Inhibitors of human respiratory syncytial virus and metapneumovirus

Abstract

The present disclosure relates to a compound # imgabs0 # of Formula I, or a pharmaceutically acceptable salt thereof, and their use for the treatment of hRSV and hMPV.

Description

Technical Field

[0001] The present invention relates to therapeutic compounds that can be used to inhibit the replication of respiratory syncytial virus and metapneumovirus. The therapeutic compounds can be used to treat or prevent respiratory syncytial virus infection and metapneumovirus infection. Background Art

[0002] Paramyxovirus is an enveloped negative-strand RNA virus that is an important human and animal pathogen. Human respiratory syncytial virus (hRSV, RSV) belongs to the Paramyxoviridae, Pneumovirinae. Two subtypes, type A and type B, have been confirmed and are the main causes of severe and sometimes fatal respiratory infections in children less than 6 months of age. Adults with underlying diseases (such as COPD, asthma, cancer, immunocompromised states, including HIV or transplantation) are also at risk of severe RSV infection. 15% of hospitalizations in adults over the age of 50 are due to acute respiratory infections caused by RSV each year. In the United States, RSV causes more than 100,000 hospitalizations each year, and is estimated to cause 160,000 deaths worldwide each year. Other virus family members, including human metapneumovirus (hMPV) and human parainfluenza virus (hPIV) can also cause acute respiratory diseases similar to hRSV.

[0003] The RSV genome is a single-stranded negative-sense RNA molecule of about 15kb, which encodes 11 proteins. Two of these proteins are the major surface glycoproteins of virions. These are the attachment (G) proteins that mediate the binding of the virus to the cell, and the fusion (F) proteins that promote the fusion of the virus and cell membrane in the initial stage of the infection cycle and the fusion of the membrane of the infected cell with the membrane of the adjacent cell to form characteristic syncytium. Four polypeptides form RSV ribonucleoprotein (RNP) complexes together with the viral RNA genome. These proteins are nucleocapsid (N) protein, phosphoprotein (P), RNA polymerase (L) protein and transcription factor M2-1, which are also required for the transcription and replication of the viral genome and are the subject of drug discovery research.

[0004] After hRSV, hMPV is the second most common cause of lower respiratory tract infections in young children. hMPV is the cause of 5-40% of respiratory infections in hospitalized and outpatient children. In healthy adults, hMPV usually causes mild respiratory infections; however, adults over 70 years old, immunocompromised individuals, and people with comorbidities such as asthma and chronic obstructive pulmonary disease (COPD) are at higher risk for more severe illness and hospitalization due to hMPV infection. The hMPV genome is approximately 13kb and is organized similarly to hRSV. hMPV genomic RNA replication and mRNA transcription depend on the hMPV L-protein polymerase, which is highly homologous to the hRSV L-protein polymerase.

[0005] There are currently few options available for the prevention and treatment of RSV infection. There is no marketed RSV vaccine. Clinical trials with formalin-inactivated virus were associated with increased disease severity in infants following RSV infection (see Kim et al., American Journal of Epidemiology, 89:422-434 (1969)). Monoclonal antibody Palivizumab Approved for preventive use, but efficacy is limited and its use is limited to high-risk infants because of its high cost. A guanosine nucleoside analog broad-spectrum antiviral agent approved as an inhaled treatment for RSV infection in infants, but lacks clear efficacy data (Fearns et al., 2016 Antiviral Research, 134: 63-76). In addition, the teratogenic potential of ribavirin poses a huge risk to caregivers. The current standard of care for patients with RSV infection is palliative, including supplemental oxygen and intravenous fluids.

[0006] There remains a need for antiviral agents with pharmacokinetic properties that are suitable for large numbers of patients in the disease population. The present invention provides novel hRSV and hMPV replication inhibitors that are useful for inhibiting respiratory syncytial virus replication and metapneumovirus replication to meet this need. Summary of the invention

[0007] The present disclosure relates to compounds of Formula I and embodiments thereof for use as antiviral agents for inhibiting hRSV and hMPV replication and treating and / or preventing hRSV and hMPV infection. Compositions comprising the compounds of the present disclosure and methods of use are also provided. DETAILED DESCRIPTION

[0008] The present disclosure relates to compounds of formula I

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] R1 is a 5-membered aromatic heterocyclyl ring consisting of:

[0012] (i) two carbon atoms and (ii) two N and one NH or (i) three N atoms,

[0013] (2) three carbon atoms and (i) two N, (ii) N and NH, or (iii) N and one S or O, or

[0014] (3) four carbon atoms and one S or O,

[0015] wherein the heterocyclyl ring is unsubstituted or, as valence permits, substituted with 1 or 4 substituents independently selected at each occurrence from halogen and C 1-6 alkyl;

[0016] R 2 is a 5-membered aromatic heterocyclyl ring consisting of:

[0017] (1) three carbon atoms and (i) two N, (ii) N and NH, or (iii) N and one S or O, or

[0018] (2) two carbon atoms and (i) three N atoms, (ii) two N atoms and one NH atoms, or (iii) two N atoms and one S or O atoms,

[0019] wherein the heterocyclyl ring is unsubstituted or, as valency permits, substituted with 1, 2 or 3 substituents independently selected at each occurrence from:

[0020] (a) halogen,

[0021] (b) -NH2,

[0022] (c)-C 3-6 Cycloalkyl,

[0023] (d)-C 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH and -NH2, and

[0024] (e)-OC 1-6 Alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH and -NH2;

[0025]

[0026] R 3 is -H, halogen or -C 1-6 alkyl;

[0027] R 4 is -O- or -NH-;

[0028] X 1 , X 2 and X 3 One is N and the others are each CH;

[0029] R 5 Selected from:

[0030] (1)-C 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 groups independently selected at each occurrence from halogen, -OH, -NR XR Y and -C(O)NR X R Y Substituents are substituted,

[0031] (2)-C(O)NR X R Y ,

[0032] (3)

[0033] (4)

[0034] Where R X and R Y Independently selected from -H, -C 1-6 Alkyl, and R Z Yes-C 1-6 Alkyl; and

[0035] R6 is selected from:

[0036] (1) Phenyl, which is unsubstituted or substituted with 1 to 5 substituents, said substituents being independently selected at each occurrence from:

[0037] (a) halogen,

[0038] (b) -CN,

[0039] (c)-C 1-6 alkyl which is unsubstituted or substituted with 1 to 6 substituents independently at each occurrence selected from halogen and -OH;

[0040] (d)-OC 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently at each occurrence selected from halogen and -OH, and

[0041] (e)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 moieties independently selected at each occurrence from halogen, -OH, -C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups;

[0042] (2) pyridinyl, which is unsubstituted or substituted by 1 to 5 substituents, wherein the substituents are independently selected at each occurrence from (i) halogen, (ii) CN and (iii) -C which is unsubstituted or substituted by 1 to 6 -F and / or -Cl. 1-6 alkyl;

[0043] (3) Where R 7a and R 7b Each selected from -H, -C 1-6 Alkyl, where R7a and R 7b Each is selected from -H, -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-6 alkyl;

[0044] (4)

[0045] Where R 8a and R 8b Each selected from -H, -C 1-3 Alkyl and -CF3;

[0046] (5) a bicyclic ring system selected from:

[0047]

[0048] Where R 9 , R 10 and R 11 is independently selected at each occurrence from -H, -C 1-6 Alkyl, -CF3 and 1, 2 or 3 halogens;

[0049] (6)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 moieties independently selected at each occurrence from halogen, -OH, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent; and

[0050] (7) pyrazolyl, which is unsubstituted or substituted with one or more substituents, said substituents being independently selected at each occurrence from:

[0051] (a) 1 to 3 halogens,

[0052] (b) CN,

[0053] (c)-C 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 groups independently selected at each occurrence from halogen, -OH and -OC 1-6 Substitution of alkyl groups;

[0054] (d)-OC 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 groups independently selected at each occurrence from halogen, -OH and OC 1-6 The alkyl group is substituted with a substituent, and

[0055] (e)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 groups independently selected at each occurrence from halogen, -OH and -OC 1-6 The alkyl group is substituted with a substituent; and

[0056] (8)

[0057] In embodiment 1 of the present disclosure is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is a 5-membered aromatic heterocyclyl ring selected from thiazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, thienyl and furanyl, wherein each ring is unsubstituted or, as valence permits, substituted by 1 to 4 atoms independently selected at each occurrence from halogen and C 1-6 In the first class of embodiment 1, R 1 Selected from:

[0058]

[0059] wherein the heterocyclyl ring is unsubstituted or, as valence permits, substituted with 1, 2, 3 or 4 moieties independently selected at each occurrence from halogen and C 1-6 In its second class, the substituent is selected from -F, -Cl and C 1-3 In its third class, the heterocyclyl ring is unsubstituted or, as valence permits, substituted with 1, 2, 3 or 4 moieties selected at each occurrence from -F, -Cl and C 1-3 The alkyl group (eg, methyl) is substituted with a substituent.

[0060] In embodiment 2 of the present disclosure are compounds of formula I and embodiment 1 or pharmaceutically acceptable salts thereof, wherein R 2 is a 5-membered aromatic heterocyclyl ring selected from thiadiazolyl, triazolyl, pyrazolyl, thiazolyl and isothiazolyl, each of which is unsubstituted or, as valence permits, substituted with 1, 2 or 3 substituents selected from (i) halogen (e.g., -F and -Cl), (ii) -NH2, (iii) unsubstituted or substituted with 1 to 5 substituents selected from halogen (e.g., -F and -Cl), -OH and C 3-6 Substituents of cycloalkyl (e.g. cyclopropyl) substituted C 1-3 alkyl.

[0061] In one class of embodiment 2, R 2 Selected from:

[0062]

[0063] Where * is the same as R 1 The connection point,

[0064] And R a , R b , R b1 , R c , R d , R e , R e1 and R fEach independently selected from:

[0065] (a) -H, (b) halogen, (c) -NH2, (d) -C 3-6 Cycloalkyl, (e)-C 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH and -NH2, and (f) -OC 1-6 Alkyl which is unsubstituted or substituted with 1 to 6 substituents independently at each occurrence selected from halogen, -OH and -NH2.

[0066] Above structure

[0067] It may also be shown in the present disclosure as a structure

[0068] In the second class of embodiment 2, R a , R b , R b1 , R c , R d , R e , R e1 and R f Each is independently selected from: (a) -H, (b) halogen (such as -F and -Cl), (c) -NH2, (d) -C 3-6 Cycloalkyl (e.g. cyclopropyl), (e)-C 1-3 alkyl, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from halogen (eg, -F and -Cl), -OH and -NH2, and (f) -OC 1-3 Alkyl which is unsubstituted or substituted with 1, 2 or 3 substituents independently at each occurrence selected from halogen (eg, -F and -Cl), -OH and -NH2.

[0069] In embodiment 3A of the present disclosure is a compound of formula I, and each of embodiments 1 and 2 and classes thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0070] yes

[0071] In embodiment 3B of the present disclosure is a compound of Formula I, and each of embodiments 1 and 2 and classes thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0072] yes

[0073] In embodiment 4 of the present disclosure is a compound of formula I, and each of embodiments 1, 2, 3A and 3B and classes thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from -H, halogen or -C 1-3 In its first category, R 3 is -H, -F, -Cl or -C 1-3 In its first category, R 3 It is -H, -F, -Cl or -CH3.

[0074] In embodiment 5A of the present disclosure is a compound of formula I, and each of embodiments 1, 2, 3A, 3B and 4 and classes thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Yes -O-.

[0075] In embodiment 5B of the present disclosure is a compound of formula I, and each of embodiments 1, 2, 3A, 3B and 4 and classes thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -NH-.

[0076] In embodiment 6 of the present disclosure is a compound of formula I, and each of embodiments 1, 2, 3A, 3B, 4, 5A and 5B and classes thereof, or a pharmaceutically acceptable salt thereof, wherein X1 is N and X 2 and X 3 Each is CH; or X 2 is N and X 1 and X 3 Each is CH; or X 3 is N and X 1 and X 2 Each is CH.

[0077] In embodiment 7 of the present disclosure is a compound of formula I, and each of embodiments 1, 2, 3A, 3B, 4, 5A, 5B and 6 and classes thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from:

[0078] (1)-C 1-6 Alkyl (e.g. -C 1-3 alkyl or -CH3), which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH, -NH2 and -C(O)NH2,

[0079] (2) -C(O)NH2,

[0080] (3)

[0081] (4)

[0082] In a sub-embodiment of embodiment 7, R5 Is -NH 2取代的 -C 1-6 Alkyl (e.g. -C 1-3 alkyl or -CH3).

[0083] In embodiment 8 of the present disclosure is a compound of formula I, and each of embodiments 1, 2, 3A, 3B, 4, 5A, 5B, 6 and 7 and classes thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from:

[0084] (1) Phenyl, which is unsubstituted or substituted with 1 to 5 substituents, said substituents being independently selected at each occurrence from:

[0085] (a) -F and -Cl,

[0086] (b) -CN,

[0087] (c)-C 1-3 alkyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected at each occurrence from -F, -Cl and -OH,

[0088] (d)-OC 1-3 alkyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected at each occurrence from -F, -Cl and -OH, and

[0089] (e)-C 3-6 Cycloalkyl (eg, cyclopropyl) is unsubstituted or substituted with 1 to 3 moieties independently selected at each occurrence from -F, -Cl, -OH, -C 1-3 Alkyl and -OC 1-3 Substitution of alkyl groups;

[0090] (2) pyridinyl, which is unsubstituted or substituted with 1, 2 or 3 substituents, said substituents being independently selected at each occurrence from (i) -F and -Cl, (ii) CN and (iii) -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl. 1-3 Alkyl groups, such as -CH2F, -CHF2, -CF3, and -C(CH3)F2;

[0091] (3) Where R 7a and R 7b Each is selected from -H and -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-3 Alkyl groups, such as -CH2F, -CHF2, -CF3, and -C(CH3)F2;

[0092] (4)

[0093] Where R8a and R 8b Each is selected from -H, -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-3 Alkyl groups, such as -CH2F, -CHF2, -CF3, and -C(CH3)F2;

[0094] (5) a bicyclic ring system selected from:

[0095]

[0096] Where R 9 , R 10 and R 11 is independently selected at each occurrence from -H, 1, 2 or 3 halogens and -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl. 1-3 alkyl;

[0097] (6)-C 3-6 Cycloalkyl (eg cyclopropyl) which is unsubstituted or substituted by 1 to 5 moieties independently selected at each occurrence from halogen, -OH, -C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups;

[0098] (7) Pyrazolyl, for example wherein R12 is selected from (a) -H, (b) halogen, (c) CN, (d) -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-3 Alkyl and (e)-C 3-6 Cycloalkyl (eg, cyclopropyl); and

[0099] (8)

[0100] The compounds of Formula I mentioned herein include compounds of Formula I, Ia, Ib and Ic and all embodiments, classes and subclasses thereof, and include the compounds of the Examples herein. The compounds of Formula I encompass the neutral compounds or their salts (when such salts are possible), including pharmaceutically acceptable salts.

[0101] The term "eg" means "for example." When the term "eg" or "for example" is used herein, the listed examples are intended to be illustrative and are not intended to be an exhaustive list of all relevant examples.

[0102] As used herein, "alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms within a specified range. For example, the term "C 1-6"Alkyl" refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and includes each hexyl ("C6 alkyl") and pentyl ("C5 alkyl") isomer as well as n-butyl, isobutyl, sec-butyl and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively referred to as "C4 alkyl"; Bu = butyl), n-propyl and isopropyl (propyl, i-propyl, collectively referred to as "C3 alkyl" Pr = propyl), ethyl (Et) and methyl (Me). "C 1-3 The "alkyl" group has 1, 2 or 3 carbon atoms and includes each of n-propyl, isopropyl, ethyl and methyl.

[0103] "Cycloalkyl" refers to a cyclized alkyl ring having the specified number of carbon atoms in the specified range. Thus, for example, "C 3-6 "Cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and "C 3-4 "Cycloalkyl" includes each of cyclopropyl and cyclobutyl.

[0104] "Halo" or "halogen" refers to chloro, fluoro, bromo or iodo. Chloro, fluoro and bromo are one class of halogens of interest, more particularly fluoro and chloro.

[0105] A "stable" compound is one that can be prepared and isolated and whose structure and properties remain or can be made to remain substantially unchanged for a period of time sufficient to enable the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and its embodiments. For example, certain moieties as defined in Formula I may be unsubstituted or substituted, and the latter is intended to encompass substitution patterns (i.e., the number and type of substituents) that are chemically possible for the moiety and that result in a stable compound.

[0106] The present disclosure includes individual diastereomers, particularly diastereomers, i.e. compounds with the same chemical formula but different spatial arrangements around a single atom. The present disclosure also includes mixtures of diastereomers at all ratios, particularly mixtures of diastereomers. The present disclosure encompasses compounds of formula I having (R) or (S) stereoconfiguration at an asymmetric center and at any additional asymmetric center that may be present in a compound of formula I, and stereoisomer mixtures thereof. Embodiments of the present disclosure also include mixtures of enantiomers enriched in one of the enantiomers of more than 51%, including, for example, more than 60%, more than 70%, more than 80% or more than 90% of one enantiomer. A single diastereomer is preferred. A single or single enantiomer refers to an enantiomer obtained by chiral synthesis and / or using commonly known separation and purification techniques, and it may be 100% of one enantiomer or may contain a small amount (e.g., less than 10%) of the opposite enantiomer. Therefore, the individual enantiomers constitute the subject of the present disclosure in pure form (as left-handed and right-handed enantiomers), in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of cis / trans isomerism, the present disclosure includes both the cis-form and the trans-form and mixtures of these forms in all ratios.

[0107] If necessary, the preparation of a single stereoisomer can be carried out by separating the mixture by conventional methods (e.g., by chromatography or crystallization), by synthesizing using stereochemically consistent raw materials, or by stereoselective synthesis. Optionally, derivatization can be performed before separating the stereoisomers. The separation of a mixture of stereoisomers can be performed at an intermediate step in the synthesis process of the compound of formula I, or it can be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of a crystalline product or a crystalline intermediate, and if necessary, the crystalline product or crystalline intermediate is derivatized with a reagent containing a stereocenter of a known configuration. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectral analysis. The present disclosure includes all such isomers, as well as salts, solvates (including hydrates), and solvated salts of these racemates, enantiomers, diastereomers and tautomers, and mixtures thereof.

[0108] As will be appreciated by those of ordinary skill in the art, certain compounds of the present disclosure may be capable of existing as tautomers. All tautomeric forms of these compounds, whether isolated individually or in mixtures, are within the scope of the present disclosure. For example, where oxo (=O) substituents are allowed on aromatic heterocycles (also referred to as heteroaromatic rings) and keto-enol tautomerism is possible, it is understood that the substituent may actually exist in whole or in part as -OH.

[0109] The atoms in the compounds of formula I may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that is mainly present in nature. The present disclosure is intended to include all suitable isotopic variants of compounds of formula I; for example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the main hydrogen isotope present in nature. Enrichment of deuterium may provide certain therapeutic advantages, such as increasing the half-life in vivo or reducing dosage requirements, or may provide a compound that can be used as a characterization standard for biological samples. Isotopically enriched compounds of formula I can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the figures and embodiments herein using appropriate isotopically enriched reagents and / or intermediates without excessive experimentation.

[0110] The compound can be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt that has the effectiveness of the parent compound and is not biologically or otherwise undesirable (e.g., nontoxic and otherwise harmless to its recipient). When the compound of Formula I contains one or more acidic or basic groups, the present invention includes the corresponding pharmaceutically acceptable salts.

[0111] Compounds of formula I and their pharmaceutically acceptable salts containing one or more basic groups (i.e., groups that can be protonated) can be used according to the present invention in the form of acid addition salts with inorganic or organic acids, such as, but not limited to, salts with hydrogen chloride, hydrogen fluoride, hydrogen bromide, trifluoroacetic acid (trifluoroacetate), phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. In some embodiments, one or more NH2 groups (e.g., a single NH2 group, or two NH2 groups) of any compound of formula I are protonated in the form of a salt. In some embodiments, one or more NH2 groups (e.g., single NH2 groups) of any compound of formula I are protonated in the form of salts with trifluoroacetic acid (trifluoroacetate). In some embodiments, one or more NH2 groups (e.g., single NH2 groups) of any compound of formula I are protonated in the form of salts with hydrogen chloride. If the compound of formula I contains both acidic and basic groups in the molecule, in addition to the salt forms mentioned, the present invention also includes inner salts or betaines (zwitterions). Salts can be obtained by conventional methods known to those skilled in the art from the compound of formula I, for example, by combining with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present disclosure also includes all salts of compounds of formula I that cannot be directly applied to drugs due to low physiological compatibility but can be used as, for example, intermediates of chemical reactions or for preparing pharmaceutically acceptable salts.

[0112] The present disclosure encompasses any composition comprising a compound of Formula I or a compound as a salt thereof, including, for example, but not limited to, a composition comprising the compound associated with one or more additional molecular and / or ionic components, which may be referred to as a "co-crystal". The term "co-crystal" as used herein refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (usually in stoichiometric ratios) are bound together by non-ionic interactions, including but not limited to hydrogen bonding, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces (van der Waals forces). There is no proton transfer between dissimilar components, and the solid phase is neither a simple salt nor a solvate. Discussion of co-crystals can be found in, for example, S. Aitipamula et al., Crystal Growth and Design, 2012, 12 (5), pp. 2147-2152.

[0113] In addition, the compounds of the present disclosure may exist in an amorphous form and / or one or more crystalline forms, and therefore all amorphous and crystalline forms of the compounds of Formula I and their salts and mixtures thereof are intended to be included within the scope of the present disclosure. In addition, some compounds of the present disclosure may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates of the compounds of the present disclosure, particularly pharmaceutically acceptable solvates and hydrates, together with the non-solvated and anhydrous forms of such compounds, are also included within the scope of the compounds defined by Formula I and their pharmaceutically acceptable salts.

[0114] Thus, the compounds of Formula I or salts thereof (including pharmaceutically acceptable salts thereof), embodiments thereof, and specific compounds described and claimed herein encompass all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), co-crystal forms, solvates, and hydrate forms, as well as any combination of the foregoing (where such forms are possible).

[0115] Another embodiment of the present disclosure is a compound of formula I, wherein the compound or its salt is in a substantially pure form. As used herein, "substantially pure" refers to a product containing a compound of formula I or its salt (e.g., a product separated from a reaction mixture providing the compound or salt) suitably at least about 60% by weight, typically at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% by weight (e.g., about 90% by weight to about 99% by weight), more preferably at least about 95% by weight (e.g., about 95% by weight to about 99% by weight, or about 98% by weight to 100% by weight), most preferably at least about 99% by weight (e.g., 100% by weight) consisting of the compound or salt. The purity level of the compound and salt can be determined using standard analytical methods, such as high performance liquid chromatography and / or mass spectrometry or NMR techniques. If more than one analytical method is used and these methods provide experimentally significant differences in the purity level determined, the method providing the highest purity level shall prevail. A 100% pure compound or salt is one that contains no detectable impurities as determined by standard analytical methods. With respect to compounds of the present invention that have one or more asymmetric centers and that may exist as a mixture of stereoisomers, a substantially pure compound may be a substantially pure mixture of stereoisomers or a substantially pure individual stereoisomer.

[0116] The compounds of formula I herein and their pharmaceutically acceptable salts can be used to inhibit the replication of respiratory syncytial virus and metapneumovirus. Therefore, the compounds of formula I and their pharmaceutically acceptable salts can be used for:

[0117] (i) a method for treating respiratory syncytial virus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof;

[0118] (ii) a method for preventing respiratory syncytial virus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof;

[0119] (iii) a method for treating a metapneumovirus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof; and / or

[0120] (iv) A method for preventing metapneumovirus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof.

[0121] Additional embodiments of the present disclosure include the following:

[0122] (a) a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and

[0123] (b) A pharmaceutical composition comprising a product prepared by combining (eg, mixing) effective amounts of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0124] Additional embodiments of the present disclosure include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of Formula I or its salt is used therein in substantially pure form. With respect to pharmaceutical compositions comprising a compound of Formula I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is to be understood that the term "substantially pure" refers to the compound of Formula I or its salt itself.

[0125] The term "administration" and variations thereof (eg, "administering" a compound) with respect to a compound of Formula I means providing the compound to a subject in need of treatment or prevention, and includes self-administration and administration to a patient by another person or any other means.

[0126] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product resulting from the combination of the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0127] The term "subject" as used herein refers to an animal, such as a human, that is the object of treatment, observation or experiment. In various embodiments of the present disclosure, "subject" includes mammals. In some embodiments, the subject includes domesticated or companion animals, or experimental animal models. In some embodiments, the subject is a rodent, such as a mouse or rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a non-human primate, such as a macaque. In some embodiments, the subject is a human.

[0128] The term "human subject" or "patient" as used herein refers to a human (or "human") who has been the subject of treatment, observation or experiment. Patients to be treated with RSV inhibitors (RSV-i) and / or MPV inhibitors (MPV-i) include, but are not limited to, patients infected with RSV and / or MPV. Patients to be treated with RSV-i and / or MPV-i agents also include, but are not limited to, those patients who use RSV-i and / or MPV-i agents to prevent RSV and / or MPV infection or who are used for post-exposure prophylaxis after potential exposure to RSV and / or MPV to prevent or reduce the severity of symptoms of virus-related diseases or conditions or to prevent patients from being infected.

[0129] "Prevention" includes pre-exposure prophylaxis (PrEP), i.e., the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prevent hRSV and / or hMPV infection in a person who is not infected with hRSV and / or hMPV, and post-exposure prophylaxis (PEP), i.e., the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prevent or reduce the severity of symptoms of a virus-related disease or condition after exposure or potential exposure to hRSV and / or hMPV; or to prevent the person from being infected with hRSV and / or hMPV.

[0130] As used herein, the term "effective amount" refers to the amount of an active compound or agent that elicits a biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, an effective amount is a "therapeutically effective amount" for alleviating the symptoms of the disease or condition being treated. In another embodiment, an effective amount is a "prophylactically effective amount" for preventing the symptoms of the disease or condition being prevented.

[0131] When the active compound (ie, active ingredient) is administered as a salt, references to the amount of active ingredient refer to the free form (ie, non-salt form) of the compound.

[0132] In the method of the present invention, the compound of the present invention or its salt can be applied by means of contacting the active agent with the site of action of the medicament. They can be applied by conventional means that can be used in combination with drugs, as a separate therapeutic agent or with other therapeutic agents that the patient may need. The compound can be applied alone, but is usually applied together with a drug carrier selected based on the selected route of administration and standard pharmaceutical practice. The compound of the present invention can be, for example, administered orally (e.g., by tablets or capsules), parenterally (including subcutaneous injection; intravenous, intramuscular or intrasternal injection; or infusion technology), by inhalation spray or rectal administration in the form of a unit dose of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The compound can also be applied by an implantable drug delivery device suitable for providing an effective amount of the compound or a pharmaceutical composition of the compound for a long time.

