz, 1H), 4.32 - 4.14 (m, 3H), 3.95 - 3.85 (m, 1H), 3.65 (dd, J= 10.1, 4.5 Hz, 1H), 3.56 - 3.43 (m, 1H), 3.03 (td, J= 7.8, 4.0 Hz, 1H), 2.78 (td, J= 7.6, 4.0 Hz, 1H), 1.82 (br s, 1H).Example 45: 5-((l *S,2 *S,5 *R,6 *A)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3- azabicyclo [3.1.0] hexan-3-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0472] The title compound was prepared in a manner analogous to Example 29 using rac-((l*S,2*S,5*A,6*S)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 29) instead of rac-(l*A,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of (A)-3-( 1 -aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation of 5-(rac-(l*S,2*S,5*A,6*S)-6-cyano-2-(3-fluoro-2-mcthylphcnyl)-3-azabicyclo|3.1.0|hcxan-3-yl)-A-(( / ?. A')-4-cyanobiit-3-cn-2-yl)pyrimidinc-2-carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH / CO₂; Rt = 3.63 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H21FN6O, 416.2; m / z found, 417.2 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.65 (d, J= 8.4 Hz, 1H), 7.88 (s, 2H), 7.20 - 7.08 (m, 2H), 6.90 (dd, J= 16.5, 5.4 Hz, 1H), 6.84 - 6.76 (m, 1H), 5.67 (dd, J= 16.4, 1.7 Hz, 1H), 5.32 (d, J=4.5 Hz, 1H), 4.66 (dq, J=6.9, 1.6 Hz, 1H), 4.30 - 4.18 (m, 1H), 3.63 (dd, J= 10.2, 4.7 Hz, 1H), 3.08 (td, J = 7.8, 4.0 Hz, 1H), 2.75 (td, J= 7.6, 3.9 Hz, 1H), 2.45 (d, J= 1.5 Hz, 3H), 1.83 (t, J = 3.5 Hz, 1H), 1.24 (d, J= 7.0 Hz, 3H).Example 46: 5-((l*iS,2*iS,5*7?,6*A)-6-Cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0473] The title compound was prepared in a manner analogous to Example 29 using rac-((l*S,2*S,5*A,6*S)-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Intermediate 28) instead of rac-(l*A,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of (A)-3-(l-aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation of 5-(rac-(l*S,2*S,5*A,6*S)-6-cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((A, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide (Step C) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% iPrOH / CO₂; Rt = 5.81 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H18F2N6O, 420.1; m / z found, 421.0[M+H]+. 'HNMR (400 MHz, DMSO-6) 58.67 (d, J= 8.4 Hz, 1H), 7.98 (s, 2H), 7.49 - 7.37 (m, 1H), 7.20 - 7.10 (m, 1H), 6.96 - 6.80 (m, 2H), 5.69 (dd, J= 16.4, 1.7 Hz, 1H), 5.43 (d, J= 4.5 Hz, 1H), 4.72 -4.60 (m, 1H), 4.22 (d, J= 10.3 Hz, 1H), 3.65 (dd, J= 10.2, 4.7 Hz, 1H), 3.08 - 2.97 (m, 1H), 2.78 (td, J= 7.5, 4.0 Hz, 1H), 1.83 (t, J= 3.5 Hz, 1H), 1.25 (d, J = 7.0 Hz, 3H).Example 47: 5-((l*iS,2*iS,5*7?,6*A)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?, E)-4-cyanobut-3-en-2-yl)-4-methylpyrimidine-2-carboxamide.

[0474] The title compound was prepared in a manner analogous to Example 45 using methyl 5-bromo-4-methyl -2 -pyrimidinecarboxylate instead of methyl 5 -bromopyrimidine-2 -carboxylate and Pd-PEPPSI IHept-Cl instead of RuPhos Pd G4 in Step A. Separation of 5-(rac-(l*S,2*S,5*R,6*S)-6-cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0 |hcxan-3-yl)-A-(( / ?. A')-4-cyanobut-3-cn-2-yl)-4-methylpyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 20% iPrOH / CO₂; Rt = 4.71 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C24H23FN6O, 430.2; m / z found, 431.0 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.71 (br d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.12 - 7.00 (m, 2H), 6.97 - 6.82 (m, 2H), 5.69 (dd, J= 16.4, 1.7 Hz, 1H), 5.38 (br d, J= 3.6 Hz, 1H), 4.73 - 4.58 (m, 1H), 4.07 (d, J= 9.9 Hz, 1H), 3.09 (br dd, J= 9.7, 3.4 Hz, 1H), 2.88 (td, J= 12, 3.5 Hz, 1H), 2.64 - 2.56 (m, 4H), 2.46 (d, J= 1.3 Hz, 3H), 2.34 (brt, J= 3.1 Hz, 1H), 1.23 (d, J = 7.0 Hz, 3H).Example 48: 5-((l*7?,4*iS,5*7?)-4-(2-Chloro-3-fluorophenyl)-l-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-A-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0475] The title compound was prepared in a manner analogous to Example 29 using rac-(l*R,4*S,5*R)-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-l-carbonitrile (Intermediate 17) instead of rac-(l*R,2*S,5*S)-2-(2-chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane in Step A and using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of (R)-3-( 1 -aminoethyl)-2H-thiete 1,1-dioxide in Step C. Separation of 5-(rac-(l* / ?.4*. S'.5* / ?)-4-(2-chloro-3-fluorophcnyl)-l-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-A-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide (Step C) viaSFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH / CO₂; Rt = 5.62 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C22H18CIFN6O, 436.1; m / z found, 437.0 [M+H]+. ’H NMR (400 MHz, DMSO-6) 58.72 (d, J= 8.3 Hz, 1H), 7.90 (s, 2H), 7.46 - 7.37 (m, 1H), 7.31 (dt, J= 8.0, 5.6 Hz, 1H), 6.95 (br d, J= 8.0 Hz, 1H), 6.90 (dd, J= 16.5, 5.4 Hz, 1H), 5.69 (dd, J= 16.4, 1.6 Hz, 1H), 5.54 (d, J= 4.9 Hz, 1H), 4.76 - 4.60 (m, 1H), 4.44 (d, J = 9.3 Hz, 1H), 3.85 (d, J= 9.4 Hz, IH), 3.09 (td, J= 8.8, 5.0 Hz, 1H), 1.46 (dd, J= 8.6, 5.6 Hz, 1H), 1.24 (d, J = 6.9 Hz, 4H). Example 49: 5-((*iS)-3-(2-Chloro-3-fluorophenyl)morpholino)-A-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0476] The title compound was prepared in a manner analogous to Example 29 using 3-(2-chloro-3-fluorophenyl)morpholine instead of rac-(l * / ?.2*S'.5*S')-2-(2-chloro-3-fliiorophcnyl)-6.6-difliioro-3-azabicyclo[3.1.0]hexane in Step A and using ( / ?. A')-4-aminopcnt-2-cncnitrilc (Intermediate 4) instead of (R)-3-(l-aminoethyl)-2H-thiete 1,1 -dioxide in Step C. Separation of 5-(3-(2-chloro-3-fluorophenyl)morpholino)-A-((A, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide (Step C) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 40% iPrOH / CO₂ with 0.1% NH4OH; Rt = 4.80 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C20H19CIFN5O2, 415.1; m / z found, 416.0 [M+H]+.1H NMR (400 MHz, DMSO-6) 58.76 (d, J= 8.3 Hz, 1H), 8.33 (s, 2H), 7.39 -7.26 (m, 2H), 7.25 - 7.20 (m, 1H), 6.91 (dd, J= 16.4, 5.4 Hz, 1H), 5.70 (dd, J= 16.4, 1.6 Hz, 1H), 5.17 (t, J= 4.2 Hz, 1H), 4.77 - 4.60 (m, 1H), 4.14 - 4.02 (m, 2H), 3.94 - 3.77 (m, 3H), 3.69 - 3.57 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H).Example 50: 5-((17?,2iS,5iS)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-A-((?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0477] The title compound was prepared in a manner analogous to Example 29 using ( I. S',4. S'.5 / ?)-4-(2-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Intermediate 16) instead of rac-(l * / .2*S'.5*S)-2-(2-chloro-3-fIuorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane and Pd2(dba)3 / XantPhos instead of RuPhos Pd G4 in Step A and using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of (R)-3-(l-aminoethyl) -2H-thiete 1,1-dioxide in Step C. MS (ESI): mass calcd. for C21H17CIFN5O2, 425.1; m / z found, 426.2 [M+H]+. ’H NMR (400 MHz, DMSO-6) 58.94 (d, J= 8.3 Hz, 1H), 8.75 (s, 2H), 7.40 -7.29 (m, 1H), 7.21 (dt, J= 8.1, 5.6 Hz, 1H), 6.98 - 6.80 (m, 2H), 6.20 (d, J= 6.1 Hz, 1H), 5.73 (dd, J = 16.4, 1.7 Hz, 1H), 4.76 - 4.61 (m, 1H), 2.70 - 2.62 (m, 1H), 2.31 (ddd, J= 8.4, 6.1, 3.7 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H), 1.08 - 0.99 (m, 2H).Scheme 20: Synthesis of 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)-JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.Example 51: 5-((* / ?)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)-JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0478] Step A: 2-(2-Chloro-3-fluorophenyl)pyrazine. To a solution of 2-chloropyrazine (2.0 g, 17.5 mmol, 1.0 eq) in 1,4-dioxane / water (v / v 10:1, 22 mL, 0.8M) was added (2-chloro-3-fhrorophenyl)boronic acid (3.0 g, 17.5 mmol, 1.0 eq), potassium carbonate (6.0 g, 43.7 mmol, 2.5 eq) and Pd(dppf)C12 (632 mg, 0.873 mmol, 0.05 eq). The reaction was placed under N2 and stirred at 100 °C for 16 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (15-25% EtOAc in PE) to give 2-(2-chloro-3-fluorophenyl)pyrazine (2.2 g, 60% yield) as a yellow solid. MS (ESI): mass calcd. for C10H6CIFN2, 208.0; m / z found, 209.0 [M+H]+. ’HNMR (400 MHz, CDCh) 58.89 (d, J= 1.5 Hz, 1H), 8.64 (dd, J= 2.4, 1.6 Hz, 1H), 8.54 (d, J= 2.5 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.22 - 7.17 (m, 1H).

