Inhibitors of human respiratory syncytial virus and metapneumovirus

Abstract

The present disclosure is directed to compounds of formula (I) or pharma- ceutically acceptable salts thereof, and their use for treating hRSV and hMPV. [Formula 1] TIFF2025505087000216.tif38147

Description

[Technical field]

[0001] The present invention relates to therapeutic compounds useful for inhibiting respiratory syncytial virus replication and metapneumovirus replication. The therapeutic compounds of the present invention can be used in the treatment or prevention of respiratory syncytial virus and metapneumovirus infections. [Background technology]

[0002] Paramyxoviruses are enveloped negative-strand RNA viruses that are important pathogens of humans and animals. Human respiratory syncytial virus (hRSV, RSV) belongs to the Paramyxoviridae family, subfamily Pneumovirinae. Two subtypes, A and B, have been identified and are the leading cause of severe, sometimes fatal, respiratory infections in children under 6 months of age. Adults with underlying conditions such as COPD, asthma, cancer, immunocompromised conditions (including HIV), or post-transplant are also at risk for developing severe RSV infections. 15% of annual hospitalizations in adults over 50 years of age are attributable to acute respiratory infections with RSV. In the United States, RSV is estimated to result in more than 100,000 hospitalizations annually and 160,000 deaths annually worldwide. Other members of the virus family, such as human metapneumovirus (hMPV) and human parainfluenza virus (hPIV), are also responsible for acute respiratory illnesses similar to hRSV.

[0003] The RSV genome is a single-stranded negative-sense RNA molecule of approximately 15 kb and encodes 11 proteins. Two of these proteins are the major surface glycoproteins of the virion. These are the attachment (G) protein, which mediates the binding of the virus to the cell, and the fusion (F) protein, which promotes both the fusion of the virus and the cell membrane in the early stages of the infection cycle and the fusion of the membrane of the infected cell with that of the adjacent cell to form the characteristic syncytium. Four of the polypeptides form the RSV ribonucleoprotein (RNP) complex together with the viral RNA genome. These proteins are the nucleocapsid (N) protein, the phosphoprotein (P), the RNA polymerase (L) protein, and the transcription factor M2-1, which are required for transcription and replication of the viral genome, respectively, 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 responsible for 5-40% of respiratory infections in hospitalized and outpatient children. In healthy adults, hMPV generally causes mild respiratory infections. However, adults over 70 years of age, immunocompromised individuals, and individuals with comorbid conditions such as asthma and chronic obstructive pulmonary disease (COPD) are at higher risk for severe illness and hospitalization as a result of hMPV infection. The hMPV genome is approximately 13 kb in size and its organization is similar to that of hRSV. RNA replication and mRNA transcription of the hMPV genome are dependent on the hMPV L-protein polymerase, which is highly homologous to the hRSV L-protein polymerase.

[0005] Currently, few options are available for the prevention and treatment of RSV infection. No vaccine against RSV is commercially available. Clinical trials using formalin-inactivated virus have been associated with increased severity of RSV infection in infants (see Kim et al., American Journal of Epidemiology, 89:422-434 (1969)). The monoclonal antibody palivizumab (Synagis®) has been approved for prophylactic use, but its limited efficacy and high cost limit its use to high-risk infants. Ribavirin (ViraZole®), a broad-spectrum antiviral guanosine nucleoside analog, has been approved as an inhaled treatment for RSV infection in infants, but clear efficacy data are lacking (Fearns et al., 2016 Antiviral Research, 134:63-76). In addition, the teratogenic potential of ribavirin poses significant risks to caregivers. Currently, the standard of care for patients with RSV infection is symptomatic and includes supplemental oxygen and intravenous fluids. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Kim et al., American Journal of Epidemiology, 89:422-434 (1969) [Non-Patent Document 2] Fearns et al., 2016 Antiviral Research, 134:63-76 Summary of the Invention [Problem to be solved by the invention]

[0007] There is a continuing need for antiviral drugs with suitable pharmacokinetic properties for a significant portion of the affected population. The present invention addresses this need by providing novel hRSV and hMPV replication inhibitors useful for inhibiting respiratory syncytial virus replication and metapneumovirus replication. [Means for solving the problem]

[0008] The present disclosure is directed to compounds of Formula I and embodiments thereof for use as antiviral agents for inhibiting the replication of hRSV and hMPV, and for use as antiviral agents for treating and / or preventing hRSV and hMPV infection. Compositions and methods of use including the compounds of the disclosure are also provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure provides a compound of formula I [ka] [During the ceremony, R 1 teeth, (1) 2 carbon atoms and (ii) 2 N and 1 NH, or (i) 3 N; (2) 3 carbon atoms and (i) 2 N, (ii) N and NH, or (iii) N and 1 S or O; or (3) 4 carbon atoms and 1 S or O; is a 5-membered aromatic heterocyclyl ring consisting of wherein the heterocyclyl ring is unsubstituted or, where valences permit, includes halo and C 1-6 substituted with 1 to 4 substituents independently selected at each occurrence from alkyl; R 2 teeth, (1) 3 carbon atoms and (i) 2 N, (ii) N and NH, or (iii) N and 1 S or O; or (2) 2 carbon atoms and (i) 3 N, (ii) 2 N and 1 NH, or (iii) 2 N and 1 S or O; is a 5-membered aromatic heterocyclyl ring consisting of wherein the heterocyclyl ring is unsubstituted or, where valences permit, (a) Halo, (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 halo, -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 halo, -OH, and -NH2); and is substituted with one, two or three substituents independently selected at each occurrence from: [ka] teeth, 2-Azabicyclo[2.2.0]hexane [ka] or 3-Azabicyclo[3.1.0]hexane [ka] represents a bicyclic ring which is: R 3 is -H, halo or -C 1-6 is alkyl; R 4 is -O- or -NH-; X 1 , X 2 and X 3 one of is N and the remaining ones are each CH; R 5 teeth, (1) C 1-6 Alkyl (which is unsubstituted or substituted with halo, -OH, -NR X R Y and -C(O)NR X R Y and is substituted with 1 to 6 substituents independently selected at each occurrence from (2)-C(O)NR X R Y ; (3) [ka] and; (4) [ka] is selected from Here, R X and R Y -H, -C 1-6 alkyl, and R Z -C 1-6 is alkyl; and R 6 teeth, (1) Phenyl, which is unsubstituted or (a) Halo, (b)-CN, (c)-C 1-6 alkyl (which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halo and -OH); (d)-OC 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halo and -OH; and (e)-C 3-6 Cycloalkyl (which is unsubstituted or substituted with halo, -OH, -C 1-6 Alkyl and -OC 1-6 substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; and is substituted with 1 to 5 substituents independently selected at each occurrence from: (2) pyridinyl, which is unsubstituted or selected from the group consisting of (i) halo, (ii) CN and (iii) —C 1-6 alkyl (which is unsubstituted or substituted with 1 to 5 substituents independently selected at each occurrence from 1 to 6 -F and / or -Cl); (3) [ka] [Where, R 7a and R 7b are -H and -C, respectively. 1-6 alkyl, where R 7a and R 7b are -H and -C, respectively. 1-6 alkyl (which is unsubstituted or substituted with 1-6 -F and / or -Cl); (4) [ka] [Where, R 8a and R 8b are -H and -C, respectively. 1-3 alkyl and -CF3; (5) [ka] [Where, R 9 , R 10 and R 11 -H, -C 1-6 and 1, 2 or 3 halo, independently selected at each occurrence from: alkyl, -CF3, and 1, 2 or 3 halo. A bicyclic ring system selected from: (6)-C 3-6 Cycloalkyl (which is unsubstituted or substituted with halo, -OH, -C 1-6 Alkyl and -OC 1-6 substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; and (7) pyrazolyl, which is unsubstituted or (a) 1 to 3 halos, (b) C.N., (c)-C 1-6 Alkyl (which is unsubstituted or substituted with halo, -OH and -OC 1-6 substituted with 1 to 6 substituents independently selected at each occurrence from alkyl; (d)-OC 1-6 Alkyl (which is unsubstituted or substituted with halo, -OH and -OC 1-6 substituted with 1 to 6 substituents independently selected at each occurrence from alkyl; and (e)-C 3-6 Cycloalkyl, which is unsubstituted or substituted with halo, -OH and -OC 1-6 substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; and, (8) [ka] selected from or a pharma- ceutically acceptable salt thereof.

[0010] The present disclosure EMBODIMENT 1 is a compound of formula I or a pharma- ceutically acceptable salt thereof, 1 is a 5-membered aromatic heterocyclyl ring selected from thiazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, thiophenyl, and furanyl, wherein each ring is unsubstituted or, where valences permit, is selected from halo and C 1-6 In a first class of embodiment 1, R is substituted with 1 to 4 substituents independently selected at each occurrence from alkyl. 1 teeth, [ka] wherein the heterocyclyl ring is unsubstituted or, where valences permit, selected from halo and C 1-6 In a second class thereof, the substituents are substituted with 1, 2, 3, or 4 substituents independently selected at each occurrence from alkyl, -F, -Cl, and -C. 1-3 In a third class thereof, the heterocyclyl ring is unsubstituted or, where valences permit, is selected from -F, -Cl, and -C. 1-3 It is substituted with 1, 2, 3 or 4 substituents selected at each occurrence from alkyl (eg, methyl).

[0011] The present disclosure EMBODIMENT 2 is a compound of formula I and the compound of embodiment 1, or a pharma- ceutically acceptable salt thereof, 2 is a 5-membered aromatic heterocyclyl ring selected from thiadiazolyl, triazolyl, pyrazolyl, thiazolyl, and isothiazolyl, each of which is unsubstituted or, where valences permit, is selected from (i) halo (e.g., -F and -Cl), (ii) -NH, (iii) -C 1-3 Alkyl (which is unsubstituted or substituted with halo (e.g., -F and -Cl), -OH and C 3-6 cycloalkyl (eg, cyclopropyl)).

[0012] In the second embodiment, R 2 teeth, [ka] is selected from Here, * stands for R 1 and R a , R b , R b1 , R c , R d , R e , R e1 and R fEach of the following is selected from the group consisting of (a) -H, (b) halo, (c) -NH2, and (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 halo, -OH and -NH2); and (f) -OC 1-6 alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halo, -OH, and -NH.

[0013] The above structure [ka] In this disclosure, the structure [ka] It can be exemplified as follows.

[0014] In a second class of embodiment 2, R a , R b , R b1 , R c , R d , R e , R e1 and R f each of which is (a) -H, (b) halo (e.g., -F and -Cl), (c) -NH, (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 halo (e.g., -F and -Cl), -OH, and -NH2); and (f) -OC 1-3 alkyl, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from halo (e.g., -F and -Cl), -OH and -NH2.

[0015] The present disclosure Embodiment 3Ais a compound of formula I and each of the compounds of embodiments 1 and 2 and classes of compounds thereof or pharma- ceutically acceptable salts thereof, wherein [ka] teeth, [ka] is.

[0016] The present disclosure Embodiment 3B is a compound of formula I and each of the compounds of embodiments 1 and 2 and classes of compounds thereof or pharma- ceutically acceptable salts thereof, wherein [ka] teeth, [ka] is.

[0017] The present disclosure EMBODIMENT 4 is a compound of formula I and each of the compounds of embodiments 1, 2, 3A and 3B, and classes of compounds thereof, or pharma- ceutically acceptable salts thereof, where R 3 is -H, halo or -C 1-3 In the first class, R 3 is -H, -F, -Cl or -C 1-3 In the first class, R 3 is -H, -F, -Cl or -CH3.

[0018] The present disclosure Embodiment 5A is a compound of formula I and each of the compounds of embodiments 1, 2, 3A, 3B, and 4, and classes of compounds thereof, or pharma- ceutically acceptable salts thereof, where R 4 is -O-.

[0019] The present disclosure Embodiment 5Bis a compound of formula I and each of the compounds of embodiments 1, 2, 3A, 3B, and 4, and classes of compounds thereof, or pharma- ceutically acceptable salts thereof, where R 4 is -NH-.

[0020] The present disclosure EMBODIMENT 6 is a compound of formula I and each of the compounds of embodiments 1, 2, 3A, 3B, 4, 5A and 5B, and classes of compounds thereof, or pharma- ceutically acceptable salts thereof, where X 1 is N, and X 2 and X 3 are each CH; or X 2 is N, and X 1 and X 3 are each CH; or X 3 is N, and X 1 and X 2 are each CH.

[0021] The present disclosure EMBODIMENT 7 is a compound of formula I and each of the compounds of embodiments 1, 2, 3A, 3B, 4, 5A, 5B, and 6, and classes of compounds thereof, or pharma- ceutically acceptable salts thereof, where R 5 teeth, (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 halo, -OH, -NH2 and -C(O)NH2; (2) -C(O)NH2, (3) [ka] And, (4) [ka] is selected from the following:

[0022] In a subembodiment of embodiment 7, R 5is -C substituted with -NH 1-6 Alkyl (e.g., -C 1-3 alkyl or -CH3).

[0023] The present disclosure EMBODIMENT 8 is a compound of formula I and each of the compounds of embodiments 1, 2, 3A, 3B, 4, 5A, 5B, 6 and 7, and classes of compounds thereof, or pharma- ceutically acceptable salts thereof, where R 6 teeth, (1) Phenyl, which is unsubstituted or (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); (e)-C 3-6 Cycloalkyl (e.g., cyclopropyl), which is unsubstituted or substituted with -F, -Cl, -OH, -C 1-3 Alkyl and -OC 1-3 substituted with 1 to 3 substituents independently selected at each occurrence from alkyl; and is substituted with 1 to 5 substituents independently selected at each occurrence from: (2) pyridinyl, which is unsubstituted or selected from the group consisting of (i) -F and -Cl, (ii) -CN and (iii) -C 1-3 alkyl (which is unsubstituted or substituted with 1-6 -F and / or -Cl; e.g., -CHF, -CHF, -CF, and -C(CH)F); (3) [ka] [Where, R 7a and R 7b are -H and -C, respectively. 1-3 alkyl (which is unsubstituted or substituted with 1-6 -F and / or -Cl; e.g., -CH2F, -CHF2, -CF3 and -C(CH3)F2); (4) [ka] [Where, R 8a and R 8b are -H and -C, respectively. 1-3 alkyl (which is unsubstituted or substituted with 1-6 -F and / or -Cl; e.g., -CH2F, -CHF2, -CF3 and -C(CH3)F2); (5) [ka] [Where, R 9 , R 10 and R 11 is -H, 1, 2 or 3 halo and -C 1-3 alkyl, which is unsubstituted or substituted with 1-6 -F and / or -Cl, independently selected at each occurrence from A bicyclic ring system selected from: (6)-C 3-6 Cycloalkyl (e.g., cyclopropyl), which is unsubstituted or substituted with halo, -OH, -C 1-6 Alkyl and -OC 1-6 substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; (7) Pyrazolyl, for example [ka] [Where, R 12 are (a) -H, (b) halo, (c) CN, and (d) -C. 1-3alkyl (which is unsubstituted or substituted with 1 to 6 -F and / or -Cl); and (e) -C 3-6 cycloalkyl (e.g., cyclopropyl); and (8) [ka] is selected from the following:

[0024] References herein to compounds of formula I include compounds of formula I, formula Ia, formula Ib and formula Ic, and all embodiments, classes and subclasses thereof, and include the compounds of the Examples herein. Compounds of formula I include neutral compounds or salts thereof, where possible, including pharma- ceutically acceptable salts.

[0025] The term "eg" means "for example." As used herein, when the term "eg" is used, the examples being described are intended to be illustrative and not an exhaustive list of all relevant examples.

[0026] As used herein, "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms within the specified range. For example, the term "C 1-6 "Alkyl" means a straight or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and includes the hexyl ("C6 alkyl") and pentyl ("C5 alkyl") isomers, respectively, as well as n-, iso-, sec- and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively "C4 alkyl"; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively "C3 alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). 1-3"Alkyl" has 1, 2 or 3 carbon atoms and includes each of n-propyl, i-propyl, ethyl and methyl.

[0027] "Cycloalkyl" refers to a cyclized alkyl ring having a designated number of carbon atoms within the specified range. 3-6 "Cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and "C 3-4 "Cycloalkyl" includes each of cyclopropyl and cyclobutyl.

[0028] "Halo" or "halogen" refers to chloro, fluoro, bromo or iodo. Chloro, fluoro and bromo are classes of halogens of interest, more particularly fluoro and chloro.

[0029] A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged for a period of time sufficient to permit the use of the compound 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, a particular moiety defined in Formula I may be unsubstituted or substituted, and the latter is intended to encompass substitution patterns (i.e., number and type of substituents) that are chemically feasible for that moiety and result in a stable compound.

[0030] The present disclosure encompasses individual diastereomers, particularly epimers, i.e., compounds that have the same chemical formula but differ in spatial arrangement around a single atom. The present disclosure also encompasses mixtures of diastereomers, particularly mixtures of epimers, in all ratios. The present disclosure also encompasses compounds of formula I having either the (R) or (S) configuration at one asymmetric center and any additional asymmetric centers that may be present in the compounds of formula I, as well as stereoisomeric mixtures thereof. Embodiments of the present disclosure also encompass mixtures of enantiomers enriched in 51% or more of one enantiomer (e.g., 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer). Single epimers are preferred. "Individual enantiomers" or "single enantiomers" refer to enantiomers obtained by chiral synthesis and / or using commonly known separation and purification techniques, which may be 100% of one enantiomer or may contain small amounts (e.g., 10% or less) of the opposite enantiomer. Individual enantiomers are therefore subject of the present disclosure in pure form, as both levorotatory and dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of the two enantiomers in all ratios. In the case of cis / trans isomers, the present disclosure encompasses both the cis and trans forms, as well as mixtures of these forms in all ratios.

[0031] The preparation of individual stereoisomers can be carried out, if desired, by separation of the mixture in a conventional manner (e.g., by chromatography or crystallization), or by using stereochemically uniform starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out prior to separation of stereoisomers. Separation of stereoisomeric mixtures can be carried out at an intermediate stage during the synthesis of the compounds of formula I, or on the final racemic product. Absolute stereochemistry can be confirmed by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing a stereoisomeric center of known configuration. Alternatively, absolute stereochemistry can be confirmed by vibrational circular dichroism (VCD) spectroscopy. The present disclosure encompasses all such isomers, as well as the salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers, and mixtures thereof.

[0032] As will be recognized by those skilled in the art, certain compounds of the present disclosure may exist as tautomers.All tautomeric forms of such compounds, whether isolated individually or in mixture, are within the scope of the present disclosure.For example, if an oxo (=O) substituent is permitted on an aromatic heterocyclic ring (also referred to as a heteroaromatic ring), and keto-enol tautomerism is possible, it is understood that the substituent may actually exist in whole or in part in the -OH form.

[0033] Atoms in the compounds of formula I may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that found predominantly in nature. The present disclosure is intended to encompass all suitable isotopic variations of the compounds of formula I; for example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium can provide therapeutic benefits such as increased in vivo half-life or reduced dosage requirements, or can provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds of formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0034] 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., is not toxic or toxic to the recipient). When the compound of formula I contains one or more acidic or basic groups, the present invention includes the corresponding pharmaceutically acceptable salt.