[0133] The term "administration" and variations thereof (eg, "administering" a compound) with respect to a compound of Formula I means providing the compound to a subject in need of treatment or prevention, and includes self-administration and administration to a patient by another person or any other means.

[0134] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product resulting from the combination of the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0135] As used herein, the term "subject" or "patient" refers to a human (or "human") who has been the subject of treatment, observation or experiment. Examples of patients to be treated with the antiviral agents described herein include, but are not limited to, patients who have been infected with hRSV or hMPV, and patients who use antiviral agents to prevent hRSV and hMPV infection.

[0136] "Prevention" includes pre-exposure prophylaxis (PrEP), i.e., the use of a compound of Formula I or a pharmaceutically acceptable salt thereof to prevent hRSV or hMPV infection in a person who is not infected with hRSV and / or hMPV, and post-exposure prophylaxis (PEP), i.e., the use of a compound of Formula I or a pharmaceutically acceptable salt thereof to prevent or reduce the severity of symptoms of a virus-related disease after potential exposure to hRSV or hMPV; or to prevent the person from being infected with hRSV or hMPV.

[0137] As used herein, the term "effective amount" refers to an amount of a compound that is sufficient to cause a therapeutic effect and / or a preventive effect after administration. One embodiment of an "effective amount" is a "therapeutically effective amount," which is the amount of a compound that effectively treats hRSV or hMPV infection. Another embodiment of an "effective amount" is a "preventive effective amount," which is the amount of a compound that effectively prevents hRSV or hMPV infection.

[0138] preparation

[0139] Solid preparations suitable for oral administration (e.g., powders, pills, capsules, and tablets) can be prepared according to techniques known in the art, and solid excipients such as starch, sugar, kaolin, lubricants, adhesives, disintegrants, etc. can be used. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art, and any conventional medium, such as water, glycols, oils, alcohols, etc., can be used. Parenteral compositions can be prepared according to techniques known in the art, and sterile water is usually used as a carrier and optional other ingredients, such as dissolution aids. Injectable solutions can be prepared according to methods known in the art, wherein the carrier comprises a solution of a mixture of saline solution, glucose solution, or salt water and glucose. Implantable compositions can be prepared according to methods known in the art, wherein the carrier comprises active chemical components and polymers and suitable excipients, or utilizes an implantable device to deliver drugs. Further description of methods suitable for preparing pharmaceutical compositions for use in the present disclosure and ingredients suitable for use in the compositions are provided in Remington - The Science and Practice of Pharmacy, 22nd edition, 2012, ISBN 978 0 85711-062-6 and previous editions, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences.

[0140] The preparation of the compound of formula I that makes drug supersaturation and / or rapid dissolution can be used to promote oral drug absorption. The preparation method that causes drug supersaturation and / or rapid dissolution includes but is not limited to nanoparticle system, amorphous system, solid solution, solid dispersion and lipid system. Such preparation method and preparation technology thereof are known in the art. For example, excipients and methods described in review articles (such as ATM Serayuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)) can be used to prepare solid dispersions. In review articles such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)), nanoparticle systems based on attrition and direct synthesis have also been described.

[0141] The compound of formula I can be administered in a single dose or divided dose, for example, within a dosage range of 1 to 20 mg / kg, or 1 to 10 mg / kg, or about 5 mg / kg of mammal (e.g., human) body weight per day (or at other time intervals as appropriate). The compound of formula I can be administered in a single dose or divided dose within a dosage range of 0.001 to 2000 mg per day. An example of a dosage range is 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, administered orally in a single dose or divided dose or by other routes of administration.

[0142] For oral administration (e.g., tablets or capsules) or other routes of administration, the dosage unit can be about 100 mg to 1500 mg of active ingredient, such as, but not limited to, 0.1 mg to about 1500 mg of active ingredient, such as, but not limited to, 0.1, 0.25, 0.5, 1, 2, 2.5, 5, 10, 15, 20, 25, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 1000, 1250 or 1500 mg of active ingredient to adjust the dose according to the symptoms of the patient to be treated. In addition, the compound can be formulated into an oral formulation of immediate or modified release, such as extended or controlled release. When the compound of Formula I is administered as a salt, the amount of the compound in milligrams or grams is based on the free form (i.e., non-salt form) of the compound.

[0143] Daily administration can be by any suitable administration route, but is preferably by oral administration, and can be a single dose or more than one dose at staggered times (daily divided doses) within each 24 hours. Each dose can be administered using one or more dosage units as appropriate.

[0144] The specific dosage level and frequency of administration for any particular patient may vary and depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the effects of other drugs taken by the patient concurrently with the use of the RSP-i or MPV-i compounds described herein, the severity of the particular condition, and the host being treated. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upward or downward from a given dose. The amount and frequency of administration are adjusted according to the judgment of the attending clinician taking these factors into account.

[0145] The compounds of the present invention can also be used to prepare and conduct screening assays for antiviral compounds. For example, the compounds of the present invention can be used to isolate enzyme mutants, which are excellent screening tools for more potent antiviral compounds. In addition, the compounds of the present invention can be used to establish or determine binding sites for other antiviral agents.

[0146] The following acronyms and abbreviations have the indicated meanings:

[0147] Ad-BippyPhos is 5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole; (Ad-BippyPhos)2PdCl2 is bis[5-(di(1-adamantyl)phosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole]palladium(II) chloride; aq. is aqueous; BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; CPM E is cyclopentyl methyl ether; CV is column volume; d is day; DCM is dichloromethane; DEA is N,N-diethylamine; DIPEA is N,N-diisopropyl-N-ethylamine; DMA is N,N-dimethylacetamide; DME is dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; Et is ethyl; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Ex. is example; h is hour; HATU is 1-[bis( [Ir(cod)Ome]2 is (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; Int. is an intermediate; MeCN is acetonitrile; MTBE is methyl tert-butyl ether; NMP is 1-methyl-2-pyrrolidone; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl 2 is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dtbpf)Cl2 is [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); Pd(Oac)2 is palladium(II) acetate; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0); PhCF3 is α,α,α-trifluorotoluene; PhMe is toluene; PyBOP is (benzotriazole-1-oxy)tripyrrolidinophosphonium hexafluorophosphate; RockPhos Pd G3 is [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)] methanesulfonate palladium(II); rpm is revolutions per minute; rt is room temperature; SFC is supercritical fluid chromatography; T3P is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TBDPS is tert-butyldiphenylsilyl; t-BuXPhos is 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; TFA is trifluoroacetic acid; THF is tetrahydrofuran; Xphos Pd G2 is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenylyl)[2-(2′-amino-1,1′-biphenylyl)]palladium(II).

[0148] It is understood that the chiral center in the compound can exist in the "S" or "R" stereo configuration, or as a mixture of the two. Within the molecule, unless otherwise specified, each bond drawn from the chiral center as a straight line encompasses each of the (R) and (S) stereoisomers and mixtures thereof. For the compounds containing chiral centers in the examples, the isomeric mixture may have been separated to provide one or both of Isomer 1 (the faster eluting isomer) and Isomer 2 (the slower eluting isomer) - based on their elution order observed by the separation performed in the examples. If carried out under conditions different from those used herein, the elution time and / or order of the separated isomers may be different. The absolute stereochemistry (R or S) of the chiral center in each of the separated stereoisomers of Isomer "1" and / or Isomer "2" in the intermediates and examples is not determined, and "1" and "2" refer only to the elution order resulting from the purification conditions performed.

[0149] General Procedure

[0150] The following reaction schemes and examples illustrate methods that can be used to synthesize compounds of formula (I) described in the present invention. These reaction schemes and examples are provided to illustrate the present invention and should not be construed as limiting the present invention in any way. Unless otherwise indicated, all substituents are as defined above. Several strategies based on synthetic transformations known in the organic synthesis literature can be used to prepare compounds of structural formula I.

[0151] The compounds of the present disclosure can be prepared using appropriate materials according to the procedures of the following examples. However, the compounds exemplified in the examples should not be construed as constituting the only category considered as the present invention. The examples further illustrate the details of preparing the compounds of the present disclosure. It is readily understood by those skilled in the art that known variations of protecting groups and known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. It is also understood that whenever a chemical reagent such as an organic boronic acid or a boric ester is not available, such a chemical reagent can be easily prepared according to one of the many methods described in the literature.

[0152] Reactions that are sensitive to moisture or air were performed using anhydrous solvents and reagents under nitrogen or argon. Analyses were performed by liquid chromatography-mass spectrometry (LC-MS) or usually using Merck KGaA glass-backed TLC plates, silica gel 60F 254 Analytical thin layer chromatography (TLC) was performed to determine the progress of the reaction. Unless otherwise indicated, all temperatures are in degrees Celsius. Mass spectra (MS) were measured by electrospray ionization mass spectrometry (ESI) or atmospheric pressure chemical ionization mass spectrometry (APCI).

[0153] In general, compounds of formula (I) can be prepared by amide coupling of a carboxylic acid of formula (II) and an amine of formula (III) that is suitably functionalized. Acids of formula (II) and amines of formula (III) are commercially available or can be synthesized from suitable intermediates. To illustrate compounds, other synthetic methods for preparing compounds of formula (I) are provided. In addition, compounds of formula (I) can be prepared by reaction procedures generally known in the art.

[0154]

[0155] In some sub-embodiments, the compounds of formula (I) can be prepared by the following reaction procedure:

[0156]

[0157] Analytical LC-MS was typically performed on a Waters SQD single quadrupole mass spectrometer with electrospray ionization in positive ion detection mode (mass range set to 150-900 Daltons, data collected in centroid mode, scan time set to 0.2 seconds) and a Waters Acquity UPLC system (binary solvent manager, sample manager, and TUV). The column used was a Waters Acquity BEH C18 1×50 mm, 1.7 μm, heated to 50° C. The mobile phase used was modified with an acidic or basic additive. The acidic mobile phase consisted of water (containing 0.1% TFA modifier) ​​for solvent A and 100% MeCN for solvent B. A two-minute run was established at a flow rate of 0.3 mL / min with an initial condition of 95% solvent A and ramped to 99% solvent B at 1.60 minutes and held at 99% solvent B for 0.40 minutes. Use partial loop needle overfill injection mode, the injection volume is 0.5 μ L. TUV monitors wavelength 215 or 254 nm with a sampling rate of 20 points / second, normal filter constant and absorbance data mode. The alkaline mobile phase is composed of water (containing 0.05% NH4OH modifier) ​​(for solvent A) and 100% MeCN (for solvent B). Two minutes of operation are established with a flow rate of 0.3 mL / min, and the initial condition is 99% solvent A and ramps up to 99% solvent B at 1.90 minutes and keeps 0.10 minutes at 99% solvent B. Five minutes of operation are established with a flow rate of 0.3 mL / min, and the initial condition is 95% solvent A and ramps up to 99% solvent B at 4.90 minutes and keeps 0.10 minutes at 99% solvent B. For both methods, the injection volume is 5.0 μ L, using the partial loop needle overfill injection mode. TUV monitors at 215 nm with a sampling rate of 20 points / sec, normal filter constant, and absorbance data mode. Alternatively, a commonly used system consists of a Waters ZQ TM and an Agilent 1100 series HPLC with an autosampler. The column is usually Waters Xterra MS C18, 3.0×50 mm, 5 μm or Waters Acquity BEHC18 1.0x 50mm, 1.7μm. The flow rate was 1mL / min and the injection volume was 10μL. UV detection was in the range of 210–400nm. The mobile phase consisted of solvent A (water with 0.05% TFA modifier) ​​and solvent B (MeCN with 0.05% TFA modifier) ​​with a gradient of 100% solvent A for 0.7 minutes, changing to 100% solvent B over 3.75 minutes, holding for 1.1 minutes, and then returning to 100% solvent A over 0.2 minutes.

[0158] Preparative reverse phase chromatography is typically performed on a Teledyne ISCO ACCQ Prep HP 125 or HP 150 apparatus equipped with UV and ELSD detectors. The UV detector typically monitors wavelengths of 215 and 254 nm. The column was typically one of the following: Waters XBridge Prep C18 OBD 5 μm 30×150 mm, Waters XBridge Prep C18 OBD 5 μm 30×250 mm, Waters XBridge Prep C18 OBD 5 μm 50×250 mm, Waters SunFire Prep C18 OBD 5 μm 30×150 mm, Waters SunFire Prep C18 OBD 10 μm 30×150 mm, Waters SunFire Prep C18 OBD 5 μm 50×250 mm, Waters SunFire Prep C18 OBD 10 μm 50×250 mm, or Phenomenex Luna Prep C18 5 μm 50×250 mm. The mobile phase consisted of a mixture of MeCN (containing 0.1% TFA modifier) ​​and water (containing 0.1% TFA modifier). Alternatively, a commonly used system is a Waters Chromatography Workstation configured with an LCMS system consisting of a Waters ZQ TMSingle quadrupole MS system, Waters 2525 gradient pump, Waters 2767 injector / collector, Waters 996PDA detector are formed.MS conditions are: 150-750amu, positive electrospray, collected by MS trigger.Used column is Waters SunFire C18 5μm 30×150mm, Boston Green ODS 5μm 150×30mm or YMC-Actus Triart C18 5μm 150×30mm column normally.Mobile phase is made up of the mixture of MeCN (10%-100%) in water (containing 0.1% TFA modifier).Flow rate is maintained at 50mL / min, and UV detection range is 210-400nm. Another preparative HPLC system used was a Gilson Workstation consisting of a Gilson GX-281 injector / collector, a Gilson UV / VIS-155 detector, Gilson 333 and 334 pumps, and a Phenomenex Gemini-NX C18 5 μm 50×250 mm column, a Waters XBridge Prep C18 OBD 5 μm 30×250 mm, or a Welch Xtimate C18 5 μm 150×25 mm. The mobile phase consisted of a mixture of acetonitrile (0-75%) in water containing 5 mM (NH4)HCO3. The flow rate was maintained at 50 mL / min for the Waters XBridge column, 90 mL / min for the Phenomenex Gemini column, and 25 mL / min for the Welch Xtimate column. The UV detection range was 210-400 nm. The mobile phase gradient was optimized for each compound.

[0159] Silica gel chromatography is usually performed using an ISCO CombiFlash Rf unit, Flash chromatography apparatus (DyaxCorp.) or ISCO Companion XL is mounted on silica gel in prepacked RediSep Rf, RediSep RfGold or SepaFlash columns ( The mobile phase was usually composed of a mixture of hexane, petroleum ether or DCM with EtOAc, 3:1 EtOAc:EtOH or MeOH. The mobile phase gradient was optimized for each compound.

[0160] Chiral chromatography is typically performed by supercritical fluid chromatography with a column selected from one of the following: ChiralPak AD, ChiralPak AD-3, ChiralPak AD-H, ChiralPak AS, ChiralPak AS-3, ChiralPak AS-H, ChiralPak IB-N, ChiralPak OD-H, ChiralPak OJ-3, ChiralPak OJ-H, Phenomenex-Cellulose-2, or (S,S) Whelk-O1. The mobile phase consists of a mixture of CO2 or hexane with MeOH, EtOH, or IPA, using 0.05-0.1% DEA or NH4OH modifiers. The mobile phase gradient is optimized for each compound. The pressure is typically maintained at 100 bar with a flow range of 50-200 mL / min. UV monitoring is typically performed at 220 or 205 nm.

[0161] 1 H NMR data were typically acquired using a Bruker NEO 500 MHz NMR spectrometer equipped with a room temperature 5 mm BBF iProbe, a Bruker Avance NEO 400 MHz NMR spectrometer equipped with a Bruker PI HR-BBO400S1-BBF / H / D-5.0-ZSP probe, or a Bruker Avance III 500 MHz NMR spectrometer equipped with a Bruker 5 mm PABBO probe. Chemical shift values ​​are reported in delta (δ) units, parts per million (ppm). 1 Chemical shifts for H NMR spectra are given relative to the signal of the residual non-deuterated solvent (δ 7.26 ppm for CDCl3 reference; δ 2.50 ppm for DMSO-d6 reference, δ 3.31 ppm for CD3OD reference). Multiplets are reported by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = overlap of multiplets or non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz). When a compound was shown by NMR to be a mixture of rotamers, the spectral data corresponding to the major species observed in solution are reported.

[0162] Schema:

[0163]

[0164] Intermediate A-1

[0165] Benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate

[0166]

[0167] Step 1: 2-(2,6-dichloropyridin-4-yl)propan-2-amine

[0168] The solution of methylmagnesium bromide (3.0M in Et2O, 1.7L, 5.2mol) was added dropwise to 0°C mixture of 2,6-dichloroisonicotinonitrile (0.30kg, 1.7mol) in PhMe (1.5L) over 1 hour. The mixture was warmed to 25°C and stirred for 1 hour. The mixture was cooled to 0°C and titanium isopropoxide (IV) (490g, 1.7mol) was added dropwise over 0.5 hour. The mixture was heated to 100°C and stirred for 1 hour. The mixture was cooled to 5-10°C and treated with a solution of Na2CO3 (saturated aqueous solution, 5L) at 5-10°C. The mixture was filtered, and the filter cake was washed with EtOAc (800mL x 3). The filtrate was separated, and the organic phase was concentrated to provide the title compound.

[0169] Step 2: Benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate

[0170] Benzyl chloroformate (250g, 1.5mol) was added dropwise over 0.5 hours to a 0°C mixture of 2-(2,6-dichloropyridin-4-yl)propan-2-amine (270g, 1.3mol), DIPEA (190g, 1.5mol) and DCM (2.7L). The mixture was warmed to 25°C and stirred for 12 hours. The mixture was washed with hydrochloric acid (1N, 800mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The material was triturated at 25°C (MTBE / EtOAc=10:1, 800mL) for 12 hours. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0171] The following compounds were prepared using the procedure described in the preparation of Intermediate A-1, substituting the appropriate reagent for 2,6-dichloroisonicotinonitrile.

[0172]

[0173] Schema:

[0174]

[0175] Intermediate A-3

[0176] rac-2-(2,6-dichloropyridin-4-yl)-2-methylazetidine-1-carboxylic acid tert-butyl ester

[0177]

[0178] Step 1: tert-Butyl rac-2-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate

[0179] 4-Bromo-2,6-dichloropyridine (0.50 g, 2.2 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (0.49 mg, 2.4 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridyl-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (25 mg, 0.022 mmol) and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridyl]dichloronickel(II) tetrahydrate (11 mg, 0.023 mmol) were combined in a screw cap vial. DMSO (22 mL) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.90 mL, 4.4 mmol) were added. N2 was bubbled through the mixture for 5 minutes. The vial was capped and then (wavelength: 450nm; LED intensity: 100%; fan speed: 5000rpm; stirring: 1200rpm). After 4 hours, the mixture was diluted with H2O and then extracted with EtOAc (4x). The combined organic layers were washed with H2O and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-25% (25% EtOH / EtOAc) / heptane) to provide the title compound.

[0180] Step 2: tert-butyl rac-2-(2,6-dichloropyridin-4-yl)-2-methylazetidine-1-carboxylate

[0181] A solution of rac-2-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.79 mmol) in THF (4.0 mL) was cooled to -78 ° C. Diisopropyl lithium amide (2.0 M in THF / heptane / ethylbenzene, 0.56 mL, 1.1 mmol) was slowly added thereto. After 30 minutes, iodomethane (0.10 mL, 1.6 mmol) was added. After 10 minutes, the cooling bath was removed and the mixture was warmed to room temperature. After stirring for another 3 hours, the mixture was treated with MeOH and then concentrated. The residue was dissolved in DMSO (3 mL) and subjected to reverse phase HPLC (5-95% MeCN / water containing 0.1% TFA modifier). The fractions containing the product were combined and concentrated to provide the title compound.

[0182] Schema:

[0183]

[0184] Intermediate A-4

[0185] Methyl 2-(2,6-dichloropyridin-4-yl)-2-methylpropanoate

[0186]

[0187] 4-Bromo-2,6-dichloropyridine (0.50 g, 2.2 mmol) and ZnF2 (0.11 g, 1.1 mmol) were combined in a screw cap vial. DMF (9.0 mL) was added and N2 was pumped through the mixture for 1 minute. Bis(tri-tert-butylphosphine)palladium(0) (57 mg, 0.11 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.68 mL, 3.3 mmol) were added. N2 was pumped through the mixture for 1 minute. The vial was capped and then heated to 85°C for 18 hours. The mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (3x). The combined organic layers were washed with H2O and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-25% EtOAc / hexanes) to provide the title compound.

[0188] Schema:

[0189]

[0190] Intermediate A-5

[0191] N-(1-(2,6-dichloropyridin-4-yl)cyclobutyl)-2-methylpropane-2-sulfenamide

[0192]

[0193] Phase 2,6-dichloro-4-iodopyridine (1.0g, 3.7mmol) in THF (12mL) -78 ° C solution was added with n-butyl lithium (2.5M in hexane, 2.9mL, 7.3mmol) and the mixture was stirred for 30 minutes. A solution of N-cyclobutylene-2-methylpropane-2-sulfinamide (0.63g, 3.7mmol) in THF (8.0mL) was slowly added. The mixture was warmed to room temperature and stirred for 1 hour. Water (10mL) was added and the mixture was extracted with EtOAc (20mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-60% EtOAc / petroleum ether) to provide the title compound.

[0194] The following compounds were prepared using the procedure described in the preparation of intermediate A-5, substituting the appropriate reagent for N-cyclobutylene-2-methylpropane-2-sulfenamide.

[0195]

[0196] Schema:

[0197]

[0198] Intermediate B

[0199] Methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate

[0200]

[0201] Step 1: Methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)acetate

[0202] Under nitrogen atmosphere, a mixture of methyl 2-(2,6-dichloropyridin-4-yl)acetate (0.030 kg, 0.14 mol), (4-fluorophenyl)boronic acid (19 g, 0.14 mol), Pd(dppf)Cl2 (5.0 g, 6.8 mmol), potassium carbonate (38 g, 0.27 mol), 1,4-dioxane (0.40 L) and water (0.040 L) was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-8% EtOAc / petroleum ether) to provide the title compound.

[0203] Step 2: Methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate

[0204] Under nitrogen atmosphere, to a solution of 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)methyl acetate (14g, 0.050mol) in THF (0.15L) at -78°C was added a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 0.060L, 0.060mol). The mixture was stirred for 30 minutes and iodomethane (6.3mL, 0.10mol) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. Water (100mL) was added and the mixture was extracted with EtOAc (100mL x 3). The combined organic extracts were washed with brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-5% EtOAc / petroleum ether) to provide the title compound.

[0205] The following compounds were prepared using the procedure described in the preparation of Intermediate A-1, substituting the appropriate reagents for 2,6-dichloroisonicotinonitrile and benzyl chloroformate.

[0206]

[0207] Schema:

[0208]

[0209] Intermediate C-03

[0210] Benzyl (2-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)propan-2-yl)carbamate

[0211]

[0212] To a mixture of (2-(2,6-dichloropyridin-4-yl)propan-2-yl)benzylcarbamate (Int.A-1, 2.0 g, 5.9 mmol) and (4-(trifluoromethyl)phenyl)boric acid (1.0 g, 5.3 mmol) in H2O (4.0 mL) and 1,4-dioxane (0.020 L) was added K2CO3 (1.6 g, 12 mmol). The resulting mixture was degassed (evacuated and backfilled with nitrogen x 3) and then Pd(dppf)Cl2 (0.43 g, 0.59 mmol) was added. The mixture was heated at 100°C for 2 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-10% EtOAc / petroleum ether) to provide the title compound.

[0213] The following compounds were prepared using the procedure described in the preparation of intermediate C-03, substituting appropriate reagents for benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate and (4-(trifluoromethyl)phenyl)boronic acid.

[0214]

[0215]

[0216] Schema:

[0217]

[0218] Intermediate C-09

[0219] rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylic acid benzyl ester

[0220]

[0221] Step 1: rac-2-methyl-2-(pyridin-4-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0222] Isonicotinonitrile (0.30 g, 2.9 mmol), 1-((benzyloxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.5 g, 5.8 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridyl-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (65 mg, 0.060 mmol) and K2HPO4 (1.5 g, 8.7 mmol) were combined in a screw cap vial. DMSO (28 mL) was added. N2 was bubbled through the mixture for 10 min. The vial was capped and then placed in a PennOC (wavelength: 450nm; LED intensity: 100%; fan speed: 5000rpm; stirring: 1200rpm). After 24 hours, the mixture was diluted with a solution of NaHCO3 (saturated aqueous solution) and extracted with EtOAc (3x). The combined organic extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-50% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0223] Step 2: rac-4-(1-((benzyloxy)carbonyl)-2-methylpyrrolidin-2-yl)pyridine 1-oxide

[0224] To a room temperature solution of rac-2-methyl-2-(pyridin-4-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.51 g, 1.7 mmol) in DCM (0.010 L) was added 3-chloroperoxybenzoic acid (0.64 g, 2.6 mmol). After 3 hours, the mixture was concentrated. The residue was subjected to silica gel chromatography (0-100% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0225] Step 3: rac-4-(1-((benzyloxy)carbonyl)-2-methylpyrrolidin-2-yl)-2-(4-fluorophenyl)pyridine 1-oxide

[0226] Combine 1-bromo-4-fluorobenzene (0.13 mL, 1.2 mmol), rac-4-(1-((benzyloxy)carbonyl)-2-methylpyrrolidin-2-yl)pyridine 1-oxide (0.44 g, 1.4 mmol) and K2CO3 (0.33 g, 2.4 mmol) in a screw cap vial. Add toluene (4.0 mL). Bubble N2 through the mixture for 1 min. Add Pd(OAc)2 (27 mg, 0.12 mmol) and tri-tert-butylphosphonium tetrafluoroborate (42 mg, 0.15 mmol). Cap the vial and heat to 120°C overnight. Cool the resulting mixture to room temperature, dilute with EtOAc, and Filter through a pad of Celite® (eluting with EtOAc) and concentrate. The residue was subjected to silica gel chromatography (0-100% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0227] Step 4: rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylic acid benzyl ester

[0228] A solution of rac-4-(1-((benzyloxy)carbonyl)-2-methylpyrrolidin-2-yl)-2-(4-fluorophenyl)pyridine 1-oxide (0.19 g, 0.47 mmol) in DCM (2.5 mL) was cooled to 0°C. Triethylamine (0.27 mL, 1.9 mmol) was added thereto followed by the slow addition of oxalyl chloride (0.085 mL, 0.97 mmol). After 30 minutes, the mixture was warmed to room temperature and stirred for 3.5 hours. The mixture was diluted with a solution of NaHCO3 (saturated aqueous solution) and then extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-50% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0229] Schema:

[0230]

[0231] Intermediate C-10

[0232] Benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropyl)carbamate

[0233]

[0234] Step 1: 2-(2-Chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropionitrile

[0235] A solution of 2-chloro-6-(4-fluorophenyl)isonicotinonitrile (0.83 g, 3.6 mmol) and isobutyronitrile (0.42 mL, 4.7 mmol) in THF (18 mL) was cooled to -78 ° C. A solution of bis(trimethylsilyl)lithium amide (1.5 M in THF, 3.0 mL, 4.5 mmol) was slowly added thereto. After the addition was complete, the cooling bath was removed and the mixture was warmed to room temperature. After 2 hours, the mixture was diluted with a solution of NH4Cl (saturated aqueous solution) and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The mixture was subjected to silica gel chromatography (0-25% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0236] Step 2: 2-(2-Chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropan-1-amine hydrochloride

[0237] To a solution of 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropionitrile (0.10 g, 0.36 mmol) in THF (2.0 mL) was slowly added BH3-THF (1.0 M in THF, 1.0 mL, 1.0 mmol) at room temperature. After stirring for 18 hours, hydrochloric acid (6N, 1.0 mL) was slowly added, followed by MeOH (2.0 mL), and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated to provide the title compound as the HCl salt.