[0479] Step B: 2-(2-Chloro-3-fluorophenyl)piperazine. To a solution of 2-(2-chloro-3-fluorophenyl)pyrazine (2.0 g, 9.59 mmol, 1.0 eq) in toluene (30 mL, 0.3M) was added / V-phenylaniline (3.2 g, 19.2 mmol, 2.0 eq) and pinacolborane (6.1 g, 47.9 mmol, 5.0 eq). The mixture was placed under N2 before tris(2,3,4,5,6-pentafluorophenyl)borane (491 mg, 0.959 mmol, 0.1 eq) was added. The reaction was stirred at 110 °C for 6 h. After cooling to rt, the mixture was quenched with MeOH and stirred for 30 min. After concentrating under reduced pressure, 2-(2-chloro-3-fluorophenyl)piperazine (2.0 g, 97% yield) was obtained as a yellow solid, which was used directly without further purification. MS (ESI): mass calcd. for C10H12CIFN2, 214.1; m / z found, 214.9 [M+H]+.

[0480] Step C: tert-Butyl 3 -(2 -chloro-3-fluorophenyl)piperazine-l -carboxylate. To a solution of 2-(2-chloro-3-fluorophenyl)piperazine (2.0 g, 9.32 mmol, 1.0 eq) in DCM (50 mL, 0.2M) was added DIPEA (3.6 g, 28.0 mmol, 3.0 eq) and BOC2O (1.8 g, 8.39 mmol, 0.9 eq). The reaction was stirred at 25 °C for 16 h before being poured into water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by FCC (30-60% EtOAc in PE) to give tert-butyl 3 -(2-chloro-3-fluorophenyl)piperazine-l -carboxylate (3.0 g, 92% yield) as a yellow oil. MS (ESI): mass calcd. for C15H20CIFN2O2, 314.1; m / z found, 315.1 [M+H]+. ’HNMR (400 MHz, CDCh) 57.44 (brd, J= 7.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.09 (dt, J= 8.5, 1.3 Hz, 1H), 4.30 - 3.97 (m, 3H), 3.09 (br d, J= 6.0 Hz, 1H), 3.02 - 2.83 (m, 2H), 2.63 (dd, J= 12.6, 10.0 Hz, 1H), 1.48 (s, 9H).

[0481] Step D: Methyl 5-(4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-l-yl)pyrazine-2 -carboxylate. To a mixture of tert-butyl 3-(2-chloro-3-fluorophenyl)piperazine-l-carboxylate (3.2 g, 10.1 mmol, 1.0 eq) in DMSO (35 mL, 0.3M) was added methyl 5-fluoro-2-pyrazinecarboxylate (1.9 g, 12.1 mmol, 1.2 eq) and TEA (3.1 g, 30.3 mmol, 3.0 eq). The mixture was placed under N2 and stirred at 100 °C for 16 h. After cooling to rt, the residue was purified by FCC (50-100% EtOAc in PE) to give methyl 5-(4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)piperazin-l-yl)pyrazine-2-carboxylate (3.7 g, 81% yield) as a pale yellow solid. MS (ESI): mass calcd. for C21H24CIFN4O4, 450.2; m / z found, 451.1 [M+H]+. ’H NMR (400 MHz, CDCh) 58.82 (d, J= 1.1 Hz, 1H), 7.77 (br s, 1H), 7.20 - 7.08 (m, 2H), 7.05 - 6.92 (m, 1H), 5.52 - 5.42 (m, 1H), 4.74 - 4.36 (m, 1H), 4.16 (br s, 1H), 4.01 - 3.91 (m, 5H), 3.88 - 3.73 (m, 1H), 3.66 - 3.52 (m, 1H), 1.41 - 1.14 (m, 9H).

[0482] Step E: Methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-l-yl)pyrazine-2-carboxylate. Methyl 5 -(4-(tert-butoxycarbony 1 )-2-(2-ch lo ro-3 -fluorophenyl)piperazin- 1 -yl)pyrazine-2-carboxylate ( 1.5 g, 3.33 mmol, 1.0 eq) was taken up in DCM / TFA (v / v 3: 1, 20 mL, 0.2M). The reaction was stirred at 20 °C for 2 h before being concentrated under reduced pressure to provide methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-l-yl)pyrazine-2 -carboxylate (1.1 g, 94% yield) as a yellow oil, which was used directly without further purification. MS (ESI): mass calcd. for C16H16CIFN4O2, 350.1; m / z found, 351.1 [M+H]+.

[0483] Step F: Methyl 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)pyrazine-2-carboxylate. To a solution of methyl 5-(2-(2-chloro-3-fluorophenyl)piperazin-l-yl)pyrazine-2-carboxylate (500 mg, 1.43 mmol, 1.0 eq) in MeOH / THF (v / v 1:1, 10 mL, 0.14M) was added (1-ethoxycyclopropoxy)trimethylsilane (497 mg, 2.85 mmol, 2.0 eq) and acetic acid (257 mg, 4.28 mmol, 3.0 eq). Sodium cyanoborohydride (134 mg, 2.14 mmol, 1.5 eq) was added in portions at 25 °C. The reaction was stirred for 16 h at 60 °C. After cooling to rt, the mixture was concentrated under vacuum then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by FCC (30-50% EtOAc in PE) to give methyl 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)pyrazine-2 -carboxylate (220 mg, 39% yield) as a pale yellow oil. MS (ESI): mass calcd. forC19H20ClFN4O2, 390.1; m / z found, 391.1 [M+H]+. ’H NMR (400 MHz, CDC13) 58.81 (d, J = 0.9 Hz, 1H), 8.00 (d, J= 0.9 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.13 - 7.00 (m, 2H), 5.68 (dd, J= 4.8, 2.2 Hz, 1H), 4.39 - 4.28 (m, 1H), 3.93 (s, 3H), 3.66 - 3.52 (m, 1H), 3.27 - 3.13 (m, 2H), 2.94 (dd, J= 12.1, 5.1 Hz, 1H), 2.63 (dt, J= 11.4, 4.2 Hz, 1H), 1.74 - 1.64 (m, 1H), 0.54 - 0.36 (m, 3H), 0.17 (dt, J= 5.9, 3.5 Hz, 1H).

