Orexin receptor antagonists: 2-azabicyclic compounds

Abstract

The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts, solvates, adducts, polymorphs, isomers such as stereoisomers and diastereomers, or derivatives thereof, that are useful as orexin antagonists, their preparation, their use in pharmaceutical compositions, and methods of using orexin antagonists to treat or prevent a disease or disorder mediated by orexin receptor activity.

Description

[0001] OREXIN RECEPTOR ANTAGONISTS: 2-AZABICYCLIC COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compounds, or pharmaceutically acceptable salts, or derivatives thereof, that are useful as orexin antagonists; pharmaceutical compositions comprising such compounds, salts or derivatives thereof and, methods of using such compounds to treat or prevent a disease or disorder associated with orexin receptor activity.

[0004] BACKGROUND OF THE INVENTION

[0005] Orexins are a family of homologous peptides including species orexin A (OX-A) and orexin B (OX-B). Orexins are produced in neurons of the lateral hypothalamus and bind to at least two distinct G-protein-coupled receptors, termed 0X1 and 0X2 receptors (0X1 R or 0X2R). The 0X1 receptor is selective for OX-A, while the 0X2 receptor can bind both OX-A and OX-B with similar affinities.

[0006] Orexins are involved in the regulation of appetite, states of sleep and wakefulness, and may also be involved in neural mechanisms of drug abuse and addiction. The neuronal pathways and receptors via which orexins are involved in these processes seem to be partly overlapping and partly distinct. For example, findings have suggested that the arousal-promoting function of orexins is mainly promoted by 0X2 receptor whereas the role of orexin in regulating reward and feeding is predominantly mediated by 0X1 receptor.

[0007] Orexin receptors are suitable targets for the development of drug candidates for the treatment of a variety of orexin-related pathologies and symptoms, such as, but not limited to, central nervous system (CNS) disorders, sleep / wake disorders, anxiety, and obesity. Orexin receptor antagonists have been developed as potential treatments for sleep disorders such as insomnia and narcolepsy. These antagonists block the binding of orexins to their receptors, thereby reducing orexin signalling and promoting sleep. The development of orexin receptor antagonists has focused primarily on 0X2 receptor antagonists, for the regulation of arousal and wakefulness. However, there is also interest in the development of 0X1 receptor antagonists for the treatment of substance addiction, obesity and other metabolic disorders.

[0008] Patent application WO 2009 / 104155 discloses 2-azabicyclo[2.2.1]heptane derivatives as orexin receptor antagonists. Patent application WO 2014 / 165070 discloses substituted 2-azabicyclic compounds which are preferably selective towards 0X1 R over 0X2R. Patent application US 2010 / 0016401 discloses 3-azabicyclo[3.1.0]hexane derivatives as orexin receptor antagonists. Patent application WO 2014 / 159591 discloses 7-azabicyclo[2.2.1]heptane derivatives as orexin receptor agonists.

[0009] However, there is still a need for developing novel and potent selective 0X1 receptor antagonists for the treatment of a disease or disorder mediated by orexin receptor activity such as central nervous system (CNS) disorders, neurological diseases or eating disorder, sleep disorder and substance addiction. There is also a need for developing an improved brain penetrant for the treatment of a disease or disorder at least partially linked to orexin receptor activity or the associated orexin receptor cell signalling pathways such as central nervous system (CNS) disorders, neurological diseases, eating disorders, sleep disorders, or substance addiction.

[0010] The aim of the invention is to develop novel, potent and brain penetrant selective 0X1 receptor antagonist (vs. 0X2 receptor) for the treatment of binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction (opioid use disorder) and similar disorders.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention provides novel compounds, or pharmaceutically acceptable salts, or derivatives thereof, compositions and use of the compounds in the treatment or prevention of diseases or disorders mediated by orexin receptor activity. The present invention provides novel 0X1 receptor antagonists having good selectivity and binding properties, good potency, good brain penetration, improved pharmacokinetic properties, biological activities, improved solubility, improved residence time, good metabolic stability and chemical stability.