[0238] Step 3: Benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropyl)carbamate

[0239] 2-(2-Chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropan-1-amine hydrochloride (0.12 g, 0.36 mmol) was dissolved in DCM (3.0 mL) and treated with DIPEA (0.35 mL, 2.0 mmol). The mixture was cooled to 0 °C and benzyl chloroformate (0.080 mL, 0.56 mmol) was added. The mixture was warmed to room temperature while stirring overnight. The mixture was concentrated and the residue was subjected to silica gel chromatography (0-25% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0240] Schema:

[0241]

[0242] Intermediate C-11

[0243] rac-(1-((tert-butyldiphenylsilyl)oxy)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester

[0244]

[0245] Step 1: rac-2-bromo-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester

[0246] Bromine (0.39 mL, 7.5 mmol) was added to a solution of 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)methyl propionate (Int.B, 2.0 g, 6.8 mmol) in acetic acid (0.020 L). The mixture was placed in a preheated oil bath at 100 ° C and stirred for 8 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. EtOAc (40 mL) was added, and the mixture was washed with Na2S2O3 (saturated aqueous solution, 20 mL), NaHCO3 (saturated aqueous solution, 20 mL) and brine (20 mL x3). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound.

[0247] Step 2: rac-2-azido-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester

[0248] To a solution of methyl 2-bromo-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (1.6 g, 4.3 mmol) in MeOH (0.020 L) was added sodium azide (1.3 g, 0.020 mol). The mixture was placed in a preheated oil bath at 60 ° C and stirred for 5 hours. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was treated with NaHCO3 (saturated aqueous solution) until pH = 9. The mixture was extracted with EtOAc (30 mL x 3), and the combined organic extracts were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0249] Step 3: rac-2-amino-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester

[0250] To a solution of rac-2-azido-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester (1.4 g, 4.2 mmol) in MeOH (0.020 L) was added tin (II) chloride dihydrate (2.8 g, 13 mmol). The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0251] Step 4: rac-2-(((benzyloxy)carbonyl)amino)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester

[0252] To a solution of rac-2-amino-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester (1.2 g, 3.1 mmol) in DCM (12 mL) was added NaHCO (1.0 g, 12 mmol) and benzyl chloroformate (2.2 mL, 16 mmol). The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (25% EtOAc / petroleum ether) to provide the title compound.

[0253] Step 5: rac-(2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-1-hydroxypropan-2-yl)carbamic acid benzyl ester

[0254] To a room temperature mixture of rac-2-(((benzyloxy)carbonyl)amino)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoic acid methyl ester (1.2 g, 2.7 mmol) in THF (15 mL) was added lithium borohydride (0.35 g, 16 mmol). The mixture was stirred at room temperature for 1 hour. A solution of NH4Cl (saturated aqueous solution, 30 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (30-50% EtOAc / petroleum ether) to provide the title compound.

[0255] Step 6: rac-(1-((tert-butyldiphenylsilyl)oxy)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester

[0256] To a solution of rac-(2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-1-hydroxypropyl-2-yl)benzylcarbamate (0.50 g, 1.2 mmol) in DCM (0.010 L) was added imidazole (0.16 g, 2.4 mmol) and tert-butyl(chloro)diphenylsilane (0.66 g, 2.4 mmol). The mixture was stirred at room temperature for 12 hours. Water (20 mL) was added and the mixture was extracted with DCM (30 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound.

[0257] Schema:

[0258]

[0259] Intermediate C-12

[0260] rac-3-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-2-one

[0261]

[0262] Step 1: rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-cyano-2-methylpropanoic acid methyl ester

[0263] To a -78°C solution of methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (Int.B, 1.9 g, 6.5 mmol) in THF (0.030 L) was slowly added lithium bis(trimethylsilyl)amide (1.0 M in THF, 8.4 mL, 8.4 mmol). After 1 hour, 2-bromoacetonitrile (1.0 g, 8.4 mmol) was added, the cooling bath was removed, and the mixture was warmed to room temperature. After 2 hours, the mixture was treated with H2O (20 mL) and then extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound.

[0264] Step 2: rac-3-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-2-one

[0265] Methyl rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-cyano-2-methylpropanoate (2.0 g, 6.0 mmol) and cobalt(II) chloride hexahydrate (1.4 g, 6.0 mmol) were dissolved in MeOH (0.030 L). After stirring at 0°C for 5 minutes, sodium borohydride (1.4 g, 36 mmol) was added in portions over 5 minutes, the cooling bath was removed, and the mixture was warmed to room temperature. After 16 hours, the mixture was treated with NH4Cl (saturated aqueous solution, 20 mL) and then extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-35% EtOAc / petroleum ether) to provide the title compound.

[0266] Schema:

[0267]

[0268] Intermediate C-13

[0269] Benzyl (2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-yl)carbamate

[0270]

[0271] Step 1: 2-Chloro-4-(4-fluorophenyl)pyridine 1-oxide

[0272] 3-Chloroperoxybenzoic acid (15 g, 84 mmol) was added to a solution of 2-chloro-4-(4-fluorophenyl)pyridine (5.8 g, 28 mmol) in DCM (0.10 mL) at room temperature. The mixture was then heated at 50 ° C for 12 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, NaHCO (saturated aqueous solution, 100 mL) and Na2SO3 (saturated aqueous solution, 100 mL) were added, and the mixture was extracted with EtOAc (50 mL x 4). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-70% EtOAc / petroleum ether) to provide the title compound.

[0273] Step 2: 6-Chloro-4-(4-fluorophenyl)pyridinecarbonitrile

[0274] A solution of 2-chloro-4-(4-fluorophenyl)pyridine 1-oxide (4.3 g, 19 mmol), trimethylsilyl cyanide (11 g, 0.12 mol) and triethylamine (5.4 mL, 39 mmol) was heated at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (0-40% EtOAc / petroleum ether) to provide the title compound.

[0275] Step 3: 2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-amine

[0276] Methylmagnesium bromide (3.0M in Et2O, 19mL, 58mmol) was slowly added to a solution of 6-chloro-4-(4-fluorophenyl)picolinonitrile (2.7g, 12mmol) in THF (0.080L) at 0°C. The mixture was warmed to 25°C and stirred for 30 minutes. Titanium isopropoxide (3.4mL, 12mmol) was added and then the mixture was heated at 80°C for 12 hours. The mixture was cooled to room temperature, treated with NH4Cl (saturated aqueous solution, 50mL), and extracted with EtOAc (50mL x 3). The combined organic extracts were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound.

[0277] Step 4: Benzyl (2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-yl)carbamate

[0278] To a mixture of 2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-amine (2.0 g, 7.6 mmol) and DIPEA (4.0 mL, 23 mmol) in DCM (0.040 L) was added benzyl chloroformate (2.2 mL, 15 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 12 hours. The mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound.

[0279] Schema:

[0280]

[0281] Intermediate D-ent-1

[0282] rel-(1R,4R,5R)-5-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (enantiomer 1)

[0283] and

[0284] Intermediate D-ent-2

[0285] rel-(1R,4R,5R)-5-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (Enantiomer 2)

[0286]

[0287] Step 1: Benzyl pyridine-1(2H)-carboxylate

[0288] Under argon, sodium borohydride (5.7 g, 0.15 mol) was added to a -78 ° C solution of anhydrous pyridine (12 g, 0.15 mol) in anhydrous MeOH (0.10 L). Benzyl chloroformate (21 mL, 0.15 mol) was added dropwise and the mixture was stirred for 3 hours. MTBE (100 mL) and water (100 mL) were added, and the mixture was warmed to room temperature. The mixture was extracted with MTBE (100 mL x 2), and the combined organic extracts were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0289] Step 2: Benzyl 2-azabicyclo[2.2.0]hex-5-ene-2-carboxylate

[0290] Under nitrogen atmosphere, a solution of benzyl pyridine-1(2H)-carboxylate (6.0 g, 25 mmol) in DCM (0.75 L) was irradiated (300 W, Photo-reactor, Hg lamp) for 6 h. The mixture was concentrated under reduced pressure and subjected to silica gel chromatography (0-17% EtOAc / petroleum ether) to provide the title compound.

[0291] Step 3: Benzyl 5-hydroxy-6-iodo-2-azabicyclo[2.2.0]hexane-2-carboxylate

[0292] N-iodosuccinimide (15 g, 67 mmol) was added to a -5°C solution of 2-azabicyclo[2.2.0]hex-5-ene-2-carboxylic acid benzyl ester (4.8 g, 22 mmol) in DMSO (72 mL) and water (72 mL) in portions. The mixture was warmed to room temperature and stirred for 12 hours. Water (100 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / petroleum ether) to provide the title compound.

[0293] Step 4: rac-(1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester

[0294] The mixture of freshly dried indium chloride (III) (4.4g, 0.020mol) and sodium borohydride (1.5g, 0.040mol) in MeCN (41mL) was stirred at -78 ° C for 10 minutes. The mixture was warmed to room temperature and added dropwise to 5-hydroxy-6-iodo-2-azabicyclo [2.2.0] hexane-2-benzyl formate (5.5g, 15mmol) in MeCN (82mL). The mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60mL) and extracted with EtOAc (40mL x 3). The combined organic extracts were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (0-50% EtOAc / petroleum ether) was applied to the residue to provide the title compound.

[0295] Step 5: rac-(1R,4R,5R)-5-((4-nitrobenzoyl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester

[0296] To a 0°C solution of rac-(1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (2.6 g, 11 mmol) and 4-nitrobenzoic acid (2.8 g, 17 mmol) in THF (0.080 L) was added triphenylphosphine (4.4 g, 17 mmol). Diisopropyl azodicarboxylate (4.6 g, 0.020 mol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (0-17% EtOAc / petroleum ether) to provide the title compound.

[0297] Step 6: rac-(1R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester

[0298] To a solution of rac-(1R,4R,5R)-5-((4-nitrobenzoyl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (5.5 g, 11 mmol) in MeOH (0.10 L) was added K2CO3 (6.0 g, 43 mmol). The mixture was stirred at room temperature for 2 hours. Water (100 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to provide the title compound.

[0299] Step 7: rel-(1R,4R,5R)-5-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (enantiomers 1 and 2)

[0300] Under nitrogen atmosphere, a mixture of tert-butyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.C-02, 5.2 g, 14 mmol), rac-(1R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylate (2.2 g, 9.4 mmol), (Ad-BippyPhos)2PdCl2 (0.99 g, 0.66 mmol), Cs2CO3 (9.2 g, 28 mmol) and PhMe (0.18 L) was stirred at 90°C for 24 hours. The mixture was cooled to room temperature, filtered through a thin pad of silica gel (eluting with EtOAc), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-15% EtOAc / petroleum ether). The resulting mixture of two stereoisomers was subjected to chiral SFC (ChiralPak AD-3, 5-40% IPA (containing 0.05% DEA modifier) / CO2) to provide rel-(1R,4R,5R)-5-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (Enantiomer 1, faster eluting, Int.D-ent-1) and rel-(1R,4R,5R)-5-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (Enantiomer 2, slower eluting, Int.D-ent-2).

[0301] Schema:

[0302]

[0303] Intermediate E

[0304] (1R,5S,6s)-6-Hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0305]

[0306] Step 1: Benzyl(diiodomethyl)dimethylsilane

[0307] 10 reactions were carried out in parallel.Bis (trimethylsilyl) lithium amide solution (1.0M, 1.5L, 1.5mol) in isopropyl ether (3.0L) was loaded into a 10L container. At -65 ° C, diiodomethane (130mL, 1.6mol) was added to the mixture. The mixture was stirred for 0.25 hours at -65 ° C. Benzyl chloride dimethyl silane (0.20kg, 1.1mol, 0.20L) was added and the mixture was stirred for 3 hours at -65 ° C, then stirred for 12 hours at 25 ° C. These reactions were merged and processed with water (10L). MTBE (5L x 2) was used for the mixture extraction. Organic layers were merged, washed with salt water, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (2-100% EtOAc / petroleum ether) was applied to the residue to provide the title compound.

[0308] Step 2: (1R,5S,6s)-6-(Benzyldimethylsilyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0309] 14 reactions were carried out in parallel.Chromium chloride (II) (150g, 1.2mol) was loaded into a 5L container.THF (2.5L) and N,N,N,N-tetramethylethylenediamine (360mL, 2.4mol) were added to the mixture at 25°C over 0.5 hour.Benzyl (diiodomethyl) dimethylsilane (240g, 560mmol) was added and the mixture was stirred at 25°C for 0.5 hour.2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (0.050kg, 0.30mol) was added to the mixture at 25°C.The mixture was stirred at 50°C for 18 hours.Merge these reactions, the mixture is treated with water (15L) and extracted with MTBE (7L x 3).The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (1-100% EtOAc / petroleum ether) to provide the title compound.

[0310] Step 3: (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0311] 14 reactions were carried out in parallel.(1R, 5S, 6s)-6-(benzyldimethylsilyl)-3-azabicyclo[3.1.0]hexane-3-tert-butyl formate (0.070kg, 210mmol) in THF (2.1L) was loaded into a 10L container.Tetrabutylammonium fluoride solution (1.0M in THF, 630mL) was added, and the mixture was stirred for 0.5 hour at 25°C.MeOH (2.1L) and potassium bicarbonate (0.20kg, 2.1mol) were added to the reaction vessel at 0°C, followed by addition of hydrogen peroxide (30% by weight aqueous solution, 0.10L, 1.1mol). The mixture was stirred for 0.5 hour at 0°C and stirred for 16 hours at 25°C. These reactions were combined, and the mixture was treated with Na2SO3 (saturated aqueous solution, 25L) and extracted with EtOAc (7L x 2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-100% EtOAc / hexanes) and then recrystallized from n-heptane:MTBE=20:1 (9 L) to provide the title compound.

[0312] Intermediate F

[0313] 6-Hydroxy-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0314]

[0315] Step 1: tert-Butyl 6,6-dibromo-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0316] A mixture of tert-butyl 3-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (15g, 82mmol), bromoform (62g, 0.25mol) and N-benzyl-N,N,N-triethylammonium chloride (0.75g, 3.3mmol) in DCM (0.40L) and EtOH (8.0mL) was cooled to 0°C under a nitrogen atmosphere. Sodium hydroxide solution (50% by weight aqueous solution, 66g, 0.82mol) was added at 0°C. The mixture was warmed to 45°C and stirred for 12 hours. Water (150mL) was added, and the mixture was extracted with DCM (80mL x 3). The combined organic solution was washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-5% EtOAc / petroleum ether) to provide the title compound.

[0317] Step 2: tert-Butyl 6-hydroxy-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0318] A solution of tert-butyl 6,6-dibromo-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, 5.6 mmol) in THF (0.040 L) was cooled to -78 °C. A solution of n-butyl lithium (2.5 M in hexane, 2.7 mL, 6.8 mmol) was added dropwise, and the mixture was stirred for 15 minutes. A solution of catechol borane (1.0 M in THF, 11 mL, 11 mmol) was added, and the mixture was warmed to 50 °C and stirred for 12 hours. The mixture was cooled to 0 °C, and hydrogen peroxide (30% (w / w) aqueous solution, 2.9 mL, 28 mmol) and sodium hydroxide (2.5 M aqueous solution, 9.0 mL, 23 mmol) were added. The mixture was warmed to room temperature and stirred for 12 hours. Na2SO3 (saturated aqueous solution, 5 mL) and water (20 mL) were added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-60% EtOAc / petroleum ether) to provide the title compound.

[0319] Schema:

[0320]

[0321] Intermediate G

[0322] (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0323]

[0324] A mixture of benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate (Int.A-1, 66 g, 65 mmol), tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.E, 0.030 kg, 0.050 mol), tripotassium phosphate (96 g, 150 mmol), Ad-BippyPhos (3.0 g, 1.5 mmol) and 1-4-dioxane (1.2 L) was purged and degassed with N2 at 15°C (5x). Pd2(dba)3 (1.7 g, 0.63 mmol) was added and the mixture was purged and degassed with N2 (5x). The mixture was stirred at 70°C for 16 hours. The mixture was cooled to 15°C, washed with NaHCO (saturated aqueous solution, 1.0 L), and filtered. The filter cake was washed with EtOAc (1.5 L) and the organic phase was separated. The aqueous phase was extracted with EtOAc (500 mL x 4), and the combined organic mixture was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (1-17% EtOAc / petroleum ether). The mixture was subjected to reversed phase HPLC (40-70% MeCN / water) to provide the title compound.

[0325] Intermediate G-01

[0326] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-chloropyridin-4-yl)propan-2-yl)carbamate

[0327]

[0328] To a solution of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int. G, 3.0 g, 6.0 mmol) in DCM (16 mL) was added TFA (4.0 mL) under N2. The mixture was stirred at 25 °C for 2 hours. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0329] Schema:

[0330]

[0331] Intermediate H-01

[0332] 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine

[0333]

[0334] Step 1: (1R,5S,6s)-6-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0335] Under nitrogen atmosphere, a mixture of tert-butyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.C-02, 1.0 g, 2.7 mmol), tert-butyl (1R, 5S, 6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.E, 0.60 g, 3.0 mmol), Cs2CO3 (2.7 g, 8.2 mmol), Ad-BippyPhos (0.18 g, 0.27 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol) and 1,4-dioxane (14 mL) was stirred at 85°C for 2 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-50% EtOAc / hexanes) to provide the title compound.

[0336] Step 2: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine

[0337] To a 0°C solution of tert-butyl (1R,5S,6s)-6-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.3 g, 2.4 mmol) in DCM (0.020 L) was added a solution of HCl (4.0 M in 1,4-dioxane, 6.1 mL, 24 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure, suspended in Et2O, cooled to 0°C, and filtered. The filter cake was dried under reduced pressure to provide the title compound as the HCl salt.

[0338] Intermediate H-02

[0339] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0340]

[0341] Step 1: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0342] Under nitrogen atmosphere, a mixture of benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.C-01, 1.0 g, 2.5 mmol), tert-butyl (1R, 5S, 6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.E, 0.50 g, 2.5 mmol), K3PO4 (1.6 g, 7.5 mmol), Ad-BippyPhos (0.17 g, 0.25 mmol), Pd(OAc)2 (28 mg, 0.13 mmol), CPME (0.010 L) and PhCF3 (0.010 L) was stirred at 90° C. for 16 hours. The mixture was cooled to room temperature, filtered through a thin pad of silica gel (eluted with EtOAc), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-45% EtOAc / petroleum ether) to provide the title compound.

[0343] Step 2: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0344] To a mixture of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.4 g, 2.5 mmol) in DCM (0.010 L) was added TFA (2.0 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-10% MeOH / DCM) to provide the title compound.

[0345] The following compounds were prepared using the procedure described in the synthesis of intermediate H-02, substituting the appropriate reagent for benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate.

[0346]

[0347]

[0348]

[0349]

[0350] Schema:

[0351]

[0352] Intermediate H-12-ent-1

[0353] Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (Enantiomer 1)

[0354] and

[0355] Intermediate H-12-ent-2

[0356] Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (Enantiomer 2)

[0357]

[0358] Step 1: tert-butyl ent-(1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(5,9,9-trimethyl-3-oxo-1,8,8-triphenyl-2,7-dioxa-4-aza-8-siladecan-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomers 1 and 2)

[0359] Under argon atmosphere, a mixture of benzyl rac-(1-((tert-butyldiphenylsilyl)oxy)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.C-11, 0.80 g, 1.2 mmol) and tert-butyl (1R, 5S, 6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.E, 0.27 g, 1.3 mmol), Ad-BippyPhos (81 mg, 0.12 mmol), Pd2(dba)3 (56 mg, 0.061 mmol), Cs2CO3 (1.2 g, 3.7 mmol) and PhMe (15 mL) was stirred at 90° C. for 12 hours. The mixture was cooled to room temperature, filtered through a thin pad of silica gel (eluted with EtOAc), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / petroleum ether). The mixture of the two enantiomers was subjected to chiral SFC ((S,S) Whelk-01, 40% MeOH (with 0.05% DEA modifier) / CO2) to provide the title compound ent-(1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(5,9,9-trimethyl-3-oxo-1,8,8-triphenyl-2,7-dioxa-4-aza-8-siladecan-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (enantiomer). Enantiomer 1, faster eluting) and tert-butyl ent-(1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(5,9,9-trimethyl-3-oxo-1,8,8-triphenyl-2,7-dioxa-4-aza-8-siladecan-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomer 2, slower eluting).

[0360] Step 2-1: Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (Enantiomer 1)

[0361] To a solution of tert-butyl ent-(1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(5,9,9-trimethyl-3-oxo-1,8,8-triphenyl-2,7-dioxa-4-aza-8-siladecan-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Enantiomer 1, faster eluting, 0.31 g, 0.38 mmol) in DCM (5.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound (Int.H-12-ent-1).

[0362] Step 2-2: Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (Enantiomer 2)

[0363] To a solution of tert-butyl ent-(1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(5,9,9-trimethyl-3-oxo-1,8,8-triphenyl-2,7-dioxa-4-aza-8-siladecan-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Enantiomer 2, slower eluting, 0.31 g, 0.38 mmol) in DCM (5.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound (Int.H-12-ent-2).

[0364] Schema:

[0365]

[0366] Intermediate H-13

[0367] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(2,4-difluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0368]

[0369] Step 1: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0370] Under nitrogen atmosphere, a mixture of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int. G, 0.50 g, 0.10 mmol), 2,4-difluorophenylboronic acid (0.19 g, 1.2 mmol), XPhos Pd G2 (78 mg, 0.10 mmol), K3PO4 (1.0 M aqueous solution, 3.0 mL, 3.0 mmol) and 1,4-dioxane (5.0 mL) was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-20% (3:1 EtOAc / EtOH) / hexanes) to provide the title compound.

[0371] Step 2: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(2,4-difluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0372] To a solution of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.50 g, 0.86 mmol) in DCM (0.050 L) was added a solution of HCl (4.0 M in 1,4-dioxane, 1.0 mL, 4.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to provide the title compound as the HCl salt.

[0373] Schema:

[0374]

[0375] Intermediate H-14

[0376] 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)pyridin-4-yl)propan-2-amine

[0377]

[0378] Step 1: (4,8-di-tert-butyl-2,10-dimethyl-6-oxido-12H-dibenzo[d,g][1,3,2]dioxaphosphocin-6-yl)(4-iodo-2-methylphenyl)methanone

[0379] To a solution of 4-iodo-2-methylbenzoic acid (4.1g, 16mmol) in DCM (31mL), a solution of oxalyl chloride (2.0M in DCM, 2.7mL, 31mmol) was added, followed by the addition of DMF (2 drops). The mixture was heated at reflux for 1 hour. The mixture was concentrated under reduced pressure. DCM (31mL) and DIPEA (14mL, 78mmol) were added, followed by the addition of 4,8-di-tert-butyl-2,10-dimethyl-12H-dibenzo [d, g] [1,3,2] dioxaphosphocene 6-oxide (6.0g, 16mmol) in DCM (31mL) dropwise over 1 hour. The mixture was stirred at room temperature for 6 hours. DCM (50mL) was added, and the mixture was washed with hydrochloric acid (1N, 50mL) and a solution of NaHCO3 (saturated aqueous solution, 50mL). The organic fraction was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to silica gel chromatography (0-30% EtOAc / hexanes) to provide the title compound.

[0380] Step 2: 3-Iodobicyclo[4.2.0]octa-1(6),2,4-trien-7-one

[0381] A solution of (4,8-di-tert-butyl-2,10-dimethyl-6-oxido-12H-dibenzo[d,g][1,3,2]dioxaphosphocyclooctan-6-yl)(4-iodo-2-methylphenyl)methanone (4.7 g, 7.4 mmol) in PhMe (15 mL) was added to a PennOC (wavelength: 420 nm; LED intensity: 100%; fan speed: 5000 rpm; stirring: 1200 rpm) for 12 hours. Triethylamine (1.0 mL, 7.4 mmol) was added, and the mixture was heated to 45 °C for 4 hours. The mixture was subjected to silica gel chromatography (0-15% EtOAc / hexanes) to provide the title compound.

[0382] Step 3: 7,7-difluoro-3-iodobicyclo[4.2.0]octa-1(6),2,4-triene

[0383] A mixture of bis(2-methoxyethyl)aminosulfur trifluoride (0.93 mL, 5.0 mmol) and 3-iodobicyclo[4.2.0]octa-1(6),2,4-triene-7-one (250 mg, 1.0 mmol) was stirred at 50°C for 16 hours. A 0°C solution of NaHCO3 (saturated aqueous solution, 30 mL) was added dropwise and the mixture was extracted with DCM (30 mL x 3). The combined organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexanes) to provide the title compound.

[0384] Step 4: (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0385] Under nitrogen atmosphere, a mixture of 7,7-difluoro-3-iodobicyclo[4.2.0]octa-1(6),2,4-triene (0.20 g, 0.74 mmol), XPhos Pd G2 (58 mg, 0.074 mmol), XPhos (0.070 g, 0.15 mmol), tetrahydroxydiboron (0.20 g, 2.2 mmol), potassium acetate (0.22 g, 2.2 mmol) and ethanol (7.4 mL) was stirred at 80 °C for 2 hours. A solution of K2CO3 (1.8 M aqueous solution, 1.2 mL, 2.2 mmol) and tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int. G, 0.37 g, 0.74 mmol) were added and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, a solution of KH2PO4 (saturated aqueous solution, 20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic solutions were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0386] Step 5: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)pyridin-4-yl)propan-2-amine

[0387] A mixture of (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-triene-3-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.41 g, 0.68 mmol) and hydrochloric acid (37%, 6.7 mL) was stirred at 80 °C for 10 minutes. The mixture was cooled to room temperature, diluted with water (10 mL) and loaded onto a Flash SCX-2 column (pre-conditioned with MeOH). The column was washed with MeOH (2CV) and eluted with a methanol solution of NH3 (2N, 2CV). The eluate was concentrated under reduced pressure. The residue was dissolved in DCM (0.010 L) and then HCl (4.0 M in 1,4-dioxane, 1.7 mL, 6.8 mmol) was added. The mixture was stirred at room temperature for 15 minutes and concentrated under reduced pressure to afford the title compound as an HCl salt.