[0035] Compounds of formula I and pharma- ceutically acceptable salts thereof that contain one or more basic groups (i.e., groups that can be protonated) can be used in accordance with 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, naphthalenedisulfonic 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, sulfamic 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 of the compounds of formula I are protonated in the form of a salt. In some embodiments, one or more NH2 groups (e.g., a single NH2 group) of any of the compounds of formula I are protonated in the form of a salt with trifluoroacetic acid (trifluoroacetate). In some embodiments, one or more NH2 groups (e.g., a single NH2 group) of any of the compounds of formula I are protonated in the form of a salt with hydrogen chloride. When the compounds of formula I contain both acidic and basic groups in the molecule, the present invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Salts can be obtained from the compounds of formula I by conventional methods known to those skilled in the art, for example, by combination with organic or inorganic acids or bases in a solvent or dispersion medium, or by anion or cation exchange from other salts. The present disclosure also includes all salts of the compounds of formula I that are not directly suitable for use in medicines due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0036] The present disclosure encompasses any composition of a compound represented by formula I or a salt thereof, including, but not limited to, a composition composed of said compound in association with one or more additional molecular and / or ionic components(s), which may be referred to as a "co-crystal". As used herein, the term "co-crystal" refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (generally in a stoichiometric ratio) are held together by non-ionic interactions (which include, but are not limited to, hydrogen bonds, dipole-dipole interactions, dipole-quadrupole interactions, or dispersion forces (van der Waals)). There is no proton transfer between the different components, and the solid phase is not a simple salt or solvate. A discussion of co-crystals can be found, for example, in S. Aitipamula et al., Crystal Growth and Design, 2012, 12(5), pp. 2147-2152.

[0037] In addition, the compounds of the present disclosure can exist in amorphous form and / or one or more crystalline forms, and as such, all amorphous and crystalline forms and mixtures thereof of the compounds of formula I and their salts are intended to be included within the scope of the present disclosure. In addition, some of the 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 pharma- ceutically acceptable solvates and hydrates, are also included within the scope of the compounds of formula I and their pharma-ceutically acceptable salts, in addition to the unsolvated and anhydrous forms of such compounds.

[0038] Thus, the compounds of Formula I or salts thereof (including pharma- ceutically acceptable salts thereof), embodiments thereof, and specific compounds described and claimed herein include all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), co-crystal forms, solvates and hydrates, as well as any combination of the foregoing forms, where such forms are possible.

[0039] Another embodiment of the present disclosure is a compound of formula I, wherein the compound or salt thereof is in substantially pure form. As used herein, "substantially pure" means that a product comprising a compound of formula I or a salt thereof (e.g., a product isolated from a reaction mixture yielding the compound or salt) is 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% to about 99% by weight), even more preferably at least about 95% by weight (e.g., about 95% to about 99% by weight, or about 98% to about 100% by weight), and most preferably at least about 99% by weight (e.g., 100% by weight) of the compound or salt. The purity level of the compounds and salts can be confirmed using standard analytical methods, such as high performance liquid chromatography and / or mass spectrometry or NMR techniques. When two or more analytical methods are employed, and there is an experimentally significant difference in the purity levels determined among the methods, the method providing the highest purity level will prevail. A compound or salt that is 100% pure is one that is free of detectable impurities as determined by standard analytical methods. For compounds of the invention that have one or more asymmetric centers and may exist as a mixture of stereoisomers, a substantially pure compound can be either a substantially pure mixture of stereoisomers or a substantially pure individual stereoisomer.

[0040] The compounds of formula I and pharma- ceutically acceptable salts thereof herein are useful for inhibiting the replication of respiratory syncytial virus and metapneumovirus. Thus, the compounds of formula I and pharma-ceutically acceptable salts thereof are useful for: (i) a method of treating a respiratory syncytial virus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof; (ii) a method of preventing respiratory syncytial virus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof; (iii) a method of treating a metapneumovirus infection in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof; and / or (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 of formula I or a pharma- ceutical acceptable salt thereof.

[0041] Further embodiments of the present disclosure include: (a) a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier; and (b) A pharmaceutical composition comprising the product prepared by combining (eg, mixing) an effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0042] Further embodiments of the present disclosure include each of the pharmaceutical compositions, methods and uses described in the preceding paragraphs, wherein the compound of formula I or a salt thereof used is substantially pure. It will be understood that with respect to a pharmaceutical composition comprising a compound of formula I or a salt thereof and a pharma- ceutically acceptable carrier and optionally one or more excipients, the term "substantially pure" refers to the compound of formula I or a salt thereof per se.

[0043] The term "administration" and variations thereof (e.g., "administering" a compound) with respect to a compound of Formula I means providing the compound to an individual in need of treatment or prevention, and includes both self-administration and administration to a patient by another person or any other means.

[0044] As used herein, the term "composition" is intended to encompass products containing the specified ingredients, as well as any products resulting from combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharma- ceutically acceptable ingredients, meaning that the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0045] As used herein, the term "subject" refers to an animal (e.g., a human) that is the object of treatment, observation, or experiment. In various embodiments of the present disclosure, "subject" includes mammalian animals. In some embodiments, the subject includes domestic or companion animals or experimental animal models. In some embodiments, the subject is a rodent, such as a mouse or a 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.

[0046] As used herein, the term "human subject" or "patient" refers to a human (or "person") who has been the subject of treatment, observation, or experiment. Patients 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. Furthermore, patients treated with RSV-i and / or MPV-i drugs include, but are not limited to, patients who use RSV-i and / or MPV-i drugs for the prevention of RSV and / or MPV infection, or for post-exposure prophylaxis after potential exposure to RSV and / or MPV to prevent or reduce the severity of symptoms of a disease or condition associated with the virus or to prevent the patient from becoming infected.

[0047] "Prevention" includes pre-exposure prophylaxis (PrEP) (i.e., using a compound of formula I or a pharma- ceutically acceptable salt thereof to prevent hRSV and / or hMPV infection in humans not infected with hRSV and / or hMPV) and post-exposure prophylaxis (PEP) (i.e., using a compound of formula I or a pharma- ceutically acceptable salt thereof to prevent or reduce the severity of symptoms of a virus-associated disease or condition after exposure or potential exposure to hRSV and / or hMPV; or to prevent a human from becoming infected with hRSV and / or hMPV).

[0048] As used herein, the term "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, or human. In one embodiment, the effective amount is a "therapeutically effective amount" for alleviating the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for preventing the symptoms of the disease or condition being prevented.

[0049] When the active compound (ie, active ingredient) is administered as the salt, references to the amount of active ingredient are to the free form (ie, the non-salt form) of the compound.

[0050] In the method of the present invention, the compounds of the present invention or their salts can be administered by any means that brings the active agent into contact with its site of action. They can be administered by any conventional means available for use in combination with pharmaceuticals, either as individual therapeutic agents or together with other therapeutic agents that the patient may require. The compounds can be administered on their own, but are typically administered together with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice. The compounds of the present invention can be administered orally (e.g., via tablets or capsules), parenterally (e.g., subcutaneous injection; intravenous, intramuscular, or intrasternal injection; or infusion techniques), by inhalation spray, or rectally, for example, in the form of a unit dosage of a pharmaceutical composition that contains an effective amount of the compound and conventional non-toxic pharmacologic carriers, adjuvants, and vehicles. The compounds can also be administered via an implantable drug delivery device adapted to provide an effective amount of the compound or a pharmaceutical composition of the compound over an extended period of time.

[0051] The term "administration" and variations thereof (e.g., "administering" a compound) with respect to a compound of Formula I means providing the compound to an individual in need of treatment or prevention, and includes both self-administration and administration to a patient by another person or any other means.

[0052] As used herein, the term "composition" is intended to encompass products containing the specified ingredients, as well as any products resulting from combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharma- ceutically acceptable ingredients, meaning that the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0053] As used herein, the terms "subject" or "patient" refer to a human (or "person") who has been the object of treatment, observation or experiment. Examples of patients who may be treated with the antiviral agents described herein include, but are not limited to, patients infected with hRSV or hMPV, and patients who use the antiviral agents for the prevention of hRSV and hMPV infection.

[0054] "Prevention" includes pre-exposure prophylaxis (PrEP) (i.e., using a compound of formula I or a pharma- ceutically acceptable salt thereof to prevent hRSV and / or hMPV infection in humans not infected with hRSV or hMPV) and post-exposure prophylaxis (PEP) (i.e., using a compound of formula I or a pharma- ceutically acceptable salt thereof to prevent or reduce the severity of symptoms of a virus-associated disease after potential exposure to hRSV or hMPV; or to prevent a human from becoming infected with hRSV or hMPV).

[0055] As used herein, the term "effective amount" refers to an amount of a compound sufficient to exert a therapeutic effect and / or a prophylactic effect following administration. One embodiment of an "effective amount" is a "therapeutically effective amount," which is an amount of a compound effective to treat hRSV or hMPV infection. Another embodiment of an "effective amount" is a "prophylactically effective amount," which is an amount of a compound effective to prevent hRSV or hMPV infection.

[0056] formulation Solid formulations suitable for oral administration (e.g., powders, pills, capsules, and tablets) can be prepared according to techniques known in the art, and can use solid excipients such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. Liquid formulations suitable for oral administration (e.g., suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art, and can use any of the usual vehicles, such as water, glycols, oils, alcohols, etc. Parenteral compositions can be prepared according to techniques known in the art, and typically use sterile water as a carrier, and optionally other ingredients such as solubilizing agents. Injectable solutions can be prepared according to methods known in the art, where the carrier comprises a solution containing saline, glucose solution, or a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art, where the carrier comprises the active chemical ingredient and a polymer and suitable excipients, or utilize an implantable device for drug delivery. Further description of suitable methods for use in preparing pharmaceutical compositions for use in this disclosure and suitable ingredients for use in such compositions is provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6 and previous editions.

[0057] Formulations of the compounds of formula I that result in drug supersaturation and / or rapid dissolution can be utilized to enhance oral drug absorption. Formulation approaches that result in drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for their preparation are known in the art. For example, solid dispersions can be prepared using excipients and processes described in reviews (e.g., ATM Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticulate systems based on both milling and direct synthesis have also been described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

[0058] The compound of formula I can be administered in a dosage range of, for example, 1-20 mg / kg or 1-10 mg / kg or about 5 mg / kg per kg of mammalian (e.g., human) body weight per day, or at other time intervals as needed, in a single dose or in divided doses. The compound of formula I can be administered in a dosage range of 0.001-2000 mg per day, in a single dose or in divided doses. Exemplary dosage ranges are 0.01-1500 mg per day, or 0.1-1000 mg per day, administered orally or via another route of administration, in a single dose or in divided doses.

[0059] For oral (e.g., tablet or capsule) or other routes of administration, the dosage unit can be from about 100 mg to about 1500 mg of active ingredient, for example, but not limited to, 0.1 mg to about 1500 mg of active ingredient, for example, 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 milligrams of active ingredient, to symptomatically adjust the dosage to the patient being treated. Additionally, the compound can be formulated into oral formulations for immediate or modified release (e.g., sustained or controlled release). When a compound of formula I is administered as a salt, references to the amount of the compound in milligrams or grams are based on the free form (i.e., non-salt form) of the compound.

[0060] Daily administration can be via any suitable route of administration, but is preferably via oral administration, and can be a single dose or multiple doses staggered over time (daily divided doses) within each 24 hour period. Each dose can be administered using one dosage unit or multiple dosage units, as appropriate.

[0061] 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 particular compound employed, 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 influence of other drugs taken by the patient during use of the RSP-i compounds or MPV-i compounds described herein, the severity of the particular condition and the host being treated. In some cases, it may be necessary to deviate upwards or downwards from the prescribed dose depending on the efficacy of the compound or individual response. The dosage and frequency of administration are adjusted according to the judgment of the attending clinician, taking into account such factors.

[0062] The compounds of the present invention are also useful in preparing and carrying out screening assays for antiviral compounds.For example, the compounds of the present invention are useful for isolating enzyme mutants, which are excellent screening tools for more potent antiviral compounds.Furthermore, the compounds of the present invention are also useful in establishing or determining the binding site of other antiviral drugs.

[0063] The following acronyms and abbreviations have the meanings indicated: 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) dichloride; aq. is aqueous; BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene; CPME is cyclopentyl methyl ether; CV is column volume; d is days; 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 dimethylsulfoxide; Et is ethyl; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Ex. is example; h is hour; HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; IPA is 2-propanol; [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-pyrrolidinone; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 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 (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; RockPhos Pd G3 is [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate; 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'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0064] It is understood that the chiral centers in the compounds may exist as an "S" or "R" configuration, or a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center encompasses each of the (R) and (S) stereoisomers, and mixtures thereof, unless otherwise indicated. For compounds in the examples that contain chiral centers, the isomeric mixtures can be separated to give one or both of isomer 1 (the faster eluting isomer) and isomer 2 (the slower eluting isomer), based on the elution order observed from the separations performed in the examples. The elution time and / or order of the separated isomers may be different if performed under conditions different from those employed herein. The absolute stereochemistry (R or S) of the chiral centers in each of the stereoisomers, isomer "1" and / or isomer "2", separated in the intermediates and examples, has not been determined, and "1" and "2" refer only to the elution order resulting from the purification conditions performed.

[0065] General Procedure The following reaction schemes and examples illustrate the methods that can be adopted to synthesize the 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.All substituents are as defined above unless otherwise indicated.Several strategies based on synthetic transformations known in the organic synthesis literature can be adopted to prepare compounds of structural formula I.

[0066] The compounds of the present disclosure can be prepared according to the procedures of the following examples using appropriate materials.However, the compounds illustrated in the examples should not be construed as forming the only type considered as the present invention.The examples further illustrate the details for preparing the compounds of the present disclosure.Those skilled in the art will easily understand that known variations of protecting groups and known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.Furthermore, it is also understood that whenever a chemical reagent such as boronic acid or boronate is not commercially available, such a chemical reagent can be easily prepared according to one of many methods described in the literature.

[0067] Moisture- and air-sensitive reactions were carried out under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was monitored by either liquid chromatography-mass spectrometry (LC-MS) or analytical thin-layer chromatography (TLC), typically using Merck KGaA glass-backed TLC plates, silica gel 60F. 254 All temperatures are in degrees Celsius unless otherwise indicated. Mass spectra (MS) were measured by either electrospray ionization mass spectrometry (ESI) or atmospheric pressure chemical ionization mass spectrometry (APCI).

[0068] In general, compounds of formula (I) can be prepared by amide coupling of appropriately functionalized carboxylic acids of formula (II) and amines of formula (III). Acids of formula (II) and amines of formula (III) are commercially available or can be synthesized from suitable intermediates. Other synthetic methods for preparing compounds of formula (I) are provided for the purposes of compound illustration. Furthermore, compounds of formula (I) can be prepared by reaction procedures generally known in the art. [ka]

[0069] In some subembodiments, compounds of formula (I) can be prepared by the following reaction sequence: [ka]

[0070] 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, and scan time set to 0.2 seconds) and a Waters Acquity UPLC system (Binary Solvent Manager, Sample Manager, and TUV). The column used was the following: Waters Acquity BEH C18 1×50 mm, 1.7 μm, heated to 50° C. The mobile phases used were either modified with an acidic or basic additive. The acidic mobile phase consisted of water (with 0.1% TFA modifier) ​​as solvent A and 100% MeCN as solvent B. A 2-minute run was set with a flow rate of 0.3 mL / min, with initial conditions of 95% solvent A, increasing to 99% solvent B at 1.60 minutes, and held at 99% solvent B for 0.40 minutes. The injection volume was 0.5 μL and a partial loop needle overfill injection mode was used. The TUV was monitored at wavelengths of 215 nm or 254 nm with normal filter constant and absorbance data modes at a sampling rate of 20 points / s. The basic mobile phase consisted of water (with 0.05% NH4OH modifier) ​​as solvent A and 100% MeCN as solvent B. A 2-minute run was set with a flow rate of 0.3 mL / min, with initial conditions of 99% solvent A, increasing to 99% solvent B at 1.90 min and holding at 99% solvent B for 0.10 min. A 5-minute run was set with a flow rate of 0.3 mL / min, with initial conditions of 95% solvent A, increasing to 99% solvent B at 4.90 min and holding at 99% solvent B for 0.10 min. For both methods, the injection volume was 5.0 μL and a partial loop needle overfill injection mode was used. TUV was monitored at a wavelength of 215 nm with normal filter constant and absorbance data mode at a sampling rate of 20 points / s. Alternatively, a commonly used system is a Waters ZQ in positive ion detection mode with electrospray ionization. TMThe platform consisted of an Agilent 1100 series HPLC with autosampler. The columns were typically Waters Xterra MS C18, 3.0×50 mm, 5 μm or Waters Acquity UPLC® BEH C18 1.0×50 mm, 1.7 μm. The flow rate was 1 mL / min and the injection volume was 10 μL. UV detection was in the range of 210-400 nm. 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 min, changing to 100% solvent B over 3.75 min, holding for 1.1 min, then returning to 100% solvent A over 0.2 min.

[0071] Preparative reversed-phase chromatography was typically performed on a Teledyne ISCO ACCQPrep HP125 or HP150 instrument equipped with UV and ELSD detectors. The UV detector typically monitored wavelengths of 215 nm and 254 nm. Columns were typically either: 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 (with 0.1% TFA modifier) ​​and water (with 0.1% TFA modifier). Alternatively, a commonly used system was a Waters Chromatography Workstation modified with an LCMS system consisting of: Waters ZQ TMSingle Quad MS system (electrospray ionization), Waters 2525 Gradient pump, Waters 2767 injector / collector, Waters 996 PDA detector. MS conditions were as follows: 150-750 amu, positive electrospray, MS triggered collection. Columns used were typically Waters SunFire C18 5 μm 30×150 mm, Boston Green ODS 5 μm 150×30 mm, or YMC-Actus Triart C18 5 μm 150×30 mm. The mobile phase consisted of a mixture of MeCN (10-100%) in water (with 0.1% TFA modifier). The flow rate was maintained at 50 mL / min and the UV detection range was 210-400 nm. An additional preparative HPLC system used was a Gilson Workstation consisting of a Gilson GX-281 injector / collector, a Gilson UV / VIS-155 detector, a Gilson 333 and 334 pumps, and either a Phenomenex Gemini-NX C18 5 μm 50×250 mm column, a Waters XBridge Prep C18 OBD 5 μm 30×250 mm column, or a Welch Xtimate C18 5 μm 150×25 mm column. The mobile phase was 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 individual compound.

[0072] Silica gel chromatography was typically performed on silica gel (pore size 60A) in prepacked RediSep Rf, RediSep Rf Gold or SepaFlash columns using an ISCO CombiFlash Rf instrument, a Biotage® flash chromatography instrument (Dyax Corp.), or an ISCO CombiFlash® Companion XL instrument. The mobile phase generally consisted of a mixture of hexane, petroleum ether or DCM with EtOAc, EtOAc:EtOH (3:1) or MeOH. The mobile phase gradient was optimized for each individual compound.