[0484] Step G: 5-(2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)pyrazine-2-carboxylic acid. To a solution of methyl 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)pyrazine-2-carboxylate (220 mg, 0.563 mmol, 1.0 eq) in THF / water (v / v 3:1, 4.0 mL, 0.14M) was added LiOH. H2O (71 mg, 1.69 mmol, 3.0 eq). The reaction was stirred at 25 °C for 2 h. The mixture was adjusted to pH 4-5 with 2N HC1 and concentrated under vacuum to give 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)pyrazine-2 -carboxylic acid (210 mg, quant, yield) as a white solid. This was used in the next step without further purification. MS (ESI): mass calcd. for C18H18ClFN4O2, 376.1; m / z found, 377.1 [M+H]+.

[0485] Step H: 5-((* / ?)-2-(2-Chloro-3-fliiorophcnyl)-4-cyclopropylpipcrazin-l-yl)-A-(( / ?)-l-( 1.1-dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide. To a solution of 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)pyrazine-2 -carboxylic acid (210 mg, 0.557 mmol, 1.0 eq) in DMF (3.0 mL, 0.2M) was added DIPEA (0.3 mL, 1.67 mmol, 3.0 eq), HATU (318 mg, 0.836 mmol, 1.5 eq), and (R)-3-( l-aminocthyl)-2 / / -thictc 1,1-dioxide (Intermediate 1, 123 mg, 0.669 mmol, 1.2 eq). The reaction was stirred at 20 °C for 2 h before being diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by RP-HPLC (47-77% ACN in 10 mM aq. NH4HCO3) to afford 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin- 1 -y I )- A-(( / ?)- 1 -( 1, 1 -dioxido-2H-th iet-3 -yl)ethyl)pyrazine-2-carboxamide (168 mg, 59% yield) as a pale yellow solid. Separation via SFC (Stationary phase: IM (3x25 cm); Mobile phase: 60% iPrOH / CO2; Rt = 10.8 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H25CIFN5O3S, 505.1; m / z found, 506.0 [M+H]+. ’HNMR (400 MHz, DMSO-d6) 58.82 (d, J= 8.4 Hz, 1H), 8.61 (s, 1H), 8.17 (s, 1H), 7.36 - 7.19 (m, 3H), 6.93 (d, J= 1.4 Hz, 1H), 5.82 (br d, J= 3.1 Hz, 1H), 4.94 (q, J= 7.3 Hz, 1H), 4.51 (s, 2H), 4.30 (br d, J= 12.0 Hz, 1H), 3.49 (dt, J= 12.4, 4.0 Hz, 1H), 3.23 (brd, J= 12.1 Hz, 1H), 3.10 (br d, J= 10.1 Hz, 1H), 2.87 (dd, J= 12.0, 4.9 Hz, 1H), 2.55 (br d, J= 3.9 Hz, 1H), 1.74 - 1.66 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H), 0.49 - 0.33 (m, 3H), 0.07 (br dd, J= 8.4, 3.6 Hz, 1H).Example 52: 5-((*7?)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)-A-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0486] The title compound was prepared in a manner analogous to Example 51 using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1 -dioxide in Step H. Separation of 5-(2-(2-chloro-3-fhiorophcnyl)-4-cyclopropylpipcrazin-l-yl)-A-(( / ?. A')-4-cyanobiit-3-cn-2-yl)pyrazine-2 -carboxamide (Step H) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 53% ACN / CO2; Rt = 9.25 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H24CIFN6O, 454.2; m / z found, 455.0 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.60 (d, J= 1.1 Hz, 1H), 8.58 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 1.0 Hz, 1H), 7.33 - 7.22 (m, 3H), 6.92 (dd, J= 16.4, 5.3 Hz, 1H), 5.82 (brd, J= 3.1 Hz, 1H), 5.69 (dd, J= 16.4, 1.7 Hz, 1H), 4.71 (dq, J= 6.9, 1.5 Hz, 1H), 4.30 (br d, J = 12.0 Hz, 1H), 3.56 - 3.44 (m, 1H), 3.23 (br d, J= 12.0 Hz, 1H), 3.10 (br d, J= 11.4 Hz, 1H), 2.87 (dd, J= 12.1, 4.9 Hz, 1H), 2.56 - 2.52 (m, 1H), 1.69 (td, J = 6.5, 3.1 Hz, 1H), 1.27 (d, J= 7.0 Hz, 3H), 0.51 - 0.32 (m, 3H), 0.11 - 0.03 (m, 1H).Example 53: 5-((* / ?)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)- / V-(( / ?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrimidine-2-carboxamide.

[0487] The title compound was prepared in a manner analogous to Example 51 using the conditions of Example 29, Step A in place of Step D. Separation of 5-(2-(2-chloro-3-fluorophenyl)-4-cyclopropylpiperazin- 1 -y I )-A-(( / ?)- 1 -( 1, 1 -dioxido-2H-th iet-3 -yl)ethyl)pyrimidine-2-carboxamide (Step H) via SFC (Stationary phase: IM (3x25 cm); Mobile phase: 60% iPrOH / CO₂; Rt = 11.2 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H25CIFN5O3S, 505.1; m / z found, 506.0 [M+H]+.1H NMR (400 MHz, DMSO-6) 59.01 (d, J= 8.4 Hz, 1H), 8.34 (s, 2H), 7.42 -7.14 (m, 3H), 6.93 (d, J= 1.8 Hz, 1H), 5.20 (t, J= 4.6 Hz, 1H), 4.91 (br t, J= 7.0 Hz, 1H), 4.50 (s, 2H), 3.74 - 3.60 (m, 2H), 2.99 (br dd, J= 11.7, 4.3 Hz, 2H), 2.84 (br dd, J= 11.8, 4.8 Hz, 1H), 2.75 (ddd, J = 11.4, 7.4, 4.5 Hz, 1H), 1.73 (tt, J= 6.4, 3.4 Hz, 1H), 1.34 (d, J= 7.0 Hz, 3H), 0.51 - 0.29 (m, 3H), 0.20 -0.04 (m, 1H).Example 54: 5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide.

[0488] The title compound was prepared in a manner analogous to Example 53 using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1 -dioxide in Step H. Separation of 5-(2-(2-chloro-3-fhiorophcnyl)-4-cyclopropylpipcrazin-l-yl)- '-(( / . A')-4-cyanobiit-3-cn-2-yl)pyrimidine-2 -carboxamide (Step H) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% MeOH / CO₂; Rt = 4.62 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H24CIFN6O, 454.2; m / z found, 455.0 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.75 (d, J= 8.4 Hz, 1H), 8.34 (s, 2H), 7.43 - 7.11 (m, 3H), 6.90 (dd, J= 16.5, 5.4 Hz, 1H), 5.70 (dd, J= 16.4, 1.7 Hz, lH), 5.19 (t, J=4.5 Hz, 1H), 4.67 (ddd, J= 13.8, 7.0, 1.6 Hz, 1H), 3.71 - 3.54 (m, 2H), 3.07 - 2.90 (m, 2H), 2.84 (dd, J= 11.8, 4.6 Hz, 1H), 2.76 (dt, J= 7.5, 4.1 Hz, 1H), 1.78 - 1.62 (m, 1H), 1.25 (d, J=7.0 Hz, 3H), 0.52 - 0.29 (m, 3H), 0.18 - 0.06 (m, 1H).Scheme 21: Synthesis of 5-((7*5,9a*7?)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(EH)-yl)-JV-((7?)-l-(l,l-dioxido-2 / f-thiet-3-yl)ethyl)pyrazine-2-carboxamide.Example 55: 5-((7*5,9a*7?)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c] [l,4]oxazin- 8(l / / )-yl)- / V-(( / ?)-l-(l,l-dioxido-2 / / -thiet-3-yl)ethyl)pyrazine-2-carboxamide.

[0489] Step A: Methyl 5-(2-chloro-3-fluorophenyl)pyrazine-2-carboxylate. To a solution of methyl 5-chloropyrazine-2-carboxylate (5.0 g, 29.0 mmol, 1.0 eq) in 1,4-dioxane / water (v / v 5:1, 60 mL, 0.5M) was added (2-chloro-3-fluorophenyl)boronic acid (5.1 g, 29.0 mmol, 1.0 eq), potassium carbonate (10 g, 72.4 mmol, 2.5 eq), and Pd(dppf)C12 (1.1 g, 1.45 mmol, 0.05 eq). The reaction was placed under N2 and stirred at 100 °C for 2 h. After cooling to rt, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was slurried with MTBE and purified by FCC (100% DCM) to give methyl 5 -(2-chloro-3-fluorophenyl)pyrazine-2 -carboxylate (18 g, 78% yield) as awhite solid. ’HNMR (400 MHz, CDCh) 59.42 (d, J= 1.5 Hz, 1H), 9.10 (d, J= 1.5 Hz, 1H), 7.51 -7.47 (m, 1H), 7.43 (dt, J = 7.9, 4.9 Hz, 1H), 7.33 (dt, J= 8.3, 1.7 Hz, 1H), 4.09 (s, 3H).