[0013] According to an aspect of the present invention, a compound or a pharmaceutically acceptable salt, or derivative thereof, is provided, wherein the compound has the structure of general Formula I:

[0014] HN— Het

[0015]

[0016] Formula I Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein said heteroaromatic group is unsubstituted, mono-substituted, di-substituted, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4) straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, fluoroalkyl, cycloalkyl, cyano, alkoxy and halogen. Preferably, the substituent of the heteroaromatic group in Het is (C1-C4)-alkyl, (C1-C4)-fluoroalkyl, (C3-C8)-cycloalkyl, a cyano group, (C1-C4)-alkoxy or a halogen. More preferably, the substituent of the heteroaromatic group in Het may be F, Cl, CHF2, CF3, methyl, ethyl, methoxy or nitrile.

[0017] R group in the compound of Formula I may be selected from the group consisting of a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.

[0018] Preferably, R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered aromatic group which is an unsubstituted aryl, or substituted aryl, or any derivatives thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, unsubstituted pyrazine, unsubstituted pyridazine, unsubstituted pyrimidine, unsubstituted triazine, substituted pyridine, substituted pyrazine, substituted pyridazine, substituted pyrimidine, substituted triazine or a derivative thereof.

[0019] The substituent of the R group may be independently selected from the group consisting of: a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the substituent is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, The substituents, if present, may be independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-straight chain or branched alkyl group, unsubstituted or substituted (C1-C4)-alkoxy group, and halogen; preferably, the halogen is F, Cl, or Br. According to another aspect of the present invention, the compound of Formula I is a stereoisomer:

[0020]

[0021] Preferably, the compound of Formula I is a 1S,4S,5R stereoisomer.

[0022] According to another aspect of the present invention, a compound, or a pharmaceutically acceptable salt, or derivative thereof is provided, wherein the compound has the structure of Formula la:

[0023]

[0024] Formula la

[0025] wherein:

[0026] X and Y may be each independently N or C-Re, where Re may be H, F, Cl, CHF2, CF3, methyl, ethyl, methoxy or nitrile; and

[0027] Z represents an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the Z is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, and any derivative thereof, wherein the substituents are independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-alkyl group, unsubstituted or substituted (C1-C4)-alkoxy group, and halogen; preferably, the halogen is F, Cl, or Br. The aromatic group or heteroaromatic group of Z may be substituted with F or -O-alkyl, wherein the alkyl group comprises 1-4 carbon atoms, preferably O-alkyl is -OCH3.

[0028] According to another aspect of the present invention, a compound, or a pharmaceutically acceptable salt, or derivative thereof is provided, wherein the compound has the structure of Formula lb or Ic:

[0029]

[0030] wherein:

[0031] R1 may be selected from the group consisting of: hydrogen, unsubstituted (C1-C6)-straight chain alkyl, unsubstituted (C1-C6)-branched alkyl, substituted (C1-C6)-straight chain alkyl, substituted (C1-C6)-branched alkyl, and halogen such as F or Cl;

[0032] X and Y may be each independently N or C-Re, where Re may be H, F, Cl, CHF2, CF3, methyl, ethyl, methoxy or nitrile; and

[0033] Het’ may be selected from the group consisting of: a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein said heteroaromatic group is unsubstituted, mono-, di-, trisubstituted. The substituents of the heteroaromatic group, if present, may be independently selected from the group consisting of: (Ci-C4)-straight chain or branched alkyl, substituted straight chain or branched (Ci-C4)-alkyl, and halogen, preferably the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: F, Cl, and CH3. According to another aspect of the present invention, a compound, or a pharmaceutically acceptable salt, or a derivative thereof is provided, wherein the compound has the structure of Formula Id or le:

[0034]

[0035] Formula Id Formula le

[0036] wherein:

[0037] R2, R3 and R4 may be each independently selected from the group consisting of: hydrogen, unsubstituted (C1-C6)-straight chain alkyl, unsubstituted (C1-C6)-branched alkyl, substituted (C1-C6)-straight chain alkyl, substituted (C1-C6)-branched alkyl, and halogen such as F or Cl; X, Y and Het’ may be each independently as defined in Formula lb or Ic;

[0038] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I or la-le described herein; and one or more pharmaceutically acceptable excipients.