[0073] Chiral chromatography was typically performed with supercritical fluid chromatography using columns 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 consisted of a mixture of CO2 or hexane with MeOH, EtOH, or IPA, with 0.05-0.1% DEA or NH4OH modifier. The mobile phase gradient was optimized for each individual compound. Pressure was typically maintained at 100 bar, and flow rates ranged from 50-200 mL / min. UV monitoring was typically performed at 220 or 205 nM.

[0074] 1H NMR data were typically acquired at room temperature using a Bruker NEO 500 MHz NMR spectrometer equipped with a 5 mm BBF iProbe, a Bruker Avance NEO 400 MHz NMR spectrometer equipped with a Bruker PI HR-BBO400S1-BBF / H / D-5.0-Z SP 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 (ppm). 1 Chemical shifts for H NMR spectra are given relative to signals for residual non-deuterated solvent (δ 7.26 ppm for CDCl3; δ 2.50 ppm for DMSO-d6; and δ 3.31 ppm for CD3OD). Multiplets are reported with the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet or overlap of unequal resonances. Coupling constants (J) are reported in Hertz (Hz). When a compound appears as a mixture of rotamers in NMR, the spectral data corresponding to the major species observed in solution are reported. EXAMPLES

[0075] Scheme: [ka]

[0076] Intermediate A-1 Benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate [ka]

[0077] Step 1: 2-(2,6-dichloropyridin-4-yl)propan-2-amine A solution of methylmagnesium bromide (3.0 M in Et2O, 1.7 L, 5.2 mol) was added dropwise over 1 h to a 0 °C mixture of 2,6-dichloroisonicotinonitrile (0.30 kg, 1.7 mol) in PhMe (1.5 L). The mixture was warmed to 25 °C and stirred for 1 h. The mixture was cooled to 0 °C and titanium(IV) isopropoxide (490 g, 1.7 mol) was added dropwise over 0.5 h. The mixture was heated to 100 °C and stirred for 1 h. The mixture was cooled to 5-10 °C and treated with a solution of Na2CO3 (sat. aq., 5 L) at 5-10 °C. The mixture was filtered and the filter cake was washed with EtOAc (800 mL x 3). The filtrate was separated and the organic layer was concentrated to give the title compound.

[0078] Step 2: Benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate Benzyl chloroformate (250 g, 1.5 mol) was added dropwise over 0.5 h to a 0° C. mixture of 2-(2,6-dichloropyridin-4-yl)propan-2-amine (270 g, 1.3 mol), DIPEA (190 g, 1.5 mol) and DCM (2.7 L). The mixture was warmed to 25° C. and stirred for 12 h. The mixture was washed with hydrochloric acid (1N, 800 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The material was triturated at 25° C. for 12 h (MTBE / EtOAc=10:1, 800 mL). The mixture was filtered and concentrated under reduced pressure to give the title compound.

[0079] Utilizing the procedure described in the preparation of intermediate A-1, substituting the appropriate reagents for 2,6-dichloroisonicotinonitrile, the following compounds were prepared. [Table 1]

[0080] Scheme: [ka]

[0081] Intermediate A-3 tert-Butyl rac-2-(2,6-dichloropyridin-4-yl)-2-methylazetidine-1-carboxylate [ka]

[0082] Step 1: tert-Butyl rac-2-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate 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'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (25 mg, 0.022 mmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride tetrahydrate (11 mg, 0.023 mmol) were combined in a screw-cap vial. To this was added DMSO (22 mL) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.90 mL, 4.4 mmol). The mixture was bubbled with N2 for 5 min. The vial was capped and then irradiated with a PennOC Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: 5000 rpm; stirring: 1200 rpm). After 4 h, the mixture was diluted with H2O and 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 give the title compound.

[0083] Step 2: tert-Butyl rac-2-(2,6-dichloropyridin-4-yl)-2-methylazetidine-1-carboxylate A solution of tert-butyl rac-2-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate (0.24 g, 0.79 mmol) in THF (4.0 mL) was cooled to -78°C. To this was slowly added lithium diisopropylamide (2.0 M in THF / heptane / ethylbenzene, 0.56 mL, 1.1 mmol). After 30 min, iodomethane (0.10 mL, 1.6 mmol) was added. After 10 min, the cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring for an additional 3 h, 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 with 0.1% TFA modifier). Fractions containing product were combined and concentrated to give the title compound.

[0084] Scheme: [ka]

[0085] Intermediate A-4 [ka]

[0086] Methyl 2-(2,6-dichloropyridin-4-yl)-2-methylpropanoate 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 the mixture was bubbled with N2 for 1 min. Bis(tri-t-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. The mixture was bubbled with N2 for 1 min. The vial was capped and then heated at 85 °C for 18 h. 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 chromatographed on silica gel (0-25% EtOAc / hexanes) to give the title compound.

[0087] Scheme: [ka]

[0088] Intermediate A-5 N-(1-(2,6-dichloropyridin-4-yl)cyclobutyl)-2-methylpropane-2-sulfinamide [ka]

[0089] To a solution of 2,6-dichloro-4-iodopyridine (1.0 g, 3.7 mmol) in THF (12 mL) at −78° C. was added n-butylithiu (2.5 M in hexanes, 2.9 mL, 7.3 mmol) and the mixture was stirred for 30 min. A solution of N-cyclobutylidene-2-methylpropane-2-sulfinamide (0.63 g, 3.7 mmol) in THF (8.0 mL) was added slowly. The mixture was allowed to warm to room temperature and stirred for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL×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 give the title compound.

[0090] Utilizing the procedure described in the preparation of intermediate A-5, substituting the appropriate reagents for N-cyclobutylidene-2-methylpropane-2-sulfinamide, the following compounds were prepared. [Table 2]

[0091] Scheme: [ka]

[0092] Intermediate B Methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate [ka]

[0093] Step 1: Methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)acetate 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 h. 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 give the title compound.

[0094] Step 2: Methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate Under nitrogen atmosphere, to a solution of methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)acetate (14 g, 0.050 mol) in THF (0.15 L) at −78° C. was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.060 L, 0.060 mol). The mixture was stirred for 30 min and iodomethane (6.3 mL, 0.10 mol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 h. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-5% EtOAc / petroleum ether) to give the title compound.

[0095] Utilizing the procedure described in the preparation of intermediate A-1, substituting 2,6-dichloroisonicotinonitrile and benzyl chloroformate with the appropriate reagents, the following compounds were prepared. [Table 3]

[0096] Scheme: [ka]

[0097] Intermediate C-03 Benzyl (2-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)propan-2-yl)carbamate [ka]

[0098] To a mixture of benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate (Int.A-1, 2.0 g, 5.9 mmol) and (4-(trifluoromethyl)phenyl)boronic 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 (evacuation and backfill with nitrogen × 3) and then Pd(dppf)Cl2 (0.43 g, 0.59 mmol) was added. The mixture was heated at 100 °C for 2 h. 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 give the title compound.

[0099] Utilizing the procedure described in the preparation of intermediate C-03, substituting benzyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate and (4-(trifluoromethyl)phenyl)boronic acid with the appropriate reagents, the following compounds were prepared. [Table 4]

[0100] Scheme: [ka]

[0101] Intermediate C-09 Benzyl rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylate [ka]

[0102] Step 1: Benzyl rac-2-methyl-2-(pyridin-4-yl)pyrrolidine-1-carboxylate 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'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-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. To this was added DMSO (28 mL). The mixture was bubbled with N2 for 10 min. The vial was capped and then irradiated with a PennOC Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: 5000 rpm; stirring: 1200 rpm). After 24 h, the mixture was diluted with a solution of NaHCO3 (saturated aqueous) 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 give the title compound.

[0103] Step 2: rac-4-(1-((benzyloxy)carbonyl)-2-methylpyrrolidin-2-yl)pyridine 1-oxide To a solution of benzyl rac-2-methyl-2-(pyridin-4-yl)pyrrolidine-1-carboxylate (0.51 g, 1.7 mmol) in DCM (0.010 L) at room temperature was added 3-chloroperoxybenzoic acid (0.64 g, 2.6 mmol). After 3 h, the mixture was concentrated. The residue was chromatographed on silica gel (0-100% (25% EtOH:EtOAc) / heptane) to give the title compound.

[0104] Step 3: rac-4-(1-((benzyloxy)carbonyl)-2-methylpyrrolidin-2-yl)-2-(4-fluorophenyl)pyridine 1-oxide 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) were combined in a screw-cap vial. To this was added toluene (4.0 mL). The mixture was bubbled with N2 for 1 min. Pd(OAc)2 (27 mg, 0.12 mmol) and tri-tert-butylphosphonium tetrafluoroborate (42 mg, 0.15 mmol) were added. The vial was capped and then heated to 120 °C overnight. The resulting mixture was cooled to room temperature, diluted with EtOAc, filtered through a pad of Celite® (eluted with EtOAc) and concentrated. The residue was subjected to silica gel chromatography (0-100% (25% EtOH:EtOAc) / heptane) to provide the title compound.

[0105] Step 4: Benzyl rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylate 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. To this was added triethylamine (0.27 mL, 1.9 mmol) followed by slow addition of oxalyl chloride (0.085 mL, 0.97 mmol). After 30 min, the mixture was allowed to warm to room temperature and stirred for 3.5 h. The mixture was diluted with a solution of NaHCO3 (saturated aqueous) and then extracted with DCM (3×). 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 give the title compound.

[0106] Scheme: [ka]

[0107] Intermediate C-10 Benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropyl)carbamate [ka]

[0108] Step 1: 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanenitrile 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. To this was slowly added a solution of lithium bis(trimethylsilyl)amide (1.5 M in THF, 3.0 mL, 4.5 mmol). After the addition was complete, the cooling bath was removed and the mixture was allowed to warm to room temperature. After 2 h, the mixture was diluted with a solution of NH4Cl (saturated aqueous) 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 give the title compound.

[0109] Step 2: 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropan-1-amine hydrochloride To a solution of 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanenitrile (0.10 g, 0.36 mmol) in THF (2.0 mL) was added BH3-THF (1.0 M in THF, 1.0 mL, 1.0 mmol) slowly at room temperature. After stirring for 18 hours, hydrochloric acid (6N, 1.0 mL) was added slowly, followed by MeOH (2.0 mL) and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated to give the title compound as the HCl salt.

[0110] Step 3: Benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropyl)carbamate 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 allowed to warm to room temperature with stirring overnight. The mixture was concentrated and the residue was subjected to silica gel chromatography (0-25% (25% EtOH:EtOAc) / heptane) to give the title compound.

[0111] Scheme: [ka]

[0112] Intermediate C-11 Benzyl rac-(1-((tert-butyldiphenylsilyl)oxy)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate [ka]

[0113] Step 1: Methyl rac-2-bromo-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate To a solution of methyl 2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (Int.B, 2.0 g, 6.8 mmol) in acetic acid (0.020 L) was added bromine (0.39 mL, 7.5 mmol). The mixture was placed in a preheated 100 °C oil bath and stirred for 8 h. The mixture was cooled to room temperature and concentrated under reduced pressure. EtOAc (40 mL) was added and the mixture was washed with Na2S2O3 (sat. aq., 20 mL), NaHCO3 (sat. aq., 20 mL) and brine (20 mL x 3). 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 give the title compound.

[0114] Step 2: Methyl rac-2-azido-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate 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 60° C. oil bath and stirred for 5 h. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was treated with NaHCO3 (aq, sat) until pH=9. The mixture was extracted with EtOAc (30 mL×3), and the combined organic extracts were washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.

[0115] Step 3: Methyl rac-2-amino-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate To a solution of methyl rac-2-azido-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (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 h. 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 give the title compound.

[0116] Step 4: Methyl rac-2-(((benzyloxy)carbonyl)amino)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate To a solution of methyl rac-2-amino-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (1.2 g, 3.1 mmol) in DCM (12 mL) was added NaHCO3 (1.0 g, 12 mmol) and benzyl chloroformate (2.2 mL, 16 mmol). The mixture was stirred at room temperature for 1 h. 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 give the title compound.

[0117] Step 5: Benzyl rac-(2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-1-hydroxypropan-2-yl)carbamate To a room temperature mixture of methyl rac-2-(((benzyloxy)carbonyl)amino)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propanoate (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 h. A solution of NH4Cl (saturated aqueous, 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 give the title compound.

[0118] Step 6: Benzyl rac-(1-((tert-butyldiphenylsilyl)oxy)-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate To a solution of benzyl rac-(2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-1-hydroxypropan-2-yl)carbamate (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 h. Water (20 mL) was added and the mixture was extracted with DCM (30 mL×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 give the title compound.

[0119] Scheme: [ka]

[0120] Intermediate C-12 rac-3-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-2-one [ka]

[0121] Step 1: Methyl rac-2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-cyano-2-methylpropanoate To a 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) at −78° C. was slowly added lithium bis(trimethylsilyl)amide (1.0 M in THF, 8.4 mL, 8.4 mmol). After 1 h, 2-bromoacetonitrile (1.0 g, 8.4 mmol) was added, the cooling bath was removed, and the mixture was allowed to warm to room temperature. After 2 h, the mixture was treated with H2O (20 mL) and then 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 silica gel chromatography (0-20% EtOAc / petroleum ether) to give the title compound.

[0122] Step 2: rac-3-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-2-one 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 min, sodium borohydride (1.4 g, 36 mmol) was added portionwise over 5 min, the cooling bath was removed, and the mixture was allowed to warm to room temperature. After 16 h, the mixture was treated with NH4Cl (sat. aq., 20 mL) and then 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 silica gel chromatography (0-35% EtOAc / petroleum ether) to give the title compound.

[0123] Scheme: [ka]

[0124] Intermediate C-13 Benzyl (2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-yl)carbamate [ka]

[0125] Step 1: 2-chloro-4-(4-fluorophenyl)pyridine 1-oxide To a solution of 2-chloro-4-(4-fluorophenyl)pyridine (5.8 g, 28 mmol) in DCM (0.10 mL) was added 3-chloroperoxybenzoic acid (15 g, 84 mmol) at room temperature. The mixture was then heated at 50° C. for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature, NaHCO3 (sat. aq., 100 mL) and Na2SO3 (sat. aq., 100 mL) were added, and the mixture was extracted with EtOAc (50 mL×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 give the title compound.

[0126] Step 2: 6-chloro-4-(4-fluorophenyl)picolinonitrile 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 h 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 give the title compound.

[0127] Step 3: 2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-amine To a solution of 6-chloro-4-(4-fluorophenyl)picolinonitrile (2.7 g, 12 mmol) in THF (0.080 L) at 0° C. was slowly added methylmagnesium bromide (3.0 M in Et2O, 19 mL, 58 mmol). The mixture was warmed to 25° C. and stirred for 30 min. Titanium isopropoxide (3.4 mL, 12 mmol) was added and the mixture was then heated at 80° C. for 12 h. The mixture was cooled to room temperature, treated with NH4Cl (sat. aq., 50 mL), and extracted with EtOAc (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound.

[0128] Step 4: Benzyl (2-(6-chloro-4-(4-fluorophenyl)pyridin-2-yl)propan-2-yl)carbamate 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 allowed to warm to room temperature and stirred for 12 h. The mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to give the title compound.

[0129] Scheme: [ka]

[0130] Intermediate D-ent-1 Benzyl 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-carboxylate (enantiomer 1) And, Intermediate D-ent-2 Benzyl 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-carboxylate (enantiomer 2) [ka]

[0131] Step 1: Benzyl pyridine-1(2H)-carboxylate To a solution of anhydrous pyridine (12 g, 0.15 mol) in anhydrous MeOH (0.10 L) at −78° C. under argon was added sodium borohydride (5.7 g, 0.15 mol). Benzyl chloroformate (21 mL, 0.15 mol) was added dropwise and the mixture was stirred for 3 h. MTBE (100 mL) and water (100 mL) were added and the mixture was allowed to warm to room temperature. The mixture was extracted with MTBE (100 mL×2) and the combined organic extracts were washed with water (100 mL×2) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound.

[0132] Step 2: Benzyl 2-azabicyclo[2.2.0]hex-5-ene-2-carboxylate A solution of benzyl pyridine-1(2H)-carboxylate (6.0 g, 25 mmol) in DCM (0.75 L) was irradiated (300 W, photoreactor, Hg lamp) under nitrogen atmosphere for 6 h. The mixture was concentrated under reduced pressure and subjected to silica gel chromatography (0-17% EtOAc / petroleum ether) to give the title compound.

[0133] Step 3: Benzyl 5-hydroxy-6-iodo-2-azabicyclo[2.2.0]hexane-2-carboxylate To a solution of benzyl 2-azabicyclo[2.2.0]hex-5-ene-2-carboxylate (4.8 g, 22 mmol) in DMSO (72 mL) and water (72 mL) at 5° C. was added N-iodosuccinimide (15 g, 67 mmol) in portions. The mixture was allowed to warm to room temperature and stirred for 12 h. Water (100 mL) was added and the mixture was extracted with EtOAc (50 mL×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 give the title compound.

[0134] Step 4: Benzyl rac-(1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylate A mixture of freshly dried indium(III) chloride (4.4 g, 0.020 mol) and sodium borohydride (1.5 g, 0.040 mol) in MeCN (41 mL) was stirred at −78° C. for 10 min. The mixture was allowed to warm to room temperature and benzyl 5-hydroxy-6-iodo-2-azabicyclo[2.2.0]hexane-2-carboxylate (5.5 g, 15 mmol) in MeCN (82 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was poured into water (60 mL) and extracted with EtOAc (40 mL×3). 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 (0-50% EtOAc / petroleum ether) to give the title compound.

[0135] Step 5: Benzyl rac-(1R,4R,5R)-5-((4-nitrobenzoyl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylate To a solution of benzyl rac-(1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylate (2.6 g, 11 mmol) and 4-nitrobenzoic acid (2.8 g, 17 mmol) in THF (0.080 L) at 0° C. 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 h. The mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (0-17% EtOAc / petroleum ether) to give the title compound.

[0136] Step 6: Benzyl rac-(1R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.0]hexane-2-carboxylate To a solution of benzyl rac-(1R,4R,5R)-5-((4-nitrobenzoyl)oxy)-2-azabicyclo[2.2.0]hexane-2-carboxylate (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 h. 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 give the title compound.

[0137] Step 7: Benzyl 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-carboxylate (Enantiomer 1 and Enantiomer 2) 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), benzyl 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 h. 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 (0-15% EtOAc / petroleum ether). The resulting mixture of the two stereoisomers was subjected to chiral SFC (ChiralPak AD-3, 5-40% IPA (with 0.05% DEA modifier) / CO2) to give benzyl 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-carboxylate (enantiomer 1, fast elution, Int.D-ent-1) and benzyl 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-carboxylate (enantiomer 2, slow elution, Int.D-ent-2) was obtained.

[0138] Scheme: [ka]

[0139] Intermediate E tert-Butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka]

[0140] Step 1: Benzyl(diiodomethyl)dimethylsilane Ten reactions were run in parallel. A solution of lithium bis(trimethylsilyl)amide (1.0 M, 1.5 L, 1.5 mol) in isopropyl ether (3.0 L) was charged to a 10 L vessel. Diiodomethane (130 mL, 1.6 mol) was added to the mixture at -65°C. The mixture was stirred at -65°C for 0.25 h. Benzylchlorodimethylsilane (0.20 kg, 1.1 mol, 0.20 L) was added and the mixture was stirred at -65°C for 3 h and then at 25°C for 12 h. The reactions were combined and treated with water (10 L). The mixture was extracted with MTBE (5 L x 2). The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (2-100% EtOAc / petroleum ether) to give the title compound.