[0388] Intermediate H-15

[0389] 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(bicyclo[1.1.1]pent-1-ylmethoxy)pyridin-4-yl)propan-2-amine

[0390]

[0391] Step 1: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(bicyclo[1.1.1]pentan-1-ylmethoxy)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0392] (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int. G, 0.050 g, 0.10 mmol), bicyclo[1.1.1]pentan-1-ylmethanol (15 mg, 0.15 mmol) and Cs2CO3 (97 mg, 0.30 mmol) were combined in a screw cap vial. PhMe (0.50 mL) was added and nitrogen was bubbled through the mixture for 1 min. RockPhos Pd G3 (9.0 mg, 11 μmol) was added and the vial was capped and then heated to 90 °C overnight. The mixture was cooled to room temperature, EtOAc was added and the mixture was filtered through a 0.45 μm syringe filter (eluting with EtOAc). The filtrate was concentrated under reduced pressure to give a mixture of the title compound and tert-butyl (1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(bicyclo[1.1.1]pentan-1-ylmethoxy)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate.

[0393] Step 2: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(bicyclo[1.1.1]pentan-1-ylmethoxy)pyridin-4-yl)propan-2-amine

[0394] The mixture from step 1 was placed in hydrochloric acid (37%, 0.50 mL) and then placed in a preheated block at 80°C. After 10 minutes, the mixture was cooled to room temperature. The mixture was diluted with DMSO (0.50 mL) and then subjected to reverse phase HPLC (5-50% MeCN / water containing 0.1% TFA modifier). The fractions containing the product were combined and then concentrated. The residue was placed in MeCN and then transferred to a screw cap vial. 2 volumes of hydrochloric acid (1N aqueous solution) were added. The mixture was frozen (dry ice / acetone) and then lyophilized to provide the title compound as the HCl salt.

[0395] Intermediate H-16

[0396] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-4-yl)propan-2-yl)carbamate

[0397]

[0398] Step 1: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0399] Under nitrogen atmosphere, a mixture of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int. G, 0.19 g, 0.38 mmol), 4-cyclopropyl-1H-pyrazole (83 mg, 0.77 mmol), Pd2(dba)3 (18 mg, 0.019 mmol), t-BuXPhos (16 mg, 0.038 mmol), K3PO4 (0.25 g, 1.2 mmol) and tert-butanol (6.0 mL) was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound.

[0400] Step 2: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-4-yl)propan-2-yl)carbamate

[0401] To a solution of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.19 g, 0.29 mmol) in DCM (5.0 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to provide the title compound.

[0402] Schema:

[0403]

[0404] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-yl)carbamate

[0405]

[0406] Step 1: Benzyl (2-(2-chloropyridin-4-yl)propan-2-yl)carbamate 1-oxide

[0407] To a solution of benzyl (2-(2-chloropyridin-4-yl)propan-2-yl)carbamate (Int.A-2, 4.4 g, 14 mmol) in DCM (72 mL) was added 3-chloroperoxybenzoic acid (77 wt% / water, 4.8 g, 22 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was diluted with DCM (75 mL) and washed with Na2SO3 (saturated aqueous solution, 100 mL), NaHCO3 (saturated aqueous solution, 100 mL) and brine (100 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-20% (25% EtOH / EtOAc) / DCM) to provide the title compound.

[0408] Step 2: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate N-oxide

[0409] To a solution of benzyl (2-(2-chloropyridin-4-yl)propan-2-yl)carbamate 1-oxide (2.0 g, 6.3 mmol) and tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int E, 1.3 g, 6.3 mmol) in THF (63 mL) was added potassium tert-butoxide (1.0 M in THF, 6.9 mL, 6.9 mmol). The mixture was heated to 60 °C for 3 days. The mixture was cooled to room temperature and diluted with water (100 mL) and EtOAc (200 mL). The organic solution was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% (25% EtOH / EtOAc) / DCM) to provide the title compound.

[0410] Step 3: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0411] To a mixture of (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester N-oxide (0.55 g, 1.1 mmol) and 4,4-dimethylpiperidine HCl (0.21 g, 1.4 mmol) in DCM (4.6 mL) were added DIPEA (0.99 mL, 5.7 mmol) and bromotripyrrolidiniumphosphonium hexafluorophosphate (0.69 g, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (40 mL) and washed with NaHCO3 (saturated aqueous solution, 40 mL), water (40 mL) and brine (40 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-15% (25% EtOH / EtOAc) / hexanes) to provide the title compound.

[0412] Step 4: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-yl)carbamate

[0413] To a solution of (1R, 5S, 6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.36 g, 0.62 mmol) in DCM (4.7 mL) was added TFA (1.6 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into sodium hydroxide (1N aqueous solution, 50 mL) and the pH was adjusted to>12 with sodium hydroxide (6N aqueous solution). The mixture was extracted with DCM (50 mL x 3), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0414] The following compounds were prepared using the procedure described in the synthesis of intermediate H-17, substituting the appropriate reagents for 4,4-dimethylpiperidine·HCl.

[0415]

[0416] Schema:

[0417]

[0418] Intermediate H-19

[0419] 3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-3-methylazetidin-2-one

[0420]

[0421] Step 1: (1R,5S,6s)-tert-butyl 6-((6-(4-fluorophenyl)-4-(1-methoxy-1-oxopropan-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0422] In a glove box, a mixture of methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (Int.B, 1.0 g, 3.5 mmol), tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.E, 0.70 g, 3.5 mmol), Pd2(dba)3 (0.16 g, 0.18 mmol), Ad-BippyPhos (0.23 g, 0.35 mmol) and Cs2CO3 (3.4 g, 11 mmol) in PhMe (0.040 L) was heated to 90°C. After 16 hours, the mixture was cooled to room temperature, filtered and concentrated. The residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound.

[0423] Step 2: rac-(1R,5S,6s)-6-((4-(3-(1,3-dioxoisoindolin-2-yl)-1-methoxy-2-methyl-1-oxopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0424] To a -78°C solution of (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(1-methoxy-1-oxopropan-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.0 g, 2.2 mmol) in THF (15 mL) was slowly added lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.9 mL, 2.9 mmol). After 1 hour, a solution of 2-(bromomethyl)isoindoline-1,3-dione (0.79 g, 3.3 mmol) in THF (5.0 mL) was added. After 2 hours, the mixture was warmed to 0°C and a solution of NH4Cl (saturated aqueous solution) was added. The resulting mixture was warmed to room temperature and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to provide the title compound.

[0425] Step 3: rac-(1R,5S,6s)-6-((4-(3-amino-1-methoxy-2-methyl-1-oxopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0426] To a room temperature mixture of rac-(1R,5S,6s)-tert-butyl 6-((4-(3-(1,3-dioxoisoindolin-2-yl)-1-methoxy-2-methyl-1-oxopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.60 g, 0.98 mmol) in EtOH (15 mL) was added hydrazine hydrate (0.49 g, 9.8 mmol). After 12 hours, the mixture was filtered and concentrated. The residue was subjected to silica gel chromatography (EtOAc) to provide the title compound.

[0427] Step 4: rac-3-amino-2-(2-(((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanoic acid

[0428] To a room temperature mixture of rac-(1R,5S,6s)-6-((4-(3-amino-1-methoxy-2-methyl-1-oxopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.30 g, 0.61 mmol) in THF (5.0 mL) and H2O (5.0 mL) was added LiOH (73 mg, 3.0 mmol). After 12 hours, the mixture was concentrated to remove volatile organic solvents and then washed with DCM (2x). The aqueous solution was acidified with hydrochloric acid (1N) (pH=6) and concentrated under reduced pressure. DCM (10 mL) and MeOH (10 mL) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0429] Step 5: rac-(1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(3-methyl-2-oxoazetidin-3-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0430] To a room temperature solution of rac-3-amino-2-(2-(((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanoic acid (240 mg, 0.41 mmol) in DMF (8.0 mL) was added DIPEA (0.20 mL, 1.2 mmol) and T3P (50 wt% in EtOAc, 390 mg, 0.61 mmol). After 1 hour, the mixture was diluted with H2O (10 mL) and then extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (67% EtOAc / petroleum ether) to provide the title compound.

[0431] Step 6: rac-3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-3-methylazetidin-2-one

[0432] To a room temperature solution of rac-(1R,5S,6s)-tert-butyl 6-((6-(4-fluorophenyl)-4-(3-methyl-2-oxoazetidin-3-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (110 mg, 0.24 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). After 30 minutes, the mixture was concentrated to afford the title compound as a TFA salt.

[0433] Schema:

[0434]

[0435] Intermediate H-20

[0436] rac-2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-aminopropanamide

[0437]

[0438] Step 1: (1R,5S,6s)-tert-butyl 6-((4-cyano-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0439] Under nitrogen atmosphere, a mixture of (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Int.E, 420 mg, 2.1 mmol), 2-chloro-6-(4-fluorophenyl)isonicotinonitrile (470 mg, 2.0 mmol), Pd2(dba)3 (92 mg, 0.10 mmol), Ad-BippyPhos (130 mg, 0.20 mmol), Cs2CO3 (2.0 g, 6.0 mmol) and 1,4-dioxane (0.010 L) was stirred at 85°C for 18 hours. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with NaHCO3 (saturated aqueous solution, 50 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (DCM) to provide the title compound.

[0440] Step 2: (1R,5S,6s)-tert-butyl 6-((4-acetyl-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0441] To a room temperature solution of (1R,5S,6s)-tert-butyl 6-((4-cyano-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.30 g, 0.76 mmol) in THF (6.0 mL) was slowly added MeMgBr (3.0 M in Et2O, 2.6 mL, 7.7 mmol). After 3 h, the mixture was quenched with NH4Cl (saturated aqueous solution), diluted with H2O, and extracted with EtOAc (3x). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% (25% EtOAc / EtOH) / heptane) to provide the title compound.

[0442] Step 3: rac-(1R,5S,6s)-6-((4-(1-amino-1-cyanoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0443] To a mixture of tert-butyl (1R,5S,6s)-6-((4-acetyl-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (75 mg, 0.18 mmol) and ammonia in methanol (7.0 M, 1.0 mL) was added NH4Cl (0.030 g, 0.56 mmol) followed by trimethylsilyl cyanide (0.075 mL, 0.56 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was taken up in EtOAc, filtered and concentrated. The residue was subjected to silica gel chromatography (0-25% (25% EtOAc / EtOH) / heptane) to provide the title compound.

[0444] Step 4: rac-(1R,5S,6s)-6-((4-(1,2-diamino-1-oxopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0445] To a room temperature solution of rac-(1R,5S,6s)-6-((4-(1-amino-1-cyanoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.060 g, 0.14 mmol) in DMSO (1.0 mL) was added KCO (76 mg, 0.55 mmol) followed by H0 (30 wt % in water, 0.14 mL, 1.4 mmol). The mixture was stirred overnight, diluted with H0, and extracted with EtOAc (3x). The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.

[0446] Step 5: rac-2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-aminopropanamide

[0447] A mixture of rac-(1R,5S,6s)-tert-butyl 6-((4-(1,2-diamino-1-oxopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (65 mg, 0.14 mmol) and HCl (4.0 N in 1,4-dioxane, 1.0 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated to provide the title compound as the HCl salt.

[0448] Schema:

[0449]

[0450] Intermediates I-1-ent-1 and I-1-ent-2

[0451] rel-(benzyl 2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomers 1 and 2)

[0452]

[0453] Step 1: rel-(1R,5S,6S)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomers 1 and 2)

[0454] Under nitrogen atmosphere, a mixture of tert-butyl 6-hydroxy-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.F, 1.3 g, 4.3 mmol), benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.C-01, 1.7 g, 1.3 mmol), Pd(OAc)2 (48 mg, 0.21 mmol), Ad-BippyPhos (0.28 g, 0.43 mmol), K3PO4 (2.7 g, 13 mmol), PhCF3 (0.010 L) and CPME (0.010 L) was stirred at 95°C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-15% EtOAc / petroleum ether) to provide the title compound. This material was subjected to chiral SFC (ChiralPak OJ-H, 5-40% EtOH (with 0.05% DEA modifier) / CO2) to afford rel-(lR,5S,6S)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-l-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Enantiomer 1, faster eluting) and rel-(lR,5S,6S)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-l-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Enantiomer 2, slower eluting).

[0455] Step 2-1: rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester (enantiomer 1, Int.I-1-ent-1)

[0456] To a mixture of rel-(1R,5S,6S)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Enantiomer 1, 0.31 mg, 0.53 mmol) in DCM (5.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound.

[0457] Step 2-2: rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester (enantiomer 2, Int.I-1-ent-2)

[0458] To a mixture of rel-(1R,5S,6S)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Enantiomer 2, 0.30 mg, 0.52 mmol) in DCM (5.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to provide the title compound.

[0459] The following compounds were prepared using the procedure described in the synthesis of intermediate 1-1, substituting the appropriate reagent for benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate.

[0460]

[0461] Intermediate J

[0462] Benzyl (2-(2-(((1R,5S,6s)-3-(2-chloro-4-(difluoromethyl)thiazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0463]

[0464] A mixture of 2-chloro-4-(difluoromethyl)thiazole-5-carboxylic acid (0.12 g, 0.54 mmol), benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.H-02, 0.25 g, 0.54 mmol), HATU (0.21 g, 0.54 mmol), DIPEA (0.28 mL, 1.6 mmol) and DCM (2.7 mL) was stirred at room temperature for 1 hour. The mixture was subjected to silica gel chromatography (0-40% (25% EtOH / EtOAc) / hexanes) to provide the title compound.

[0465] Schema:

[0466]

[0467] Intermediate K-01

[0468] 4-Methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid

[0469]

[0470] Step 1: Ethyl 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylate

[0471] Under nitrogen atmosphere, a mixture of ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.15 g, 0.60 mmol), 2-(tributylstannyl)oxazole (0.21 g, 0.60 mmol), Pd(PPh3)4 (69 mg, 0.060 mmol) and 1,4-dioxane (3.0 mL) was stirred at 100°C for 16 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-60% (3:1 EtOAc / EtOH) / hexanes) to provide the title compound.

[0472] Step 2: 4-Methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid

[0473] To a solution of ethyl 4-methyl-2-(oxazole-2-yl)thiazole-5-carboxylate (94 mg, 0.40 mmol) in EtOH (1.0 mL) and THF (1.0 mL) was added sodium hydroxide (1.0 N aqueous solution, 0.60 mL, 0.60 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude residue was dissolved in MeOH (1.0 mL), hydrochloric acid (1 N, 0.20 mL) was added, and the mixture was concentrated under reduced pressure to provide the title compound.

[0474] The following compounds were prepared using the procedure described in the synthesis of intermediate K-01, substituting the appropriate reagents for 2-(tributylstannyl)oxazole and ethyl 2-bromo-4-methylthiazole-5-carboxylate.

[0475]

[0476]

[0477] Intermediate K-09

[0478] 1-Methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylic acid

[0479]

[0480] Step 1: 1-Methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylic acid ethyl ester

[0481] Under N2, 4-(tributylstannyl)thiazole (0.29g, 0.77mmol) and Pd(PPh3)4 (44mg, 0.040mmol) were added to a solution of 3-bromo-1-methyl-1H-1,2,4-triazole-5-formic acid ethyl ester (0.090g, 0.39mmol) in 1,4-dioxane (8.0mL), and the mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature, and a solution of potassium fluoride (saturated aqueous solution, 5mL) was added. After 30 minutes, the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (50% EtOAc / petroleum ether) to provide the title compound.

[0482] Step 2: 1-Methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylic acid

[0483] To a mixture of 1-methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylic acid ethyl ester (0.080 g, 0.34 mmol) in THF (5.0 mL) and H2O (3.0 mL) was added LiOH (16 mg, 0.67 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to remove the volatile organic solvents and then washed with DCM (2x). The aqueous solution was acidified with hydrochloric acid (1N) (pH=6) and concentrated under reduced pressure. MeOH (5 mL) and DCM (5 mL) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0484] Schema:

[0485]

[0486] Intermediate K-10

[0487] 4-Acetyl-[2,4'-bithiazole]-5-carboxylic acid

[0488]

[0489] Step 1: 4-Hydroxy-[2,4'-bithiazole]-5-carboxylic acid ethyl ester

[0490] A solution of thiazole-4-thiocarboxamide (0.70 g, 4.9 mmol), diethyl 2-bromomalonate (1.3 g, 5.3 mmol) and pyridine (1.6 mL, 19 mmol) in EtOH (0.020 L) was stirred at 80 °C for 12 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to provide the title compound.

[0491] Step 2: Ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-[2,4'-bithiazole]-5-carboxylate

[0492] Trifluoromethanesulfonic anhydride (0.20 mL, 1.2 mmol) was added dropwise to a solution of ethyl 4-hydroxy-[2,4'-bithiazole]-5-carboxylate (0.20 mL, 2.3 mmol) in DCM (7.0 mL) at 0°C under a nitrogen atmosphere. The mixture was then warmed to room temperature and stirred for 12 hours. The mixture was concentrated under reduced pressure, and the residue was subjected to preparative TLC (25% EtOAc / petroleum ether) to provide the title compound.

[0493] Step 3: 4-acetyl-[2,4'-bithiazole]-5-carboxylic acid ethyl ester

[0494] Under nitrogen atmosphere, a mixture of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-[2,4'-bithiazole]-5-carboxylate (0.49 g, 1.2 mmol), PhMe (0.010 L), triethylamine (0.50 mL, 3.8 mmol), 1,3-bis(diphenylphosphino)propane (77 mg, 0.19 mmol), ethoxyethylene (1.1 g, 15 mmol) and Pd(OAc)2 (42 mg, 0.19 mmol) was stirred at 110°C for 12 hours. The mixture was concentrated under reduced pressure. EtOAc (30 mL) was added, and the solution was washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. THF (8.0 mL) and hydrochloric acid (3.0 N, 2.0 mL, 6.0 mmol) were added and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the mixture and extracted with EtOAc (15 mL x 3). The combined organic solution was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to provide the title compound.

[0495] Step 4: 4-Acetyl-[2,4'-bithiazole]-5-carboxylic acid

[0496] To a mixture of 4-acetyl-[2,4'-bithiazole]-5-carboxylic acid ethyl ester (0.050 g, 0.18 mmol) in EtOH (2.0 mL) and water (2.0 mL) was added LiOH (11 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the aqueous layer was washed with DCM (10 mL x 2). The aqueous phase was acidified with hydrochloric acid (1N) (pH=4) and extracted with EtOAc (10 mL x 3). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0497] Schema:

[0498]

[0499] Intermediate K-11

[0500] Ethyl 3-(thiazol-4-yl)-1,2,4-thiadiazole-5-carboxylate

[0501]

[0502] Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0503] Under nitrogen atmosphere, a mixture of 3,5-dichloro-1,2,4-thiadiazole (6.3 g, 41 mmol), tributyl(1-ethoxyvinyl)stannane (14 mL, 41 mmol), bis(triphenylphosphine)palladium(II) chloride (2.9 g, 4.1 mmol) and DMF (0.060 L) was stirred at 60 ° C for 12 hours. The mixture was cooled to room temperature, and a solution of potassium fluoride (saturated aqueous solution, 10 mL) was added. The mixture was stirred for 30 minutes and extracted with EtOAc (30 mL x 3). The combined organic mixture was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-5% EtOAc / petroleum ether) to provide the title compound.

[0504] Step 2: Ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate

[0505] To a mixture of 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (2.0 g, 11 mmol), 1,4-dioxane (15 mL) and H2O (5.0 mL) was added NaIO4 (4.5 g, 21 mmol) and KMnO4 (0.33 g, 2.1 mmol). The mixture was stirred at room temperature for 1 hour. A solution of NaHCO3 (saturated aqueous solution, 0.010 L) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with EtOAc (20 mL x 3). The combined organic solution was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-5% EtOAc / petroleum ether) to provide the title compound.

[0506] Step 3: Ethyl 3-(thiazol-4-yl)-1,2,4-thiadiazole-5-carboxylate

[0507] To a solution of 3-chloro-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (0.18 g, 0.93 mmol) in 1,4-dioxane (0.010 L) was added 4-(tributylstannyl)thiazole (0.42 g, 1.1 mmol) and Pd(PPh3)4 (0.11 g, 0.093 mmol) under N2. The mixture was heated at 100 °C for 15 hours. The mixture was cooled to room temperature and a solution of potassium fluoride (saturated aqueous solution, 10 mL) was added. The mixture was stirred at room temperature for 30 minutes and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to provide the title compound.

[0508] Schema:

[0509]

[0510] Intermediate L-1

[0511] 1-Methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid

[0512]

[0513] Step 1: 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid methyl ester

[0514] To a mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester (2.0 g, 7.5 mmol), 4-bromothiazole (1.2 g, 7.5 mmol) and Na2CO3 (2.4 g, 23 mmol) in DME (0.040 L) and water (4.0 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.25 g, 0.38 mmol) at 25°C. The mixture was stirred at 90°C for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic solution was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (20-35% EtOAc / petroleum ether) to provide the title compound.

[0515] Step 2: 1-Methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid

[0516] To a mixture of 1-methyl-3-(thiazole-4-yl)-1H-pyrazole-5-formic acid methyl ester (1.2g, 5.4mmol) in THF (0.010L) and water (0.010L) was added LiOH (0.64g, 27mmol). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure and washed with DCM (10mL x 2). The aqueous solution was acidified (pH=4) with HCl solution (1N aqueous solution) and concentrated under reduced pressure. MeOH (10mL) and DCM (10mL) were added, and the mixture was stirred at 25°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title compound.

[0517] Schema:

[0518]

[0519] Intermediate L-2

[0520] 1-Ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid

[0521]

[0522] Step 1: 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0523] 3,4-dihydro-2H-pyran (3.2 g, 38 mmol) and TFA (0.027 mL, 0.36 mmol) were added to a solution of 1H-pyrazole-5-carboxylic acid ethyl ester (5.0 g, 36 mmol) in PhMe (0.030 L). The mixture was stirred at 80 ° C for 2 hours. The mixture was concentrated under reduced pressure. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-60% EtOAc / petroleum ether) to provide the title compound.

[0524] Step 2: 1-(Tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0525] Under nitrogen atmosphere, a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (4.8 g, 21 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (5.4 g, 21 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.57 g, 2.1 mmol), [Ir(cod)OMe]2 (0.71 g, 1.1 mmol) and THF (0.080 L) was stirred at 80 ° C for 12 hours. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic solution was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase chromatography (35% MeCN / water) to provide the title compound.

[0526] Step 3: 1-(Tetrahydro-2H-pyran-2-yl)-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0527] A mixture of 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (1.0 g, 2.9 mmol), 4-bromothiazole (0.70 g, 4.3 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.19 g, 0.29 mmol), Na2CO3 (0.91 g, 8.6 mmol), DME (0.040 L) and water (4.0 mL) was stirred at 100° C. for 12 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic solution was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound.

[0528] Step 4: Ethyl 3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate

[0529] A solution of ethyl 1-(tetrahydro-2H-pyran-2-yl)-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (0.85 g, 2.8 mmol) in hydrochloric acid (37%, 2.0 mL) was stirred at 80° C. for 10 minutes. The mixture was concentrated under reduced pressure to provide the title compound.

[0530] Step 5: 1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0531] Under nitrogen atmosphere, a mixture of ethyl 3-(thiazole-4-yl)-1H-pyrazole-5-carboxylate (0.52 g, 2.3 mmol), K2CO3 (0.97 g, 7.0 mmol), iodoethane (0.90 mL, 12 mmol) and acetone (0.030 L) was heated at 70 ° C for 19 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. EtOAc (50 mL) was added, and the mixture was washed with water (50 mL), hydrochloric acid (1N, 50 mL) and saline (50 mL). The mixture was concentrated under reduced pressure and subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound.

[0532] Step 6: 1-Ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid

[0533] To a mixture of 1-ethyl-3-(thiazole-4-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (0.030g, 0.12mmol) in THF (2.0mL) and water (2.0mL) was added LiOH (8.6mg, 0.36mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and washed with DCM (10mL x 2). The aqueous solution was acidified (pH=4) with hydrochloric acid (1N), and the mixture was concentrated under reduced pressure. MeOH / DCM (1:5, 20mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0534] Schema:

[0535]

[0536] Intermediate M-1

[0537] 4-Fluoro-1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester

[0538]

[0539] Step 1: 3-((tert-Butyldimethylsilyl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

[0540] To a room temperature solution of 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (5.0 g, 32 mmol) in MeCN (0.050 L) was added imidazole (3.5 g, 51 mmol) and tert-butyldimethylsilyl chloride (7.2 g, 48 mmol). After 1 hour, the mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound.

[0541] Step 2: 4-Fluoro-3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

[0542] To a solution of methyl 3-((tert-butyldimethylsilyl)oxy)-1-methyl-1H-pyrazole-5-carboxylate (7.5 g, 28 mmol) in MeCN (0.10 L) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (15 g, 42 mmol). The mixture was heated at 90° C. for 30 minutes. The mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to reverse phase liquid chromatography (74% MeCN / water) to provide the title compound.

[0543] Step 3: 4-Fluoro-1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylic acid methyl ester

[0544] To a 0°C solution of 4-fluoro-3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (1.1 g, 6.3 mmol) in DCM (12 mL) was added pyridine (0.50 mL, 6.3 mmol) followed by dropwise addition of trifluoromethanesulfonic anhydride (1.2 mL, 7.0 mmol). The mixture was slowly warmed to room temperature and stirred for 2 hours. The mixture was diluted with H2O and then extracted with DCM (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound.

[0545] Step 4: 4-Fluoro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester

[0546] In a glove box, to a solution of methyl 4-fluoro-1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate (1.5 g, 4.9 mmol), bis(pinacolato)diboron (1.9 g, 7.4 mmol) and potassium acetate (1.4 g, 15 mmol) in 1,4-dioxane (15 mL) was added Pd(dppf)Cl2 (0.18 g, 0.25 mmol). The mixture was stirred at 90 °C for 12 hours. The mixture was cooled to room temperature, diluted with PhMe and H2O, and filtered through a pad of celite. The filtrate layers were separated and the aqueous layer was extracted with PhMe (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was slurried in pentane, filtered and the filtrate was concentrated to provide the title compound.