[0490] Step B: (5-(2-Chloro-3-fluorophenyl)pyrazin-2-yl)methanol. To a solution of methyl 5 -(2-chloro-3-fluorophenyl)pyrazine-2-carboxylate (25 g, 93.8 mmol, 1.0 eq) in MeOH (50 mL, 1.9M) was added CaCl2(47 g, 422 mmol, 4.5 eq) and NaBH4(25 g, 656 mmol, 7.0 eq). The reaction was stirred at 25 °C for 2 h under N2. The mixture was quenched with water at 0 °C and concentrated under reduced pressure. The residue was extracted with EtOAc and the combined organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (5-(2-chloro-3-fluorophenyl)pyrazin-2-yl)methanol (20 g, 89% yield) as a white solid. 'H NMR (400 MHz, CDCh) 58.91 (d, J= 1.1 Hz, 1H), 8.76 (s, 1H), 7.46 - 7.36 (m, 2H), 7.32 - 7.27 (m, 1H), 4.94 (d, J= 4.6 Hz, 2H).

[0491] Step C: (rac-(2* / ?.5*. S)-5-(2-Chloro-3-fliiorophcnyl)pipcrazin-2-yl)mcthanol. To a solution of PtO2(1.9 g, 8.38 mmol, 0.1 eq) in MeOH (200 mL, 0.4M) was added (5-(2-chloro-3-fluorophenyl)pyrazin-2-yl)methanol (20 g, 83.8 mmol, 1.0 eq). The reaction was placed under H2 (30 psi) and stirred at 40 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give (rac-(2*R,5*5)-5-(2-chloro-3-fluorophenyl)piperazin-2-yl)methanol (17 g, 83% yield) as a colorless oil. ’H NMR (400 MHz, CDCh) 57.44 (t, J= 8.2 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.10 - 7.03 (m, 1H), 4.25 - 4.19 (m, 1H), 4.18 - 4.11 (m, 1H), 3.55 (dd, J= 10.8, 6.7 Hz, 1H), 3.27 - 3.17 (m, 1H), 3.16 - 3.06 (m, 1H), 3.03 - 2.94 (m, 2H), 2.89 - 2.82 (m, 1H), 2.81 - 2.74 (m, 1H), 2.63 (dd, J= 11.9, 10.2 Hz, 1H).

[0492] Step D: / crt-Butyl rac-(2*R,5*S)-5-(2-chloro-3-fluorophenyl)-2-(hydroxymethyl)piperazine- 1-carboxylate. To a solution of (rac-(2* / ?.5*. S)-5-(2-chloro-3-fluorophcnyl)pipcrazin-2-yl)mcthanol (11 g, 36.0 mmol, 1.0 eq) in DCM (110 mL, 0.3M) was added BOC2O (7.8 g, 36.0 mmol, 1.0 eq). The reaction was stirred at 25 °C for 16 h before being filtered. The filtrate was concentrated under reduced pressure and purified by LCC (PE: EtOAc = 3: 1) to give tert-butyl rac-(2* / ?.5*. S)-5-(2-chloro-3-fluorophcnyl)-2-(hydroxymethyl)piperazine-l -carboxylate (8.0 g, 65% yield) as a light yellow oil. ’H NMR (400 MHz, CDCh) 57.43 - 7.34 (m, 1H), 7.27 - 7.19 (m, 1H), 7.14 - 7.06 (m, 1H), 4.31 - 4.17 (m, 1H), 4.16 - 4.02 (m, 3H), 4.00 - 3.95 (m, 1H), 3.40 - 3.31 (m, 1H), 3.18 (dd, J= 11.9, 4.1 Hz, 1H), 3.08 - 2.95 (m, 1H), 1.47 (d, J = 5.5 Hz, 9H).

[0493] Step E: Methyl 5-(rac-(2*. S'.5* / ?)-4-( / e / 7-biitoxycarbonyl)-2-(2-chloro-3-fluorophcnyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2-carboxylate. To a mixture of tert-butyl rac-(2* / ?.5*. S)-5-(2-chloro-3-fluorophenyl)-2-(hydroxymethyl)piperazine-l-carboxylate (8.0 g, 23.2 mmol, 1.0 eq) in DMSO (80 mL, 0.3M) was added methyl 5 -fluoropyrazine-2 -carboxylate (5.4 g, 34.8 mmol, 1.5 eq) and TEA (7.0 g, 69.6 mmol, 3.0 eq). The reaction was placed under N2 and stirred for 16 h at 80 °C. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (PE: EtOAc = 1: 1) to give methyl 5-(rac-(2*S,5*R)-4-(tert-butoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2 -carboxylate (6.0 g, 54% yield) as a pale yellow oil. ’HNMR (400 MHz, CDCI3) 58.82 (d, J= 0.8 Hz, 1H), 7.65 (br s, 1H), 7.24 - 7.17 (m, 1H), 7.16 - 7.09 (m, 1H), 6.99 (br d, J= 7.4 Hz, 1H), 5.39 - 5.21 (m, 2H), 4.87 - 4.44 (m, 1H), 4.36 -4.19 (m, 1H), 3.97 - 3.83 (m, 5H), 3.79 - 3.71 (m, 1H), 3.61 - 3.46 (m, 1H), 3.35 - 3.22 (m, 1H), 1.51 (s, 9H).

[0494] Step F: Methyl 5-(rac-(2*. S'.5* / )-2-(2-chloro-3-fluorophcnyl)-5-(hydroxymcthyl)pipcrazin-l-yl)pyrazine-2 -carboxylate. To a solution of methyl 5-(rac-(2*. S'.5* / )-4-( / c77-biitoxycarbonyl)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2-carboxylate (1.6 g, 2.70 mmol, 1.0 eq) in ACN (15 mL, 0.2M) was added TsOH-H2O (626 mg, 3.30 mmol, 1.2 eq). The reaction was stirred at 40 °C for 12 h. The mixture was concentrated under reduced pressure to give methyl 5-(rac-(2*S,5*A)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2 -carboxylate (1.5 g, quant, yield) as a light yellow oil. MS (ESI): mass calcd. for C17H18CIFN4O3, 380.1; m / z found, 381.0 [M+H]+.

[0495] Step G: Methyl 5-(rac-(2*. S'.5* / )-2-(2-chloro-3-fliiorophcnyl)-4-(2-chloroacctyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2-carboxylate. To a solution of methyl 5-(rac-(2*. S'.5* / ?)-2-(2-chloro-3-fluorophenyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2-carboxylate (1.5 g, 2.70 mmol, 1.0 eq, TsOH salt) and TEA (829 mg, 8.19 mmol, 3.0 eq) in DCM (15 mL, 0.2M) was added 2-chloroacetyl chloride (308 mg, 2.73 mmol, 1.0 eq) dropwise over 5 mins at 0 °C. The reaction was stirred at 20 °C for 2 h before being poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (100% EtOAc) to give methyl 5-(rac-(2*S,5*R)-2-(2-chloro-3-fluorophenyl)-4-(2-chloroacetyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2-carboxylate (900 mg, 72% yield) as a light yellow oil. ’H NMR (400 MHz, CDCh) 58.81 (d, J= 1.0 Hz, 1H), 7.70 (d, J= 0.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.17 (dt, J= 8.3, 1.3 Hz, 1H), 7.05 (d, J= 7.8 Hz, 1H), 5.46 (dd, J= 11.3, 5.9 Hz, 1H), 5.32 (dd, J= 14.5, 6.5 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.32 (dd, J= 14.8, 5.8 Hz, 1H), 4.20 (d, J= 5.8 Hz, 2H), 4.03 (dd, J= 11.4, 3.7 Hz, 1H), 3.93 (s, 3H), 3.82 - 3.66 (m, 3H).