[0141] Step 2: tert-Butyl (1R,5S,6s)-6-(benzyldimethylsilyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 14 reactions were run in parallel. Chromium(II) chloride (150 g, 1.2 mol) was charged to a 5 L vessel. To the mixture was added THF (2.5 L) and N,N,N,N-tetramethylethylenediamine (360 mL, 2.4 mol) over 0.5 h at 25 °C. Benzyl(diiodomethyl)dimethylsilane (240 g, 560 mmol) was added and the mixture was stirred at 25 °C for 0.5 h. To the mixture was added tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (0.050 kg, 0.30 mol) at 25 °C. The mixture was stirred at 50 °C for 18 h. The reactions were combined and the mixture was treated with water (15 L) and extracted with MTBE (7 L x 3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (1-100% EtOAc / petroleum ether) to give the title compound.

[0142] Step 3: tert-Butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate 14 reactions were run in parallel. tert-Butyl (1R,5S,6s)-6-(benzyldimethylsilyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.070 kg, 210 mmol) in THF (2.1 L) was charged to a 10 L vessel. Tetrabutylammonium fluoride solution (1.0 M in THF, 630 mL) was added and the mixture was stirred at 25 °C for 0.5 h. MeOH (2.1 L) and potassium bicarbonate (0.20 kg, 2.1 mol) were added to the reaction vessel at 0 °C, followed by hydrogen peroxide (30 wt% in water, 0.10 L, 1.1 mol). The mixture was stirred at 0 °C for 0.5 h and at 25 °C for 16 h. The reactions were combined and the mixture was treated with Na2SO3 (sat. aq., 25 L) and extracted with EtOAc (7 L x 2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was subjected to silica gel chromatography (0-100% EtOAc / hexanes) and then recrystallized from n-heptane:MTBE=20:1 (9 L) to give the title compound.

[0143] Intermediate F [ka]

[0144] tert-Butyl 6-hydroxy-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate Step 1: tert-Butyl 6,6-dibromo-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate A mixture of tert-butyl 3-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (15 g, 82 mmol), bromoform (62 g, 0.25 mol) and N-benzyl-N,N,N-triethylammonium chloride (0.75 g, 3.3 mmol) in DCM (0.40 L) and EtOH (8.0 mL) was cooled to 0° C. under nitrogen atmosphere. A solution of sodium hydroxide (50 wt % aqueous, 66 g, 0.82 mol) was added at 0° C. The mixture was warmed to 45° C. and stirred for 12 h. Water (150 mL) was added and the mixture was extracted with DCM (80 mL×3). The combined organic solution was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-5% EtOAc / petroleum ether) to give the title compound.

[0145] Step 2: tert-Butyl 6-hydroxy-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 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-butyllithium (2.5 M in hexane, 2.7 mL, 6.8 mmol) was added dropwise and the mixture was stirred for 15 min. A solution of catecholborane (1.0 M in THF, 11 mL, 11 mmol) was added and the mixture was warmed to 50°C and stirred for 12 h. The mixture was cooled to 0°C and hydrogen peroxide (30% (w / w) aqueous, 2.9 mL, 28 mmol) and sodium hydroxide (2.5 M aqueous, 9.0 mL, 23 mmol) were added. The mixture was warmed to room temperature and stirred for 12 h. Na2SO3 (saturated aqueous, 5 mL) and water (20 mL) were added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic solutions were 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 give the title compound.

[0146] Scheme: [ka]

[0147] intermediate G 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 [ka]

[0148] 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), potassium phosphate tribasic (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 (5x) at 15 °C. 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 h. The mixture was cooled to 15° C., washed with NaHCO3 (saturated aqueous, 1.0 L), and filtered. The filter cake was washed with EtOAc (1.5 L) and the organic layer was separated. The aqueous layer was extracted with EtOAc (500 mL×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 reverse phase HPLC (40-70% MeCN / water) to give the title compound.

[0149] Intermediate G-01 Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-chloropyridin-4-yl)propan-2-yl)carbamate [ka]

[0150] 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 h. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0151] Scheme: [ka]

[0152] Intermediate H-01 2-(2-(((1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine [ka]

[0153] Step 1: 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 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 chromatographed on silica gel (0-50% EtOAc / hexanes) to give the title compound.

[0154] Step 2: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-amine To a 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) at 0° C. was added a solution of HCl (4.0 M in 1,4-dioxane, 6.1 mL, 24 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. 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.

[0155] Intermediate H-02 Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate [ka]

[0156] Step 1: 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 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 h. 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 chromatographed on silica gel (0-45% EtOAc / petroleum ether) to give the title compound.

[0157] Step 2: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate 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 h and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-10% MeOH / DCM) to give the title compound.

[0158] Utilizing the procedure described in the synthesis of intermediate H-02, substituting benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate with the appropriate reagents, the following compounds were prepared. [Table 5] TIFF2025505087000067.tif125169

[0159] Scheme: [ka]

[0160] Intermediate H-12-ent-1 Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (enantiomer 1) And, Intermediate H-12-ent-2 Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (enantiomer 2) [ka]

[0161] 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-siladecane-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Enantiomer 1 and Enantiomer 2) Under an 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), 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 w / 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 give the title compounds 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-siladecane-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomer 1, fast eluting) and ...2, fast eluting) and tert-butyl ent-(1R,5S,6s)-6-((6-(4- 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-siladecane-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomer 2, slower eluting) was obtained.

[0162] Step 2-1: Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (enantiomer 1) 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-siladecane-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomer 1, fast 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 h. The mixture was concentrated under reduced pressure to give the title compound (Int.H-12-ent-1).

[0163] Step 2-2: Benzyl ent-(2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate (enantiomer 2) 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-siladecane-5-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (enantiomer 2, slow 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 h. The mixture was concentrated under reduced pressure to give the title compound (Int.H-12-ent-2).

[0164] Scheme: [ka]

[0165] Intermediate H-13 Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(2,4-difluorophenyl)pyridin-4-yl)propan-2-yl)carbamate [ka]

[0166] Step 1: 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 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, 3.0 mL, 3.0 mmol), and 1,4-dioxane (5.0 mL) was stirred at 100 °C for 2 h. 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.

[0167] Step 2: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(2,4-difluorophenyl)pyridin-4-yl)propan-2-yl)carbamate 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 h. The reaction was concentrated under reduced pressure to provide the title compound as the HCl salt.

[0168] Scheme: [ka]

[0169] Intermediate H-14 2-(2-(((1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)pyridin-4-yl)propan-2-amine [ka]

[0170] 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 To a solution of 4-iodo-2-methylbenzoic acid (4.1 g, 16 mmol) in DCM (31 mL) was added a solution of oxalyl chloride (2.0 M in DCM, 2.7 mL, 31 mmol) followed by DMF (2 drops). The mixture was heated at reflux for 1 h. The mixture was concentrated under reduced pressure. DCM (31 mL) and DIPEA (14 mL, 78 mmol) were added followed by a solution of 4,8-di-tert-butyl-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin 6-oxide (6.0 g, 16 mmol) in DCM (31 mL) added dropwise over 1 h. The mixture was stirred at room temperature for 6 h. DCM (50 mL) was added and the mixture was washed with hydrochloric acid (1N, 50 mL) and a solution of NaHCO3 (saturated aqueous, 50 mL). The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (0-30% EtOAc / Hexanes) to provide the title compound.

[0171] Step 2: 3-Iodobicyclo[4.2.0]octa-1(6),2,4-trien-7-one A solution of (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 (4.7 g, 7.4 mmol) in PhMe (15 mL) was irradiated with a PennOC Photoreactor® (wavelength: 420 nm; LED intensity: 100%; fan speed: 5000 rpm; stirring: 1200 rpm) for 12 h. Triethylamine (1.0 mL, 7.4 mmol) was added and the mixture was heated to 45° C. for 4 h. The mixture was subjected to silica gel chromatography (0-15% EtOAc / Hexanes) to give the title compound.

[0172] Step 3: 7,7-Difluoro-3-iodobicyclo[4.2.0]octa-1(6),2,4-triene 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-trien-7-one (250 mg, 1.0 mmol) was stirred at 50 °C for 16 h. A solution of NaHCO3 (saturated aqueous, 30 mL) at 0 °C was added dropwise and the mixture was extracted with DCM (30 mL × 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 (hexane) to give the title compound.

[0173] Step 4: tert-Butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate Under a 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 h. A solution of K2CO3 (1.8 M aqueous, 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 h. The mixture was cooled to room temperature, a solution of KH2PO4 (saturated aqueous, 20 mL) was added and the mixture was extracted with EtOAc (20 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 (0-100% EtOAc / Hexane) to give the title compound.

[0174] Step 5: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)pyridin-4-yl)propan-2-amine A mixture of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.41 g, 0.68 mmol) and hydrochloric acid (37%, 6.7 mL) was stirred at 80° C. for 10 min. The mixture was cooled to room temperature, diluted with water (10 mL), and loaded onto a Flash SCX-2 cartridge (preconditioned with MeOH). The cartridge was washed with MeOH (2 CV) and eluted with NH3 in methanol (2 N, 2 CV). The eluent 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 min and concentrated under reduced pressure to give the title compound as the HCl salt.

[0175] Intermediate H-15 2-(2-(((1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(bicyclo[1.1.1]pentan-1-ylmethoxy)pyridin-4-yl)propan-2-amine [ka]

[0176] Step 1: tert-Butyl (1R,5S,6s)-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 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, 0.050 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 the mixture was bubbled with nitrogen 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 (eluted 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.

[0177] Step 2: 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(bicyclo[1.1.1]pentan-1-ylmethoxy)pyridin-4-yl)propan-2-amine 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 min, 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 with 0.1% TFA modifier). Fractions containing product were pooled and concentrated. The residue was taken up in MeCN and then transferred to a screw cap vial. Two volumes of hydrochloric acid (1N aqueous) were added. The mixture was frozen (dry ice / acetone) and then lyophilized to give the title compound as the HCl salt.

[0178] Intermediate H-16 Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-4-yl)propan-2-yl)carbamate [ka]

[0179] Step 1: 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 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 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (0-50% EtOAc / petroleum ether) to give the title compound.

[0180] Step 2: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-4-yl)propan-2-yl)carbamate 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 h and concentrated under reduced pressure to provide the title compound.

[0181] Scheme: [ka]

[0182] Intermediate H-17 Benzyl (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-yl)carbamate [ka]

[0183] Step 1: Benzyl (2-(2-chloropyridin-4-yl)propan-2-yl)carbamate 1-oxide 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% in water, 4.8 g, 22 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with DCM (75 mL) and washed with Na2SO3 (saturated aqueous, 100 mL), NaHCO3 (saturated aqueous, 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 give the title compound.

[0184] Step 2: tert-Butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate N-oxide 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 give the title compound.

[0185] Step 3: tert-Butyl (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-carboxylate To a mixture of tert-butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate N-oxide (0.55 g, 1.1 mmol) and 4,4-dimethylpiperidine·HCl (0.21 g, 1.4 mmol) in DCM (4.6 mL) was added DIPEA (0.99 mL, 5.7 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (0.69 g, 1.5 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with NaHCO3 (sat. aq., 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 chromatographed on silica gel (0-15% (25% EtOH / EtOAc) / hexanes) to provide the title compound.

[0186] Step 4: Benzyl (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-yl)carbamate To a solution of tert-butyl (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-carboxylate (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 h. The mixture was poured into sodium hydroxide (1N aqueous, 50 mL) and the pH was adjusted to >12 with sodium hydroxide (6N aqueous). 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.

[0187] Utilizing the procedure described in the synthesis of intermediate H-17, substituting the appropriate reagent for 4,4-dimethylpiperidine·HCl, the following compounds were prepared. [Table 6]

[0188] Scheme: [ka]

[0189] Intermediate H-19 3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-3-methylazetidin-2-one [ka]

[0190] Step 1: tert-Butyl (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-carboxylate 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 h, the mixture was cooled to room temperature, filtered, and concentrated. The residue was subjected to silica gel chromatography (0-20% EtOAc / petroleum ether) to give the title compound.

[0191] Step 2: tert-Butyl 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-carboxylate To a solution of tert-butyl (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-carboxylate (1.0 g, 2.2 mmol) in THF (15 mL) at -78 °C was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.9 mL, 2.9 mmol) slowly. After 1 h, a solution of 2-(bromomethyl)isoindoline-1,3-dione (0.79 g, 3.3 mmol) in THF (5.0 mL) was added. After 2 h, the mixture was warmed to 0 °C and a solution of NH4Cl (sat. aq.) 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, and the residue was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to give the title compound.

[0192] Step 3: tert-Butyl 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-carboxylate To a room temperature mixture of tert-butyl 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-carboxylate (0.60 g, 0.98 mmol) in EtOH (15 mL) was added hydrazine hydrate (0.49 g, 9.8 mmol). After 12 h, the mixture was filtered and concentrated. The residue was subjected to silica gel chromatography (EtOAc) to provide the title compound.

[0193] Step 4: rac-3-amino-2-(2-(((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanoic acid To a room temperature mixture of tert-butyl 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-carboxylate (0.30 g, 0.61 mmol) in THF (5.0 mL) and HO (5.0 mL) was added LiOH (73 mg, 3.0 mmol). After 12 h, the mixture was concentrated to remove volatile organic solvents and then washed with DCM (2×). The aqueous solution was acidified (pH=6) with hydrochloric acid (1N) and concentrated under reduced pressure. DCM (10 mL) and MeOH (10 mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0194] Step 5: tert-Butyl 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-carboxylate To a solution of rac-3-amino-2-(2-(((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanoic acid (240 mg, 0.41 mmol) in DMF (8.0 mL) at room temperature was added DIPEA (0.20 mL, 1.2 mmol) and T3P (50 wt% in EtOAc, 390 mg, 0.61 mmol). After 1 h, the mixture was diluted with HO (10 mL) and then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (67% EtOAc / petroleum ether) to give the title compound.

[0195] 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 To a solution of tert-butyl 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-carboxylate (110 mg, 0.24 mmol) in DCM (3.0 mL) at room temperature was added TFA (1.0 mL). After 30 min, the mixture was concentrated to give the title compound as a TFA salt.

[0196] Scheme: [ka]

[0197] Intermediate H-20 rac-2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-aminopropanamide [ka]

[0198] Step 1: tert-Butyl (1R,5S,6s)-6-((4-cyano-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate Under nitrogen atmosphere, a mixture of tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (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 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with NaHCO3 (sat. aq., 50 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (DCM) to give the title compound.

[0199] Step 2: tert-Butyl (1R,5S,6s)-6-((4-acetyl-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a room temperature solution of tert-butyl (1R,5S,6s)-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 added MeMgBr (3.0 M in EtO, 2.6 mL, 7.7 mmol) slowly. After 3 h, the mixture was quenched with NH4Cl (sat. aq.), 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 give the title compound.

[0200] Step 3: tert-Butyl rac-(1R,5S,6s)-6-((4-(1-amino-1-cyanoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate 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 overnight at room temperature 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 give the title compound.

[0201] Step 4: tert-Butyl 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-carboxylate To a room temperature solution of tert-butyl rac-(1R,5S,6s)-6-((4-(1-amino-1-cyanoethyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.060 g, 0.14 mmol) in DMSO (1.0 mL) was added K2CO3 (76 mg, 0.55 mmol) followed by H2O2 (30 wt% in water, 0.14 mL, 1.4 mmol). The mixture was stirred overnight, diluted with H2O, 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.

[0202] Step 5: rac-2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-aminopropanamide A mixture of tert-butyl 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-carboxylate (65 mg, 0.14 mmol) and hydrochloric acid (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.

[0203] Scheme: [ka]

[0204] Intermediate I-1-ent-1 and Intermediate I-1-ent-2 Benzyl rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1 and Enantiomer 2) [ka]

[0205] Step 1: tert-Butyl 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-carboxylate (Enantiomer 1 and Enantiomer 2) 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 h. The mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-15% EtOAc / petroleum ether) to give the title compound. This material was subjected to chiral SFC (ChiralPak OJ-H, 5-40% EtOH (with 0.05% DEA modifier) / CO2) to give tert-butyl 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-carboxylate (enantiomer 1, fast eluting) and tert-butyl 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-carboxylate (enantiomer 2, slower eluting) was obtained.

[0206] Step 2-1: Benzyl rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1, Int.I-1-ent-1) To a mixture of tert-butyl 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-carboxylate (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 h. The mixture was concentrated under reduced pressure to provide the title compound.

[0207] Step 2-2: Benzyl rel-(2-(2-(4-fluorophenyl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2, Int.I-1-ent-2) To a mixture of tert-butyl 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-carboxylate (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 h. The mixture was concentrated under reduced pressure to provide the title compound.

[0208] Utilizing the procedures described in the synthesis of intermediate I-1 and substituting benzyl (2-(2-chloro-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate with the appropriate reagents, the following compounds were prepared. [Table 7]

[0209] Intermediate J 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 [ka]

[0210] 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]hexan-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 h. The mixture was subjected to silica gel chromatography (0-40% (25% EtOH / EtOAc) / hexanes) to give the title compound.

[0211] Scheme: [ka]

[0212] Intermediate K-01 4-Methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid [ka]

[0213] Step 1: Ethyl 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylate 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 h under a nitrogen atmosphere. 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 give the title compound.

[0214] Step 2: 4-Methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid To a solution of ethyl 4-methyl-2-(oxazol-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, 0.60 mL, 0.60 mmol). The reaction mixture was stirred at room temperature for 1 h 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 give the title compound.

[0215] Utilizing the procedure described in the synthesis of intermediate K-01, substituting 2-(tributylstannyl)oxazole and ethyl 2-bromo-4-methylthiazole-5-carboxylate with the appropriate reagents, the following compounds were prepared. [Table 8]

[0216] Intermediate K-09 1-Methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylic acid [ka]

[0217] Step 1: Ethyl 1-methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylate To a solution of ethyl 3-bromo-1-methyl-1H-1,2,4-triazole-5-carboxylate (0.090 g, 0.39 mmol) in 1,4-dioxane (8.0 mL) under N2 was added 4-(tributylstannyl)thiazole (0.29 g, 0.77 mmol) and Pd(PPh3)4 (44 mg, 0.040 mmol), and the mixture was then heated at 110° C. for 12 h. The mixture was cooled to room temperature, and then a solution of potassium fluoride (saturated aqueous, 5 mL) was added. After 30 min, the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (50% EtOAc / petroleum ether) to give the title compound.

[0218] Step 2: 1-Methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylic acid To a mixture of ethyl 1-methyl-3-(thiazol-4-yl)-1H-1,2,4-triazole-5-carboxylate (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 h. The mixture was concentrated to remove volatile organic solvents and then washed with DCM (2x). The aqueous solution was acidified (pH = 6) with hydrochloric acid (1N) and concentrated under reduced pressure. MeOH (5 mL) and DCM (5 mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was filtered and concentrated under reduced pressure to give the title compound.