[0547] Step 5: 4-Fluoro-1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester

[0548] Under nitrogen atmosphere, a mixture of 4-fluoro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester (1.5 g, 2.6 mmol), 2-bromooxazole (0.39 g, 2.6 mmol), Na2CO3 (0.84 g, 7.9 mmol), Pd(dtbpf)Cl2 (0.086 g, 0.13 mmol), DME (0.020 L) and H2O (2.0 mL) was heated to 90°C for 2 hours. The mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (25% EtOAc / petroleum ether) to provide the title compound.

[0549] The following compounds were prepared using the procedure described in the synthesis of intermediate M-1, substituting the appropriate reagent for 2-bromooxazole in step 5.

[0550]

[0551] Schema:

[0552]

[0553] Intermediate N

[0554] 1-Methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid

[0555]

[0556] Step 1: 1-Methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0557] To a -15°C solution of oxazole (0.42 mL, 6.4 mmol) in THF (21 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 8.6 mL, 8.6 mmol) dropwise over 15 minutes. The mixture was stirred at -15°C for 30 minutes. A solution of zinc chloride (0.50 M in THF, 28 mL, 14 mmol) was injected and the mixture was stirred at -15°C for 15 minutes. The solution was warmed to room temperature, stirred for 30 minutes, and added to a mixture of ethyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.0 g, 4.3 mmol) and Pd(dppf)Cl2 (0.16 g, 0.22 mmol). The mixture was stirred at 75°C for 12 hours. The mixture was cooled to room temperature, NH4Cl (saturated aqueous solution, 50 mL) and EtOAc (75 mL) were added, and the mixture was washed with water (75 mL) and brine (75 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-15% (25% EtOH / EtOAc) / hexane) to provide the title compound.

[0558] Step 2: 1-Methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid

[0559] To a solution of 1-methyl-3-(oxazole-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester (0.85g, 3.8mmol) in EtOH (9.6mL) and THF (9.6mL) was added a solution of sodium hydroxide (1.0N aqueous solution, 5.8mL, 5.8mmol). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The mixture was dissolved in a solution of sodium hydroxide (0.05M aqueous solution, 75mL) and washed with DCM (50mL x 3). The aqueous solution was acidified with hydrochloric acid (1N) (pH=1). The mixture was stirred at room temperature for 12 hours, filtered and the filter cake was washed with water (10mL x 3). The filter cake was subjected to reverse phase HPLC (0-90% MeCN / water containing 0.1% TFA modifier) ​​to provide the title compound.

[0560] Schema:

[0561]

[0562] Intermediate O-1

[0563] 2-(Isoxazolyl-3-yl)-4-methylthiazole-5-carboxylic acid

[0564]

[0565] Step 1: Methyl 2-formyl-4-methylthiazole-5-carboxylate

[0566] To a solution of methyl 2-(hydroxymethyl)-4-methylthiazole-5-carboxylate (0.50 g, 2.7 mmol) in DCM (13 mL) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzidoyl-3-(1H)-one (1.4 g, 3.2 mmol). The mixture was stirred at ambient temperature for 1 hour. DCM (10 mL), Na2S2O3 (saturated aqueous solution, 5 mL), NaHCO3 (saturated aqueous solution, 5 mL) were added and the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was back extracted with DCM (10 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0567] Step 2: Methyl 2-((Hydroxyimino)methyl)-4-methylthiazole-5-carboxylate

[0568] To a mixture of methyl 2-formyl-4-methylthiazole-5-carboxylate (0.50 g, 2.7 mmol) and hydroxylamine hydrochloride (0.19 g. 2.7 mmol) in EtOH (13 mL) was added pyridine (0.22 mL, 2.7 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure to provide the title compound.

[0569] Step 3: Methyl 4-methyl-2-(5-(trimethylsilyl)isoxazol-3-yl)thiazole-5-carboxylate

[0570] A mixture of methyl 2-((hydroxyimino)methyl)-4-methylthiazole-5-carboxylate (0.15 g, 0.75 mmol), CrO2 (0.63 g, 7.5 mmol), trimethylsilylacetylene (0.32 mL, 2.3 mmol) and MeCN (7.5 mL) was stirred at 80°C overnight. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-20% EtOAc / hexanes) to provide the title compound.

[0571] Step 4: Methyl 2-(isoxazol-3-yl)-4-methylthiazole-5-carboxylate

[0572] A suspension of methyl 4-methyl-2-(5-(trimethylsilyl)isoxazol-3-yl)thiazole-5-carboxylate (0.080 g, 0.27 mmol) and potassium carbonate (37 mg, 0.27 mmol) in MeOH (1.5 mL) was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. EtOAc (5 mL) was added, and the mixture was washed with NaHCO (saturated aqueous solution, 5 mL) and brine (5 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0573] Step 5: 2-(Isoxazolyl-3-yl)-4-methylthiazole-5-carboxylic acid

[0574] To a solution of methyl 2-(isoxazol-3-yl)-4-methylthiazole-5-carboxylate (58 mg, 0.26 mmol) in MeOH (1.0 mL) was added a solution of sodium hydroxide (1.0 N aqueous solution, 0.26 mL, 0.52 mmol). The reaction mixture was stirred at 80 °C for 1 hour and concentrated under reduced pressure. The crude residue was dissolved in EtOAc (3.0 mL), washed with hydrochloric acid (1 N), dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound.

[0575] The following compounds were prepared using the procedure described in the synthesis of intermediate 0-1, substituting the appropriate reagents for methyl 2-formyl-4-methylthiazole-5-carboxylate.

[0576]

[0577] Schema:

[0578]

[0579] Intermediate P

[0580] 3-(Thiazol-4-yl)isothiazole-5-carboxylic acid

[0581]

[0582] Step 1: 5-(thiazol-4-yl)-1,3,4-oxathiazol-2-one

[0583] To a mixture of thiazole-4-carboxamide (0.50 g, 3.9 mmol) in THF (8.0 mL) was added carbonochloridic hypochlorous thioanhydride (0.60 mL, 7.0 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 12 hours. The organic layer was concentrated under reduced pressure to provide the title compound.

[0584] Step 2: Methyl 3-(thiazol-4-yl)isothiazole-5-carboxylate

[0585] To a mixture of 5-(thiazol-4-yl)-1,3,4-oxathiazol-2-one (0.30 g, 1.6 mmol) in xylene (5.0 mL) was added methyl propiolate (2.0 mL, 32 mmol) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 145 °C for 3 days. The mixture was concentrated under reduced pressure. The residue was subjected to preparative TLC (25% EtOAc / petroleum ether) to provide the title compound.

[0586] Step 3: 3-(Thiazol-4-yl)isothiazole-5-carboxylic acid

[0587] To a mixture of methyl 3-(thiazole-4-yl)isothiazole-5-carboxylate (130 mg, 0.55 mmol) in MeOH (3.0 mL) and water (3.0 mL) was added LiOH (27 mg, 1.1 mmol), the mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure, and the aqueous layer was washed with DCM (5 mL x 2). The aqueous solution was acidified with hydrochloric acid (1N) (pH = 4). The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic solution was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound.

[0588] Intermediate Q

[0589] 3-(5-Fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0590]

[0591] Step 1: 3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

[0592] To a solution of methyl 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (prepared as in step 1 of L-1, 0.60 g, 2.2 mmol) in MeCN (25 mL) was added (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.1 g, 3.2 mmol), and the mixture was stirred at 80°C for 12 hours. A solution of NaHCO3 (saturated aqueous solution, 10 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The combined organic solutions were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The mixture was subjected to reverse phase HPLC (29-49% MeCN / water containing 0.1% TFA modifier) ​​and lyophilized to provide the title compound.

[0593] Step 2: 3-(5-Fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0594] To a mixture of 3-(5-fluorothiazole-4-yl)-1-methyl-1H-pyrazole-5-formic acid methyl ester (0.14g, 0.58mmol) in THF (3.0mL) and water (3.0mL) was added LiOH (28mg, 1.2mmol). The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure and extracted with DCM (10mL x 2). The aqueous solution was acidified (pH=4) with hydrochloric acid (1N) and concentrated under reduced pressure. DCM (10mL) and MeOH (10mL) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title compound.

[0595] Schema:

[0596]

[0597] Intermediate R

[0598] 3-Methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylic acid

[0599]

[0600] Step 1: 3-Methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0601] A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (0.50 g, 3.2 mmol), trans-1,2-diaminocyclohexane (74 mg, 0.65 mmol), 4-bromothiazole (1.1 g, 6.5 mmol), Cs2CO3 (2.1 g, 6.5 mmol), CuI (62 mg, 0.32 mmol) and DMA (15 mL) was stirred at 100 ° C for 12 hours. The mixture was cooled to room temperature, poured into water (20 mL) and extracted with MTBE (20 mL x 3). The combined organic solution was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-80% EtOAc / petroleum ether) to provide the title compound.

[0602] Step 2: 3-Methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylic acid

[0603] To a mixture of 3-methyl-1-(thiazole-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.080g, 0.34mmol) in THF (3.0mL) and water (3.0mL) was added LiOH (81mg, 3.4mmol). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and washed with DCM (10mL x 2). The aqueous mixture was acidified (pH=4) with hydrochloric acid (1N) and concentrated under reduced pressure. The material was stirred at room temperature for 1 hour in MeOH / DCM (20mL of 1:10 mixture). The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0604] Schema:

[0605]

[0606] Intermediate S

[0607] N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0608]

[0609] Step 1: 2-Chloro-6-(4-fluorophenyl)isonicotinic acid methyl ester

[0610] To a mixture of methyl 2,6-dichloroisonicotinate (0.010 kg, 49 mmol), (4-fluorophenyl)boronic acid (6.6 g, 47 mmol) and CsCO (24 g, 73 mmol) in 1,4-dioxane (0.50 L) and water (26 mL) was added PdCl(dppf) (2.7 g, 3.6 mmol) at 25°C. The mixture was stirred at 25°C for 12 hours. The mixture was filtered and the filtrate was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-10% EtOAc / petroleum ether) to provide the title compound.

[0611] Step 2: (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(methoxycarbonyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester

[0612] In a glove box, Pd(OAc)2 (85 mg, 0.38 mmol) was added to a solution of (1R, 5S, 6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (1.8 g, 7.5 mmol), 2-chloro-6-(4-fluorophenyl)isonicotinic acid methyl ester (2.0 g, 7.5 mmol), K3PO4 (4.8 g, 23 mmol), 5-(bis((3S, 5S, 7S)-adamantan-1-yl)phosphanyl)-1', 3', 5'-triphenyl-1'H-1, 4'-bipyrazole (0.50 g, 0.75 mmol) in CPME (0.020 L) and CF3Ph (0.020 L). The mixture was heated to 90°C. After 16 hours, the mixture was cooled, filtered through silica gel (eluted with EtOAc) and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / petroleum ether) to provide the title compound.

[0613] Step 3: (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(hydroxymethyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester

[0614] To a mixture of (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(methoxycarbonyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (1.5 g, 3.2 mmol) in THF (15 mL) was added LiAlH4 (1.0 M in THF) (8.1 mL, 8.1 mmol) at -78 °C. After 30 minutes, the reaction was quenched with water (0.20 mL), 15% NaOH (0.60 mL aqueous solution) and additional water (0.20 mL). The reaction was warmed to 0 °C and stirred for 10 minutes. Anhydrous magnesium sulfate was added, the mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0615] Step 4: (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-formylpyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester

[0616] To a mixture of benzyl (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(hydroxymethyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.90 g, 2.1 mmol) in DCM (0.020 L) at 25° C. was added manganese (IV) oxide (1.8 g, 21 mmol). The resulting mixture was stirred at 40° C. for 18 hours. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0617] Step 5: (1R,5S,6s)-6-((4-((Z)-((tert-butylsulfinyl)imino)methyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester

[0618] To a mixture of (1R, 5S, 6s)-6-((6-(4-fluorophenyl)-4-formylpyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (0.85 g, 2.0 mmol) and 2-methylpropane-2-sulfinamide (0.29 g, 2.4 mmol) in THF (0.020 L) was added tetraethoxytitanium (0.90 g, 3.9 mmol) at 25 ° C. After 18 hours, the reaction mixture was quenched with brine (25 mL). The mixture was filtered and extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to provide the title compound.

[0619] Step 6: (1R,5S,6s)-6-((4-(1-((tert-butylsulfinyl)amino)ethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester

[0620] To a mixture of (1R, 5S, 6s)-6-((4-((Z)-((tert-butylsulfinyl)imino)methyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (0.45 g, 0.84 mmol) in THF (0.010 L) was added methylmagnesium bromide (1.0 M in EtO) (0.42 mL, 1.3 mmol) at 0 ° C. The resulting mixture was stirred at 25 ° C. After 1 hour, the reaction mixture was quenched with NH4Cl (saturated aqueous solution, 20 mL) and extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0621] Step 7: N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0622] To a solution of benzyl (1R,5S,6s)-6-((4-(1-((tert-butylsulfinyl)amino)ethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.43 g, 0.78 mmol) in THF (5.0 mL) was added triethylamine (0.40 mL, 3.1 mmol), triethylsilane (0.45 g, 3.9 mmol) and palladium(II) chloride (28 mg, 0.16 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0623] Schema:

[0624]

[0625] Intermediate T

[0626] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate

[0627]

[0628] Step 1: 1-Methylcyclopentane-1-carbonyl chloride

[0629] To a solution of 1-methylcyclopentane-1-carboxylic acid (1.3 g, 9.8 mmol) in DCM (0.050 L) was added oxalyl chloride (1.1 mL, 13 mmol) followed by two drops of DMF (gas evolution). After 3 hours, gas evolution ceased and the reaction was concentrated under reduced pressure to afford the title compound.

[0630] Step 2: 2-(1-Methylcyclopentyl)isonicotinonitrile

[0631] To a solution of 4-cyanopyridine 1-oxide (0.98 g, 8.1 mmol) and [Ir[(ppy)2(dtbbpy)]PF6 (74 mg, 0.081 mmol) in MeCN (2.0 mL) was added a solution of 1-methylcyclopentane-1-carbonyl chloride (1.4 g, 9.8 mmol) in MeCN (2.0 mL). The reaction was placed under N2 and irradiated with a Photobox (50% blue LED, fan: 6800 rpm, stirring rate: 1200 rpm) at 25 ° C. After 18 hours, the mixture was poured into NaHCO3 (saturated aqueous solution). The resulting mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / heptane) to provide the title compound

[0632] Step 3: 2-(2-(1-methylcyclopentyl)pyridin-4-yl)propan-2-amine

[0633] To a 0°C solution of 2-(1-methylcyclopentyl)isonicotinonitrile (0.34 g, 1.8 mmol) in toluene (0.010 L) was slowly added MeMgBr (3.0 M, 1.9 mL, 5.7 mmol). After 30 minutes, titanium (IV) isopropoxide (0.55 mL, 1.9 mmol) was slowly added. After 30 minutes, the reaction was warmed to 25°C. After 18 hours, the mixture was quenched with NaOH (2 M aqueous solution, 1 mL). After 30 minutes, the mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0634] Step 4: Benzyl (2-(2-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate

[0635] A solution of 2-(2-(1-methylcyclopentyl)pyridin-4-yl)propan-2-amine (0.40 g, 1.8 mmol) in DCM (0.010 L) was cooled to 0°C. To this was added DIPEA (0.48 mL, 2.8 mmol) followed by CbzCl (0.79 mL, 2.4 mmol). After 30 minutes, the reaction was warmed to 25°C. After 1 hour, the reaction was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / heptane) to provide the title compound.

[0636] Step 5: 4-(2-(((Benzyloxy)carbonyl)amino)propan-2-yl)-2-(1-methylcyclopentyl)pyridine 1-oxide

[0637] To a solution of benzyl (2-(2-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate (0.41 g, 1.1 mmol) in DCM (6.0 mL) was added m-CPBA (0.34 g, 1.5 mmol). After 5 hours, the mixture was diluted with NaHCO3 (saturated aqueous solution) and extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-100% 3:1 EtOAc:EtOH / heptane) to provide the title compound.

[0638] Step 6: Benzyl (2-(2-chloro-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate

[0639] To a solution of 4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-2-(1-methylcyclopentyl)pyridine 1-oxide (0.33 g, 0.90 mmol) in MeCN (5.0 mL) was added POCl (0.30 mL, 3.2 mmol). The mixture was heated to 80 °C. After 18 hours, additional POCl (1.0 mL, 11 mmol) was added and the reaction continued to be heated at 80 °C. After 18 hours, the reaction was concentrated under reduced pressure. The reaction was quenched with NaHCO (saturated aqueous solution) and extracted with DCM. The organic mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-100% 3:1 EtOAc:EtOH / heptane) to provide the title compound.

[0640] Step 7: (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(1-methylcyclopentyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0641] A mixture of benzyl (2-(2-chloro-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate (68 mg, 0.18 mmol), tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int.E, 44 mg, 0.22 mmol), Cs2CO3 (0.18 g, 0.53 mmol), Pd2(dba)3 (9.0 mg, 9.8 μmol), AdBippyPhos (13 mg, 0.020 mmol) and toluene (1.5 mL) was placed under N2 and stirred at 85°C. After 4 hours, the reaction was cooled, diluted with EtOAc, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-100% EtOAc / heptane) to provide the title compound.

[0642] Step 8: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate

[0643] A solution of (1R,5S,6s)-tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(1-methylcyclopentyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (45 mg, 0.082 mmol) in HCl (4.0 M in dioxane, 1.0 mL) was stirred at 25° C. After 3 hours, the reaction was concentrated under reduced pressure to provide the title compound.

[0644] Schema:

[0645]

[0646] Intermediate U

[0647] Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-yl)carbamate

[0648]

[0649] Step 1: tert-Butyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate

[0650] To a solution of 2-(2,6-dichloropyridin-4-yl)propan-2-amine (2.0 g, 9.8 mmol) in toluene (0.020 L) was added di-tert-butyl dicarbonate (2.7 mL, 12 mmol) and triethylamine (4.1 mL, 29 mmol). The resulting mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-10% EtOAc / petroleum ether) to provide the title compound.

[0651] Step 2: tert-Butyl (2-(2-chloro-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-yl)carbamate

[0652] A mixture of tert-butyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate (4.4 g, 14 mmol), 4,4-dimethylpiperidine (1.9 g, 13 mmol), Pd2(dba)3 (0.30 g, 0.33 mmol), BINAP (0.41 g, 0.65 mmol), Cs2CO3 (11 g, 33 mmol) and toluene (0.10 L) was stirred at 100°C for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), and washed with brine (200 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-10% 3:1 EtOAc:EtOH / hexanes) to provide the title compound.

[0653] Step 3: (1R,5S,6s)-6-((4-(2-((tert-butoxycarbonyl)-12-azanyl)propan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0654] A mixture of tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.94 g, 4.7 mmol), tert-butyl (2-(2-chloro-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-yl)carbamate (1.5 g, 3.9 mmol), Pd2(dba)3 (0.072 g, 0.079 mmol), 5-(bis((3S,5S,7S)-adamantan-1-yl)phosphanyl)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (0.10 g, 0.16 mmol), Cs2CO3 (3.8 g, 12 mmol) and 1,4-dioxane (0.020 L) was stirred at 85°C for 14 hours. The mixture was cooled to room temperature, diluted with EtOAc (60 mL) and washed with water (60 mL) and brine (60 mL). The organic mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-20% EtOAc / hexanes) to provide the title compound.

[0655] Step 4: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-amine

[0656] To a solution of (1R,5S,6s)-6-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.0 g, 1.9 mmol) in DCM (14 mL) was added TFA (4.7 mL). The reaction was stirred at 25 °C for 16 hours. The mixture was poured into NaOH (1N aqueous solution, 50 mL), the pH was adjusted to pH>12, and extracted with DCM (50 mL x 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0657] Schema:

[0658]

[0659] Intermediate V

[0660] 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid

[0661]

[0662] Step 1: 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid methyl ester

[0663] To a solution of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester (1.0 g, 3.8 mmol) and 1H-pyrazole (0.34 g, 5.0 mmol) in DMF (0.030 L) was added pyridine (1.5 mL, 19 mmol) and copper (II) acetate monohydrate (0.75 g, 3.8 mmol). The reaction was placed under an O2 atmosphere and heated to 80 °C. After 12 hours, the reaction was cooled to room temperature, diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / petroleum ether) to provide the title compound.

[0664] Step 2: 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid

[0665] To a solution of 1'-methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid methyl ester (0.12 g, 0.58 mmol) in MeOH (3.0 mL) and water (2.0 mL) was added LiOH (28 mg, 1.2 mmol). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. Water (5 mL) was added and the pH was adjusted to ~3 with HCl (1M aqueous solution). The mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0666] Schema:

[0667]

[0668] Intermediate W

[0669] 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid

[0670]

[0671] Step 1: 3-Hydrazino-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester hydrochloride

[0672] A solution of sodium nitrite (0.11 g, 1.6 mmol) in water (1.5 mL) was added to a 0°C solution of methyl 3-amino-1-methyl-1H-pyrazole-5-carboxylate (0.17 g, 1.1 mmol) in hydrochloric acid (37%, 2.0 mL). After stirring for 30 minutes, a solution of SnCl2·2H2O (0.45 g, 2.1 mmol) in hydrochloric acid (37%, 3.3 mL) was added. The mixture was warmed to 25°C and stirred for 2 hours. The mixture was concentrated under reduced pressure and co-evaporated with EtOH (5 mL x 2) to provide the title compound.

[0673] Step 2: 1-methyl-3-(2-(2-oxoethylidene)hydrazino)-1H-pyrazole-5-carboxylic acid methyl ester

[0674] To a solution of 3-hydrazino-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (0.020 g, 0.12 mmol) in water (2.0 mL) was added a solution of glyoxal (17 mg, 0.12 mmol) in water (0.50 mL), followed by a solution of sodium acetate (9.6 mg, 0.12 mmol) in water (0.50 mL). The mixture was stirred at 25 ° C for 30 minutes. The mixture was lyophilized to provide the title compound.

[0675] Step 3: 3-(2-(2-(2,2-dimethylhydrazono)ethylidene)hydrazinyl)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

[0676] To a solution of 1-methyl-3-(2-(2-oxoethylidene)hydrazine)-1H-pyrazole-5-carboxylic acid methyl ester (0.080 g, 0.38 mmol) in MeOH (5.0 mL) and toluene (2.5 mL) was added sodium acetate (47 mg, 0.57 mmol) followed by 1,1-dimethylhydrazine hydrochloride (44 mg, 0.46 mmol). The mixture was stirred at 25 °C. After 12 hours, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0677] Step 4: 2-(2-(2-(5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide

[0678] To a solution of methyl 3-(2-(2-(2,2-dimethylhydrazono)ethylidene)hydrazinyl)-1-methyl-1H-pyrazole-5-carboxylate (0.090 g, 0.36 mmol) in MeCN (3.0 mL) was added iodomethane (0.11 mL, 1.8 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was diluted with EtOAc (5 mL) and concentrated under reduced pressure to provide the title compound.

[0679] Step 5: 1-methyl-3-(2H-1,2,3-triazol-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester

[0680] To a solution of 2-(2-(2-(5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide (0.13 g, 0.33 mmol) in DMF (3.0 mL) was added K2CO3 (91 mg, 0.66 mmol). The mixture was stirred at 50 °C for 2 hours. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to preparative TLC (25% EtOAc / petroleum ether) to provide the title compound.

[0681] Step 6: 1-Methyl-3-(2H-1,2,3-triazol-2-yl)-1H-pyrazole-5-carboxylic acid

[0682] A mixture of 1-methyl-3-(2H-1,2,3-triazol-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester (65 mg, 0.31 mmol), LiOH (15 mg, 0.63 mmol), MeOH (3.0 mL) and water (3.0 mL) was stirred at 25 °C. After 2 hours, the mixture was concentrated under reduced pressure. The mixture was diluted with water (5 mL) and extracted with DCM (3 mL x 2). The aqueous layer was acidified to pH ~ 3 with HCl (1M aqueous solution) and extracted with EtOAc (10 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0683] Example

[0684] Schema:

[0685]

[0686] Example 1

[0687] rel-((1R,4R,5R)-5-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hex-2-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 2)

[0688]

[0689] Step 1: tert-butyl rel-(2-(2-(((1R,4R,5R)-2-azabicyclo[2.2.0]hex-5-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2)

[0690] To a mixture of rel-(1R,4R,5R)-5-((4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylic acid benzyl ester (Int.D-ent-2, 0.10 g, 0.18 mmol) and palladium(II) chloride (3.2 mg, 0.018 mmol) in DCM (1.8 mL) was added triethylamine (0.25 mL, 1.8 mmol) and triethylsilane (0.14 mL, 0.89 mmol). The mixture was stirred at room temperature for 1 hour and filtered through a pad of celite (eluted with DCM, 5 mL x 3) to provide the title compound.

[0691] Step 2: rel-((1R,4R,5R)-5-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-2-azabicyclo[2.2.0]hexan-2-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 2)

[0692] To a mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (37 mg, 0.18 mmol), tert-butyl rel-(2-(2-(((1R,4R,5R)-2-azabicyclo[2.2.0]hex-5-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2, 76 mg, 0.18 mmol), DIPEA (0.093 mL, 0.53 mmol) and DCM (1.8 mL) was added HATU (68 mg, 0.18 mmol). The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. DCM (1.3 mL) and TFA (0.45 mL) were injected, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into NaOH (1N aqueous solution, 30 mL) and extracted with DCM (25 mL x 3). The combined organic solutions were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The mixture was subjected to reverse phase HPLC (10-100% MeCN / water containing 0.1% TFA modifier). The appropriate fractions were passed through an SCX-2 column, which was washed with MeOH (2 mL x 3) and eluted with ammonia in methanol (2N, 2 mL x 3) to provide the title compound. MS m / z (M+H) + : Calculated value 519.2, observed value 519.5. 1 H NMR (500 MHz, DMSO-d 6 ) Rotamer mixture: δ 9.20–9.15 (m, 1H), 8.16–8.09 (m, 2H), 8.01–7.96 (m, 1H), 7.76–7.69 (m, 1H), 7.36–7.26 (m, 2H), 7.13 and 6.81 (s, 1H), 6.94–6.89 (m, 1H), 5.62–5.52 (m, 1H), 5.11–5. 04 and 4.88–4.80 (m, 1H), 4.88–4.80 and 4.49–4.42 (m, 1H), 4.73–4.67 and 4.34–4.28 (m, 1H), 4.12 (s, 3H), 3.18–3.09 (m, 1H), 3.06–2.97 (m, 1H), 2.80–2.70 and 2.68–2.58 (m, 1H), 2.35 (br s, 2H), 1.39 (s, 6H) ppm.

[0693] The following compound was prepared using the procedure described in Example 1 substituting the appropriate reagent for 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid. The compound was isolated as a TFA salt.