[0496] Step H: Methyl 5-(rac-(7*. S'.9*a / )-7-(2-chloro-3-fliiorophcnyl)-4-oxohcxahydropyrazino|2.1-c][l,4]oxazin-8(127)-yl)pyrazine-2 -carboxylate. A solution of methyl 5-(rac-(2*. S'.5* / ?)-2-(2-chloro-3-fluorophenyl)-4-(2-chloroacetyl)-5-(hydroxymethyl)piperazin-l-yl)pyrazine-2-carboxylate (870 mg, 1.90 mmol, 1.0 eq) in THF (9.0 mL, 0.2M) was placed under N2and cooled to 0 °C. To the mixture was added sodium hydride (60% in mineral oil, 228 mg, 5.70 mmol, 3.0 eq) in portions. The reaction was stirred at 25 °C for 2 h. The mixture was quenched with MeOH and stirred for 20 min then concentrated under reduced pressure. The residue was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (PE: EtOAc = 1:1) to give methyl 5-(rac-(7*. S'.9*a / ?)-7-(2-chloro-3-fluorophcnyl)-4-oxohexahydropyrazino[2,l-c][l,4]oxazin-8(H7)-yl)pyrazine-2-carboxylate (470 mg, 59% yield) as a light yellow solid. ’HNMR(400 MHz, DMSO-6) 58.87 (d, J= 1.3 Hz, 1H), 8.14 (d, J= 1.1 Hz, 1H), 7.18 (dd, J = 7.9, 5.4 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.04 (d, J = 7.7Hz, 1H), 5.84 (br d, J= 3.6 Hz, 1H), 4.99 (dd, J= 14.1, 1.9 Hz, 1H), 4.53 (dd, J= 13.6, 3.5 Hz, 1H), 4.20 (d, J= 9.3 Hz, 2H), 4.16 - 4.08 (m, 3H), 3.96 (s, 3H), 3.87 - 3.79 (m, 1H), 3.71 (dd, J= 12.0, 6.3 Hz, 1H).

[0497] Step I: Methyl 5-(rac-(7* / ?.9a*. S')-7-(2-chloro-3-fliiorophcnyl)hcxahydropyrazino|2.l-c][l,4]oxazin-8(H7)-yl)pyrazine-2 -carboxylate. A solution of methyl 5-(rac-(7*. S'.9*a / ?)-7-(2-chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,l-c][l,4]oxazin-8(170-yl)pyrazine-2 -carboxylate (470 mg, 1.12 mmol, 1.0 eq) in THF (5.0 mL, 0.2M) was placed under N2 and cooled to 0 °C. To the solution was added BH3 (0.34 mL, 3.35 mmol, 3.0 eq, 10M in Me2S) dropwise. The reaction was stirred at rt for 2 h. The mixture was quenched with MeOH (3.0 mL) dropwise at 20 °C under N2 and stirred at 0 °C for 15 min. After concentrating under reduced pressure, the residue was purified by FCC (PE: EtOAc = 1: 1) to give methyl 5-(rac-(7*S,9*a / ?)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(127)-yl)pyrazine-2 -carboxylate (170 mg, 37% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-tL) 58.82 (s, 1H), 7.99 (s, 1H), 7.23 - 7.19 (m, 1H), 7.15 (dt, J=7.9, 5.3 Hz, 1H), 7.11 - 7.04 (m, 1H), 5.71 (br s, 1H), 4.41 - 4.27 (m, 1H), 3.94 (s, 3H), 3.92 - 3.83 (m, 2H), 3.70 (dt, J= 11.4, 2.1 Hz, 1H), 3.40 (t, J = 10.5 Hz, 1H), 3.20 - 3.09 (m, 2H), 2.83 (dd, J= 12.1, 5.2 Hz, 1H), 2.62 (br d, J= 11.7 Hz, 1H), 2.52 -2.43 (m, 1H), 2.34 (dt, J= 11.5, 3.3 Hz, 1H).

[0498] Step J: 5-(rac-(7*S,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8( l / / )-yl)pyrazinc-2 -carboxylic acid. To a solution of methyl 5-(rac-(7*. S'.9*a / ?)-7-(2-chloro-3-fhrorophenyl)hexahydropyrazino[2, l-c][ l,4]oxazin-8(H7)-yl)pyrazine-2 -carboxylate (170 mg, 0.418 mmol, 1.0 eq) in THF / water (v / v 2: 1, 3.0 mL, 0.14M) was added LiOH. H2O (26 mg, 0.627 mmol, 1.5 eq). The reaction was stirred at 20 °C for 2 h before being concentrated under reduced pressure. The residue was diluted with ACN and water and adjusted to pH 4-5 with 2N HC1. The mixture was lyophilized to give 5-(rac-(7*S,9a*R)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(H7)-yl)pyrazine-2 -carboxylic acid (160 mg, 97% yield) as a yellow solid. MS (ESI): mass calcd. for C18H18CIFN4O3, 392.1; m / z found, 393.1 [M+H]+. ’HNMR(400 MHz, DMSO-d6) δ 8.81 (d, J= 1.1 Hz, 1H), 7.82 (s, 1H), 7.16 - 7.13 (m, 1H), 7.13 - 7.06 (m, 1H), 7.05 - 6.99 (m, 1H), 5.62 (br s, 1H), 4.43 -4.26 (m, 1H), 3.87 - 3.79 (m, 2H), 3.69 - 3.60 (m, 1H), 3.34 (brt, J= 10.6 Hz, 1H), 3.19 - 3.01 (m, 2H), 2.77 (brdd, J= 12.0, 5.1 Hz, 1H), 2.61 - 2.53 (m, 1H), 2.47 - 2.38 (m, 1H), 2.29 (dt, J= 11.5, 3.0 Hz, 1H).