[0219] Scheme: [ka]

[0220] Intermediate K-10 4-Acetyl-[2,4'-bithiazole]-5-carboxylic acid [ka]

[0221] Step 1: Ethyl 4-hydroxy-[2,4'-bithiazole]-5-carboxylate A solution of thiazole-4-carbothioamide (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 h under nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to give the title compound.

[0222] Step 2: Ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-[2,4'-bithiazole]-5-carboxylate To a solution of ethyl 4-hydroxy-[2,4'-bithiazole]-5-carboxylate (0.20 mL, 2.3 mmol) in DCM (7.0 mL) under nitrogen atmosphere was added trifluoromethanesulfonic anhydride (0.20 mL, 1.2 mmol) dropwise at 0°C. The mixture was then allowed to warm to room temperature and stirred for 12 h. The mixture was concentrated under reduced pressure and the residue was subjected to prep-TLC (25% EtOAc / petroleum ether) to give the title compound.

[0223] Step 3: Ethyl 4-acetyl-[2,4'-bithiazole]-5-carboxylate 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), ethoxyethene (1.1 g, 15 mmol), and Pd(OAc)2 (42 mg, 0.19 mmol) was stirred at 110 °C for 12 h. The mixture was concentrated under reduced pressure. EtOAc (30 mL) was added, and the solution was washed with brine (10 mL x 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 h. The mixture was added with water (10 mL) and extracted with EtOAc (15 mL×3). The combined organic solutions were 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 give the title compound.

[0224] Step 4: 4-Acetyl-[2,4'-bithiazole]-5-carboxylic acid To a mixture of ethyl 4-acetyl-[2,4'-bithiazole]-5-carboxylate (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 h. The mixture was concentrated and the aqueous layer was washed with DCM (10 mL x 2). The aqueous layer was acidified (pH = 4) with hydrochloric acid (1 N) 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 give the title compound.

[0225] Scheme: [ka]

[0226] Intermediate K-11 Ethyl 3-(thiazol-4-yl)-1,2,4-thiadiazole-5-carboxylate [ka]

[0227] Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole 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) dichloride (2.9 g, 4.1 mmol) and DMF (0.060 L) was stirred at 60 °C for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature and a solution of potassium fluoride (saturated aqueous, 10 mL) was added. The mixture was stirred for 30 min 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 give the title compound.

[0228] Step 2: Ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate 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 h. A solution of NaHCO3 (saturated aqueous, 0.010 L) was added and the mixture was stirred at room temperature for 30 min. 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 give the title compound.

[0229] Step 3: Ethyl 3-(thiazol-4-yl)-1,2,4-thiadiazole-5-carboxylate To a solution of ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (0.18 g, 0.93 mmol) in 1,4-dioxane (0.010 L) under N2 was added 4-(tributylstannyl)thiazole (0.42 g, 1.1 mmol) and Pd(PPh3)4 (0.11 g, 0.093 mmol). The mixture was heated at 100 °C for 15 h. The mixture was cooled to room temperature and a solution of potassium fluoride (saturated aqueous, 10 mL) was added. The mixture was stirred at room temperature for 30 min 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 give the title compound.

[0230] Scheme: [ka]

[0231] Intermediate L-1 1-Methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid [ka]

[0232] Step 1: Methyl 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate To a mixture of methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (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 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL × 3). The combined organic solution was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (20-35% EtOAc / petroleum ether) to give the title compound.

[0233] Step 2: 1-Methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid To a mixture of methyl 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (1.2 g, 5.4 mmol) in THF (0.010 L) and water (0.010 L) was added LiOH (0.64 g, 27 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and washed with DCM (10 mL x 2). The aqueous solution was acidified (pH = 4) with a solution of HCl (1N aqueous) and concentrated under reduced pressure. MeOH (10 mL) and DCM (10 mL) were added and the mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound.

[0234] Scheme: [ka]

[0235] Intermediate L-2 1-Ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid [ka]

[0236] Step 1: Ethyl 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate To a solution of ethyl 1H-pyrazole-5-carboxylate (5.0 g, 36 mmol) in PhMe (0.030 L) was added 3,4-dihydro-2H-pyran (3.2 g, 38 mmol) and TFA (0.027 mL, 0.36 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×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 give the title compound.

[0237] Step 2: Ethyl 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate A mixture of ethyl 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (4.8 g, 21 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(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 h under nitrogen atmosphere. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic solution was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to reverse phase chromatography (35% MeCN / water) to afford the title compound.

[0238] Step 3: Ethyl 1-(tetrahydro-2H-pyran-2-yl)-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate A mixture of ethyl 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (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 h. 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 chromatographed on silica gel (0-50% EtOAc / petroleum ether) to give the title compound.

[0239] Step 4: Ethyl 3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate 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 for 10 minutes at 80° C. The mixture was concentrated under reduced pressure to provide the title compound.

[0240] Step 5: Ethyl 1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate Under nitrogen atmosphere, a mixture of ethyl 3-(thiazol-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 h. 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 brine (50 mL). The mixture was concentrated under reduced pressure and subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to give the title compound.

[0241] Step 6: 1-Ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid To a mixture of ethyl 1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (0.030 g, 0.12 mmol) in THF (2.0 mL) and water (2.0 mL) was added LiOH (8.6 mg, 0.36 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and washed with DCM (10 mL x 2). The aqueous solution was acidified (pH = 4) with hydrochloric acid (1 N) and the mixture was concentrated under reduced pressure. MeOH / DCM (1:5, 20 mL) was added and the mixture was stirred at room temperature for 1 h. The mixture was filtered and concentrated under reduced pressure to give the title compound.

[0242] Scheme: [ka]

[0243] Intermediate M-1 Methyl 4-fluoro-1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylate [ka]

[0244] Step 1: Methyl 3-((tert-butyldimethylsilyl)oxy)-1-methyl-1H-pyrazole-5-carboxylate To a room temperature solution of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (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 h, the mixture was diluted with HO and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound.

[0245] Step 2: Methyl 4-fluoro-3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate 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 min. 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 give the title compound.

[0246] Step 3: Methyl 4-fluoro-1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate To a solution of methyl 4-fluoro-3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (1.1 g, 6.3 mmol) in DCM (12 mL) at 0° C. 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 allowed to warm slowly to room temperature and stirred for 2 h. The mixture was diluted with HO and extracted with DCM (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound.

[0247] Step 4: Methyl 4-fluoro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate 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 h. 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 give the title compound.

[0248] Step 5: Methyl 4-fluoro-1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylate Under nitrogen atmosphere, a mixture of methyl 4-fluoro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (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 h. The mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (25% EtOAc / petroleum ether) to give the title compound.

[0249] Utilizing the procedures described in the synthesis of intermediate M-1, substituting the appropriate reagent for 2-bromooxazole in step 5, the following compounds were prepared. [Table 9]

[0250] Scheme: [ka]

[0251] Intermediate N 1-Methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid [ka]

[0252] Step 1: Ethyl 1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylate To a solution of oxazole (0.42 mL, 6.4 mmol) in THF (21 mL) at −15° C., a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 8.6 mL, 8.6 mmol) was added dropwise over 15 min. The mixture was stirred at −15° C. for 30 min. 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 min. The solution was allowed to warm to room temperature, stirred for 30 min, 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 h. The mixture was cooled to room temperature, NH4Cl (saturated aqueous, 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) / hexanes) to provide the title compound.

[0253] Step 2: 1-Methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylic acid To a solution of ethyl 1-methyl-3-(oxazol-2-yl)-1H-pyrazole-5-carboxylate (0.85 g, 3.8 mmol) in EtOH (9.6 mL) and THF (9.6 mL) was added a solution of sodium hydroxide (1.0 N aqueous, 5.8 mL, 5.8 mmol). The mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The mixture was dissolved in a solution of sodium hydroxide (0.05 M aqueous, 75 mL) and washed with DCM (50 mL x 3). The aqueous solution was acidified (pH = 1) with hydrochloric acid (1 N). The mixture was stirred at room temperature for 12 h, filtered, and the filter cake was washed with water (10 mL x 3). The filter cake was subjected to reverse phase HPLC (0-90% MeCN / water (with 0.1% TFA modifier)) to give the title compound.

[0254] Scheme: [ka]

[0255] Intermediate O-1 2-(Isoxazol-3-yl)-4-methylthiazole-5-carboxylic acid [ka]

[0256] Step 1: Methyl 2-formyl-4-methylthiazole-5-carboxylate 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(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.4 g, 3.2 mmol). The mixture was stirred at ambient temperature for 1 h. DCM (10 mL), Na2S2O3 (saturated aqueous, 5 mL), NaHCO3 (saturated aqueous, 5 mL) were added and the mixture was stirred for 10 min. 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.

[0257] Step 2: Methyl 2-((hydroxyimino)methyl)-4-methylthiazole-5-carboxylate 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 give the title compound.

[0258] Step 3: Methyl 4-methyl-2-(5-(trimethylsilyl)isoxazol-3-yl)thiazole-5-carboxylate 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 give the title compound.

[0259] Step 4: Methyl 2-(isoxazol-3-yl)-4-methylthiazole-5-carboxylate 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 h and concentrated under reduced pressure. EtOAc (5 mL) was added and the mixture was washed with NaHCO3 (sat. aq., 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.

[0260] Step 5: 2-(isoxazol-3-yl)-4-methylthiazole-5-carboxylic acid 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, 0.26 mL, 0.52 mmol). The reaction mixture was stirred at 80° C. for 1 h 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 give the title compound.

[0261] Utilizing the procedures described in the synthesis of intermediate O-1, substituting the appropriate reagents for methyl 2-formyl-4-methylthiazole-5-carboxylate, the following compounds were prepared. [Table 10]

[0262] Scheme: [ka]

[0263] Intermediate P 3-(Thiazol-4-yl)isothiazole-5-carboxylic acid [ka]

[0264] Step 1: 5-(thiazol-4-yl)-1,3,4-oxathiazol-2-one To a mixture of thiazole-4-carboxamide (0.50 g, 3.9 mmol) in THF (8.0 mL) under nitrogen atmosphere was added carbonochloridic hypochlorous thioanhydride (0.60 mL, 7.0 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 12 h. The organic layer was concentrated under reduced pressure to give the title compound.

[0265] Step 2: Methyl 3-(thiazol-4-yl)isothiazole-5-carboxylate 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 propionate (2.0 mL, 32 mmol) at 25° C. under 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 prep-TLC (25% EtOAc / petroleum ether) to give the title compound.

[0266] Step 3: 3-(thiazol-4-yl)isothiazole-5-carboxylic acid To a mixture of methyl 3-(thiazol-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 h. The mixture was concentrated under reduced pressure and the aqueous layer was washed with DCM (5 mL x 2). The aqueous solution was acidified (pH = 4) with hydrochloric acid (1 N). The aqueous layer 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 give the title compound.

[0267] Intermediate Q 3-(5-Fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid [ka]

[0268] Step 1: Methyl 3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate To a solution of methyl 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (prepared as in L-1 step 1, 0.60 g, 2.2 mmol) in MeCN (25 mL) was added (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.1 g, 3.2 mmol) and the mixture was stirred at 80 °C for 12 h. A solution of NaHCO3 (saturated aqueous, 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 (with 0.1% TFA modifier)) and lyophilized to give the title compound.

[0269] Step 2: 3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid To a mixture of methyl 3-(5-fluorothiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.14 g, 0.58 mmol) in THF (3.0 mL) and water (3.0 mL) was added LiOH (28 mg, 1.2 mmol). The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure and extracted with DCM (10 mL×2). The aqueous solution was acidified (pH=4) with hydrochloric acid (1N) and concentrated under reduced pressure. DCM (10 mL) and MeOH (10 mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound.

[0270] Scheme: [ka]

[0271] Intermediate R 3-Methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylic acid [ka]

[0272] Step 1: Ethyl 3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylate 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 h. 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 give the title compound.

[0273] Step 2: 3-Methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylic acid To a mixture of ethyl 3-methyl-1-(thiazol-4-yl)-1H-pyrazole-4-carboxylate (0.080 g, 0.34 mmol) in THF (3.0 mL) and water (3.0 mL) was added LiOH (81 mg, 3.4 mmol). The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and washed with DCM (10 mL x 2). The aqueous mixture was acidified (pH = 4) with hydrochloric acid (1N) and concentrated under reduced pressure. The material was stirred in MeOH / DCM (1:10 mixture, 20 mL) at room temperature for 1 h. The mixture was filtered and concentrated under reduced pressure to give the title compound.

[0274] Scheme: [ka]

[0275] Intermediate S N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide [ka]

[0276] Step 1: Methyl 2-chloro-6-(4-fluorophenyl)isonicotinate To a mixture of methyl 2,6-dichloroisonicotinate (0.010 kg, 49 mmol), (4-fluorophenyl)boronic acid (6.6 g, 47 mmol), and Cs2CO3 (24 g, 73 mmol) in 1,4-dioxane (0.50 L) and water (26 mL) was added PdCl2(dppf) (2.7 g, 3.6 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was filtered and the filtrate was extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine (50 mL × 2), 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 give the title compound.

[0277] Step 2: Benzyl (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(methoxycarbonyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate In a glove box, Pd(OAc)2 (85 mg, 0.38 mmol) was added to a solution of benzyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.8 g, 7.5 mmol), methyl 2-chloro-6-(4-fluorophenyl)isonicotinate (2.0 g, 7.5 mmol), K3PO4 (4.8 g, 23 mmol), and 5-(di((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 h, the mixture was cooled, filtered through silica gel (eluted with EtOAc) and concentrated under reduced pressure. The residue was chromatographed on silica gel (0-25% EtOAc / petroleum ether) to give the title compound.

[0278] Step 3: Benzyl (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(hydroxymethyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a mixture of benzyl (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-(methoxycarbonyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (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 min, the reaction was quenched with water (0.20 mL), 15% NaOH (0.60 mL, aq.) and additional water (0.20 mL). The reaction was allowed to warm to 0 °C and stirred for 10 min. Anhydrous magnesium sulfate was added and the mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0279] Step 4: Benzyl (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-formylpyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate 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) was added manganese(IV) oxide (1.8 g, 21 mmol) at 25° C. The resulting mixture was stirred at 40° C. for 18 h. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0280] Step 5: Benzyl (1R,5S,6s)-6-((4-((Z)-((tert-butylsulfinyl)imino)methyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a mixture of benzyl (1R,5S,6s)-6-((6-(4-fluorophenyl)-4-formylpyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (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 h, 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 give the title compound.

[0281] Step 6: 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 To a mixture of benzyl (1R,5S,6s)-6-((4-((Z)-((tert-butylsulfinyl)imino)methyl)-6-(4-fluorophenyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (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 h, the reaction mixture was quenched with NH4Cl (sat. aq., 20 mL) and extracted with EtOAc (25 mL×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.

[0282] Step 7: N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide 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 h. The mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0283] Scheme: [ka]

[0284] Intermediate T Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate [ka]

[0285] Step 1: 1-Methylcyclopentane-1-carbonyl chloride 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 2 drops of DMF (gas evolution). After 3 h, gas evolution ceased and the reaction was concentrated under reduced pressure to give the title compound.

[0286] Step 2: 2-(1-methylcyclopentyl)isonicotinonitrile 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, stir speed: 1200 rpm) at 25 °C. After 18 h, the mixture was poured into NaHCO3 (sat. aq.). 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 give the title compound.

[0287] Step 3: 2-(2-(1-methylcyclopentyl)pyridin-4-yl)propan-2-amine To a solution of 2-(1-methylcyclopentyl)isonicotinonitrile (0.34 g, 1.8 mmol) in toluene (0.010 L) at 0° C. was added MeMgBr (3.0 M, 1.9 mL, 5.7 mmol) slowly. After 30 min, titanium(IV) isopropoxide (0.55 mL, 1.9 mmol) was added slowly. After 30 min, the reaction was allowed to warm to 25° C. After 18 h, the mixture was quenched with NaOH (2 M aqueous, 1 mL). After 30 min, the mixture was filtered and concentrated under reduced pressure to provide the title compound.

[0288] Step 4: Benzyl (2-(2-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate 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 min, the reaction was allowed to warm to 25° C. After 1 h, the reaction was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-25% EtOAc / heptane) to afford the title compound.

[0289] Step 5: 4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-2-(1-methylcyclopentyl)pyridine 1-oxide 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 h, the mixture was diluted with NaHCO3 (sat. aq.) 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 give the title compound.

[0290] Step 6: Benzyl (2-(2-chloro-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate 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 POCl3 (0.30 mL, 3.2 mmol). The mixture was heated to 80 °C. After 18 h, additional POCl3 (1.0 mL, 11 mmol) was added and the reaction continued to heat at 80 °C. After 18 h, the reaction was concentrated under reduced pressure. The reaction was quenched with NaHCO3 (sat. aq.) 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 give the title compound.

[0291] Step 7: tert-Butyl (1R,5S,6s)-6-((4-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-6-(1-methylcyclopentyl)pyridin-2-yl)oxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate 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 h, 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 give the title compound.

[0292] Step 8: Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(1-methylcyclopentyl)pyridin-4-yl)propan-2-yl)carbamate A solution of tert-butyl (1R,5S,6s)-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 h, the reaction was concentrated under reduced pressure to provide the title compound.

[0293] Scheme: [ka]

[0294] Intermediate U Benzyl (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-yl)carbamate [ka]

[0295] Step 1: tert-Butyl (2-(2,6-dichloropyridin-4-yl)propan-2-yl)carbamate 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 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×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 give the title compound.

[0296] Step 2: tert-Butyl (2-(2-chloro-6-(4,4-dimethylpiperidin-1-yl)pyridin-4-yl)propan-2-yl)carbamate 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 h. 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 give the title compound.

[0297] Step 3: tert-Butyl (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-carboxylate tert-Butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.94 g, 4.7 mmol) and tert-Butyl A mixture of (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-(di((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 h. 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 chromatographed on silica gel (0-20% EtOAc / hexanes) to give the title compound.

[0298] 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 To a solution of tert-butyl (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-carboxylate (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 h. The mixture was poured into NaOH (1N aqueous, 50 mL), the pH was adjusted to pH>12, and extracted with DCM (50 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.

[0299] Scheme: [ka]

[0300] Intermediate V 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid [ka]

[0301] Step 1: Methyl 1'-methyl-1'H-[1,3'-bipyrazole]-5'-carboxylate To a solution of methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (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 atmosphere of O2 and heated to 80 °C. After 12 h, 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 give the title compound.

[0302] Step 2: 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid To a solution of methyl 1'-methyl-1'H-[1,3'-bipyrazole]-5'-carboxylate (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 h. The mixture was concentrated under reduced pressure. Water (5 mL) was added and the pH was adjusted to about 3 with HCl (1M aqueous). The mixture was extracted with EtOAc (10 mL×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.

[0303] Scheme: [ka]

[0304] Intermediate W 1'-Methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid [ka]

[0305] Step 1: Methyl 3-hydrazinyl-1-methyl-1H-pyrazole-5-carboxylate hydrochloride A solution of sodium nitrite (0.11 g, 1.6 mmol) in water (1.5 mL) was added to a solution of methyl 3-amino-1-methyl-1H-pyrazole-5-carboxylate (0.17 g, 1.1 mmol) in hydrochloric acid (37%, 2.0 mL) at 0 °C. After stirring for 30 min, 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 h. The mixture was concentrated under reduced pressure and coevaporated with EtOH (5 mL × 2) to give the title compound.