[0694]

[0695]

[0696] Schema:

[0697]

[0698] Example 3

[0699] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-methyl-2-(oxazol-2-yl)thiazol-5-yl)methanone

[0700]

[0701] A mixture of 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine HCl (Int.H-01, 0.050 g, 0.13 mmol), 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid (Int.K-01, 19 mg, 0.090 mmol), DMF (0.70 mL), DIPEA (65 μL, 0.38 mmol) and HATU (33 mg, 0.090 mmol) was stirred at room temperature for 16 hours. The mixture was subjected to reverse phase HPLC (10-100% MeCN / water with 0.1% TFA modifier). The appropriate fractions were combined, treated with NaHCO (saturated aqueous solution, 5 mL) and extracted with DCM (3×5 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound. MS m / z: (M+H) + : Calculated value 520.2; measured value 520.1. 1 H NMR (500MHz, CDCl3) δ8.04–7.97(m,2H),7.82(s,1H),7.51(s,1H),7.34(s,1H),7.20–7.13(m,2H),6.78(s,1H),4.24(br s,1H),4.05(s,1H),3.85(br s,1H),3.79–3.72(m,2H),2.61(s,3H),2.14–1.92(m,2H),1.66–1.53(br s,2H),1.50(s,6H)ppm.

[0702] The following compounds were prepared using the procedure described in Example 3, substituting the appropriate reagents for 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid. After HPLC purification, the examples were concentrated to afford the TFA salt or extracted under basic conditions to afford the free base.

[0703]

[0704]

[0705]

[0706] Embodiment 14

[0707] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-(difluoromethyl)-[2,4'-bithiazole]-5-yl)methanone

[0708]

[0709] A mixture of benzyl (2-(2-(((1R,5S,6s)-3-(2-chloro-4-(difluoromethyl)thiazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.J, 15 mg, 0.023 mmol), 4-(tributylstannyl)thiazole (17 mg, 0.046 mmol), Pd(PPh3)4 (2.6 mg, 2.3 μmol) and 1,4-dioxane (0.50 mL) was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. Hydrochloric acid (37%, 0.25 mL) was added, and the mixture was stirred at 80°C for 10 minutes and concentrated. The residue was dissolved in DMSO (1 mL), subjected to mass-directed reverse phase HPLC (MeCN / water containing 0.1% TFA modifier), and the appropriate fractions were concentrated to afford the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 572.2; measured value 572.3. 1 H NMR (500 MHz, DMSO-d 6)δ9.33–9.30(m,1H),8.58–8.50(m,1H),8.24–8.17(m,2H),7.75(s,1H),7.38–7.31(m,2H),7.23(t,J=53.4Hz,1H),6.87(s,1H), 4.15(s,1H),4.05(d,J=12.2Hz,1H),3.82–3.63(m,2H),3.45–3.40(m,1H),2.18–2.10(m,1H),2.02–1.95(m,1H),1.65(s,6H)ppm.

[0710] Using the procedure described in Example 14, substituting the appropriate reagent for 4-(tributylstannyl)thiazole, the following compounds were prepared.

[0711]

[0712]

[0713] Schema:

[0714]

[0715] Example 16A

[0716] ent-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-yl)methanone (enantiomer 1)

[0717] and

[0718] Example 16B

[0719] ent-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-yl)methanone (Enantiomer 2)

[0720]

[0721] Step 1: Benzyl (2-(2-(((1R,5S,6s)-3-(4-acetyl-[2,4'-bithiazole]-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0722] A mixture of 4-acetyl-[2,4'-bithiazole]-5-carboxylic acid (Int.K-10, 0.040 g, 0.16 mmol), DIPEA (0.10 mL, 0.47 mmol), benzyl (2-(2-(((1R, 5S, 6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.H-02, 0.080 g, 0.17 mmol) and T3P (0.20 g, 0.32 mmol, 50 wt % in EtOAc) in DMF (5.0 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL) and concentrated under reduced pressure. The residue was subjected to preparative TLC (50% EtOAc / petroleum ether) to provide the title compound.

[0723] Step 2: Benzyl ent-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6R)-3-(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomers 1 and 2)

[0724] To a solution of benzyl (2-(2-(((1R,5S,6s)-3-(4-acetyl-[2,4'-bithiazole]-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (0.090 g, 0.13 mmol) in MeOH (3.0 mL) was added sodium borohydride (9.8 mg, 0.26 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 40 minutes. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to preparative TLC (50% EtOAc / petroleum ether) to provide the title compound as a racemic mixture. The mixture of two stereoisomers was subjected to chiral SFC (ChiralPak AS-3, 40% EtOH (with 0.05% DEA modifier) / CO2) to provide the title compound, Enantiomer 1 (faster eluting) and Enantiomer 2 (slower eluting).

[0725] Step 3-1: ent-((1R,5S,6R)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-yl)methanone (enantiomer 1)

[0726] To a solution of benzyl ent-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6R)-3-(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1, 35 mg, 0.050 mmol) in DCM (3.0 mL) was added HBr (33% in AcOH, 49 mg, 0.20 mmol). The mixture was stirred at 25° C. for 40 minutes. The pH of the mixture was adjusted to pH=9 with NH4OH. The mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (25-55% MeCN / water containing 0.1% TFA modifier) ​​to provide the title compound as a TFA salt. MS m / z (M+Na) + : Calculated value 588.2, observed value 588.1. 1 H NMR (400MHz, CD3OD) δ9.10(d,J=1.6Hz,1H),8.33(s,1H),8.21–8.11(m,2H),7.61(s,1H),7.22(t,J=8.8Hz,2H),6.80(s,1H),5.11 –5.02(m,1H),4.25–4.06(m,2H),3.96–3.66(m,3H),2.19–2.09(m,1H),2.02–1.87(m,1H),1.75(s,6H),1.59(d,J=6.0Hz,3H)ppm.

[0727] Step 3-2: ent-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-yl)methanone (enantiomer 2)

[0728] To a solution of benzyl ent-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6R)-3-(4-(1-hydroxyethyl)-[2,4'-bithiazole]-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2, 38 mg, 0.054 mmol) in DCM (3.0 mL) was added HBr (33% in AcOH, 53 mg, 0.22 mmol). The mixture was stirred at 25° C. for 40 minutes. The pH of the mixture was adjusted to pH=9 with NH 4 OH. The mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (25-55% MeCN / water containing 0.1% TFA modifier) ​​to afford the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 566.2, observed value 566.3. 1 H NMR (500MHz, CD3OD) δ9.10(d,J=1.8Hz,1H),8.33(d,J=1.8Hz,1H),8.20–8.13(m,2H),7.61(d,J=1.2Hz,1H),7.27–7.20(m,2H),6.80(d,J=1.2Hz ,1H),5.06(q,J=6.0Hz,1H),4.24–4.09(m,2H),3.95–3.69(m,3H),2.19 –2.09(m,1H),2.02–1.88(m,1H),1.76(s,6H),1.59(d,J=6.0Hz,3H)ppm.

[0729] Embodiment 17

[0730] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(oxazol-2-yl)-1H-pyrazol-5-yl)methanone

[0731]

[0732] HATU (0.35 g, 0.92 mmol) was added to a solution of 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine HCl (Int.H-01, 0.40 g, 0.92 mmol), 1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid (Int.N, 0.18 g, 0.92 mmol) and N-methylmorpholine (0.51 mL, 4.6 mmol) in DMSO (4.6 mL), and the mixture was stirred at room temperature for 1 hour. A solution of NaHCO3 (saturated aqueous solution, 30 mL) was added, and the mixture was extracted with DCM (30 mL x 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The mixture was subjected to reverse phase HPLC (5-95% MeCN / water containing 0.1% TFA modifier). The appropriate fractions were concentrated under reduced pressure. A solution of NaHCO3 (saturated aqueous solution, 30 mL) was added, and the mixture was extracted with DCM (30 mL x 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound. MS m / z (M+H) + : Calculated value 503.2, observed value 503.3. 1 H NMR (500MHz, CD3OD) δ8.11–8.06(m,2H),7.99(d,J=0.6Hz,1H),7.62(d,J=1.2Hz,1H),7.32(d,J=0.6Hz,1H),7.19–7.14(m,3H),6.85(d, J=1.2Hz,1H),4.24(d,J=12.5Hz,1H),4.07(s,3H),4.03–3.96(m,3H),3.75(dd,J=12.5,3.3Hz,1H),2.11–2.05(m,2H),1.50(s,6H)ppm.

[0733] Embodiment 18

[0734] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0735]

[0736] 1-Methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 0.31 g, 1.5 mmol) and HATU (0.84 mg, 2.2 mmol) were suspended in DMF (9.0 mL). 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine HCl (Int.H-01, 0.80 g, 1.8 mmol) and triethylamine (0.77 mL, 5.5 mmol) were added. The mixture was stirred at room temperature for 30 minutes and then subjected to reverse phase HPLC (15-95% MeCN / water with 0.1% TFA modifier). The appropriate fractions were poured into a solution of NaHCO3 (saturated aqueous solution, 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with NaHCO3 (saturated aqueous solution, 30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound. MS m / z (M+H) + : Calculated value 519.2, observed value 519.3. 1 H NMR(500MHz,CD3OD)δ9.08(s,1H),8.13–8.05(m,2H),7.91(s,1H),7.61(s,1H),7.16(t,J=7.8Hz,2H),7.07(s,1H),6.84(s,1H), 4.25(d,J=12.6Hz,1H),4.12–4.06(m,1H),4.04(s,3H),3.99(m,2H),3.75(d,J=11.1Hz,1H),2.13–2.03(m,2H),1.53(s,6H)ppm.

[0737] Embodiment 19

[0738] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-ethyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0739]

[0740] Step 1: Benzyl (2-(2-(((1R,5S,6s)-3-(1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0741] To a solution of 1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-2, 0.040 g, 0.18 mmol) and benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.H-02, 83 mg, 0.18 mmol) in DMF (3.0 mL) was added DIPEA (0.10 mL, 0.54 mmol) and T3P (50 wt % in EtOAc, 0.34 g, 0.54 mmol). The mixture was stirred at room temperature for 30 minutes, water (5 mL) was added, and the mixture was extracted with EtOAc (5 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to preparative TLC (50% EtOAc / petroleum ether, R f =0.3) to provide the title compound.

[0742] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-ethyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0743] A mixture of benzyl (2-(2-(((1R,5S,6s)-3-(1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (95 mg, 0.14 mmol) and hydrochloric acid (37%, 1.0 mL) was stirred at 80°C for 10 minutes. The mixture was cooled to room temperature and subjected to reverse phase HPLC (23-53% MeCN / water with 0.1% TFA modifier) ​​and lyophilized to afford the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 533.2, observed value 533.2. 1H NMR(400MHz,CD3OD)δ9.09(s,1H),8.16–8.08(m,2H),7.93(d,J=1.2Hz,1H),7.61(s,1H),7.17(t,J=8.8Hz,2H),7.04(s,1H),6.82(s,1H),4.46– 4.35(m,2H),4.26(d,J=12.2Hz,1H),4.08–3.93(m,3H),3.74(dd,J=12. 2,4.4Hz,1H),2.15–2.03(m,2H),1.76(s,6H),1.44(t,J=7.2Hz,3H)ppm.

[0744] Embodiment 20

[0745] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0746]

[0747] Step 1: Benzyl (2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate

[0748] A mixture of 3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (Int.Q, 35 mg, 0.15 mmol), HATU (88 mg, 0.23 mmol), DIPEA (0.20 mL, 0.77 mmol) and DMF (4.0 mL) was stirred at room temperature for 10 minutes. Benzyl (2-(2-(((1R, 5S, 6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate TFA (Int.H-02, 89 mg, 0.15 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-100% EtOAc / petroleum ether) to provide the title compound.

[0749] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0750] A mixture of benzyl (2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (83 mg, 0.12 mmol) and hydrochloric acid (37% aqueous solution, 1.0 mL) was stirred at 80° C. for 10 minutes. The mixture was adjusted to pH=7 with NH 4 OH and subjected to reverse phase HPLC (25-45% MeCN / water containing 0.1% TFA modifier). The appropriate fractions were lyophilized to provide the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 537.2, observed value 537.2. 1 H NMR (400MHz, CD3OD) δ8.62(d,J=2.0Hz,1H),8.13(dd,J=8.5,5.5Hz,2H),7.60(s,1H),7.21(t,J=9.0Hz,2H),6.98(s,1H),6.81(d,J=1.5Hz, 1H),4.25(d,J=13.0Hz,1H),4.05(s,1H),4.04(s,3H),4.03–3.95(m,2H),3.76(dd,J=12.5,4.5Hz,1H),2.14–2.03(m,2H),1.76(s,6H)ppm.

[0751] Embodiment 21

[0752] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0753]

[0754] To a mixture of 3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (Int.O-2, 35 mg, 0.18 mmol) and HATU (0.10 g, 0.28 mmol) in DMF (1.0 mL) was added 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine HCl (Int.H-01, 0.10 g, 0.23 mmol) and triethylamine (0.10 mL, 0.69 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was subjected to reverse phase HPLC (10-95% MeCN / water with 0.1% TFA modifier). The appropriate fractions were diluted with EtOAc (75 mL), washed with NaHCO 3 (saturated aqueous solution, 75 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound. MS m / z (M+H) + : Calculated value 503.2, observed value 503.2. 1 H NMR(500MHz,CD3OD)δ8.73(s,1H),8.12–8.05(m,2H),7.61(s,1H),7.16(t,J=8.6Hz,2H),7.10(s,1H),6.88(s,1H),6.8 5(s,1H),4.25(d,J=12.5Hz,1H),4.05(s,3H),4.02–3.94(m,3H),3.78–3.72(m,1H),2.11–2.04(m,2H),1.51(s,6H)ppm.

[0755] The following compounds were prepared using the procedure described in Example 21 substituting the appropriate reagents for 3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid. Compounds prepared as TFA salts were lyophilized following HPLC purification (MeCN / water with 0.1% TFA modifier).

[0756]

[0757]

[0758] Schema:

[0759]

[0760] Embodiment 25

[0761] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0762]

[0763] Step 1: Benzyl (2-(2-(((1R,5S,6s)-3-(4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate

[0764] To a room temperature solution of methyl 4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (Int.M-2, 99 mg, 0.22 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.12 g, 0.83 mmol) in THF (2.0 mL) was added Molecular sieves (0.050 g). After 10 minutes, benzyl (2-(2-(((1R, 5S, 6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.H-02, 0.040 g, 0.17 mmol) was added. After 12 hours, the mixture was concentrated and the residue was purified by preparative TLC (67% EtOAc / petroleum ether) to provide the title compound.

[0765] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0766] A solution of benzyl (2-(2-(((1R,5S,6s)-3-(4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (0.040 g, 0.060 mmol) in hydrochloric acid (37% in water, 0.50 mL) was heated at 80°C for 10 minutes. The mixture was cooled to room temperature, concentrated and subjected to reverse phase HPLC (15-35% MeCN / water with 0.05% TFA modifier). The appropriate fractions were concentrated to provide the title compound. MS m / z (M+H)+ : Calculated value 537.2, observed value 537.2. 1 H-NMR (400MHz, CD3OD) δ9.47(d,J=2.0Hz,1H),8.17(dd,J=8.8,5.6Hz,2H),8.03(d,J=2.0Hz,1H),7.66(d,J=1.2Hz,1H),7.25(t,J=8.8Hz,2H),6.88(d ,J=1.2Hz,1H),4.25(d,J=12.4Hz,1H),4.13–4.05(m,2H),4.01–3.92(m,4H ),3.81–3.72(m,1H),2.19–2.12(m,1H),2.11–2.04(m,1H),1.77(s,6H)ppm.

[0767] The following compounds were prepared using the procedure described in Example 25 substituting the appropriate reagents for methyl 4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate.

[0768]

[0769]

[0770] The following compounds were prepared using the procedure described in Example 19, substituting the appropriate reagents for 1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid. Examples were purified by HPLC (MeCN / water with 0.1% TFA or 0.05% HCl modifier) ​​and concentrated under reduced pressure to afford the title compounds as TFA or HCl salts.

[0771]

[0772]

[0773]

[0774] Embodiment 31

[0775] ((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(4-methyl-2-(oxazol-2-yl)thiazol-5-yl)

[0776]

[0777] To a stirred solution of benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(2,4-difluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.H-13, 15 mg, 0.029 mmol) and 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid (Int.K-01 6.1 mg, 0.029 mmol) in DCM (0.50 mL) was added HATU (11 mg, 0.029 mmol) followed by DIPEA (15 μL, 0.087 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Hydrochloric acid (37% aqueous solution, 0.20 mL) was added and the mixture was heated at 80° C. for 10 minutes, cooled to room temperature, and concentrated. The residue was dissolved in DMSO (1 mL) and subjected to mass-directed reverse phase HPLC (MeCN / water containing 0.1% TFA modifier) ​​to afford the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 538.2; measured value 538.2. 1 H NMR (500 MHz, DMSO-d 6 )8.37–8.34(m,1H),8.05–7.97(m,1H),7.55(s,1H),7.53–7.50(m,1H),7.43–7.36(m,1H),7.26–7.20 (m,1H),6.93(s,1H),4.04(s,1H),3.77–3.34(m,4H),2.43(s,3H),2.14–1.93(m,2H),1.62(s,6H)ppm.

[0778] The following compounds were prepared using the procedure described in Example 31 substituting the appropriate reagents for benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(2,4-difluorophenyl)pyridin-4-yl)propan-2-yl)carbamate and 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid. After HPLC purification, the examples were directly concentrated to afford the TFA or HCl salts or extracted under basic conditions to afford the free base.

[0779]

[0780]

[0781]

[0782]

[0783]

[0784] Example 43A

[0785] rel-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0786]

[0787] Step 1: rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester (Enantiomer 1)

[0788] To a solution of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 26 mg, 0.13 mmol) and benzyl rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Int.I-1-ent-1, 0.040 g, 0.084 mmol) in DMF (2.0 mL) was added DIPEA (0.10 mL, 0.25 mmol) and T3P (50 wt% in EtOAc, 0.080 g, 0.13 mmol). The mixture was stirred at room temperature for 1 hour, water (5 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to preparative TLC (50% EtOAc / petroleum ether, R f =0.35) to provide the title compound.

[0789] Step 2: rel-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0790] A mixture of benzyl rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1, 42 mg, 0.063 mmol) and hydrochloric acid (37%, 2.0 mL) was stirred at 80°C for 10 minutes. The mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and subjected to reverse phase HPLC (15-35% MeCN / water with 0.05% HCl modifier). The appropriate fractions were lyophilized to afford the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 533.2, observed value 533.2. 1 H NMR(CD3OD,400MHz)δ9.64(s,1H),8.30–8.04(m,3H),7.66(s,1H),7.20–7.15(m,3H),6.92(s,1 H),4.29–4.25(m,1H),4.07–3.98(m,5H),3.95–3.52(m,2H),1.78–1.72(m,7H),1.35(s,3H)ppm.

[0791] The following compounds were prepared using the procedure described in Example 43A, substituting the appropriate reagents for 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid and Int. J-1-ent-1. The examples were subjected to reverse phase HPLC (MeCN / water containing 0.1% TFA or 0.05% HCl modifier) ​​and lyophilized to provide TFA or HCl salts.

[0792]

[0793]

[0794] Example 46A

[0795] rel-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0796] and

[0797] Example 46B

[0798] rel-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 2)

[0799]

[0800] Step 1: rel-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester (enantiomers 1 and 2)

[0801] A mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 26 mg, 0.12 mmol), benzyl rac-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Int.I-2, 0.060 g, 0.12 mmol), DMF (2.0 mL), DIPEA (0.10 mL, 0.37 mmol) and T3P (50 wt% in EtOAc, 120 mg, 0.18 mmol) was stirred at room temperature for 1 hour. Water (5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (25% EtOAc / petroleum ether) to provide the title compound. The mixture of the two stereoisomers was subjected to chiral SFC (ChiralPak AS, 35% IPA (containing 0.1% NH4OH modifier) / CO2) to provide rel-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamic acid benzyl ester (Enantiomer 1, faster eluting) and benzyl rel-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2, slower eluting).

[0802] Step 2-1: rel-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (enantiomer 1)

[0803] A mixture of benzyl rel-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1, 23 mg, 0.034 mmol) and hydrochloric acid (37%, 2.0 mL) was stirred at 80° C. for 10 minutes. The mixture was cooled to room temperature, diluted with MeOH (2 mL), and filtered. The mixture was subjected to reverse phase HPLC (25-45% MeCN / water with 0.05% HCl modifier) ​​and lyophilized to provide Example 46A as the HCl salt. MS m / z (M+H) + : Calculated value 550.3, observed value 550.2. 1 H NMR (500MHz, CD3OD) δ9.19–9.04(m,1H),7.97–7.89(m,1H),7.03(d,J=4.9Hz,1H),6.42–6.32(m,1H),6.10(s,1H),4.29–4.20(m,1H),4. 04(s,3H),4.00–3.90(m,1H),3.85–3.67(m,2H),3.65–3.47(m,5H),1.73–1.60(m,7H),1.40–1.21(m,7H),0.96(s,3H),0.91(s,3H)ppm.

[0804] Step 2-2: rel-((1R,5S,6S)-6-((4-(2-aminopropan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-1-methyl-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (enantiomer 2)

[0805] A mixture of benzyl rel-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2, 22 mg, 0.032 mmol) and hydrochloric acid (37%, 3.0 mL) was stirred at 80° C. for 10 minutes. The mixture was cooled to room temperature, diluted with MeOH (2 mL), and filtered. The mixture was subjected to reverse phase HPLC (25-45% MeCN / water with 0.05% HCl modifier) ​​and lyophilized to provide Example 46B as the HCl salt. MS m / z (M+H) + : Calculated value 550.3, observed value 550.2. 1 H NMR (500MHz, CD3OD) δ9.14–9.04(m,1H),7.97–7.88(m,1H),7.03(d,J=4.9Hz,1H),6.41–6.28(m,1H),6.10(s,1H),4.29–4.20(m,1H),4. 04(s,3H),4.01–3.94(m,1H),3.84–3.68(m,2H),3.66–3.46(m,5H),1.74–1.58(m,7H),1.40–1.22(m,7H),0.96(s,3H),0.91(s,3H)ppm.

[0806] Schema:

[0807]

[0808] Embodiment 47

[0809] 2-(4-Fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)isonicotinamide

[0810]

[0811] Step 1: 2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)isonicotinic acid methyl ester

[0812] To a stirred solution of 2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)isonicotinic acid methyl ester (Int.H-10, 120 mg, 0.36 mmol) and 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 75 mg, 0.36 mmol) in DCM (2.0 mL) was added HATU (210 mg, 0.54 mmol) followed by DIPEA (0.18 mL, 1.1 mmol). The mixture was stirred at room temperature for 1 hour, poured into water (5 mL) and extracted with DCM (3x5 mL). The combined organic extracts were washed with NaHCO (saturated aqueous solution, 5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-70% (25% EtOH / EtOAc) / hexanes) to provide the title compound.

[0813] Step 2: 2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)isonicotinic acid

[0814] To a solution of methyl 2-(4-fluorophenyl)-6-((3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)isonicotinate (96 mg, 0.19 mmol) in MeOH (1.0 mL) was added a solution of sodium hydroxide (1.0 M aqueous solution, 0.37 mL, 0.37 mmol). The mixture was heated at 80 °C for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in EtOAc (3.0 mL), washed with hydrochloric acid (1 N aqueous solution), dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound.

[0815] Step 3: 2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)isonicotinamide

[0816] A mixture of 2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)isonicotinic acid (0.050 g, 0.10 mmol), ammonium chloride (16 mg, 0.30 mmol), DMF (0.50 mL), DIPEA (52 μL, 0.30 mmol) and HATU (56 mg, 0.10 mmol) was stirred at room temperature for 1 hour. The mixture was subjected to reverse phase HPLC (10-100% MeCN / water containing 0.1% TFA modifier). The appropriate fractions were treated with NaHCO3 (saturated aqueous solution, 5 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound. MS m / z:(M+H) + : Calculated value 505.2; measured value 505.2. 1 H NMR (500 MHz, DMSO-d 6 )δ9.18(s,1H),8.28(s,1H),8.21–8.14(m,2H),7.98(d,J=8.5Hz,2H),7.77(s,1H),7.34(t,J=8.3Hz,2H),7.20(s,1H),7. 05(s,1H),4.13–4.07(m,1H),4.07–4.04(m,1H),3.97(s,3H),3.96–3.90(m,2H),3.70–3.64(m,1H),2.14–2.05(m,2H)ppm.

[0817] Schema:

[0818]

[0819] Embodiment 48

[0820] 2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropanamide

[0821]

[0822] Step 1: methyl 2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropanoate

[0823] To a room temperature mixture of methyl 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanoate (Int.H-09, 0.040 g, 0.10 mmol), 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 27 mg, 0.13 mmol) and DMF (1.0 mL) was added DIPEA (0.090 mL, 0.52 mmol) followed by HATU (49 mg, 0.13 mmol). The mixture was stirred at room temperature for 18 hours and then subjected to reverse phase HPLC (5-95% MeCN / water with 0.1% TFA modifier). The appropriate fractions were concentrated to provide the title compound.

[0824] Step 2: 2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropanoic acid

[0825] A mixture of methyl 2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)-2-methylpropanoate (34 mg, 0.060 mmol), EtOH (0.50 mL) and NaOH (2.0 N aqueous solution, 0.15 mL, 0.30 mmol) was stirred at 90 ° C for 4 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in a 2:1 mixture of H2O:CH3CN, hydrochloric acid (1N aqueous solution, 0.31 mL) was added thereto, and the resulting mixture was lyophilized to provide the title compound.

[0826] Step 3: 2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropanamide

[0827] To a room temperature mixture of 2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)-2-methylpropanoic acid (33 mg, 0.060 mmol), NH4Cl (16 mg, 0.31 mmol), DMF (1.0 mL) and DIPEA (0.060 mL, 0.34 mmol) was added HATU (35 mg, 0.090 mmol). After 4 hours, the mixture was subjected to reverse phase HPLC (5-65% MeCN / water with 0.1% TFA modifier). The appropriate fractions were concentrated, neutralized, extracted and concentrated to provide the title compound. MS m / z (M+H) + : Calculated value 547.2, observed value 547.1. 1 H-NMR (500 MHz, DMSO-d 6 )δ9.18(s,1H),8.11(dd,J=8.4,5.7Hz,2H),7.97(s,1H),7.49(s,1H),7.31(t,J=8.7Hz,2H),7.11–6.98(m,3H),6.70(s,1H) ,4.06(d,J=12.2Hz,1H),4.01(s,1H),3.91(m,3H),3.95–3.88(m,2H),3.70–3.64(m,1H),2.10–2.01(m,2H),1.48(s,6H)ppm.