[0039] According to another aspect of the present invention, there is provided a compound of Formula I described herein or a pharmaceutical composition comprising the compound of Formula I or la-le for use as a medicament. Preferably, the pharmaceutical composition is in a solid form such as a tablet or a capsule.

[0040] According to another aspect of the present invention, there is provided a method of treating or preventing a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula I or la-le described herein or a pharmaceutically acceptable salt, or derivative thereof, preferably in a dose, at a frequency, and for a duration to provide a beneficial effect a pharmaceutical composition described herein. According to another aspect of the present invention, there is provided use of a compound of Formula I or la-le described herein, or a pharmaceutical composition described therein, in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment or prevention of such diseases and disorders.

[0041] According to yet another aspect of the present invention, there is provided a method of modulating the activity of orexin receptors OX1, OX2, or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of Formula I or la-le described herein, or a pharmaceutical composition described herein.

[0042] According to another aspect of the present invention, a method for the preparation of the compounds of the present invention is provided.

[0043] DETAILED DESCRIPTION OF THE INVENTION

[0044] HN— Het

[0045]

[0046] Formula I

[0047] According to one aspect of the present invention, a compound of Formula I, or a pharmaceutically acceptable salt or derivative thereof is provided.

[0048] Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein said heteroaromatic group is unsubstituted or substituted. The substituted heteroaromatic group may be mono-, di-substituted, ortri-substituted. The substituents of the heteroaromatic group, if present, may be independently selected from the group consisting of: unsubstituted (C1-C4) straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, fluoroalkyl, cycloalkyl, cyano, alkoxy and halogen. The R group may be selected from the group consisting of a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.

[0049] Preferably, the compound provided by Formula I is a stereoisomer:

[0050] HN Het

[0051] Formula I

[0052]

[0053] The compound of Formula I may be 1S,4S,5R stereoisomer. The 1 S,4S,5R-stereoisomer provided by the compound of Formula I may bind stronger to the orexin receptors and may be more selective at binding to the 0X1 receptor in comparison to other stereoisomers provided by compounds of Formula I.

[0054] The term “heteroaromatic group” as used herein refers to an aromatic compound which contains heteroatoms such as oxygen, nitrogen or sulfur as part of the cyclic conjugated TT system.

[0055] The term “alkyl” as used herein refers to univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom -CnH2n+1. The term substituted alkyl refers to an alkyl wherein one or more hydrogen atoms of the alkyl group are replaced with one or more substituents selected from but not limited to halogen (such as fluorine, chlorine, or bromine), -OH, -CN.

[0056] The term “fluoroalkyl” as used herein refers to an alkyl substituted by at least one fluorine atom.

[0057] The term “alkoxy” as used herein refers to an alkyl bonded to oxygen (i.e. R-O). The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is an example of a monocyclic aromatic or aryl ring system.

[0058] “Halogen” can be F, Cl, Br or I, however, in preferred examples the halogen is F or Cl.

[0059] The term “substituted” as used herein refers to, for a particular group (e.g, alkyl, aryl, heteroaryl, aromatic), the replacement of one functional group by another (e.g., the substitution of an alkyl hydrogen by fluorine to provide fluoroalkyl).

[0060] The term “solvate” is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when the said solvent is water.

[0061] By “pharmaceutically acceptable” is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.

[0062] The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which / whom it is administered.

[0063] Preferably, where the R group in the compound of Formula I is a five-membered heteroaromatic group, it may comprise an unsubstituted pyrazole, oxazole, thiazole, imidazole, a substituted pyrazole, oxazole, thiazole, imidazole or a derivative thereof. Preferably, where the R group in the compound of Formula I is a six-membered aromatic group, it may comprise an unsubstituted aryl, substituted aryl, or a derivative thereof.