[0499] Step K: 5-((7*S,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2, l-c][ l,4]oxazin-8( 177)-yl)-A-((R)- 1-( 1, l-dioxido-2H-thiet-3-yl)ethyl)pyrazine-2-carboxamide. To a solution of 5-(rac-(7*S,9a*R)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(n7)-yl)pyrazine-2-carboxylic acid (140 mg, 0.356 mmol, 1.0 eq) in DCM (3.0 mL, 0.12M) was added (R)-3-(l-aminoethyl)-2H-thiete 1,1-dioxide (Intermediate 1, 126 mg, 0.39 mmol, 1.1 eq), DIPEA (0.2 mL, 1.07 mmol, 3.0 eq), and T4P (385 mg, 0.534 mmol, 1.5 eq). The reaction was stirred at 15 °C for 2 h before being diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (50% EtOAc in PE) to give 5-(rac-(7*S,9a*R)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,l-c] [ 1,4] oxazi n-8( 17 / )-y I )- A-(( / ?)- 1 -( 1, 1 -dioxido-2 / / -th ict-3 -y I )cthy I )py razi nc-2-carboxam ide (100 mg, 53%) as a white solid. Separation via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 50% EtOH / CO₂; Rt = 6.42 min, first eluting product) provided the title compound. MS (ESI): mass calcd. forC23H25ClFN5O4S, 521.1; m / z found, 522.2 [M+H]+. ’HNMR(400 MHz, DMSO-6) 58.83 (d, J= 8.5 Hz, 1H), 8.61 (s, 1H), 8.13 (br s, 1H), 7.41 - 7.24 (m, 3H), 6.93 (d, J= 1.6 Hz, 1H), 5.87 (br d, J= 2.8 Hz, 1H), 4.94 (brt, J = 7.7 Hz, 1H), 4.51 (s, 2H), 4.34 - 4.25 (m, 1H), 3.92 - 3.82 (m, 1H), 3.76 (br d, J = 10.3 Hz, 1H), 3.51 (brt, J= 10.4 Hz, 1H), 3.25 (brt, J= 10.4 Hz, 1H), 3.18 - 3.09 (m, 2H), 2.73 (brdd, J = 11.8, 4.8 Hz, 1H), 2.65 (brd, J= 12.1 Hz, 1H), 2.33 (brd, J= 1.8 Hz, 1H), 2.22 - 2.12 (m, 1H), 1.36 (d, J=7.1 Hz, 3H).Example 56: 5-((7*iS,9a*?)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c] [l,4]oxazin-8(EH)-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0500] The title compound was prepared in a manner analogous to Example 55 using (R, E)-4-aminopent-2-enenitrile (Intermediate 4) instead of ( / ?)-3-( l-aminocthyl)-2 / / -thictc 1,1 -dioxide in Step K. Separation of 5-(rac-(7*S,9a*R)-7-(2-chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(H7)-yl)-jV-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide (Step K) via SFC (Stationary phase: IG (3x25 cm); Mobile phase: 40% McOH / CCf with 0.1% NH4OH; Rt = 5.46 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C23H24ClFN6O2, 470.2; m / z found, 471.2 [M+H]+. 'HNMR (400 MHz, DMSO-6) 58.60 (s, 1H), 8.57 (d, J= 8.3 Hz, 1H), 8.12 (br s, 1H), 7.39 -7.24 (m, 3H), 6.92 (dd, J= 16.6, 5.3 Hz, 1H), 5.87 (br s, 1H), 5.74 - 5.63 (m, 1H), 4.80 - 4.63 (m, 1H), 4.35 -4.22 (m, 1H), 3.92 - 3.82 (m, 1H), 3.76 (br d, J= 10.5 Hz, 1H), 3.57 - 3.47 (m, 1H), 3.25 (brt, J= 10.5 Hz, 1H), 3.17 - 3.09 (m, 2H), 2.74 (br dd, J= 12.3, 5.1 Hz, 1H), 2.65 (br d, J= 11.4 Hz, 1H), 2.33 (brs, lH), 2.16 (dt, J= 11.6, 3.4 Hz, 1H), 1.26 (d, J= 7.0 Hz, 3H).Example 57: 5-((7*7?,9a*iS)-7-(2-Chloro-3-fluorophenyl)-4-oxohexahydropyrazino [2,1-c][l,4]oxazin-8(EH)-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0501] 5-(rac-(7*S,9*aJ?)-7-(2-Chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,l-c][l,4]oxazin-8( l / / )-yl)pyrazinc-2 -carboxylate was isolated from Example 55, Step H and elaborated to the title compound analogous to Example 56, Step K. Separation of 5-(rac-(7*R,9a*S)-7-(2-chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,l-c][l,4]oxazin-8(H7)-yl)-jV-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide (Step K) via SFC (Stationary phase: IM (3x25 cm); Mobile phase: 50% MeOH / CO₂; Rt = 15.5 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C23H22CIFN6O3, 484.1; m / z found, 485.1 [M+H]+. ’H NMR (400 MHz, DMSO-6) 58.68 - 8.58 (m, 2H), 8.24 (s, 1H), 7.40 - 7.28 (m, 2H), 7.10 (d, J= 8.2 Hz, 1H), 6.93 (dd, J= 16.5, 5.3 Hz, 1H), 6.03 (br d, J= 3.4 Hz, 1H), 5.71 (dd, J= 16.6, 1.6 Hz, 1H), 4.78 (d, J= 13.3 Hz, 1H), 4.75 - 4.67 (m, 1H), 4.51 -4.43 (m, 1H), 4.11 - 3.98 (m, 3H), 3.89 - 3.80 (m, 1H), 3.73 (dd, J= 12.1, 6.3 Hz, 1H), 3.45 - 3.35 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H).Example 58: 5-((7*iS,9a*?)-7-(2-Chloro-3-fluorophenyl)-l,l-dimethylhexahydropyrazino[2,l-c][l,4]oxazin-8(LH)-yl)-A-((7?,£)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0502] Methyl 5 -(2-chloro-3-fluorophenyl)pyrazine-2 -carboxylate (Example 55, Step A) (6.0 g, 22.5 mmol, 1.0 eq) was taken up in THF (120 mL, 0.2M), cooled to 0 °C, and placed under N2.Methylmagnesium bromide (19 mL, 56.3 mmol, 2.5 eq, 3M in THF) was added dropwise and the reaction was stirred for 2 h at 20 °C. The reaction was quenched with sat. aq. NH4CI and extracted with EtOAc. The crude product was purified by FCC on silica (hexane: EtOAc = 1: 1) to give 2-(5-(2-chloro-3-fluorophenyl)pyrazin-2-yl)propan-2-ol (3.0 g, 50% yield) as a yellow oil. ’H NMR (400 MHz, CDCI3) 58.80 (dd, J= 14.0, 1.3 Hz, 2H), 7.37 - 7.30 (m, 2H), 7.22 - 7.18 (m, 1H), 3.81 - 3.68 (m, 1H), 1.61 – 1.54 (s, 6H).

[0503] The title compound was prepared in a manner analogous to Example 56, Steps C-K, using 2-(5-(2-chloro-3 -fluorophenyl)pyrazin-2-yl)propan-2-ol instead of (5 -(2-chloro-3 -fluorophenyl)pyrazin-2-yl)methanol in Step C. Separation of 5-(rac-(7*. S'.9a* / ?)-7-(2-chloro-3-fluorophcnyl)-l.l-dimcthylhcxahydropyrazino|2. l-c|| l.4|oxazin-8(l / / )-yl)- '-(( / ?. A')-4-cyanobut-3-cn-2-yl)pyrazinc-2-carboxamide (Step K) via SFC (Stationary phase: AD (3x25 cm); Mobile phase: 30% iPrOH / CO2; Rt = 4.25 min, first eluting product) provided the title compound. MS (ESI): mass calcd. for C25H28CIFN6O2, 498.2; m / z found, 499.2 [M+H]+. 'H NMR (400 MHz, DMSO-6) 58.66 (s, 1H), 8.60 - 8.49 (m, 1H), 8.38 - 8.28 (m, 1H), 7.92 (d, J= 3.9 Hz, 1H), 7.46 - 7.29 (m, 2H), 6.95 (dd, J= 16.4, 5.4 Hz, 1H), 6.02 -5.87 (m, 1H), 5.79 - 5.66 (m, 1H), 4.80 - 4.65 (m, 1H), 4.33 - 4.18 (m, 1H), 3.90 - 3.73 (m, 1H), 3.55 -3.48 (m, 1H), 3.25 (br d, J= 12.6 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.68 (br s, 1H), 2.59 (br dd, J= 12.4, 4.8 Hz, 1H), 2.12 -1.99 (m, 2H), 1.32 - 1.27 (d, 3H), 1.27 - 1.23 (s, 3H), 1.20 - 1.16 (s, 3H).Example 59: 5-((7*7?,9a*5)-7-(2-Chloro-3-fluorophenyl)-l,l-dimethyl-4-oxohexahydropyrazino[2,l-c][l,4]oxazin-8(LH)-yl)-A-((7?,£)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide.

[0504] The title compound was prepared in a manner analogous to Example 58, omitting Step I.Separation of 5-(rac-(7* / ?.9a*. S)-7-(2-chloro-3-fliiorophcnyl)-l. l-dimcthyl-4-oxohcxahydropyrazino|2.1-c][l,4]oxazin-8(127)-yl)-A-((R,. E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide (Step K) via SFC (Stationary phase: IK (3x25 cm); Mobile phase: 50% iPrOH / CO2; Rt = 13.2 min, second eluting product) provided the title compound. MS (ESI): mass calcd. for C25H26CIFN6O3, 512.2; m / z found, 513.1 [M+H]+.1HNMR(400 MHz, DMSO-6) 58.67 (s, 1H), 8.58 (d, J= 8.1 Hz, 1H), 8.16 (s, 1H), 7.41 -7.34 (m, 1H), 7.23 - 7.16 (m, 1H), 6.92 (dd, J= 16.4, 5.3 Hz, 1H), 5.93 - 5.88 (m, 1H), 5.95 - 5.87 (m, 1H), 5.71 (dd, J= 16.3, 1.3 Hz, 1H), 4.78 - 4.67 (m, 1H), 4.62 - 4.54 (m, 1H), 4.51 -4.43 (m, 1H), 4.13 -4.02 (m, 1H), 4.15 - 3.99 (m, 1H), 3.73 - 3.61 (m, 2H), 3.40 - 3.35 (m, 1H), 1.35 - 1.22 (m, 9H).Scheme 39: Synthesis of methyl 5-(rac-(6* / ?,8a*A)-6-(2-chloro-3-fluorophenyl)-3-oxotetrahydro-3 / f-oxazolo[3,4-a]pyrazin-7(EH)-yl)pyrazine-2-carboxylate.Example 60: 5-((6*7?,8a*5)-6-(2-Chloro-3-fluorophenyl)-3-oxotetrahydro-3 / f-oxazolo[3,4-a]pyrazin-7(EH)-yl)-JV-((7?, E)-4-cyanobut-3-en-2-yl)pyrazine-2-car...