[0828] Example 49A

[0829] ent-2-amino-2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propanamide (Enantiomer 1)

[0830] and

[0831] Example 49B

[0832] ent-2-amino-2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propanamide (Enantiomer 2)

[0833]

[0834] A mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int. L-1, 0.030 g, 0.14 mmol), HATU (59 mg, 0.16 mmol), DMF (0.25 mL) and DIPEA (25 μL) was stirred at room temperature for 15 minutes. The mixture was transferred to a solution of rac-2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-aminopropanamide HCl (Int. H-20, 56 mg, 0.14 mmol) and DIPEA (0.10 mL) in DMF (0.75 mL) and stirred for 18 hours. The mixture was subjected to reverse phase HPLC (5-50% MeCN / water with 0.1% TFA modifier). The racemate was subjected to chiral SFC (AS-H, 40% EtOH (containing 0.1% DEA modifier) / CO2) to provide the title compound. Example 49A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 548.2, observed value 548.3. 1 H-NMR (500 MHz, DMSO-d 6 )δ9.18(d,J=1.9Hz,1H),8.11(dd,J=8.7,5.6Hz,2H),7.97(d,J=1.9Hz,1H),7.69(s,1H),7.40(s,1H),7.31(t,J=8.8Hz,2H),7.15(s,1H), 7.04(s,1H),6.89(s,1H),4.07(d,J=12.4Hz,1H),4.01–3.99(m,1H),3.96(s,3H),3.95–3.88(m,2H),3.67(dd,J=12.3,4.3Hz,1H),2.56(br s,2H),2.10–2.00(m,2H),1.54(s,3H)ppm. Example 49B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 548.2, observed value 548.3. 1 H-NMR (500 MHz, DMSO-d 6)δ9.20–9.16(m,1H),8.14–8.08(m,2H),7.99–7.95(m,1H),7.69(s,1H),7.41(s,1H),7.32(t,J=8.5Hz,2H),7.15(s,1H),7.0 4(s,1H),6.89(s,1H),4.07(d,J=12.4Hz,1H),4.01–3.99(m,1H),3.96(s,3H),3.95–3.88(m,2H),3.71–3.63(m,1H),2.59(br s,2H),2.11–2.00(m,2H),1.55(s,3H)ppm.

[0835] Example 50A

[0836] ent-3-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-3-methylazetidin-2-one (enantiomer 1)

[0837] and

[0838] Example 50B

[0839] ent-3-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-3-methylazetidin-2-one (enantiomer 2)

[0840]

[0841] To a room temperature solution of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 38 mg, 0.18 mmol) in DMF (0.010 L) was added DIPEA (0.10 mL, 0.18 mmol), ent-3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-3-methylazetidin-2-one (Int.H-19, 0.080 g, 0.18 mmol) and T3P (50 wt% in EtOAc, 120 mg, 0.18 mmol). After 1 hour, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (EtOAc). The racemate was subjected to chiral SFC (ChiralPak AS, 40% EtOH (containing 0.1% NH4OH modifier) / CO2) to provide the title compound. Example 50A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 545.2, observed value 545.1. 1 H-NMR (500 MHz, CD3OD) δ9.11 (s, 1H), 8.19–8.06 (m, 2H), 7.94 (s, 1H), 7.54 (s, 1H), 7.19 (t, J = 9.0 Hz, 2H), 7.10 (s, 1H), 6.84 (s, 1H), 4.27 (d, J = 12.0 Hz, 1H), 4.09–4.00 (m, 6H), 3.82–3.73 (m, 1H), 3.61 (d, J = 6.0 Hz, 1H), 3.50 (d, J = 5.5 Hz, 1H), 2.17–2.07 (m, 2H), 1.71 (s, 3H) ppm. Example 50B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 545.2, observed value 545.1. 1 H-NMR (500MHz, CD3OD) δ9.11(s,1H),8.16–8.03(m,2H),7.94(s,1H),7.54(s,1H),7.19(t,J=9.0Hz,2H),7.10(s,1H),6.84(s,1H),4.27( d,J=12.0Hz,1H),4.14–3.99(m,6H),3.82–3.73(m,1H),3.61(d,J=6.0Hz,1H),3.50(d,J=5.5Hz,1H),2.17–2.04(m,2H),1.71(s,3H)ppm.

[0842] Example 51A

[0843] ent-3-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-3-methylpyrrolidin-2-one (enantiomer 1)

[0844] and

[0845] Example 51B

[0846] ent-3-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-3-methylpyrrolidin-2-one (Enantiomer 2)

[0847]

[0848] To a room temperature solution of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 0.050 g, 0.24 mmol) in DMF (0.010 L) was added DIPEA (0.10 mL, 0.72 mmol) and rac-3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-2-one (Int.H-05, 110 mg, 0.24 mmol) followed by T3P (50 wt% in EtOAc, 230 mg, 0.36 mmol). After 30 minutes, the mixture was diluted with H2O (15 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (EtOAc). The racemate was subjected to chiral SFC (ChiralPak OD-H, 50% EtOH (containing 0.1% NH4OH modifier) / CO2) to provide the title compound. Example 51A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 559.2, observed value 559.1. 1H-NMR (500MHz, CD3OD) δ9.10 (s, 1H), 8.18–8.05 (m, 2H), 7.93 (s, 1H), 7.54 (s, 1H), 7.27–7.13 (m, 2H), 7.09 (s, 1H), 6.84 (s, 1H), 4.33–4.23 (m, 1H), 4.10–3.97 (m, 6H), 3.82–3.70 (m, 1H), 3.51–3.35 (m, 2H), 2.61–2.49 (m, 1H), 2.43–2.28 (m, 1H), 2.16–2.03 (m, 2H), 1.58 (s, 3H) ppm. Example 51B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 559.2, observed value 559.1. 1 H-NMR(500MHz,CD3OD)δ8.98(s,1H),8.01–7.93(m,2H),7.81(s,1H),7.42(s,1H),7.06(t,J=8.5Hz,2H),6.97(s,1H),6.71(s,1H),4.18–4.1 1(m,1H),3.97–3.87(m,6H),3.70–3.61(m,1H),3.36–3.23(m,2H),2.4 8–2.39(m,1H),2.28–2.18(m,1H),2.03–1.92(m,2H),1.46(s,3H)ppm.

[0849] Embodiment 52

[0850] ((1R,5S,6s)-6-((4-(1-aminocyclobutyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0851]

[0852] Step 1: N-(1-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)cyclobutyl)-2-methylpropane-2-sulfenamide

[0853] To a room temperature solution of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 57 mg, 0.27 mmol) and HATU (0.10 g, 0.27 mmol) in DMF (0.010 L) was added DIPEA (0.10 mL, 0.81 mmol) and N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (Int.H-06, 120 mg, 0.27 mmol). The mixture was stirred at room temperature for 12 hours. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was purified by preparative TLC (67% EtOAc / petroleum ether) to provide the title compound.

[0854] Step 2: ((1R,5S,6s)-6-((4-(1-aminocyclobutyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0855] A mixture of N-(1-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)cyclobutyl)-2-methylpropane-2-sulfenamide (0.070 g, 0.11 mmol) in methanol / HCl (4.0 M, 5.0 mL) was stirred at room temperature for 1 hour. The mixture was subjected to reverse phase HPLC (20-40% MeCN / water containing 0.05% HCl) and concentrated to provide the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 531.2, observed value 531.2. 1H-NMR(400MHz,CD3OD)δ9.21(s,1H),8.23–8.08(m,2H),7.98(s,1H),7.59( s,1H),7.21(t,J=8.8Hz,2H),7.10(s,1H),6.88(d,J=0.8Hz,1H),4.27(d,J =12.4Hz,1H),4.13–3.96(m,6H),3.84–3.70(m,1H),2.87–2.74(m,2H),2.6 9–2.56(m,2H),2.35–2.20(m,1H),2.16–2.06(m,2H),2.09–2.00(m,1H)ppm.

[0856] Using the procedure described in Example 52, substituting the appropriate reagents for Int. H-06, the following compounds were prepared.

[0857]

[0858] Embodiment 54

[0859] ((1R,5S,6s)-6-((4-(1-amino-2-methylpropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0860]

[0861] Step 1: Benzyl (2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropyl)carbamate

[0862] Benzyl (2-(2-(((lR,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropyl)carbamate hydrochloride (Int.H-08, 0.050 g, 0.10 mmol), 1-methyl-3-(thiazol-4-yl)-lH-pyrazole-5-carboxylic acid (Int.L-1, 25 mg, 0.12 mmol) and HATU (45 mg, 0.12 mmol) were combined in DMF (1.0 mL). DIPEA (0.085 mL, 0.49 mmol) was added and the mixture was stirred for 18 hours. The mixture was subjected to reverse phase HPLC (5-95% MeCN / water with 0.1% TFA modifier) ​​to provide the title compound.

[0863] Step 2: ((1R,5S,6s)-6-((4-(1-amino-2-methylpropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0864] A mixture of benzyl (2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)-2-methylpropyl)carbamate (44 mg, 0.070 mmol) and hydrochloric acid (37% in water, 0.50 mL) was placed in a preheated block at 80°C. After 10 minutes, the mixture was removed, diluted with ice-cold H2O (1.5 mL) and applied to an SCX ion exchange column. The column was washed with H2O and MeOH, eluted with 10% NH4OH / MeOH, and the filtrate was concentrated to provide the title compound. MS m / z (M+H) + : Calculated value 533.2, observed value 533.3. 1 H-NMR (500 MHz, DMSO-d 6 )δ9.18(d,J=1.9Hz,1H),8.17(dd,J=8.6,5.7Hz,2H),7.97(d,J=1.9Hz,1H),7.56(s,1H),7.29(t,J=8.8Hz,2H),7.04(s,1H),6.71(s,1H),4.09 –4.04(m,1H),4.02–4.00(m,1H),3.96(s,3H),3.95–3.88(m,2H),3.67( dd,J=12.3,4.7Hz,1H),2.78(s,2H),2.11–2.00(m,2H),1.27(s,6H)ppm.

[0865] Example 55A

[0866] ent-((1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(2-methylazetidin-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0867] and

[0868] Example 55B

[0869] ent-((1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(2-methylazetidin-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 2)

[0870]

[0871] To a room temperature solution of rac-6-((6-(4-fluorophenyl)-4-(2-methylazetidin-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane.HCl (Int. H-03, 36 mg, 0.090 mmol) in DMF (1.0 mL) was added 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int. L-1, 18 mg, 0.090 mmol), HATU (43 mg, 0.12 mmol), and then DIPEA (0.080 mL, 0.46 mmol). The mixture was stirred for 18 hours and then subjected to reverse phase HPLC (5-65% MeCN / water with 0.1% TFA modifier). The racemate was subjected to chiral SFC (ChiralPak AD-H, 50% EtOH (containing 0.1% DEA modifier) / CO2) to provide the title compound. Example 55A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 531.2, observed value 531.3. 1 H-NMR (500 MHz, DMSO-d 6 )δ9.18 (s, 1H), 8.13 (dd, J = 8.4, 5.8 Hz, 2H), 7.97 (s, 1H), 7.53 (s, 1H), 7.31-7.27 (m, 2H), 7.04 (s, 1H), 6.79 (s, 1H), 4.07 (d, J = 12.4 Hz, 1H), 4.00 (s, 1H), 3.96 (s, 3H), 3.95-3.88 (m, 2H), 3.70-3.58 (m, 2H), 3.18-3.13 (m, 1H), 2.40-2.32 (m, 2H), 2.10-2.00 (m, 2H), 1.60 (s, 3H) ppm. Example 55B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 531.2, observed value 531.3. 1 H-NMR (500 MHz, DMSO-d 6)δ9.18(s,1H),8.13(dd,J=8.4,5.8Hz,2H),7.97(s,1H),7.53(s,1H),7.31–7.27(m,2H),7.03(s,1H),6.79(s,1H),4.07(d,J=12.3Hz,1H) ,4.00(s,1H),3.96(s,3H),3.95–3.88(m,2H),3.70–3.58(m,2H),3.1 8–3.12(m,1H),2.40–2.32(m,2H),2.10–1.98(m,2H),1.60(s,3H)ppm.

[0872] Example 56A

[0873] ent-((1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(2-methylpyrrolidin-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hex-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0874] and

[0875] Example 56B

[0876] ent-((1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(2-methylpyrrolidin-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 2)

[0877]

[0878] Step 1: rac-2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylic acid benzyl ester

[0879] A mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int. L-1, 25 mg, 0.12 mmol), HATU (45 mg, 0.12 mmol), DMF (0.50 mL) and DIPEA (32 μL) was stirred at room temperature for 30 minutes. The mixture was added to a solution of rac-2-(2-((3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylic acid benzyl ester HCl (Int. H-04, 47 mg, 0.090 mmol) in DMF (0.50 mL) and DIPEA (48 μL). The mixture was stirred at room temperature for 18 hours and then subjected to reverse phase HPLC (5-95% MeCN / water with 0.1% TFA modifier). The appropriate fractions were concentrated and the residue was dissolved in NaHCO3 (aq., sat.) and extracted with DCM (3x).The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to provide the title compound.

[0880] Step 2: ent-((1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(2-methylpyrrolidin-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (enantiomers 1 and 2)

[0881] A mixture of rac-2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylic acid benzyl ester (0.040 g, 0.060 mmol) and hydrochloric acid (37% in water, 0.50 mL) was placed in a preheated block at 80° C. for 10 minutes. The mixture was removed, diluted with ice-cold H 2 O (1.5 mL) and applied to an SCX ion exchange column. The column was washed with H 2 O and MeOH, eluted with 10% NH 4 OH / MeOH, and the filtrate was concentrated. The mixture was subjected to chiral SFC (ChiralPak OD-H, 30% EtOH (containing 0.1% DEA modifier) / CO2) to provide the title compound. Example 56A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 545.2, observed value 545.3. 1 H-NMR (500 MHz, DMSO-d 6)δ9.18(d,J=1.9Hz,1H),8.14(dd,J=8.8,5.6Hz,2H),7.97(d,J=1.8Hz,1H),7.67(s,1H) ,7.29(t,J=8.7Hz,2H),7.04(s,1H),6.92(d,J=3.9Hz,1H),4.07(d,J=12.4Hz,1H),3.99( s, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 2H), 3.67 (dd, J = 12.3, 4.3 Hz, 1H), 3.08-3.00 (m, 1H), 2.80-2.72 (m, 1H), 2.10-1.97 (m, 3H), 1.86-1.72 (m, 2H), 1.56-1.46 (1H), 1.39 (s, 3H) ppm. Example 56B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 545.2, observed value 545.3. 1 H-NMR (500 MHz, DMSO-d 6 )δ9.18(d,J=1.9Hz,1H),8.14(dd,J=8.8,5.6Hz,2H),7.97(d,J=1.9Hz,1H),7.68(s,1H), 7.30(t,J=8.8Hz,2H),7.04(s,1H),6.92(d,J=3.5Hz,1H),4.07(d,J=12.2Hz,1H),4.00(s ,1H),3.96(s,3H),3.95–3.88(m,2H),3.67(dd,J=12.2,4.4Hz,1H),3.15–3.07(m,1H),2. 90–2.81(m,1H),2.10–2.00(m,3H),1.96–1.79(m,2H),1.67–1.55(m,1H),1.43(s,3H)ppm.

[0882] Example 57A

[0883] ent-((1R,5S,6s)-6-((4-(2-amino-1-hydroxypropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0884]

[0885] Step 1: Benzyl ent-(1-((tert-butyldimethylsilyl)oxy)-2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1)

[0886] A mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 15 mg, 0.070 mmol), benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (Int.H-12-ent-1, 0.050 g, 0.070 mmol), DMF (3.0 mL), DIPEA (0.10 mL, 0.070 mmol) and T3P (50 wt% in EtOAc, 22 mg, 0.070 mmol) was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture was extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The mixture was subjected to preparative TLC (50% EtOAc / petroleum ether) to provide the title compound.

[0887] Step 2: ent-((1R,5S,6s)-6-((4-(2-amino-1-hydroxypropan-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (Enantiomer 1)

[0888] A mixture of benzyl ent-(1-((tert-butyldimethylsilyl)oxy)-2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1, 0.050 g, 0.055 mmol) and hydrochloric acid (37% aq., 1.0 mL) was stirred at 80° C. for 10 minutes. The mixture was cooled to room temperature, concentrated under reduced pressure, subjected to reverse phase HPLC (19-39% MeCN / water containing 0.1% TFA) and lyophilized to afford the title compound as a TFA salt. MS m / z (M+H) +: Calculated value 535.2, observed value 535.1. 1 H-NMR (400MHz, CD3OD) δ9.09(s,1H),8.16–8.10(m,2H),7.92(d,J=2.0Hz,1H),7.58(d,J=1.2Hz,1H),7.20(t,J=8.8Hz,2H),7.08(s,1H),6 .80(d,J=1.2Hz,1H),4.26(d,J=12.4Hz,1H),4.09-3.99(m,6H),3.91-3.86(m,1H),3.82-3.73(m,2H),2.12-2.06(m,2H),1.70(s,3H)ppm.

[0889] Using the procedure described in Example 57A, substituting the appropriate reagents for 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid and Int. H-12-ent-1, the following compounds were prepared.

[0890]

[0891]

[0892] Embodiment 59

[0893] ((1R,5S,6s)-6-((6-(2-aminopropyl-2-yl)-4-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0894]

[0895] Step 1: Benzyl (2-(4-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-2-yl)propan-2-yl)carbamate

[0896] A mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 25 mg, 0.12 mmol), benzyl (2-(6-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-4-(4-fluorophenyl)pyridin-2-yl)propan-2-yl)carbamate (Int.H-11, 55 mg, 0.12 mmol), DMF (2.0 mL), DIPEA (0.10 mL, 0.36 mmol) and T3P (50 wt % in EtOAc, 0.11 g, 0.18 mmol) was stirred at room temperature for 1 hour. Water (5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The mixture was subjected to preparative TLC (50% EtOAc / petroleum ether) to provide the title compound.

[0897] Step 2: ((1R,5S,6s)-6-((6-(2-aminopropan-2-yl)-4-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0898] A mixture of benzyl (2-(4-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-2-yl)propan-2-yl)carbamate (0.040 g, 0.061 mmol) and hydrochloric acid (37%, 1.0 mL) was stirred at 80° C. for 10 minutes. The mixture was subjected to reverse phase HPLC (15-35% MeCN / water containing 0.05% HCl) to provide the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 519.2, observed value 519.1. 1 H-NMR (400MHz, CD3OD) δ9.09(d,J=2.0Hz,1H),7.91(d,J=2.0Hz,1H),7.79–7.75(m,2H),7.44(d,J=1.0Hz,1H),7.24(t,J=8.7Hz,2H),7.09– 7.04(m,2H),4.22(d,J=12.5Hz,1H),4.14–4.09(m,1H),4.06–3.98(m,5H),3.77(dd,J=12.6,4.8Hz,1H),2.16–2.06(m,2H),1.77(s,6H)ppm.

[0899] Using the procedure described in Example 59, substituting the appropriate reagent for 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid, the following compound (Example 60) was prepared.

[0900]

[0901]

[0902] Example 61A

[0903] ent-((1R,5S,6s)-6-((4-(1-aminoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0904] (Enantiomer 1)

[0905] and

[0906] Example 61B

[0907] ent-((1R,5S,6s)-6-((4-(1-aminoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0908] (Enantiomer 2)

[0909]

[0910] Step 1: N-(1-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0911] To a solution of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 0.050 g, 0.24 mmol) in DMF (2.0 mL) was added DIPEA (0.10 mL, 0.57 mmol) and HATU (0.14 g, 0.36 mmol). The mixture was stirred at 25°C for 15 minutes, and then N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (Int.S, 0.10 g, 0.239 mmol) was added. The mixture was stirred at 25°C for 1 hour. Water (20 mL) was added and the mixture was extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by preparative TLC (10% MeOH / DCM) to provide the title compound.

[0912] Step 2: ent-((1R,5S,6s)-6-((4-(1-aminoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone (enantiomers 1 and 2)

[0913] A mixture of N-(1-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (0.12 g, 0.20 mmol) and methanol / HCl (4.0 M, 3.0 mL) was stirred at 25 °C. After 30 minutes, the mixture was concentrated under reduced pressure. The racemate was subjected to chiral SFC (DAICEL CHIRALCEL OD-H, 50% EtOH (containing 0.1% NH3·H2O modifier) / CO2) to provide the title compound. Example 61A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 505.6, observed value 505.3. 1H-NMR (400 MHz, CD3OD) δ9.10 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.8, 5.6 Hz, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.19 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.81 (s, 1H), 4.38-4.20 (m, 2H), 4.11-3.96 (m, 6H), 3.77-3.75 (m, 1H), 2.16-2.03 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H). Example 61B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 505.6, observed value 505.3. 1 H-NMR (400MHz, CD3OD) δ9.10(d,J=2.0Hz,1H),8.14-8.06(m,2H),7.92(d,J=2.0Hz,1H),7.54(s,1H),7.18(t,J=8.4Hz,2H),7.08(s,1H),6.7 9(s,1H),4.28-4.26(m,1H),4.14(q,J=6.4Hz,1H),4.10-3.97(m,6H),3.76(dd,J=12.4,4.4Hz,1H),2.15-2.04(m,2H),1.45(d,J=6.8Hz,3H).

[0914] Example 62A

[0915] ent-((1R,5S,6s)-6-((4-(1-aminoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0916] (Enantiomer 1)

[0917] and

[0918] Example 62B

[0919] ent-((1R,5S,6s)-6-((4-(1-aminoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0920] (Enantiomer 2)

[0921]

[0922] Step 1: N-(1-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide

[0923] To a solution of 3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (Int.O-2, 0.050 g, 0.26 mmol) in DMF (0.010 L) was added DIPEA (0.20 mL, 0.78 mmol), PyBOP (0.16 g, 0.31 mmol) and N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (Int.S, 0.11 g, 0.26 mmol). The mixture was stirred at 25 °C for 30 minutes. Water (10 mL) was added and the mixture was extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by preparative TLC (EtOAc) to provide the title compound.

[0924] Step 2: ent-((1R,5S,6s)-6-((4-(1-aminoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone (enantiomers 1 and 2)

[0925] A mixture of N-(1-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (15 mg, 0.025 mmol) and methanol / HCl (4.0 M, 2.0 mL) was stirred at 25 °C for 1 hour. The mixture was subjected to reverse phase HPLC (MeCN / water with 0.1% TFA modifier). The racemate was subjected to chiral SFC (REGIS(R,R)WHELK-O1, 60% MeOH (with 0.1% NH3·H2O modifier) / CO2) to provide the title compound. Example 62A (faster eluting enantiomer): MS m / z (M+H) + : Calculated value 489.2, observed value 489.2. 1H-NMR (400 MHz, CD3OD) δ8.74 (d, J = 1.6 Hz, 1H), 8.17-8.06 (m, 2H), 7.58 (s, 1H), 7.21 (t, J = 8.8 Hz, 2H), 7.10 (s, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.81 (s, 1H), 4.53 (q, J = 6.8 Hz, 1H), 4.26 (d, J = 12.4 Hz, 1H), 4.06 (s, 3H), 4.05-3.97 (m, 3H), 3.76 (d, J = 12.8 Hz, 1H), 2.10 (s, 2H), 1.65 (d, J = 6.8 Hz, 3H). Example 62B (slower eluting enantiomer): MS m / z (M+H) + : Calculated value 489.2, observed value 489.2. 1 H-NMR (400MHz, CD3OD) δ8.74(d,J=1.7Hz,1H),8.19-8.04(m,2H),7.57(d,J=0.8Hz,1H),7.25-7.17(m,2H),7.11(s,1H),6.89(d,J=1.6Hz,1H),6.8 1(s,1H),4.53(q,J=6.8Hz,1H),4.26(d,J=12.4Hz,1H),4.06(s,3H),4.05 -3.97(m,3H),3.76(d,J=12.4Hz,1H),2.10(s,2H),1.65(d,J=6.8Hz,3H).

[0926] Embodiment 63

[0927] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(1-methylcyclopentyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0928]

[0929] Step 1: Benzyl (2-(2-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate

[0930] To a solution of benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate (Int.T, 37 mg, 0.082 mmol), 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 22 mg, 0.11 mmol) and HATU (41 mg, 0.11 mmol) in DMF (0.75 mL) was added DIPEA (0.072 mL, 0.41 mmol). The mixture was stirred at 25 °C for 3 hours. The mixture was filtered and concentrated under reduced pressure. The mixture was subjected to reverse phase HPLC (MeCN / water containing 0.1% TFA modifier) ​​to provide the title compound.

[0931] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(1-methylcyclopentyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0932] A mixture of benzyl (2-(2-(((1R,5S,6s)-3-(1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate (33 mg, 0.051 mmol) and hydrochloric acid (37%, 0.50 mL) was stirred at 80°C. After 10 minutes, the mixture was cooled to room temperature and diluted with water. The mixture was subjected to reverse phase HPLC (MeCN / water containing 0.1% TFA modifier) ​​to provide the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 507.3, observed value 507.2. 1 H-NMR (500MHz, CD3OD) δ9.07(s,1H),7.90(s,1H),7.08(d,J=1.4Hz,1H),7.03(s,1H),6.64(d,J=1.4Hz,1H),4.23(d,J=12.5Hz,1H),4.02( s,3H),3.98(s,2H),3.88(s,1H),3.70(dd,J=12.5,4.3Hz,1H),2.19–2.11(m,2H),2.05–1.95(m,2H),1.79–1.64(m,12H),1.35(s,3H)ppm.

[0933] Embodiment 64

[0934] ((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0935]

[0936] Step 1: 2-(2-((3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-4-yl)propan-2-amine

[0937] To a degassed solution of tert-butyl 6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-chloropyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Int. G, 45 mg, 0.090 mmol), 4-(trifluoromethyl)piperidine hydrochloride (0.020 g, 0.11 mmol) and chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7.0 mg, 9.0 μmol) in THF (0.30 mL) was added sodium tert-butoxide (0.50 M in THF, 0.13 mL, 0.27 mmol). The reaction was heated to 60 °C for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (0.30 mL), HCl (4.0 M in dioxane, 0.22 mL, 0.90 mmol) was injected, and the mixture was stirred at 25° C. After 1 hour, the reaction was concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (5-50% MeCN / water containing 0.1% TFA) to provide the title compound as a TFA salt.

[0938] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone

[0939] A mixture of 2-(2-((3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-4-yl)propan-2-amine (4.0 mg, 0.010 mmol), HATU (2.0 mg, 5.0 μmol), 3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (Int.O-2, 1.0 mg, 5.0 μmol), DMF (1.0 mL) and DIPEA (0.090 mL, 0.031 mmol) was stirred at 25 °C. After 30 minutes, the mixture was subjected to reverse phase HPLC (MeCN / water with 0.05% TFA modifier) ​​to provide the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 560.3, observed value 560.4. 1 H-NMR (500 MHz, DMSO-d 6 )δ8.99(d,J=1.6Hz,1H),8.39(s,3H),7.08(s,1H),6.90(d,J=1.6Hz,1H),6.49(s,1H),6.1 3(s,1H),4.39(d,J=12.6Hz,2H),4.02(d,J=12.5Hz,1H),3.98–3.93(m,4H),3.91(dd,J=10 .7,4.2Hz,0.6H),3.82–3.76(m,2H),3.62(dd,J=12.5,4.3Hz,0.4H),2.88(t,J=12.5Hz,2H ),2.66–2.56(m,1H),2.00–1.92(m,2H),1.86–1.74(m,2H),1.54(s,6H),1.42–1.30(m,2H).