[0064] Preferably, where the R group in the compound of Formula I is a six-membered heteroaromatic group, it may comprise an unsubstituted pyridine, pyrazine, pyridazine, pyrimidine, triazine, a substituted pyridine, pyrazine pyridazine, pyrimidine, triazine or a derivative thereof.

[0065] The substituent of the R group, if present, may be independently selected from the group consisting of: a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the substituent is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the substituents, if present, are independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-straight chain or branched alkyl group, unsubstituted or substituted (C1-C4)-alkoxy group, and halogen; preferably, the halogen is F, Cl, or Br.

[0066] Where the R group in Formula I is a five-membered heteroaromatic group, the five-membered heteroaromatic group may have the structure Formula II:

[0067]

[0068] Formula II;

[0069] wherein:

[0070] Z may represent an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group. Preferably, Z may be independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, and any derivative thereof; and Z may be unsubstituted or substituted, preferably Z may be mono-, or di-substituted, wherein the substituents may be independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy, a cyano group and halogen.

[0071] Where Z is mono-substituted, or di-substituted and the substituent(s) is a halogen, the halogen may preferably be fluorine, chlorine or bromine. Where Z is mono-substituted, or di-substituted and the substituent(s) is (C1-C4)-alkoxy, the alkoxy group may be -O-alkyl; preferably the substituent(s) is F, or -OCH3.

[0072] In some examples, Z of Formula II is selected from:

[0073]

[0074] In some examples, the R of the compound of Formula I described herein may be selected from:

[0075]

[0076] Where the R group in the compound of Formula I is a six-membered aromatic group or heteroaromatic group, the six-membered aromatic group or heteroaromatic group has the structure of Formula III, IV or V:

[0077]

[0078] Formula V

[0079] wherein:

[0080] R₁, R₂, R₃ and R₄ may be each independently selected from the group consisting of: hydrogen, unsubstituted (C₁-C₆)-straight chain alkyl, unsubstituted (C₁-C₆)-branched alkyl, substituted (C₁-C₆)-straight chain alkyl, substituted (C₁-C₆)-branched alkyl, and halogen; and

[0081] Het’ may be selected from the group consisting of: a heteroaromatic group selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof. The heteroaromatic group may be unsubstituted or substituted. The substituted heteroaromatic group may be mono-substituted, di-substituted, tri-substituted, wherein the substituents of the heteroaromatic group, if present, may be independently selected from the group consisting of: substituted or substituted straight chain or branched (C₁-C₄)-alkyl, substituted or unsubstituted (C₁-C₄)-alkoxy, substituted or unsubstituted (C₁-C₄)-fluoroalkyl and halogen. Preferably, the substituents of the heteroaromatic group, if present, is a halogen such F, Cl or Br, or a (C₁-C₄)-alkyl such as CH₃.

[0082] Preferably, R₁, R₂, R₃ and R₄ is each independently selected from the group consisting of: H, Cl, F, CF₃, methyl and methoxy. In some examples, the Het’ group of Formula of III, IV, or V may be selected from:

[0083]

[0084] In some examples, R of the compound of Formula I described herein may be selected from:

[0085]

[0086] In some examples, the substituent of the heteroaromatic group in Het of Formula 1 may be (C₁-C₄)-alkyl, (C₁-C₄)-fluoroalkyl, (C₃-C₈)-cycloalkyl, a cyano group, (C₁-C₄)-alkoxy or a halogen. Preferably, the substituent of the heteroaromatic group in Het is F, Cl, CHF₂, CF₃, methyl, ethyl, methoxy or nitrile.

[0087] In some examples, Het in the compound of Formula I has the structure of Formula VI or VII:

[0088]

[0089] Formula VI wherein:

[0090] X and Y may be each independently N or C-R₆, where R₆ may be H, F, Cl, CHF₂, CF₃, methyl, ethyl, methoxy or nitrile.

[0091] In some examples, Het in the compound of Formula I may be selected from:

[0092]

[0093] In yet another example, the compound of Formula I described herein has the structure of Formula la, lb, Ic, Id or le:

[0094]

[0095]

[0096] Formula le

[0097] wherein R1, R2, R3, R4, Het’, X, Y and Z may be each independently as defined herein with respect to Formula l-VII.