Claims

AMENDED CLAIMSreceived by the International Bureau on 31 August 2026 (31.08.2026)WHAT IS CLAIMED IS:

1. A compound having the structure of Formula (I),is a 5 or 6 membered monocyclic heterocycle comprising 1 or 2 nitrogen atoms and 0 or 1 oxygen atom substituted with 0, 1, or 2 substituents independently selected from -CH3, cyclopropyl, oxo,is a 6, 7, 8, 9, 10, or 11 membered fused bicyclic or spiro bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, 1, or 2 oxygen atoms substituted with 0, 1, 2, or 3substituents independently selected from -CH3, -CN, -CH2-CN, -CH2-OH, -CH2F, -F, oxo, - C(O)-CH3, -C(O)-OCH3, -CH2-CHF2, -CH2-CF3, -CH2-O-CH3, -O-CH3, -CH2-O-CH(CH3)2,is an 8 or 9 membered bridged heterocyclic ring system comprising 1 nitrogen atom and 1 oxygen atom substituted with 0 or 2 -F,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound of claim 1, whereinX is N, X1is CH, X2is CH; orX is CH, X1is N, X2is CH;or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.The compound of claim 1 or claim 2, wherein is 6, 7, 8, 9, or 10 membered fused bicyclic heterocyclic ring system comprising 1 or 2 nitrogen atoms and 0, 1, or 2 oxygen atoms substituted with 0, 1, 2, or 3 substituents independently selected from -CH3, -CN, -CH2-CN, -CH2- OH, -CH2F, -F,-oxo, -C(O)-CH3, -C(O)-OCH3, -CH2-CHF2, -CH2-CF3, -CH2-O-CH3, -O-CH3, -or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

4. The compound of any one of claims 1 to 3, whereinor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

5. The compound of any one of claims 1 to 4, whereinwhereinindicates attachment to the nitrogen atom ofor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. The compound of any one of claims 1 to 5, whereina pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