[0306] Step 2: Methyl 1-methyl-3-(2-(2-oxoethylidene)hydrazinyl)-1H-pyrazole-5-carboxylate To a solution of methyl 3-hydrazinyl-1-methyl-1H-pyrazole-5-carboxylate (0.020 g, 0.12 mmol) in water (2.0 mL) was added a solution of oxalaldehyde (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 give the title compound.

[0307] Step 3: Methyl 3-(2-(2-(2,2-dimethylhydrazono)ethylidene)hydrazinyl)-1-methyl-1H-pyrazole-5-carboxylate To a solution of methyl 1-methyl-3-(2-(2-oxoethylidene)hydrazinyl)-1H-pyrazole-5-carboxylate (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 h, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×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.

[0308] Step 4: 2-(2-(2-(5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)hydrazono)ethylidene)-1,1,1-trimethylhydrazin-1-ium iodide To a solution of methyl 3-(2-(2-(2,2-dimethylhydrazinylidene)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 h. The reaction was diluted with EtOAc (5 mL) and concentrated under reduced pressure to provide the title compound.

[0309] Step 5: Methyl 1-methyl-3-(2H-1,2,3-triazol-2-yl)-1H-pyrazole-5-carboxylate To a solution of 2-(2-(2-(5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)hydrazinylidene)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 h. 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 prep-TLC (25% EtOAc / petroleum ether) to give the title compound.

[0310] Step 6: 1-Methyl-3-(2H-1,2,3-triazol-2-yl)-1H-pyrazole-5-carboxylic acid A mixture of methyl 1-methyl-3-(2H-1,2,3-triazol-2-yl)-1H-pyrazole-5-carboxylate (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 h, 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 with HCl (1M aqueous) to pH ∼3 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 give the title compound.

[0311] Working Example Scheme: [ka]

[0312] Example 1 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) [ka]

[0313] Step 1: tert-Butyl rel-(2-(2-(((1R,4R,5R)-2-azabicyclo[2.2.0]hexan-5-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 2) To a mixture of benzyl 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-carboxylate (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 h and filtered through a pad of Celite (eluted with DCM, 5 mL x 3) to give the title compound.

[0314] 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) To a mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (37 mg, 0.18 mmol) and tert-butyl rel-(2-(2-(((1R,4R,5R)-2-azabicyclo[2.2.0]hexan-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, 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 (with 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 (2 N, 2 mL x 3) to give the title compound.

[0315] MS m / z (M+H) + : Calculated value 519.2, measured value 519.5. 1H 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.

[0316] Utilizing the procedure described in Example 1 and substituting the appropriate reagents for 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid, the following compound was prepared, which was isolated as the TFA salt. [ka] [Table 11]

[0317] Scheme: [ka]

[0318] Example 3 ((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-methyl-2-(oxazol-2-yl)thiazol-5-yl)methanone [ka]

[0319] A mixture of 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. The mixture was subjected to reverse phase HPLC (10-100% MeCN / water (with 0.1% TFA modifier)). The appropriate fractions were combined, treated with NaHCO3 (sat. aq., 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 give the title compound.

[0320] MS m / z: (M+H) + : Calculated value 520.2; Measured value 520.1. 1 H NMR (500 MHz, CDCl3) δ 8.04-7.97 (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.

[0321] The following compounds were prepared using the procedure described in Example 3 and substituting the appropriate reagent for 4-methyl-2-(oxazol-2-yl)thiazole-5-carboxylic acid. After HPLC purification, the examples were concentrated to give the TFA salts or extracted under basic conditions to give the free bases. [ka] [Table 12] TIFF2025505087000130.tif97168

[0322] Example 14 ((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-(difluoromethyl)-[2,4'-bithiazol]-5-yl)methanone [ka]

[0323] A mixture of 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 (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 h. 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 min and concentrated. The residue was dissolved in DMSO (1 mL) and subjected to mass directed reverse phase HPLC (MeCN / water with 0.1% TFA modifier) ​​and the appropriate fractions were concentrated to afford the title compound as the TFA salt.

[0324] MS m / z (M+H) + : Calculated 572.2; Measured 572.3. 1 H NMR (500 MHz, DMSO-d 6) δ 9.33-9.30 (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 = 53.4 Hz, 1H), 6.87 (s, 1H), 4.15 (s, 1H), 4.05 (d, J = 12.2 Hz, 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.

[0325] Utilizing the procedure described in Example 14, substituting the appropriate reagent for 4-(tributylstannyl)thiazole, the following compounds were prepared: [ka] [Table 13]

[0326] Scheme: [ka]

[0327] Example 16A 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'-bithiazol]-5-yl)methanone (enantiomer 1) And, Example 16B 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'-bithiazol]-5-yl)methanone (enantiomer 2) [ka]

[0328] 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 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]hexan-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 min. 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 prep-TLC (50% EtOAc / petroleum ether) to give the title compound.

[0329] 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 (Enantiomer 1 and Enantiomer 2) To a solution of 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 (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 min. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Prep-TLC (50% EtOAc / petroleum ether) of the residue afforded the title compound as a racemic mixture. The mixture of the two stereoisomers was subjected to chiral SFC (ChiralPak AS-3, 40% EtOH (with 0.05% DEA modifier) / CO2) to give the title compounds, Enantiomer 1 (fast eluting) and Enantiomer 2 (slow eluting).

[0330] 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'-bithiazol]-5-yl)methanone (enantiomer 1) 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]hexan-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 min. 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 with 0.1% TFA modifier) ​​to give the title compound as a TFA salt.

[0331] MS m / z (M+Na) + : Calculated value 588.2, measured value 588.1. 1 H NMR (400 MHz, CD3OD) δ 9.10 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.21-8.11 (m, 2H), 7.61 (s, 1H), 7.22 (t, J = 8.8 Hz, 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 = 6.0 Hz, 3H) ppm.

[0332] 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'-bithiazol]-5-yl)methanone (enantiomer 2) 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]hexan-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 min. 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 with 0.1% TFA modifier) ​​to give the title compound as a TFA salt.

[0333] MS m / z (M+H) + : Calculated value 566.2, measured value 566.3. 1 H NMR (500 MHz, CD3OD) δ 9.10 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.20-8.13 (m, 2H), 7.61 (d, J = 1.2 Hz, 1H), 7.27-7.20 (m, 2H), 6.80 (d, J = 1.2 Hz, 1H), 5.06 (q, J = 6.0 Hz, 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 = 6.0 Hz, 3H) ppm.

[0334] Example 17 ((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-methyl-3-(oxazol-2-yl)-1H-pyrazol-5-yl)methanone [ka]

[0335] To a solution of 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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) was added HATU (0.35 g, 0.92 mmol) and the mixture was stirred at room temperature for 1 h. A solution of NaHCO3 (saturated aqueous, 30 mL) was added and the mixture was extracted with DCM (30 mL × 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 (with 0.1% TFA modifier)). The appropriate fractions were concentrated under reduced pressure. A solution of NaHCO3 (saturated aqueous, 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.

[0336] MS m / z (M+H) + : Calculated value 503.2, measured value 503.3. 1 H NMR (500 MHz, CD3OD) δ 8.11-8.06 (m, 2H), 7.99 (d, J = 0.6 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.32 (d, J = 0.6 Hz, 1H), 7.19-7.14 (m, 3H), 6.85 (d, J = 1.2 Hz, 1H), 4.24 (d, J = 12.5 Hz, 1H), 4.07 (s, 3H), 4.03-3.96 (m, 3H), 3.75 (dd, J = 12.5, 3.3 Hz, 1H), 2.11-2.05 (m, 2H), 1.50 (s, 6H) ppm.

[0337] Example 18 ((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-methyl-3-(thiazol-4-yl)-1H-pyrazol-5-yl)methanone [ka]

[0338] 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]hexan-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 min and then subjected to reverse phase HPLC (15-95% MeCN / water (with 0.1% TFA modifier)). The appropriate fraction was poured into a solution of NaHCO3 (saturated aqueous, 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with NaHCO3 (saturated aqueous, 30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.

[0339] MS m / z (M+H) + : Calculated value 519.2, measured value 519.3. 1 H NMR (500 MHz, CD3OD) δ 9.08 (s, 1H), 8.13-8.05 (m, 2H), 7.91 (s, 1H), 7.61 (s, 1H), 7.16 (t, J = 7.8 Hz, 2H), 7.07 (s, 1H), 6.84 (s, 1H), 4.25 (d, J = 12.6 Hz, 1H), 4.12-4.06 (m, 1H), 4.04 (s, 3H), 3.99 (m, 2H), 3.75 (d, J = 11.1 Hz, 1H), 2.13-2.03 (m, 2H), 1.53 (s, 6H) ppm.

[0340] Example 19 ((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 [ka]

[0341] 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 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]hexan-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 min, 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 analyzed by prep-TLC (50% EtOAc / petroleum ether, R f =0.3) to give the title compound.

[0342] 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 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]hexan-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 min. 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 the TFA salt.

[0343] MS m / z (M+H) + : Calculated value 533.2, Measured value 533.2. 1H NMR (400MHz, CD3OD) δ 9.09 (s, 1H), 8.16-8.08 (m, 2H), 7.93 (d, J = 1.2 Hz, 1H), 7.61 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 7.04 (s, 1H), 6.82 (s, 1H), 4.46-4.35 (m, 2H), 4.26 (d, J = 12.2 Hz, 1H), 4.08-3.93 (m, 3H), 3.74 (dd, J = 12.2, 4.4 Hz, 1H), 2.15-2.03 (m, 2H), 1.76 (s, 6H), 1.44 (t, J = 7.2 Hz, 3H) ppm.

[0344] Example 20 ((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 [ka]

[0345] 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 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 min. Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. Water (10 mL) was added and the mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (0-100% EtOAc / petroleum ether) to give the title compound.

[0346] 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 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]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (83 mg, 0.12 mmol) and hydrochloric acid (37% aqueous, 1.0 mL) was stirred at 80° C. for 10 min. The mixture was adjusted to pH=7 with NH4OH and subjected to reverse phase HPLC (25-45% MeCN / water with 0.1% TFA modifier). The appropriate fractions were lyophilized to afford the title compound as the TFA salt.

[0347] MS m / z (M+H) + : Calculated value 537.2, Measured value 537.2. 1 H NMR (400MHz, CD3OD) δ 8.62 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 8.5, 5.5 Hz, 2H), 7.60 (s, 1H), 7.21 (t, J = 9.0 Hz, 2H), 6.98 (s, 1H), 6.81 (d, J = 1.5 Hz, 1H), 4.25 (d, J = 13.0 Hz, 1H), 4.05 (s, 1H), 4.04 (s, 3H), 4.03-3.95 (m, 2H), 3.76 (dd, J = 12.5, 4.5 Hz, 1H), 2.14-2.03 (m, 2H), 1.76 (s, 6H) ppm.

[0348] Example 21 ((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-(isoxazol-3-yl)-1-methyl-1H-pyrazol-5-yl)methanone [ka]

[0349] 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]hexan-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 min. 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.sub.3 (sat. aq., 75 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.

[0350] MS m / z (M+H) + : Calculated value 503.2, Measured value 503.2. 1 H NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.12-8.05 (m, 2H), 7.61 (s, 1H), 7.16 (t, J = 8.6 Hz, 2H), 7.10 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 4.25 (d, J = 12.5 Hz, 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.

[0351] The following compounds were prepared using the procedure described in Example 21, substituting the appropriate reagent for 3-(isoxazol-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid. Compounds prepared as TFA salts were lyophilized after HPLC purification (MeCN / water with 0.1% TFA modifier).

[0352] [ka] [Table 14]

[0353] Scheme: [ka]

[0354] Example 25 ((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 [ka]

[0355] 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 To a 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) at room temperature, 4 Å molecular sieves (0.050 g) were added. After 10 min, benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h, the mixture was concentrated and the residue was purified by prep-TLC (67% EtOAc / petroleum ether) to give the title compound.

[0356] 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 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]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate (0.040 g, 0.060 mmol) in hydrochloric acid (37% aqueous, 0.50 mL) was heated at 80° C. for 10 min. 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 give the title compound.

[0357] MS m / z (M+H) + : Calculated value 537.2, Measured value 537.2. 1 H-NMR (400MHz, CD3OD) δ 9.47 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 8.8, 5.6 Hz, 2H), 8.03 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.25 (t, J = 8.8 Hz, 2H), 6.88 (d, J = 1.2 Hz, 1H), 4.25 (d, J = 12.4 Hz, 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.

[0358] Utilizing the procedure described in Example 25, substituting methyl 4-fluoro-1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylate with the appropriate reagents, the following compounds were prepared: [ka] [Table 15]

[0359] The following compounds were prepared using the procedure described in Example 19, substituting the appropriate reagent for 1-ethyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid. The 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 either the TFA or HCl salts. [ka] [Table 16]

[0360] Example 31 ((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) [ka]

[0361] To a stirred solution of benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h and then concentrated under reduced pressure. Hydrochloric acid (37% aqueous, 0.20 mL) was added and the mixture was heated at 80° C. for 10 min, cooled to room temperature and concentrated. The residue was dissolved in DMSO (1 mL) and subjected to mass directed reverse phase HPLC (MeCN / water with 0.1% TFA modifier) ​​to afford the title compound as the TFA salt.

[0362] MS m / z (M+H) + : Calculated 538.2; Measured 538.2. 1H 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.

[0363] Utilizing the procedure described in Example 31 and substituting benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 with the appropriate reagents, the following compounds were prepared. Following HPLC purification, the examples were either concentrated directly to give the TFA or HCl salts or extracted under basic conditions to give the free base.

[0364] [ka] [Table 17] TIFF2025505087000152.tif231170TIFF2025505087000153.tif58170

[0365] Example 43A 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) [ka]

[0366] Step 1: 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]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (enantiomer 1) 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]hexan-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 h, 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 analyzed by prep-TLC (50% EtOAc / petroleum ether, R f =0.35) to give the title compound.

[0367] 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) 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]hexan-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 min. 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.

[0368] MS m / z (M+H) + : Calculated value 533.2, Measured value 533.2. 1H NMR (CD3OD, 400MHz) δ 9.64 (s, 1H), 8.30-8.04 (m, 3H), 7.66 (s, 1H), 7.20-7.15 (m, 3H), 6.92 (s, 1H), 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.

[0369] Utilizing the procedure described in Example 43A and substituting 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid and Int.J-1-ent-1 with the appropriate reagents, the following compounds were prepared: The examples were subjected to reverse phase HPLC (MeCN / water (with 0.1% TFA or 0.05% HCl modifier)) and lyophilized to give the TFA or HCl salts. [ka] [Table 18]

[0370] Example 46A 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) And, Example 46B 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) [ka]

[0371] Step 1: 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 1 and Enantiomer 2) A mixture of 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 26 mg, 0.12 mmol) and benzyl rac-(2-(2-(4,4-dimethylpiperidin-1-yl)-6-(((1R,5S,6S)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Int.I-2, 0.060 g, 0.12 mmol) in 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 h. Water (5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic solutions were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (25% EtOAc / petroleum ether) to give the title compound. The mixture of the two stereoisomers was subjected to chiral SFC (ChiralPak AS, 35% IPA (with 0.1% NH4OH modifier)) / CO2) to give 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 1, fast 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) was obtained.

[0372] 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) 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]hexan-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 min. 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 give Example 46A as the HCl salt.

[0373] MS m / z (M+H) + : Calculated value 550.3, measured value 550.2. 1 H NMR (500MHz, CD3OD) δ 9.19-9.04 (m, 1H), 7.97-7.89 (m, 1H), 7.03 (d, J = 4.9 Hz, 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. 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) 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]hexan-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 min. 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 give Example 46B as the HCl salt.

[0374] MS m / z (M+H) + : Calculated value 550.3, measured value 550.2. 1 H NMR (500MHz, CD3OD) δ 9.14-9.04 (m, 1H), 7.97-7.88 (m, 1H), 7.03 (d, J = 4.9 Hz, 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.

[0375] Scheme: [ka]

[0376] Example 47 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 [ka]

[0377] Step 1: Methyl 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)isonicotinate To a stirred solution of methyl 2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)isonicotinate (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 h, poured into water (5 mL) and extracted with DCM (3×5 mL). The combined organic extracts were washed with NaHCO3 (sat. aq., 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.

[0378] 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 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]hexan-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, 0.37 mL, 0.37 mmol). The mixture was heated at 80° C. for 1 h, 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), dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound.

[0379] 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 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]hexan-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 h. The mixture was subjected to reverse phase HPLC (10-100% MeCN / water with 0.1% TFA modifier). The appropriate fractions were treated with NaHCO3 (sat. aq., 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.

[0380] MS m / z: (M+H) + : Calculated 505.2; Measured 505.2. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.18 (s, 1H), 8.28 (s, 1H), 8.21-8.14 (m, 2H), 7.98 (d, J = 8.5 Hz, 2H), 7.77 (s, 1H), 7.34 (t, J = 8.3 Hz, 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.

[0381] Scheme: [ka]

[0382] Example 48 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 [ka]

[0383] 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 To a mixture of methyl 2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpropanoate (Int.H-09, 0.040 g, 0.10 mmol) and 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid (Int.L-1, 27 mg, 0.13 mmol) and DMF (1.0 mL) at room temperature 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 give the title compound.

[0384] 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 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]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropanoate (34 mg, 0.060 mmol), EtOH (0.50 mL), and NaOH (2.0 N aqueous, 0.15 mL, 0.30 mmol) was stirred at 90° C. for 4 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in a 2:1 mixture of HO:CHCN, to which was added hydrochloric acid (1 N aqueous, 0.31 mL), and the resulting mixture was lyophilized to provide the title compound.

[0385] 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 To a 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]hexan-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) at room temperature was added HATU (35 mg, 0.090 mmol). After 4 h, 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 give the title compound.

[0386] MS m / z (M+H) + : Calculated value 547.2, measured value 547.1. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 9.18 (s, 1H), 8.11 (dd, J = 8.4, 5.7 Hz, 2H), 7.97 (s, 1H), 7.49 (s, 1H), 7.31 (t, J = 8.7 Hz, 2H), 7.11~6.98 (m, 3H), 6.70 (s, 1H), 4.06 (d, J = 12.2 Hz, 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.

[0387] Example 49A 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), And, Example 49B 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) [ka]

[0388] 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 min. The mixture was transferred to a solution of rac-2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. 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 (with 0.1% DEA modifier) / CO2) to give the title compound.

[0389] Example 49A (Fast eluting enantiomer): MS m / z (M+H) + : Calculated value 548.2, measured value 548.3. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 9.18 (d, J = 1.9 Hz, 1H), 8.11 (dd, J = 8.7, 5.6 Hz, 2H), 7.97 (d, J = 1.9 Hz, 1H), 7.69 (s, 1H), 7.40 (s, 1H), 7.31 (t, J = 8.8 Hz, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 4.07 (d, J = 12.4 Hz, 1H), 4.01~3.99 (m, 1H), 3.96 (s, 3H), 3.95-3.88 (m, 2H), 3.67 (dd, J = 12.3, 4.3 Hz, 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, measured value 548.3.1 H-NMR (500 MHz, DMSO-d 6 ) δ 9.20 - 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 = 8.5 Hz, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 4.07 (d, J = 12.4 Hz, 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.