[0098] In further examples, a compound of the present invention may be selected from:

[0099] (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)- 5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0100] (compound 1)

[0101]

[0102] (3-fluoro-2-(pyrimidin-2-yl)phenyl)((7S,4S,5F?)- HN— Z / N=\ \ _ / F 5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2- v ~ \~F azabicyclo[2.1.1]hexan-2-yl)methanone $N’ (compound 2)

[0103] F 2 (5-methyl-2-(pyrimidin-2- HN- / / N==\ \ _ / F yl)phenyl)((7S,4S,5R)-5-((5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0104] (compound 3)

[0105] h j N^13 (6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)((7S,4S,5F?)-5-((5-(trifluoromethyl)pyridin-2- 4 z

[0106] / /

[0107] yl)amino)-2-azabicyclo[2.1.1]hexan-2- 'J N z'z fl— z-. yl)methanone (compound 4) o ^rNY^°

[0108] Il ] o 4 I cn (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)((7S,4S,5F?)-5-((5-(trifluoromethyl)pyridin-2- yl)amino)-2-azabicyclo[2.1.1]hexan-2- yl)methanone (compound 5)

[0109]

[0110] (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H- / N=\Fpyrazol-3-yl)((7S,4S,5F?)-5-((5- (trifluoromethyl)pyrimidin-2-yl)amino)-2- N

[0111] azabicyclo[2.1.1]hexan-2-yl)methanone

[0112] (compound 6) —NI

[0113] ' O

[0114] F

[0115] (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H- / N=\ F pyrazol-3-yl)((7S,4S,5F?)-5-((5- _5NS )-(-F (trifluoromethyl)pyrimidin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0116] (compound 7) —NI

[0117] XX F7Zz

[0118] (6-methyl-3-(pyrimidin-2-yl)pyridin-2- / / yl)((7S,4S,5F?)-5-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-2-azabicyclo[2.1.1]hexan-2- O i° yl)methanone (compound 8)

[0119] X ■ (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-N=\ F HN-— Z \ yl)((7S,4S,5 / ?9-5-((5-(trifluoromethyl)pyrimidin- t 2-yl)amino)-2-azabicyclo[2.1.1]hexan-2- N

[0120] yl)methanone (compound 9)

[0121] N 9 \ /

[0122] N= /

[0123]

[0124] (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((7S,4S,5F?)-5-((5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0125] (compound 10)

[0126] (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H- HN-Q-_ZFpyrazol-3-yl)((7S,4S,5F?)-5-((5- f (trifluoromethyl)pyridin-2-yl)amino)-2- N azabicyclo[2.1.1]hexan-2-yl)methanone

[0127] (compound 11) —NI

[0128] / o

[0129] \^\ 11 F

[0130] / /

[0131] ((7S,4S,5F?)-5-((3-fluoro-5- i’''z\= - (trifluoromethyl)pyridin-2-yl)amino)-2- W° p azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone

[0132] O' (compound 12)

[0133] X “ -nn

[0134] (6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)(( IS, 4S, 5 / ?)-5-((3-methyl-5-HZ=\ F (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone N (compound 13)

[0135] II 13 N^1

[0136]

[0137] ((7S,4S,5R)-5-((3-(difluoromethyl)-5- F F— / (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone

[0138] NN^F(compound 14)

[0139] II I 14 N^1((7S,4S,5R)-5-((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone

[0140] (compound 15)

[0141] Zz

[0142] / / / /

[0143] 2-(((7S,4S,5F?)-2-(6-methyl-3-(pyrimidin-2- N yl)picolinoyl)-2-azabicyclo[2.1.1 ]hexan-5- Gozr

[0144] ^°v z yl)amino)-5-(trifluoromethyl)nicotinonitrile

[0145] (compound 16)

[0146] U1 II 1 16 ((7S,4S,5F?)-5-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H- 1,2,3-triazol-2-yl)pyridin-2-yl)methanone

[0147] (compound 17)

[0148]

[0149] (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)(( IS, 4S, 5 / ?)-5-((3-methyl-5- HN— / V / F(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone $

[0150] (compound 18)

[0151] A 18 I /

[0152] ((1S,4S,5R)-5-((3-(difluoromethyl)-5- F— / (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H- 1,2,3-triazol-2-yl)pyridin-2-yl)methanone

[0153] ..