7. The compound of any one of claims 1 to 6, whereinpharmaceutically acceptable salt, solvate, or stereoisomer thereof.The compound of any one of claims 1-7 wherein R2isThe compound of any one of claims 1-8, wherein10. The compound of any one of claims 1-9, wherein11. The compound of any one of claims 1-10, wherein12. The compound of claim 1, wherein the compound is selected from the group consisting of:5-((S)-2-(2-Chlorophenyl)pyrrolidin- 1 -yl)-N-((R)- 1 -(1,1 -dioxido-2H-thiet-3 -yl)ethyl)pyrazine-2-carboxamide;5-((S)-2-(2-Chloro-3 -fluorophenyl)pyrro lidin- 1 -yl)-N-((R)- 1 -( 1, 1 -dioxido-2H-thiet-3 -yl)ethyl)pyrazine-2-carboxamide;(S, E)-3 -( 1 -(5-(2-(2-Chlorophenyl)pyrrolidin- 1 -yl)pyrazine-2-carbonyl)azetidin-3 -yl)acrylonitrile; 5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R)-l-(l,l-dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R)-l-(l,l-dioxido-2H-thiet-3 -yl)ethyl)pyrimidine-2 -carboxamide;(E)-3-(l-(5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile;5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R)-l-(1,1 -dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide;5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide;(E)-3-(l-(5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile;5-((lR,2S,5S,6S)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R)-l-(l,l-dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide;N-((R, E)-4-Cyanobut-3-en-2-yl)-5-((lR,2S,5S,6S)-2-(2,3-difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2 -carboxamide;(E)-3-(l-(5-((lR,2S,5S,6S)-2-(2,3-Difluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile;5-((l*S,2*R,5*R,6*R)-2-(3-Chloro-4-fluoropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R)- 1 -( 1, 1 -dioxido-2H-thiet-3 -yl)ethyl)pyrazine-2 -carboxamideN-((R, E)-4-Cyanobut-3-en-2-yl)-5-((l*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2 -carboxamide;5-((lS,2S,5R,6S)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R)-l-(1,1 -dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide;N-((R, E)-4-Cyanobut-3-en-2-yl)-5-((lS,2S,5R,6S)-2-(2,3-difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2 -carboxamide;(E)-3-(l-(5-((lS,2S,5R,6S)-2-(2,3-Difluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile;N-((R)-l-(l,l-Dioxido-2H-thiet-3-yl)ethyl)-5-((l*R,2*R,5*S,6*R)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2 -carboxamide;5-((*R)-2-(2-Chloro-3 -fluorophenyl)-4-methyl-5-oxopiperazin- 1 -yl)-N-((R)- 1 -(1,1 -dioxido-2H-thiet-3 -yl)ethyl)pyrazine-2 -carboxamide;5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-methyl-5-oxopiperazin-l-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide;5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide;5-((l*R,2*R,5*S,6*R)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide;5-((l*S,2*S,5*R,6*S)-6-Cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide;5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide;5-((l*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(cyanomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((S)-2-(2-Chlorophenyl)pyrrolidin-l-yl)-N-((R, E)-4-((*S)-S-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2 -carboxamide;5-((S)-2-(2-Chlorophenyl)pyrrolidin-l-yl)-N-((R, E)-4-((*R)-S-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R)-l-(l,l-dioxido-2H-thiet-3-yl)ethyl)pyrimidine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, Z)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-2 -carboxamide;(E)-3-(l-(5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile;(Z)-3-(l-(5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-l-cyanopent- 1 -en-3 -yl)pyrimidine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, Z)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-5-(3,3-difluoroazetidin- 1 -yl)-5-oxopent-3 -en-2-yl)pyrimidine-2 -carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((E)-4-(3,3-difluoroazetidin- 1 -yl)-4-oxobut-2-en- 1 -yl)py rimidine-2 -carboxamide;5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;(E)-3-(l-(5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo [3.1.0] hexan-3 -yl)py rimidine-2 -carbony l)azetidin-3 -yl)acry lonitrile;N-((R, E)-4-Cyanobut-3-en-2-yl)-5-((l*S,2*S,5*R,6*S)-2-(3-fluoro-2-methylphenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2 -carboxamide;5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;(E)-3-(l-(5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile;5-((lS',2S',5R,6. S -2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-7V-((R,£)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;(l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-(2-(3-((E)-2-cyanovinyl)azetidine-l-carbonyl)pyrimidin-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile;5-((l*S,2*S,5*R,6*S)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((l*S,2*S,5*R,6*S)-6-Cyano-2-(2,3-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((l*S,2*S,5*R,6*S)-6-Cyano-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)-4-methylpyrimidine-2 -carboxamide;5-((l*R,4*S,5*R)-4-(2-Chloro-3-fluorophenyl)-l-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((* S)-3 -(2-Chloro-3 -fluorophenyl)morpholino)-N-((R, E)-4-cyanobut-3 -en-2-yl)pyrimidine-2-carboxamide;5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2-carboxamide;5-((*R)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)-N-((R)-l-(l,l-dioxido-2H-thiet-3-yl)ethyl)pyrazine-2 -carboxamide;5-((*R)-2-(2-Chloro-3 -fluorophenyl)-4-cyclopropylpiperazin- 1 -yl)-N-((R, E)-4-cyanobut-3 -en-2-yl)pyrazine-2 -carboxamide;5-((*R)-2-(2-Chloro-3 -fluorophenyl)-4-cyclopropylpiperazin- 1 -yl)-N-((R)- 1 -( 1, 1 -dioxido-2H-thiet-3 -yl)ethyl)pyrimidine-2 -carboxamide;5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-cyclopropylpiperazin-l-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide;5-((7* S,9a*R)-7-(2-Chloro-3 -fluorophenyl)hexahy dropyrazino [2, 1 -c] [ 1,4]oxazin-8( lH)-yl)-N-((R)- 1 - (1,1 -dioxido-2H-thiet-3 -yl)ethyl)pyrazine-2 -carboxamide; or5-((7*S,9a*R)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide;5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)-4-oxohexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((7* S,9a*R)-7-(2-Chloro-3-fluorophenyl)-l,l-dimethylhexahy dropyrazino [2, l-c][l,4]oxazin-8(lH)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((7*R,9a* S)-7-(2-Chloro-3 -fluorophenyl)- 1, 1 -dimethyl-4-oxohexahydropyrazino [2, 1 -c] [ 1,4]oxazin- 8(lH)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((6*R,8a*S)-6-(2-Chloro-3-fluorophenyl)-3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,(E)-3-(l-(5-((l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile,(l*R,2*R,5*S,6*R)-3-(5-(3-((E)-2-Cyanovinyl)azetidine-l-carbonyl)pyrazin-2-yl)-2-(3-fluoro-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile,(l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-3-(5-(3-((E)-2-cyanovinyl)azetidine-l-carbonyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo nitrile,5-((*R)-3-(2-Chloro-3-fluorophenyl)-8-oxa-2-azaspiro[4.5] decan-2 -yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((*S)-7-(2-Chloro-3-fluorophenyl)-2-(2,2,2-trifluoroethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-(( 1 * S,4*R, 5 * S)-4-(2-Chloro-3 -fluorophenyl)- 1 -(methoxy methyl)-3 -azabicyclo [3.1,0]hexan-3 -yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,(E)-3-(l-(5-((l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl)azetidin-3-yl)acrylonitrile,5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(methoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*S,2*R,5*R,6*R)-2-(3-Chloro-4-fluoropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*R,2*S,5*S,6*S)-2-(3-Chloro-4-fluoropyridin-2-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,3a*R,6a*S)-l-(2-Chloro-3-fluorophenyl)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,Methyl(3a*S,4*S,6a*S)-4-(2-chloro-3-fluorophenyl)-5-(5-(((R, E)-4-cyanobut-3-en-2-yl)carbamoyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate,5-((3*R,10a*R)-3-(2-Chloro-3-fluorophenyl)octahydro-2H-pyrazino[l,2-d][l,4]oxazepin-2-yl)-N-((R, E)- 4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,(E)-3-(l-(5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile,5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-N-((R)-l-(1,1 -dioxido-2H-thiet-3 -yl)ethyl)pyrimidine-2 -carboxamide,N-((R, E)-4-Cyanobut-3-en-2-yl)-5-((7*S,9a*R)-7-(3-fluoro-2-methylphenyl)hexahydropyrazino[2,l-c] [ 1,4]oxazin-8( lH)-yl)pyrazine-2 -carboxamide,5-((3*R,9a*R)-3-(2-Chloro-3-fluorophenyl)-8,8-difluorooctahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((3*R,8a*R)-3-(2-Chloro-3-fluorophenyl)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,3a*S,7a*R)-l-(2-Chloro-3-fluorophenyl)hexahydropyrano[3,4-c]pyrrol-2(3H)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,N-((R, E)-4-Cyanobut-3-en-2-yl)-5-((l*S,3a*S,7a*R)-l-(2,3-difluorophenyl)hexahydropyrano[3,4-c]pyrrol-2(3H)-yl)pyrazine-2 -carboxamide,5-((l*S,3a*S,7a*R)-l-(2-Chlorophenyl)hexahydropyrano[3,4-c]pyrrol-2(3H)-yl)-N-((R, E)-4-cyanobut- 3 -en-2-yl)pyrazine-2 -carboxamide,N-((R, E)-4-Cyanobut-3 -en-2-yl)-5-(( 1 *S,3a* S,7a*R)- 1 -(3 -fluoro-2-methylphenyl)hexahydropyrano [3,4-c]pyrrol-2(3H)-yl)pyrazine-2 -carboxamide,5-((3*R,3a*S,7a*R)-3-(2-Chloro-3-fluorophenyl)hexahydropyrano[3,4-c]pyrrol-2(3H)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((4a*R,5*S,7a*S)-5-(2-Chloro-3-fluorophenyl)hexahydro-6H-[l,4]dioxino[2,3-c]pyrrol-6-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((4a*S,5*S,7a*S)-5-(2-Chloro-3-fluorophenyl)hexahydropyrano[2,3-c]pyrrol-6(2H)-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((*S)-7-(2-Chloro-3-fluorophenyl)-2-oxa-6-azabicyclo[3.4]octan-6-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*R,2*S,5*S)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.0]heptan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((3*R,6*R,6a*R)-6-(2-Chloro-3-fluorophenyl)hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((3a*S,6*S,6a*S)-4-(2-Chloro-3-fluorophenyl)hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-((*S)-S-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-((*R)-S-methylsulfonimidoyl)but-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(isopropoxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((*R)-6-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((l*S,4*R,5*R)-4-(2-Chloro-3-fluorophenyl)-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-((l-hydroxycyclopropyl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,2*R,5*R)-2-(2-Chloro-3-fluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((l*S,5*R,6*S)-6-(2-Chloro-3-fluorophenyl)-9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((2*S,3a*S,6a*R)-2-(2-Chloro-3-fluorophenyl)hexahydro-lH-furo[3,4-b]pyrrol-l-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((2*S,3a*R,6a*S)-2-(2-Chloro-3-fluorophenyl)hexahydro-lH-furo[3,4-b]pyrrol-l-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((l*S,4*R,5*R)-4-(2-Chloro-3-fluorophenyl)-l-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2-carboxamide,5-((l *S,2*R, 5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(2 -methoxy ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-ethynyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((l*R,2*S,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-ethynyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(prop-l-yn-l-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((5*S,8*R)-8-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-N-((R, E)-4-cyanobut-3-en- 2-yl)pyrazine-2 -carboxamide,5-((5*R,8*R)-8-(2-Chloro-3-fluorophenyl)-2-oxa-7-azaspiro[4.4]nonan-7-yl)-N-((R, E)-4-cyanobut-3-en- 2-yl)pyrazine-2 -carboxamide,5-((*S)-3-(2-Chloro-3-fluorophenyl)-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,5-((*S)-l-(2-Chloro-3-fluorophenyl)-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide,(l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-3-(2-((S)-3-((E)-2-cyanovinyl)pyrrolidine-l-carbonyl)pyrimidin-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile,5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, Z)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*S,2*R,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)-3-fluoropicolinamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)- 4-cyanobut-3 -en-2-yl)-3 -fluoropicolinamide,5-((l*R,2*R,5*S,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*S,2*S,5*R)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-4-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,(E)-3-(l-(5-((3a*R,4*S,6a*S)-4-(2-Chloro-3-fluorophenyl)tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)pyrimidine-2-carbonyl)azetidin-3-yl)acrylonitrile,5-((l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-cyano-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)-4-methylpyrimidine-2 -carboxamide,5-((l*S,2*S,5*R,6*S)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)-4-methylpyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3 -en-2-yl)-3 -fluoropicolinamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)-4-methylpyrimidine-2 -carboxamide,5-((l*R,2*R,5*S)-2-(2-Chloro-3-fluorophenyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3 -en-2-yl)pyrimidine-2 -carboxamide,5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)-3-fluoropicolinamide,5-((7*R,9a*S)-7-(2-Chloro-3-fluorophenyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-N-((R, E)-4-cyanobut-3 -en-2-yl)-3 -fluoropicolinamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-((*S)-S-methylsulfonimidoyl)but-3-en-2-yl)pyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-((*R)-S-methylsulfonimidoyl)but-3-en-2-yl)pyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-((*S)-N, S-dimethylsulfonimidoyl)but-3-en-2-yl)pyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-((*R)-N, S-dimethylsulfonimidoyl)but-3-en-2-yl)pyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-((*S)-S-methyl-N-phenylsulfonimidoyl)but-3-en-2-yl)pyrimidine-2 -carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-((*R)-S-methyl-N-phenylsulfonimidoyl)but-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*S,2*R,5*R,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(prop-l-yn-l-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrimidine-2 -carboxamide,5-((l*R,2*R,5*S,6*R)-2-(2-Chloro-3-fluorophenyl)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N- ((R, E)-4-cyanobut-3-en-2-yl)-4-methoxypyrimidine-2-carboxamide,5-((lR,2S,5S)-2-(2-Chloro-3-fluorophenyl)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)-4-methoxypyrimidine-2 -carboxamide,5-((*S)-2-(2-Chloro-3-fluorophenyl)-4-(oxetan-3-yl)piperazin-l-yl)-N-((R, E)-4-cyanobut-3-en-2-yl)pyrazine-2 -carboxamide, andMethyl (*R)-3-(2-chloro-3-fluorophenyl)-4-(5-(((R, E)-4-cyanobut-3-en-2-yl)carbamoyl)pyrazin-2-yl)piperazine- 1 -carboxylate,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

13. A pharmaceutical composition comprising the compound of any one of claims 1-12 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

14. A method of inhibiting RAS-PI3K, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

15. A method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-12 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. The method of claim 15, wherein the disease or condition is mediated by the inhibition of RAS-PI3K.

17. The method of claim 15 or 16, wherein the disease or condition is a cancer.

18. The method of claim 17, wherein the cancer is bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, or pancreatic cancer.

19. The method of claim 17, wherein the cancer is a solid tumor.

20. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use as a therapeutically active substance.

21. Use of the compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the treatment of cancer.

22. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the therapeutic treatment of cancer.

23. Use of the compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the preparation of a medicament for the therapeutic treatment of cancer.

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