[0940] Embodiment 65

[0941] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4,4-dimethylpiperidin-1-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(oxazol-2-yl)-1H-pyrazol-5-yl)methanone

[0942]

[0943] To a solution of 2-(2-((3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-amine (Int.U, 32 mg, 0.093 mmol) and 1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid (Int.N, 18 mg, 0.093 mmol) in DMSO (930 μl) and N-methylmorpholine (31 μl, 0.28 mmol) was added HATU (35 mg, 0.093 mmol). The reaction was stirred at 25°C for 2 hours. The mixture was subjected to reverse phase HPLC (MeCN / water with 0.1% TFA modifier). The fractions containing the product were filtered through an SPE plug, rinsed with MeOH (3 x 2 mL), and eluted with NH3 (2N in MeOH, 3 x 2 mL). This material was dissolved in MeCN / water and lyophilized to provide the title compound. MS m / z (M+H) + : Calculated value 519.3, observed value 520.4. 1 H NMR(500MHz,CD3OD)δ7.99(d,J=0.7Hz,1H),7.31(d,J=0.7Hz,1H),7.11(s,1H),6.42(s,1H),6.11(s,1H),4.18(d,J=12.5Hz,1H),4.05(s,3H ),3.97–3.88(m,2H),3.75(s,1H),3.69(dd,J=12.4,4.9Hz,1H),3.55– 3.50(m,4H),1.96(s,2H),1.42(s,6H),1.40–1.31(m,4H),0.95(s,6H).

[0944] Example 66A

[0945] ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0946] (Enantiomer 1)

[0947] and

[0948] Example 66B

[0949] ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0950] (Enantiomer 2)

[0951] and

[0952] Example 66C

[0953] ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0954] (Enantiomer 3)

[0955] and

[0956] Example 66D

[0957] ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone

[0958] (Enantiomer 4)

[0959]

[0960] Step 1: Benzyl (2-(2-chloro-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate

[0961] To a solution of 3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylic acid (Int. R, 80 mg, 0.38 mmol) in DMF (2 mL) was added DIPEA (0.20 mL, 1.2 mmol) and HATU (220 mg, 0.57 mmol). The mixture was stirred at 25 ° C. After 15 minutes, benzyl (2-(2-(((1R, 5S, 6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-chloropyridin-4-yl)propan-2-yl)carbamate (Int. G-01, 150 mg, 0.38 mmol) was added to the mixture and the mixture was stirred at 25 ° C. After 1 hour, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by preparative TLC (60% EtOAc / PE) to provide the title compound.

[0962] Step 2: Benzyl (2-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate

[0963] To a mixture of benzyl (2-(2-chloro-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (250 mg, 0.42 mmol) and 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 mg, 0.51 mmol) in water (0.3 mL) and 1,4-dioxane (3 mL) was added Cs2CO3 (280 mg, 0.84 mmol). The mixture was placed under N2 atmosphere, Pd(dppf)Cl2 (61.7 mg, 0.084 mmol) was added and heated to 90°C. After 5 hours, the reaction was cooled, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (60% EtOAc / PE) to provide the title compound.

[0964] Step 3: Benzyl dia-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (diastereomers 1 and 2)

[0965] A mixture of benzyl (2-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (180 mg, 0.27 mmol), 9-mesityl-10-methylacridine perchlorate (3.3 mg, 8.1 μmol) and 1,2-diphenyldisulfane (12 mg, 0.054 mmol) was dissolved in MeCN (5 mL) and water (0.5 mL). The reaction was placed under N2 atmosphere and irradiated with a blue LED (12 W) at 25 °C. After 12 hours, the reaction was quenched with water (15 mL) and extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by preparative TLC (60% EtOAc / PE) to provide the title compounds, Diastereomer 1 and Diastereomer 2.

[0966] Step 4-1: Benzyl ent-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomers 1A and 2A)

[0967] The mixture of enantiomers, benzyl dia-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (diastereomer 1) (40 mg, 0.058 mmol) was subjected to chiral SFC (DAICELCHIRALPAK AD, 40°C, 40% IPA (containing 0.1% NH3·H2O modifier) / CO2) to give the title compounds, Enantiomer 1A (faster eluting enantiomer) and Enantiomer 2A (slower eluting enantiomer).

[0968] Step 4-2: Benzyl ent-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomers 3A and 4A)

[0969] The mixture of enantiomers, benzyl dia-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (diastereomer 2) (50 mg, 0.073 mmol) was separated by SFC and subjected to chiral SFC (DAICEL CHIRALPAK OD-H, 40°C, 50% EtOH (containing 0.1% NH3·H2O modifier) / CO2) to give the title compounds, enantiomer 3A (faster eluting enantiomer) and enantiomer 4A (slower eluting enantiomer).

[0970] Step 5-1: ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-methyl-1-(thiazol-4-yl)-1H-pyrazol-4-yl)methanone (enantiomer 1)

[0971] A mixture of benzyl ent-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1A) (10 mg, 0.015 mmol) in HCl (12 M) (2 mL) was stirred at 80 °C. After 10 minutes, the mixture was cooled, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (24-44% MeCN / water with 0.04% HCl modifier). The appropriate fractions were lyophilized to afford the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 551.5, observed value 551.2. 1H NMR(400MHz,CD3OD)δ9.04(s,1H),8.67(s,1H),7.66(s,1H),7.29(s,1H), 7.11(s,1H),4.25(s,2H),4.14(s,1H),4.03(s,2H),3.74(s,1H),2.96-2.9 3(m,1H),2.45(s,3H),2.31-2.13(m,3H),1.77(s,6H),1.69-1.57(m,2H), 1.49(dd,J=14.0,3.2Hz,1H),1.38-1.31(m,2H),1.07(s,3H),0.93(s,3H).

[0972] Step 5-2: ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-methyl-1-(thiazol-4-yl)-1H-pyrazol-4-yl)methanone (enantiomer 2)

[0973] A mixture of benzyl ent-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomer 2A) (10 mg, 0.015 mmol) in HCl (12 M) (2 mL) was stirred at 80 °C. After 10 minutes, the mixture was cooled, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (24-44% MeCN / water with 0.04% HCl modifier). The appropriate fractions were lyophilized to afford the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 551.5, observed value 551.2. 1H NMR (400MHz, CD3OD) δ9.02 (s, 1H), 8.65 (s, 1H), 7.64 (d, J = 2.1Hz, 1H), 7.26 (s, 1 H),7.07(s,1H),4.23(s,2H),4.15-1.12(m,1H),4.00(s,2H),3.72(s,1H),2.96 -2.89(m,1H),2.45-2.42(m,3H),2.30-2.12(m,3H),1.74(s,6H),1.69-1.59(m, 2H), 1.47 (dd, J=14.0, 3.2Hz, 1H), 1.36-1.28 (m, 2H), 1.05 (s, 3H), 0.91 (s, 3H).

[0974] Step 5-3: ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-methyl-1-(thiazol-4-yl)-1H-pyrazol-4-yl)methanone (enantiomer 3)

[0975] A mixture of benzyl ent-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomer 3A) (20 mg, 0.029 mmol) in HCl (12 M) (2 mL) was stirred at 80 °C. After 10 minutes, the mixture was cooled, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (24-44% MeCN / water with 0.04% HCl modifier). The appropriate fractions were lyophilized to afford the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 551.5, observed value 551.2. 1H NMR (400MHz, CD3OD) δ9.03(d,J=1.6Hz,1H),8.65(s,1H),7.65(d,J=2.3Hz,1H),7.40-7.33(m,1H),7.19(s,1H),4.27-4.24(m,1H),4.17-4.01(m,4 H),3.73(s,1H),2.63-2.53(m,1H),2.23(s,2H),1.98-1.86(m,1H),1.80- 1.73(m,8H),1.49-1.41(m,1H),1.34-1.27(m,2H),0.95(d,J=8.0Hz,6H).

[0976] Step 5-4: ent-((1R,5S,6s)-6-((4-(2-aminopropan-2-yl)-6-(2-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(3-methyl-1-(thiazol-4-yl)-1H-pyrazol-4-yl)methanone (enantiomer 4)

[0977] A mixture of benzyl ent-(2-(2-(2-hydroxy-4,4-dimethylcyclohexyl)-6-(((1R,5S,6s)-3-(3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomer 4A) (25 mg, 0.037 mmol) in HCl (12 M) (2 mL) was stirred at 80 °C. After 10 minutes, the mixture was cooled, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (24-44% MeCN / water with 0.04% HCl modifier). The appropriate fractions were lyophilized to afford the title compound as the HCl salt. MS m / z (M+H) + : Calculated value 551.5, observed value 551.2. 1 H NMR (400MHz, CD3OD) δ9.03 (s, 1H), 8.66 (s, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.42 ( d,J=0.8Hz,1H),7.27(s,1H),4.28-4.24(m,1H),4.12(s,2H),4.06-4.02(m, 2H),3.73(s,1H),2.64-2.54(m,1H),2.44(s,3H),2.25(s,2H),1.97-1.86(m ,1H),1.83-1.74(m,8H),1.51-1.42(m,1H),1.35-1.28(m,2H),0.97(s,6H).

[0978] Embodiment 67

[0979] ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1'-methyl-1'H-[1,3'-bipyrazole]-5'-yl)methanone

[0980]

[0981] Step 1: Benzyl (2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1'-methyl-1'H-[1,3'-bipyrazole]-5'-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate

[0982] To a solution of 1'-methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid (Int.V, 30 mg, 0.16 mmol) in DMF (5 mL) was added DIPEA (0.10 mL, 0.47 mmol) and HATU (120 mg, 0.31 mmol). The reaction mixture was stirred at 25 ° C for 20 minutes, and benzyl (2-(2-(((1R, 5S, 6s)-3-azabicyclo[3.1.0]hex-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Int.H-02, 72 mg, 0.156 mmol) was added. The mixture was stirred at 25 ° C. After 1 hour, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by preparative TLC (30% EtOAc / PE) to provide the title compound.

[0983] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropyl-2-yl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexan-3-yl)(1'-methyl-1'H-[1,3'-bipyrazole]-5'-yl)methanone

[0984] A solution of benzyl (2-(2-(4-fluorophenyl)-6-(((1R,5S,6s)-3-(1'-methyl-1'H-[1,3'-bipyrazole]-5'-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (75 mg, 0.118 mmol) in HCl (12 M) (1 mL) was stirred at 80 °C. After 10 minutes, the mixture was concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (25-55% MeCN / water with 0.1% TFA modifier) ​​to provide the title compound as a TFA salt. MS m / z (M+H) + : Calculated value 502.2, observed value 502.2. 1 H NMR (400MHz, CD3OD) δ8.20(d,J=2.4Hz,1H),8.17-8.11(m,2H),7.74(d,J=1.6Hz,1H),7.61(d,J=1.2Hz,1H),7.24-7.18(m,2H),6.85-6.81(m,2 H),6.54-6.50(m,1H),4.23(d,J=12.4Hz,1H),4.09-4.04(m,2H),3.98( s, 4H), 3.76 (dd, J = 12.4, 3.2 Hz, 1H), 2.09 ( d, J = 1.6 Hz, 2H), 1.76 ( s, 6H).

[0985] Using the procedure described in Example 67, substituting the appropriate reagents for 1'-methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid, the following compound (Example 68) was prepared.

[0986]

[0987]

[0988] Assay description

[0989] Sample calibration :

[0990] Wells containing DMSO (final concentration 0.4%) or compound (at a concentration that completely inhibits viral replication with the control compound) were used as viral replication assay Min_E and Max_E controls, respectively. To set up the assay, the ARF vial was thawed in a 37°C water bath and the control compound was resuspended in assay medium DMEM (Dulbecco's modified Eagle's medium) containing 2% FBS, 100 U / ml penicillin-streptomycin.

[0991] Generation and propagation of recombinant RSV-A2-GFP virus:

[0992] GFP sequence from pJTI TM R4 Dest CMV N-EmGFP pA Vector (Invitrogen) and cloned into the intergenic sequence between the wild-type RSV-A2 P and M genes using standard recombineering techniques. Recombinant RSV-A2-GFP was propagated in Hep2 cells (human cells containing HeLa marker chromosomes and derived by HeLa contamination, ATCC CCL-23) with a multiplicity of infection (MOI) of 0.1. The virus was harvested 3 days after infection by collecting all culture materials and then freezing and thawing the mixture for 5 minutes. A working virus stock was generated by thawing the frozen virus culture in a 37°C water bath and centrifuging it at 218g for 15 minutes at 4°C. 1 / 10 of 10x SPG (Biological Industries 06-3061-01-5A) was added and then mixed. The supernatant was aliquoted, frozen in liquid nitrogen, and then transferred to a -80°C freezer for storage. Virus titers were determined by automated plaque assay in HEp-2 cells according to previously described methods (Wen Z. et al.; 2019).

[0993] Generate Calu-1 assay ready freeze-down (ARF):

[0994] Calu-1 cells were purchased from ATCC (Cat#HTB-54) and were amplified in growth medium (DMEM containing 10% FBS, 100U / ml penicillin-streptomycin). In order to make ARF, the cell culture medium was removed and discarded, and the cell layer was briefly rinsed with PBS to remove serum. 2.5mL of TrypLE Express solution was added and the cells were incubated until dislodged, growth medium was added thereto and the cells were resuspended by gentle pipetting. Count cells to measure concentration and viability as measured by ViCell. Cells were centrifuged at room temperature, 300g for 5 minutes to precipitate the cells. Supernatant was gently aspirated and the pellet was flicked to loosen the cells. Cells were resuspended in an appropriate volume of freezing medium (DMEM containing 10% DMSO, 10% FBS, 100U / ml penicillin-streptomycin) to reach 5x 10 6 1 mL aliquots of the cell suspension were transferred into cryovials. The vials were placed in an upright container in a -80 °C freezer overnight and then the vials were transferred to liquid nitrogen for storage.

[0995] RSV-A2-GFP Virus Replication Assay:

[0996] Assay ready freeze-down (ARF, generation of which is described separately) Calu-1 cells (ATCC HTB-54) were used. Compounds dissolved in DMSO were dispensed into 384-well plates using an ECHO acoustic dispenser. Compound plates were prepared in the wells of 3985 plates, and the test compounds were diluted 3 times in 10 points. Wells containing DMSO (final concentration 0.4%) or compounds (at a concentration that completely inhibits viral replication with control compounds) were used as viral replication assays Min_E and Max_E controls, respectively. In order to set up the assay, the ARF vials were thawed in a 37°C water bath and then resuspended in assay medium (DMEM containing 2% FBS, 100U / ml penicillin-streptomycin). Cells were counted using default parameters on ViCell and diluted to 20,000 cells / mL in assay medium. RSV-A2-GFP virus was added to cells at 24,000pfu / ml (MOI=1.2) and mixed by gently inverting. 100% DMSO at 10 μL / well was assigned as CellTiter-Glo (CTG) assay Max_E control wells. Cells were dispensed into compound plates at 50 μL / well using a Bravo with a 50 μL filter. The plates were covered with MicroClime covers, loaded with 7.5 mL of assay medium to minimize evaporation, and incubated for 96 hours at 37°C and 5% CO2. After incubation, clear GFP-expressing cells were counted using an Acumen imaging system with appropriate settings. The same-well CTG assay was performed by adding 10 μL / well of reconstituted CellTiter-Glo reagent (Promega G7573) and the plates were read on PerkinElmer Envision according to the manufacturer's instructions. Raw data were loaded and analyzed in ActivityBase. Antiviral IC was determined using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm. 50 and cytotoxic CC 50 Value. Model: 205-4 parameter logic.

[0997] Generation and propagation of hMPV-GFP virus:

[0998] rgHMPV#3p3 expressing GFP was generated in Dr. Buchholz's laboratory (Biacchesi S. et al., J Virol. 2007 June; 81(11): 6057–6067) and propagated in VERO cells (ATCC Cat#CCL-81) with a multiplicity of infection (MOI) of 0.1. Virus was harvested 4 days after infection by collecting culture material and freezing and thawing twice in liquid nitrogen. Working virus stock was generated by thawing frozen samples in a 37°C water bath and centrifuged at 218g for 15 minutes at 4°C. 1 / 10 of 10x SPG (Biological Industries 06-3061-01-5A) was added and then mixed. The supernatant was aliquoted, frozen in liquid nitrogen, and then transferred to a -80°C freezer for storage. Virus titers were determined by titration experiments in 96-well plates, and approximate virus titers were calculated using GFP event / well data.

[0999] hMPV-GFP Virus Replication Assay:

[1000] Compound plates were prepared by dispensing compounds dissolved in DMSO into wells of 384-well Corning 3985 polystyrene clear flat-bottom optical imaging microplates (202.5 nL / well) using an ECHO acoustic dispenser. Each compound was tested in 10-point serial 3-fold dilutions (typical final concentrations: 40,300 nM–2 nM). Wells containing DMSO (final concentration 0.4%) or compound (at a concentration that completely inhibited viral replication with control compound) were used as viral replication assay Min_E and Max_E controls, respectively. TMOptiMEM with 100U / ml penicillin-streptomycin) was used to maintain the continuous culture of VERO cells. In order to set up the assay, VERO cells were trypsinized with 0.25% trypsin-EDTA until the cells were dislodged, and then the cells were resuspended with 1mL FBS. The cells were rotated at 300g for 5 minutes, and the cells were washed twice with culture medium, and counted using default parameters on ViCell. The cells were then diluted to 100,000 cells / mL (5,000 cells / 50μL) in complete culture medium+TrypLESelect (80μL / mL). The hMPV-GFP virus was added to the cells with 125,000pfu / mL (MOI=1.25), and mixed by gently inverting. 100% DMSO of 10μL / well was distributed to CellTiter-Glo (CTG) assay Max_E control wells. Cells were distributed to the compound plate with 50μL / wells using Bravo and 50μL filter tips. The plate was covered with a MicroClime cover and loaded with 7.5 mL of assay medium to minimize evaporation. The plate was gently shaken for 10 minutes at room temperature and then incubated for 48 hours at 37°C and 5% CO2. After incubation, clear GFP-expressing cells were counted using an Acumen imaging system with appropriate settings. The same-well CTG assay was performed by adding 10 μL / well of reconstituted CellTiter-Glo reagent (Promega G7573) and the plate was read on PerkinElmer Envision according to the manufacturer's instructions. Raw data was loaded and analyzed in ActivityBase. Antiviral IC was determined using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm. 50 and cytotoxic CC 50 Value. Model: 205-4 parameter logic.

[1001] Reference: Wen Z, Citron M, Bett AJ, Espeseth AS, Vora KA, Zhang L, DiStefano DJ. Development and application of a higher throughput RSV plaque assay by immunofluorescent imaging. J Virol Methods. 2019 Jan;263:88-95. doi:10.1016 / j.jviromet.2018.10.022. Epub 2018 Oct 28. PMID:30381239.

[1002] Biacchesi S, Murphy BR, Collins PL, Buchholz UJ. Frequent frameshift and point mutations in the SH gene of human metapneumovirus passaged in vitro. J Virol. 2007 Jun;81(11):6057-67. doi:10.1128 / JVI.00128-07. Epub 2007 Mar 21. PMID:17376897; PMCID:MC1900297.

[1003] Measurement data

[1004] EC of each compound 50 are listed in Table I, and EC 50 The ranges are as follows: A ≤ 0.010 μM; B > 0.010 μM–≤ 0.10 μM; C > 0.10 μM; ND = not determined.

[1005] Table 1: Summary of activity against RSV

[1006]

[1007] EC of each compound 50 are listed in Table II, and EC 50 The ranges are as follows: A ≤ 0.010 μM; B > 0.010 μM–≤ 0.10 μM; C > 0.10 μM; ND = not determined.

[1008] Table II: Summary of activity against hMPV

[1009]

[1010]

Claims

1. Compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 is a 5-membered aromatic heterocyclyl ring consisting of: (i) two carbon atoms and (ii) two N and one NH or (i) three N atoms, (2) three carbon atoms and (i) two N, (ii) N and NH, or (iii) N and one S or O, or (3) four carbon atoms and one S or O, wherein the heterocyclyl ring is unsubstituted or, as valence permits, substituted with 1 or 4 substituents independently selected at each occurrence from halogen and C 1-6 alkyl; R2 is a 5-membered aromatic heterocyclyl ring consisting of: (1) three carbon atoms and (i) two N, (ii) N and NH, or (iii) N and one S or O, or (2) two carbon atoms and (i) three N atoms, (ii) two N atoms and one NH atoms, or (iii) two N atoms and one S or O atoms, wherein the heterocyclyl ring is unsubstituted or, as valency permits, substituted with 1, 2 or 3 substituents independently selected at each occurrence from: (a) halogen, (b) -NH2, (c)-C 3-6 Cycloalkyl, (d)-C 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH and -NH2, and (e)-OC 1-6 Alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH and -NH2; R3 is -H, halogen or -C 1-6 alkyl; R4 is -O- or -NH-; One of X1, X2 and X3 is N and the others are each CH; R5 is selected from: (1)-C 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 groups independently selected at each occurrence from halogen, -OH, -NR X R Y and -C(O)NR X R Y Substituents are substituted, (2)-C(O)NR X R Y 、 Where R X and R Y Independently selected from -H, -C 1-6 Alkyl, and R Z Yes-C 1-6 Alkyl; and R6 is selected from: (1) Phenyl, which is unsubstituted or substituted with 1 to 5 substituents, each of which is independently selected from: (a) halogen, (b) -CN, (c)-C 1-6 alkyl which is unsubstituted or substituted with 1 to 6 substituents independently at each occurrence selected from halogen and -OH; (d)-OC 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently at each occurrence selected from halogen and -OH, and (e)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 moieties independently selected at each occurrence from halogen, -OH, -C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups; (2) pyridinyl, which is unsubstituted or substituted by 1 to 5 substituents, wherein the substituents are independently selected at each occurrence from (i) halogen, (ii) CN and (iii) -C which is unsubstituted or substituted by 1 to 6 -F and / or -Cl. 1-6 alkyl; (3) wherein R7a and R7b are independently selected from -H, -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-6 alkyl; wherein R8a and R8b are each selected from -H, -C 1-3 Alkyl and -CF3; (5) A bicyclic ring system selected from: wherein R9, R10 and R11 are independently selected at each occurrence from -H, -C 1-6 Alkyl, -CF3 and 1, 2 or 3 halogens; (6)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 moieties independently selected at each occurrence from halogen, -OH, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent; and (7) pyrazolyl, which is unsubstituted or substituted with one or more substituents, said substituents being independently selected at each occurrence from: (a) 1 to 3 halogens, (b) CN, (c)-C 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 groups independently selected at each occurrence from halogen, -OH and -OC 1-6 Substitution of alkyl groups; (d)-OC 1-6 Alkyl, which is unsubstituted or substituted by 1 to 6 groups independently selected at each occurrence from halogen, -OH and OC 1-6 The alkyl group is substituted with a substituent, and (e)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 groups independently selected at each occurrence from halogen, -OH and -OC 1-6 The alkyl group is substituted with a substituent; and 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a 5-membered aromatic heterocyclyl ring selected from thiazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl and furanyl, wherein each ring is unsubstituted or, as valence permits, substituted by 1 to 4 atoms independently selected at each occurrence from halogen and C 1-6 The alkyl group is substituted with a substituent.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: wherein the heterocyclyl ring is unsubstituted or, as valence permits, substituted with 1, 2, 3 or 4 moieties independently selected at each occurrence from halogen and C 1-6 The alkyl group is substituted with a substituent.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1 is replaced by 1 or 2 each time selected from -F, -Cl and C 1-3 The alkyl group is substituted with a substituent.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from thiadiazolyl, triazolyl, pyrazolyl, thiazolyl and isothiazolyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from (i) halogen, (ii) -NH2, (iii) unsubstituted or substituted with 1 to 5 substituents selected from halogen, -OH and C 3-6 Substituents of cycloalkyl substituted C 1-3 alkyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from: Where * is the connection point with R1, and Ra, Rb, Rb1, Rc, Rd, Re, Re1, Rf, Rf1 and Rg are each independently selected from: (a) -H, (b) halogen, (c) -NH2, (d) -C 3-6 Cycloalkyl, (e)-C 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH and -NH2, and (f) -OC 1-6 Alkyl which is unsubstituted or substituted with 1 to 6 substituents independently at each occurrence selected from halogen, -OH and -NH2.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: yes 8. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: yes 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from -H, halogen or -C 1-3 alkyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R4 is -O-.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R4 is -NH-.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X1 is N and X2 and X3 are each CH; X2 is N and X1 and X3 are each CH; or X3 is N and X1 and X2 are each CH.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from: (1)-C 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halogen, -OH, -NH2 and -C(O)NH2, (2) -C(O)NH2, (c) (d) 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R6 is (1) Phenyl, which is unsubstituted or substituted with 1 to 5 substituents, each of which is independently selected from: (a) -F and -Cl, (b) -CN, (c)-C 1-3 alkyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected at each occurrence from -F, -Cl and -OH, (d)-OC 1-3 alkyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected at each occurrence from -F, -Cl and -OH, and (e)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 3 groups independently selected at each occurrence from -F, -Cl, -OH and -C 1-3 Alkyl and -OC 1-3 Substitution of alkyl groups; (2) pyridinyl, which is unsubstituted or substituted with 1, 2 or 3 substituents, said substituents being independently selected at each occurrence from (i) -F and -Cl, (ii) CN and (iii) -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl. 1-3 alkyl; (3) wherein R7a and R7b are independently selected from -H and -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl. 1-3 alkyl; (4) wherein R8a and R8b are independently selected from -H, -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-3 alkyl; (5) A bicyclic ring system selected from: wherein R9, R10 and R11 are independently selected at each occurrence from -H, 1, 2 or 3 halogens and -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl. 1-3 alkyl; (6)-C 3-6 Cycloalkyl, which is unsubstituted or substituted by 1 to 5 moieties independently selected at each occurrence from halogen, -OH, -C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups; (7) wherein R12 is selected from (a) -H, (b) halogen, (c) CN, (d) -C which is unsubstituted or substituted with 1 to 6 -F and / or -Cl 1-3 Alkyl and (e)-C 3-6 Cycloalkyl; and 15. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. A method of inhibiting hRSV replication in a human subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

18. A method of treating hRSV infection in a human subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

19. A method for preventing hRSV infection in a human subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

20. A method of inhibiting hMPV replication in a human subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

21. A method of treating hMPV infection in a human subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

22. A method for preventing hMPV infection in a human subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 1 for use in therapy.

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