[0390] Example 50A 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) and Example 50B 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)

Chemical formula

[0391] To a 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) at room temperature was added DIPEA (0.10 mL, 0.18 mmol), ent-3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h, the mixture was diluted with HO (10 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (EtOAc). The racemate was subjected to chiral SFC (ChiralPak AS, 40% EtOH (with 0.1% NH4OH modifier) / CO2) to give the title compound.

[0392] Example 50A (Fast eluting enantiomer): MS m / z (M+H) + : Calculated value 545.2, measured value 545.1. 1 H-NMR (500MHz, CD3OD) δ 9.11 (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, measured value 545.1. 1H-NMR (500MHz, CD3OD) δ 9.11 (s, 1H), 8.16-8.03 (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), 4.14-3.99 (m, 6H), 3.82-3.73 (m, 1H), 3.61 (d, J = 6.0 Hz, 1H), 3.50 (d, J = 5.5 Hz, 1H), 2.17-2.04 (m, 2H), 1.71 (s, 3H) ppm.

[0393] Example 51A 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) And, Example 51B 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) [ka]

[0394] 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 (0.010 L) at room temperature was added DIPEA (0.10 mL, 0.72 mmol) and rac-3-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 min, the mixture was diluted with HO (15 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (EtOAc). The racemate was subjected to chiral SFC (ChiralPak OD-H, 50% EtOH (with 0.1% NH4OH modifier) / CO2) to give the title compound.

[0395] Example 51A (Fast-eluting enantiomer): MS m / z (M+H) + : Calculated value 559.2, measured value 559.1. 1 H-NMR (500 MHz, CD3OD) δ 9.10 (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 (Slow-eluting enantiomer): MS m / z (M+H) + : Calculated value 559.2, measured value 559.1. 1 H-NMR (500 MHz, CD3OD) δ 8.98 (s, 1H), 8.01 - 7.93 (m, 2H), 7.81 (s, 1H), 7.42 (s, 1H), 7.06 (t, J = 8.5 Hz, 2H), 6.97 (s, 1H), 6.71 (s, 1H), 4.18 - 4.11 (m, 1H), 3.97 - 3.87 (m, 6H), 3.70 - 3.61 (m, 1H), 3.36 - 3.23 (m, 2H), 2.48 - 2.39 (m, 1H), 2.28 - 2.18 (m, 1H), 2.03 - 1.92 (m, 2H), 1.46 (s, 3H) ppm.

[0396] Example 52 ((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

Chemical Structure

[0397] 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-sulfinamide To a 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) at room temperature was added DIPEA (0.10 mL, 0.81 mmol) and N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by prep-TLC (67% EtOAc / petroleum ether) to give the title compound.

[0398] 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 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]hexan-6-yl)oxy)pyridin-4-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (0.070 g, 0.11 mmol) in methanolic hydrochloric acid (4.0 M, 5.0 mL) was stirred at room temperature for 1 h. The mixture was subjected to reverse phase HPLC (20-40% MeCN / water (containing 0.05% HCl)) and concentrated to give the title compound as the HCl salt.

[0399] MS m / z (M+H) + : Calculated value 531.2, Measured value 531.2. 1H-NMR (400 MHz, CD3OD) δ 9.21 (s, 1H), 8.23-8.08 (m, 2H), 7.98 (s, 1H), 7.59 (s, 1H), 7.21 (t, J = 8.8 Hz, 2H), 7.10 (s, 1H), 6.88 (d, J = 0.8 Hz, 1H), 4.27 (d, J = 12.4 Hz, 1H), 4.13-3.96 (m, 6H), 3.84-3.70 (m, 1H), 2.87-2.74 (m, 2H), 2.69-2.56 (m, 2H), 2.35-2.20 (m, 1H), 2.16-2.06 (m, 2H), 2.09-2.00 (m, 1H) ppm.

[0400] Utilizing the procedure described in Example 52, substituting the appropriate reagents for Int. H-06, the following compounds were prepared: [Table 19]

[0401] Example 54 ((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 [ka]

[0402] 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 Benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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)-1H-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 h. The mixture was subjected to reverse phase HPLC (5-95% MeCN / water (with 0.1% TFA modifier)) to give the title compound.

[0403] 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 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]hexan-6-yl)oxy)pyridin-4-yl)-2-methylpropyl)carbamate (44 mg, 0.070 mmol) and hydrochloric acid (37% aqueous, 0.50 mL) was placed into a preheated 80° C. block. After 10 min, 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 in MeOH, and the filtrate was concentrated to give the title compound.

[0404] MS m / z (M+H) + : Calculated value 533.2, measured value 533.3. 1 H-NMR (500 MHz, DMSO-d 6) δ 9.18 (d, J = 1.9 Hz, 1H), 8.17 (dd, J = 8.6, 5.7 Hz, 2H), 7.97 (d, J = 1.9 Hz, 1H), 7.56 (s, 1H), 7.29 (t, J = 8.8 Hz, 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, 4.7 Hz, 1H), 2.78 (s, 2H), 2.11-2.00 (m, 2H), 1.27 (s, 6H) ppm.

[0405] Example 55A 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) And, Example 55B 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) [ka]

[0406] 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 h 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 (with 0.1% DEA modifier) / CO2) to give the title compound.

[0407] Example 55A(Enantiomer with rapid dissolution): MS m / z (M+H) + : Calculated value 531.2, measured value 531.3. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 9.18 (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 (Enantiomer with slow dissolution): MS m / z (M+H) + : Calculated value 531.2, measured value 531.3. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 9.18 (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), 7.03 (s, 1H), 6.79 (s, 1H), 4.07 (d, J = 12.3 Hz, 1H), 4.00 (s, 1H), 3.96 (s, 3H), 3.95 - 3.88 (m, 2H), 3.70 - 3.58 (m, 2H), 3.18 - 3.12 (m, 1H), 2.40 - 2.32 (m, 2H), 2.10 - 1.98 (m, 2H), 1.60 (s, 3H) ppm.

[0408] Example 56A 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 1) And, Example 56B 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) [ka]

[0409] Step 1: Benzyl 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-carboxylate 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 min. The mixture was added to a solution of benzyl rac-2-(2-((3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-fluorophenyl)pyridin-4-yl)-2-methylpyrrolidine-1-carboxylate·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 h 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 (sat. aq.) and extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound.

[0410] 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 (Enantiomer 1 and Enantiomer 2) A mixture of benzyl 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-carboxylate (0.040 g, 0.060 mmol) and hydrochloric acid (37% aqueous, 0.50 mL) was placed in a preheated 80° C. block for 10 min. 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 in MeOH and the filtrate was concentrated. The mixture was subjected to chiral SFC (ChiralPak OD-H, 30% EtOH (with 0.1% DEA modifier) / CO2) to give the title compound.

[0411] Example 56A (Fast eluting enantiomer): MS m / z (M+H) + : Calculated value 545.2, measured value 545.3. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 9.18 (d, J = 1.9 Hz, 1H), 8.14 (dd, J = 8.8, 5.6 Hz, 2H), 7.97 (d, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J = 8.7 Hz, 2H), 7.04 (s, 1H), 6.92 (d, J = 3.9 Hz, 1H), 4.07 (d, J = 12.4 Hz, 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, measured value 545.3. 1 H-NMR (500 MHz, DMSO-d 6) δ 9.18 (d, J = 1.9 Hz, 1H), 8.14 (dd, J = 8.8, 5.6 Hz, 2H), 7.97 (d, J = 1.9 Hz, 1H), 7.68 (s, 1H), 7.30 (t, J = 8.8 Hz, 2H), 7.04 (s, 1H), 6.92 (d, J = 3.5 Hz, 1H), 4.07 (d, J = 12.2 Hz, 1H), 4.00 (s, 1H), 3.96 (s, 3H), 3.95 - 3.88 (m, 2H), 3.67 (dd, J = 12.2, 4.4 Hz, 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.

[0412] Example 57A 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)

Chem.

[0413] 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) 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-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. 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 prep-TLC (50% EtOAc / petroleum ether) to give the title compound.

[0414] 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) 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]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (Enantiomer 1, 0.050 g, 0.055 mmol) and hydrochloric acid (37% aqueous, 1.0 mL) was stirred at 80° C. for 10 min. The mixture was cooled to room temperature, concentrated under reduced pressure, subjected to reverse phase HPLC (19-39% MeCN / water with 0.1% TFA), and lyophilized to provide the title compound as the TFA salt.

[0415] MS m / z (M+H) + : Calculated value 535.2, measured value 535.1. 1H-NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.16-8.10 (m, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.80 (d, J = 1.2 Hz, 1H), 4.26 (d, J = 12.4 Hz, 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.

[0416] Utilizing the procedure described in Example 57A and substituting 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid and Int.H-12-ent-1 with the appropriate reagents, the following compounds were prepared: [ka] [Table 20]

[0417] Example 59 ((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 [ka]

[0418] 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 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]hexan-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 h. 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 prep-TLC (50% EtOAc / petroleum ether) to give the title compound.

[0419] 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 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]hexan-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 min. The mixture was subjected to reverse phase HPLC (15-35% MeCN / water (containing 0.05% HCl)) to give the title compound as the HCl salt.

[0420] MS m / z (M+H) + : Calculated value 519.2, measured value 519.1. 1H-NMR (400 MHz, CD3OD) δ 9.09 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.79-7.75 (m, 2H), 7.44 (d, J = 1.0 Hz, 1H), 7.24 (t, J = 8.7 Hz, 2H), 7.09-7.04 (m, 2H), 4.22 (d, J = 12.5 Hz, 1H), 4.14-4.09 (m, 1H), 4.06-3.98 (m, 5H), 3.77 (dd, J = 12.6, 4.8 Hz, 1H), 2.16-2.06 (m, 2H), 1.77 (s, 6H) ppm. Utilizing the procedure described in Example 59, substituting 1-methyl-3-(thiazol-4-yl)-1H-pyrazole-5-carboxylic acid with the appropriate reagents, the following compound (Example 60) was prepared. [ka] [Table 21]

[0421] Example 61A 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 (enantiomer 1) And, Example 61B 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 (enantiomer 2) [ka]

[0422] 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-sulfinamide 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 min, and then N-(1-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. Water (20 mL) was added and the mixture was extracted with EtOAc (25 mL×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 prep-TLC (10% MeOH / DCM) to give the title compound.

[0423] 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 (Enantiomer 1 and Enantiomer 2) 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]hexan-6-yl)oxy)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (0.12 g, 0.20 mmol) and methanolic hydrochloric acid (4.0 M, 3.0 mL) was stirred at 25 °C. After 30 min, the mixture was concentrated under reduced pressure. The racemate was subjected to chiral SFC (DAICEL CHIRALCEL OD-H, 50% EtOH (with 0.1% NH3·H2O modifier) / CO2) to give the title compound.

[0424] Example 61A (Fast eluting enantiomer): MS m / z (M+H) + : Calculated value 505.6, measured value 505.3. 1H-NMR (400 MHz, CD3OD) δ 9.10 (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 (Enantiomer eluting later): MS m / z (M+H) + : Calculated value 505.6, measured value 505.3. 1 H-NMR (400 MHz, CD3OD) δ 9.10 (d, J = 2.0 Hz, 1H), 8.14-8.06 (m, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.18 (t, J = 8.4 Hz, 2H), 7.08 (s, 1H), 6.79 (s, 1H), 4.28-4.26 (m, 1H), 4.14 (q, J = 6.4 Hz, 1H), 4.10-3.97 (m, 6H), 3.76 (dd, J = 12.4, 4.4 Hz, 1H), 2.15-2.04 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H).

[0425] Example 62A 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 (enantiomer 1) and Example 62B 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 (enantiomer 2)

Chemical Structure

[0426] 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-sulfinamide 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]hexan-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 min. Water (10 mL) was added and the mixture was extracted with EtOAc (15 mL×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 prep-TLC (EtOAc) to give the title compound.

[0427] 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 (Enantiomer 1 and Enantiomer 2) 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]hexan-6-yl)oxy)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (15 mg, 0.025 mmol) and methanolic hydrochloric acid (4.0 M, 2.0 mL) was stirred at 25° C. for 1 h. The mixture was subjected to reverse phase HPLC (MeCN / water (with 0.1% TFA modifier)). The racemic compound was subjected to chiral SFC (REGIS(R,R)WHELK-O1, 60% MeOH (with 0.1% NH3·H2O modifier) / CO2) to give the title compound.

[0428] Example 62A (Fast eluting enantiomer): MS m / z (M+H) + : Calculated value 489.2, Measured value 489.2. 11H-NMR (400 MHz, CD3OD) δ 8.74 (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 (Enantiomer eluting later): MS m / z (M+H) + : Calculated value 489.2, measured value 489.2. 1 1H-NMR (400 MHz, CD3OD) δ 8.74 (d, J = 1.7 Hz, 1H), 8.19 - 8.04 (m, 2H), 7.57 (d, J = 0.8 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.11 (s, 1H), 6.89 (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 = 12.4 Hz, 1H), 2.10 (s, 2H), 1.65 (d, J = 6.8 Hz, 3H).

[0429] Example 63 ((1R,5S,6s)-6-((4-(2-aminopropan-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 [Chemical Structure]

[0430] 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 To a solution of benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h. The mixture was filtered and concentrated under reduced pressure. The mixture was subjected to reverse phase HPLC (MeCN / water (with 0.1% TFA modifier)) to give the title compound.

[0431] Step 2: ((1R,5S,6s)-6-((4-(2-aminopropan-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 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]hexan-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 min, the mixture was cooled to room temperature and diluted with water. The mixture was subjected to reverse phase HPLC (MeCN / water with 0.1% TFA modifier) ​​to give the title compound as the TFA salt.

[0432] MS m / z (M+H) + : Calculated value 507.3, measured value 507.2. 11H-NMR (500 MHz, CD3OD) δ 9.07 (s, 1H), 7.90 (s, 1H), 7.08 (d, J = 1.4 Hz, 1H), 7.03 (s, 1H), 6.64 (d, J = 1.4 Hz, 1H), 4.23 (d, J = 12.5 Hz, 1H), 4.02 (s, 3H), 3.98 (s, 2H), 3.88 (s, 1H), 3.70 (dd, J = 12.5, 4.3 Hz, 1H), 2.19 - 2.11 (m, 2H), 2.05 - 1.95 (m, 2H), 1.79 - 1.64 (m, 12H), 1.35 (s, 3H) ppm.

[0433] Example 64 ((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

Chem.

[0434] Step 1: 2-(2-((3-azabicyclo[3.1.0]hexan-6-yl)oxy)-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-4-yl)propan-2-amine Sodium tert-butoxide (0.50 M in THF, 0.13 mL, 0.27 mmol) was added 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). The reaction was heated to 60° C. for 18 h. 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 h, the reaction was concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (5-50% MeCN / water with 0.1% TFA) to afford the title compound as a TFA salt.

[0435] 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 A mixture of 2-(2-((3-azabicyclo[3.1.0]hexan-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 min, the mixture was subjected to reverse phase HPLC (MeCN / water (with 0.05% TFA modifier)) to give the title compound as the TFA salt.

[0436] MS m / z (M+H) + : Calculated value 560.3, measured value 560.4. 1H-NMR (500 MHz, DMSO-d 6 ) δ 8.99 (d, J = 1.6 Hz, 1H), 8.39 (s, 3H), 7.08 (s, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.49 (s, 1H), 6.13 (s, 1H), 4.39 (d, J = 12.6 Hz, 2H), 4.02 (d, J = 12.5 Hz, 1H), 3.98-3.93 (m, 4H), 3.91 (dd, J = 10.7, 4.2 Hz, 0.6H), 3.82-3.76 (m, 2H), 3.62 (dd, J = 12.5, 4.3 Hz, 0.4H), 2.88 (t, J = 12.5 Hz, 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).

[0437] Example 65 ((1R,5S,6s)-6-((4-(2-aminopropan-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 [ka]

[0438] To a solution of 2-(2-((3-azabicyclo[3.1.0]hexan-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 h. The mixture was subjected to reverse phase HPLC (MeCN / water with 0.1% TFA modifier). The product containing fractions were filtered through an SPE plug, rinsed with MeOH (3 x 2 mL) and eluted with NH3 (3 x 2 mL 2N in MeOH). The material was dissolved in MeCN / water and lyophilized to give the title compound.

[0439] MS m / z (M+H) + : Calculated value 519.3, measured value 520.4. 1 H NMR (500 MHz, CD3OD) δ 7.99 (d, J = 0.7 Hz, 1H), 7.31 (d, J = 0.7 Hz, 1H), 7.11 (s, 1H), 6.42 (s, 1H), 6.11 (s, 1H), 4.18 (d, J = 12.5 Hz, 1H), 4.05 (s, 3H), 3.97 - 3.88 (m, 2H), 3.75 (s, 1H), 3.69 (dd, J = 12.4, 4.9 Hz, 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).

[0440] Example 66A 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 (enantiomer 1) and Example 66B 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 (enantiomer 2) and Example 66C 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 (enantiomer 3) and Example 66D 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 (enantiomer 4)

Chem.

[0441] 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 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 min, benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×25 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 prep-TLC (60% EtOAc / PE) to give the title compound.

[0442] 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 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]hexan-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 CsCO (280 mg, 0.84 mmol). The mixture was placed under a N2 atmosphere, Pd(dppf)Cl2 (61.7 mg, 0.084 mmol) was added, and heated to 90 °C. After 5 h, the reaction was cooled, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (60% EtOAc / PE) to give the title compound.

[0443] Step 3: dia-benzyl (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 (diastereomer 1 and diastereomer 2) 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]hexan-6-yl)oxy)pyridin-4-yl)propan-2-yl)carbamate (180 mg, 0.27 mmol), 9-mesityl-10-methylacridinium 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 a N2 atmosphere and irradiated with a blue LED (12 W) at 25 °C. After 12 h, the reaction was quenched with water (15 mL) and extracted with EtOAc (3×20 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 prep-TLC (60% EtOAc / PE) to give the title compound, diastereomer 1, and diastereomer 2.

[0444] Step 4-1: ent-benzyl (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 (Enantiomer 1A and Enantiomer 2A) The mixture of enantiomers, dia-benzyl (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 (diastereomer 1) (40 mg, 0.058 mmol), was subjected to chiral SFC (DAICEL CHIRALPAK AD, 40 °C, 40% IPA (with 0.1% NH3·H2O modifier) / CO2) to give the title compounds, Enantiomer 1A (faster eluting enantiomer) and Enantiomer 2A (slower eluting enantiomer).

[0445] Step 4-2: ent-benzyl (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 (Enantiomer 3A and Enantiomer 4A) The mixture of enantiomers, dia-benzyl (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 (diastereomer 2) (50 mg, 0.073 mmol), was separated by chiral SFC (DAICEL CHIRALPAK OD-H, 40 °C, 50% EtOH (with 0.1% NH3·H2O modifier) / CO2) to give the title compounds, Enantiomer 3A (faster eluting enantiomer) and Enantiomer 4A (slower eluting enantiomer).

[0446] 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) A mixture of ent-benzyl (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 (enantiomer 1A) (10 mg, 0.015 mmol) in HCl (12 M) (2 mL) was stirred at 80° C. After 10 min, 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.

[0447] MS m / z (M+H) + : Calculated value 551.5, measured value 551.2. 1H NMR (400 MHz, CD3OD) δ 9.04 (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), 2.96-2.93 (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, 3.2 Hz, 1H), 1.38-1.31 (m, 2H), 1.07 (s, 3H), 0.93 (s, 3H).

[0448] 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) A mixture of ent-benzyl (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 (enantiomer 2A) (10 mg, 0.015 mmol) in HCl (12 M) (2 mL) was stirred at 80° C. After 10 min, 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.

[0449] MS m / z (M+H) + : Calculated value 551.5, measured value 551.2. 1H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.65 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.26 (s, 1H), 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, 3.2 Hz, 1H), 1.36-1.28 (m, 2H), 1.05 (s, 3H), 0.91 (s, 3H).

[0450] 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) A mixture of ent-benzyl (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 (enantiomer 3A) (20 mg, 0.029 mmol) in HCl (12 M) (2 mL) was stirred at 80° C. After 10 min, 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.

[0451] MS m / z (M+H) + : Calculated value 551.5, measured value 551.2. 1H NMR (400 MHz, CD3OD) δ 9.03 (d, J = 1.6 Hz, 1H), 8.65 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.40-7.33 (m, 1H), 7.19 (s, 1H), 4.27-4.24 (m, 1H), 4.17-4.01 (m, 4H), 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 = 8.0 Hz, 6H).

[0452] 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) A mixture of ent-benzyl (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 (enantiomer 4A) (25 mg, 0.037 mmol) in HCl (12 M) (2 mL) was stirred at 80° C. After 10 min, 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.

[0453] MS m / z (M+H) + : Calculated value 551.5, measured value 551.2. 1H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 8.66 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 0.8 Hz, 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).

[0454] Example 67 ((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'-methyl-1'H-[1,3'-bipyrazol]-5'-yl)methanone [ka]

[0455] 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 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 min and benzyl (2-(2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-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 h, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×15 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 prep-TLC (30% EtOAc / PE) to give the title compound.

[0456] 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'-methyl-1'H-[1,3'-bipyrazol]-5'-yl)methanone 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]hexan-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 min, 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 give the title compound as a TFA salt.

[0457] MS m / z (M+H) + : Calculated value 502.2, measured value 502.2. 1 H NMR (400 MHz, CD3OD) δ 8.20 (d, J = 2.4 Hz, 1H), 8.17-8.11 (m, 2H), 7.74 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.24-7.18 (m, 2H), 6.85-6.81 (m, 2H), 6.54-6.50 (m, 1H), 4.23 (d, J = 12.4 Hz, 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).

[0458] Utilizing the procedure described in Example 67, substituting 1'-methyl-1'H-[1,3'-bipyrazole]-5'-carboxylic acid with the appropriate reagents, the following compound (Example 68) was prepared. [ka] [Table 22]

[0459] Assay description Sample Compensation: Wells containing DMSO (final concentration 0.4%) or a control compound at a concentration that completely inhibited viral replication were used as the viral replication assay "Min_E control" and "Max_E control", respectively. To set up the assay, ARF vials were thawed in a 37°C water bath and control compounds were resuspended in assay medium DMEM (Dulbecco's modified Eagle's medium) containing 2% FBS, 100 U / mL penicillin-streptomycin.

[0460] Generation and propagation of recombinant RSV-A2-GFP virus: The GFP sequence is pJTI TM It was derived from the R4 Dest CMV N-EmGFP pA Vector (Invitrogen) and cloned into the intergenic sequence between the P and M genes of wild-type RSV-A2 using standard recombinant techniques. Recombinant RSV-A2-GFP was propagated in Hep2 cells (human cells containing the HeLa marker chromosome and obtained via HeLa contamination, ATCC CCL-23) at a multiplicity of infection (MOI) of 0.1. Virus was harvested 3 days after infection by harvesting the entire culture and then freezing and thawing the mixture for 5 minutes. Working virus stocks were generated by thawing frozen virus cultures in a 37°C water bath and centrifuging them 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 and frozen in liquid nitrogen and then transferred to a -80°C freezer for storage. Viral titers were confirmed by automated plaque assay in HEp-2 cells according to previously described methods (Wen Z. et al.; 2019).

[0461] Preparation of Calu-1 Assay Ready Freeze-Down (ARF): Calu-1 cells were purchased from ATCC (Cat# HTB-54) and grown in growth medium (DMEM with 10% FBS, 100U / mL penicillin-streptomycin). To generate ARFs, cell culture medium was removed and discarded, and the cell layer was washed briefly with PBS to remove serum. 2.5mL of TrypLE Express solution was added and incubated until cells detached, growth medium was added, and cells were resuspended by gentle pipetting. Cell concentration was counted and viability was measured by ViCell. Cells were centrifuged at 300g for 5 min at RT to pellet. The supernatant was gently aspirated, and the pellet was flicked to loosen the cells. Cells were resuspended in an appropriate volume of freezing medium (DMEM with 10% DMSO, 10% FBS, 100U / mL penicillin-streptomycin) and frozen at 5 × 10 6 A 1 mL aliquot of the cell suspension was transferred to a cryovial, which was then placed in an upright container in a -80°C freezer overnight, after which the vial was transferred to liquid nitrogen for storage.

[0462] RSV-A2-GFP viral replication assay: Assay-Ready Freeze-Down (ARF, generation described separately) Calu-1 cells (ATCC HTB-54) were used. Compound plates were prepared by dispensing compounds dissolved in DMSO into wells of a 384-well Corning® 3985 plate using an ECHO acoustic dispenser, and compounds were tested in 10-point serial 3-fold dilutions. Wells containing DMSO (0.4% final concentration) or a concentration of compound that completely inhibited viral replication with control compound were used as viral replication assay "Min_E control" and "Max_E control", respectively. To set up the assay, ARF vials were thawed in a 37°C water bath and then resuspended in assay medium (DMEM with 2% FBS, 100U / mL penicillin-streptomycin). Cells were counted using ViCell default parameters and diluted to 20,000 cells / mL in assay medium. RSV-A2-GFP virus was added to cells at 24,000 pfu / mL (MOI=1.2) and mixed by gentle inversion. 10 μL / well of 100% DMSO was dispensed as CellTiter-Glo (CTG) assay "Max_E control" wells. Cells were dispensed at 50 μL / well into compound plates using a Bravo with a 50 μL filter tip. Plates were covered with MicroClime lids, filled with 7.5 mL of assay medium to minimize evaporation, and incubated at 37°C, 5% CO2 for 96 hours. After incubation, distinct GFP expressing cells were counted using an Acumen imaging system with appropriate settings. Identical well CTG assays were performed by adding 10 μL / well of reconstituted CellTiter-Glo reagent (Promega G7573) and plates were read on a PerkinElmer Envision according to the manufacturer's instructions. Raw data was loaded into ActivityBase and analyzed. Antiviral IC 50 Value and cytotoxicity CC 50 Values ​​were determined using a four-parameter logistic fit based on the Levenberg-Marquardt algorithm. Model: 205-4 parameter logistic.

[0463] Generation and propagation of hMPV-GFP virus: GFP-expressing rgHMPV#3 p3 was generated in Dr. Buchholz's lab (Biacchesi S. et al., J Virol. 2007 Jun; 81(11): 6057-6067) and propagated in VERO cells (ATCC Cat# CCL-81) at a multiplicity of infection (MOI) of 0.1. Virus was harvested by harvesting the culture 4 days after infection and the virus was freeze-thawed twice in liquid nitrogen. Working virus stocks were generated by thawing frozen samples in a 37°C water bath and centrifuging at 218g for 15 min 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 transferred to a -80°C freezer for storage. Viral titers were determined by titration in 96-well plates, and approximate viral titers were calculated from GFP events / well data.

[0464] hMPV-GFP viral replication assay: Compound plates were prepared by dispensing compounds dissolved in DMSO into wells of a 384-well Corning 3985 polystyrene flat clear bottom optical imaging microplate (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 (0.4% final concentration) or a concentration of compound that completely inhibited viral replication relative to the control compound were used as the viral replication assay "Min_E control" and "Max_E control", respectively. Continuous cultures of VERO cells were incubated in complete medium (2 mM GlutaMAX TMThe cells were maintained in OptiMEM supplemented with 0.25% trypsin-EDTA and 100 U / mL penicillin-streptomycin. To set up the assay, VERO cells were trypsinized with 0.25% trypsin-EDTA until the cells detached, then the cells were resuspended in 1 mL of FBS. The cells were shaken at 300g for 5 minutes, washed twice with medium, and counted using ViCell default parameters. The cells were then diluted to 100,000 cells / mL (5,000 cells / 50 μL) in complete medium + TrypLE Select (80 μL / mL). hMPV-GFP virus was added to the cells at 125,000 pfu / mL (MOI=1.25) and mixed by gentle inversion. 10 μL / well of 100% DMSO was dispensed into CellTiter-Glo (CTG) assay Max_E control wells. Cells were dispensed into compound plates at 50 μL / well using a Bravo and 50 μL filtered tips. Plates were covered with MicroClime lids and filled with 7.5 mL of assay medium to minimize evaporation. Plates were gently shaken for 10 min at room temperature and then incubated at 37°C, 5% CO2 for 48 h. After incubation, distinct GFP expressing cells were counted using an Acumen imaging system with appropriate settings. A same-well CTG assay was performed by adding 10 μL / well of reconstituted CellTiter-Glo reagent (Promega G7573) and plates were read on a PerkinElmer Envision according to the manufacturer's instructions. Raw data was loaded and analyzed in ActivityBase. Antiviral IC 50 Value and cytotoxicity CC 50 Values ​​were determined using a four-parameter logistic fit based on the Levenberg-Marquardt algorithm. Model: 205-4 parameter logistic.

[0465] References: 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. 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.

[0466] Assay Data EC of each compound 50 are listed in Table I, and EC 50 The ranges are as follows: A ≤ 0.010 μM; B >0.010μM - ≦0.10μM; C > 0.10 μM; ND=Not determined.

[0467] [Table 23]

[0468] 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.

Table 24

Claims

1. Formula I 【Chemistry 1】 [During the ceremony, R １ teeth, (1) 2 carbon atoms and (ii) 2 N and 1 NH, or (i) 3 N; (2) 3 carbon atoms and (i) 2 N, (ii) N and NH, or (iii) N and 1 S or O; or (3) 4 carbon atoms and 1 S or O; A 5-membered aromatic heterocyclyl ring consisting of wherein the heterocyclyl ring is unsubstituted or, where valences permit, is selected from halo and C １－６ substituted with 1 to 4 substituents independently selected at each occurrence from alkyl; R ２ teeth, (1) 3 carbon atoms and (i) 2 N, (ii) N and NH, or (iii) N and 1 S or O; or (2) 2 carbon atoms and (i) 3 N, (ii) 2 N and 1 NH, or (iii) 2 N and 1 S or O; A 5-membered aromatic heterocyclyl ring consisting of wherein the heterocyclyl ring is unsubstituted or, where valences permit, (a) halo, ((b)-NH) ２ 、 (c)-C ３－６ Cycloalkyl, (d)-C １―６ Alkyl, which is unsubstituted or substituted with halo, -OH and -NH ２ and substituted with 1 to 6 substituents independently selected at each occurrence from: And, (e) -OC １―６ Alkyl, which is unsubstituted or substituted with halo, -OH and -NH ２ and substituted with 1 to 6 substituents independently selected at each occurrence from: and is substituted with 1, 2 or 3 substituents independently selected at each occurrence from: 【Chemistry 2】 teeth, 2-Azabicyclo[2.2.0]hexane 【Chemistry 3】 or 3-Azabicyclo[3.1.0]hexane 【Chemistry 4】 represents a bicyclic ring which is: R ３ is -H, halo or -C １－６ is alkyl; R ４ is —O— or —NH—; X １ , X ２ and X ３ one of is N and the remaining are each CH; R ５ teeth, (1) C １－６ Alkyl (which is unsubstituted or substituted with halo, -OH, -NR Ｘ R Ｙ and -C(O)NR Ｘ R Ｙ and substituted with 1 to 6 substituents independently selected at each occurrence from: (2)-C(O)NR Ｘ R Ｙ ; （３） 【Chemistry 5】 and; （４） 【Chemistry 6】 is selected from Here, R Ｘ and R Ｙ is -H, -C １－６ alkyl, and R Ｚ is -C １－６ is alkyl; and R ６ teeth, (1) Phenyl, which is unsubstituted or (a) halo, (b) -CN, (c)-C １－６ alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halo and -OH; (d) -OC １－６ alkyl, which is unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from halo and -OH; and (e)-C ３－６ Cycloalkyl (which is unsubstituted or substituted with halo, —OH, —C １－６ Alkyl and -OC １－６ substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; and is substituted with 1 to 5 substituents independently selected at each occurrence from: (2) pyridinyl, which is unsubstituted or selected from the group consisting of (i) halo, (ii) CN and (iii) —C １－６ alkyl, which is unsubstituted or substituted with 1 to 5 substituents independently selected at each occurrence from 1 to 6 -F and / or -Cl; （３） 【Chemistry 7】 [where R ７ａ and R ７ｂ are -H and -C, respectively. １－６ alkyl, which is unsubstituted or substituted with 1 to 6 -F and / or -Cl; （４） 【Chemistry 8】 [where R ８ａ and R ８ｂ are -H and -C, respectively. １－３ Alkyl and -CF ３ selected from; （５） 【Chemistry 9】 [where R ９ , R １０ and R １１ is -H, -C １－６ Alkyl, -CF ３ and 1, 2 or 3 halo, independently selected at each occurrence. A bicyclic ring system selected from: (6)-C ３－６ Cycloalkyl (which is unsubstituted or substituted with halo, —OH, —C １－６ Alkyl and -OC １－６ substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; and (7) pyrazolyl, which is unsubstituted or (a) 1 to 3 halos; (b) C.N., (c)-C １－６ Alkyl (which is unsubstituted or substituted with halo, -OH and -OC １－６ substituted with 1 to 6 substituents independently selected at each occurrence from alkyl; (d) -OC １－６ Alkyl (which is unsubstituted or substituted with halo, -OH and -OC １－６ substituted with 1 to 6 substituents independently selected at each occurrence from alkyl; and (e)-C ３－６ Cycloalkyl, which is unsubstituted or substituted with halo, —OH and —OC １－６ substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; and is substituted with one or more substituents independently selected at each occurrence from And, （８） 【Chemistry 10】 selected from or a pharma- ceutically acceptable salt thereof.

2. R １ is a 5-membered aromatic heterocyclyl ring selected from thiazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiophenyl, and furanyl, wherein each ring is unsubstituted or, where valences permit, is selected from halo and C １－６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted with 1 to 4 substituents independently selected at each occurrence from alkyl.

3. R １ but, 【Chemistry 11】 wherein the heterocyclyl ring is unsubstituted or, where valences permit, selected from halo and C １－６ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, 3 or 4 substituents independently selected at each occurrence from alkyl.

4. R １ is -F, -Cl and C １－３ 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, substituted with 1 or 2 substituents selected at each occurrence from alkyl.

5. R ２ is selected from thiadiazolyl, triazolyl, pyrazolyl, thiazolyl and isothiazolyl, each of which is unsubstituted or selected from (i) halo, (ii) -NH ２ , (iii) C １－３ Alkyl (wherein it is unsubstituted or substituted with halo, -OH and C ３－６ 5. The compound according to claim 1, wherein the aryl group is substituted with 1, 2 or 3 substituents selected from aryl, aryl, aryl and aryl groups, or a pharma- ceutically acceptable salt thereof.

6. R ２ but, 【Chemistry 12】 【change】 is selected from Here, * is R １ is a point of attachment to R ａ , R ｂ , R ｂ１ , R ｃ , R ｄ , R ｅ , R ｅ１ , R ｆ , R ｆ１ and R ｇ each of which is (a) —H, (b) halo, (c) —NH ２ , (d)-C ３－６ Cycloalkyl, (e) -C １－６ Alkyl, which is unsubstituted or substituted with halo, -OH and -NH ２ and (f) -OC １－６ Alkyl, which is unsubstituted or substituted with halo, -OH and -NH ２ 6. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein each occurrence of the compound is independently selected from: 【Request 7】 【Chemical 13】 but, 【Chemistry 14】 7. The compound according to any one of claims 1 to 6, wherein:

8. 【Chemical 15】 but, 【Chemistry 16】 7. The compound according to any one of claims 1 to 6, wherein:

9. R ３ is -H, halo or -C １－３ 9. The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ... and aryl;

10. R ４ The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein: is -O-.

11. R ４ The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein: is -NH-.

12. X １ is N, and X ２ and X ３ are each CH; X ２ is N, and X １ and X ３ are each CH; or X ３ is N, and X １ and X ２ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 10, wherein each is CH.

13. R ５ but, (a)-C １－６ Alkyl (which is unsubstituted or substituted with halo, -OH, -NH ２ and -C(O)NH ２ and substituted with 1 to 6 substituents independently selected at each occurrence from (b)-C(O)NH ２ 、 (c) 【Chemistry 17】 And, (d) 【Chemistry 18】 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, selected from:

14. R ６ but, (1) Phenyl, which is unsubstituted or (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; (e)-C ３－６ Cycloalkyl, which is unsubstituted or substituted with -F, -Cl, -OH and -C １－３ Alkyl and -OC １－３ substituted with 1 to 3 substituents independently selected at each occurrence from alkyl; and is substituted with 1 to 5 substituents independently selected at each occurrence from: (2) pyridinyl, which is unsubstituted or is selected from the group consisting of (i) —F and —Cl, (ii) —CN, and (iii) —C １－３ alkyl, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from 1 to 6 -F and / or -Cl; （３） 【Chemistry 19】 [where R ７ａ and R ７ｂ are -H and -C, respectively. １－３ alkyl, which is unsubstituted or substituted with 1 to 6 -F and / or -Cl; （４） 【Chemistry 20】 [where R ８ａ and R ８ｂ are -H and -C, respectively. １－３ alkyl, which is unsubstituted or substituted with 1 to 6 -F and / or -Cl; （５） 【Chemistry 21】 [where R ９ , R １０ and R １１ is -H, 1, 2 or 3 halo and -C １－３ alkyl, which is unsubstituted or substituted with 1 to 6 -F and / or -Cl, independently selected at each occurrence from A bicyclic ring system selected from: (6)-C ３－６ Cycloalkyl (which is unsubstituted or substituted with halo, —OH, —C １－６ Alkyl and -OC １－６ substituted with 1 to 5 substituents independently selected at each occurrence from alkyl; （７） 【Chemical 22】 [where R １２ is (a) -H, (b) halo, (c) CN, (d) -C １－３ alkyl, which is unsubstituted or substituted with 1 to 6 -F and / or -Cl; and (e) -C ３－６ cycloalkyl; And, （８） 【Chemistry 23】 14. The compound according to any one of claims 1 to 13, wherein:

15. below 【Table 1】 2. The compound of claim 1, wherein:

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

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

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

19. 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 pharma- ceutically acceptable salt thereof.

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

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

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

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