[0154] (compound 19)

[0155] x) 19 N= /

[0156] ((7S,4S,5F?)-5-((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H- 1,2,3-triazol-2-yl)pyridin-2-yl)methanone

[0157] (compound 20)

[0158] i 7 20 N= /

[0159] 2-(((7S,4S,5R)-2-(6-methyl-3-(2H-1,2,3-triazol- N

[0160] 2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5- yl)amino)-5-(trifluoromethyl)nicotinonitrile

[0161] (compound 21)

[0162] Xf T^°

[0163] I / 21 N= /

[0164]

[0165] (6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0166] (compound 22) 1 «

[0167] 0jf Y ]M C 22 \Z= z / iz

[0168] (6-methyl-3-(pyrimidin-2-yl)pyridin-2- / \

[0169] / \A / L.'Z=- yl)((7S,4S,5 / ?)-5-((3-methyl-5- V / ° / == N F HN—Z \ _ / (trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone $

[0170] (compound 23)

[0171] ° Y Y

[0172] 1 1 23 YxN

[0173] ((7S,4S,5R)-5-((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'- bipyridin]-2'-yl)methanone (compound 24)

[0174] ° f Y

[0175] 24(6'-methyl-[2,3'-bipyridin]-2'-yl)((7S,4S,5 / ?)-5- ((5-(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0176] (compound 25)

[0177]

[0178] ((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 26)

[0179] M C I JI

[0180] \z= z / Iz

[0181] / \ ((7S,4S,5 / ?)-5-((4-methyl-5- / \A / L'z=- "= / F (trifluoromethyl)pyrimidin-2-yl)amino)-2- xJ ° HN— Z \ _ / azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'- bipyridin]-2'-yl)methanone (compound 27)

[0182] 01 J CiX27((1S,4S,5R)-5-((3-(difluoromethyl)-5-F— / (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'- bipyridin]-2'-yl)methanone (compound 28)

[0183] J

[0184] i B28

[0185] 2-(((1S,4S,5R)-2-(6'-methyl-[2,3'-bipyridine]-2'-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile

[0186] (compound 29)

[0187] zA zNx / 0A 1

[0188] L J) 29

[0189]

[0190] ((7S,4S,5R)-5-((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'- HN— < XX / Fbipyridin]-2'-yl)methanone (compound 30)

[0191] °XT J

[0192] l^JJ 30

[0193] ((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 31)

[0194] A X oz - \ V XZz= \ / _

[0195] ((1S,4S,5R)-5-((3-(difluoromethyl)-5-

[0196] Z I z F

[0197] F— / (trifluoromethyl)pyridin-2-yl)amino)-2- A M / z azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3- HN-- / \___ / FI w (pyrimidin-2-yl)pyridin-2-yl)methanone

[0198] (compound 32)

[0199] \ / N. As.

[0200] T r 1]32

[0201] 2-(((1S,4S,5R)-2-(4,6-dimethyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 33)

[0202] \ / Ns / L.

[0203] Y i0

[0204] I XJ33

[0205]

[0206] (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2- E yl)((7S,4S,5F?)-5-((3-fluoro-5- HN— / )< / F(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0207] (compound 34)

[0208] Y li

[0209] i XZ34

[0210] (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2- N=Z F yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0211] (compound 35)

[0212] T 1 1 35

[0213] (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((3-methyl-5-F(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone N

[0214] (compound 36)

[0215] Y [0

[0216] T XJ36

[0217] (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2- o' yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0218] (compound 37)

[0219] V 1i0

[0220] 1 N^J

[0221]

[0222] (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2- / =N F yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0223] (compound 38)

[0224] V «0

[0225] I Xj38

[0226] (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2- HN— Z \ / Fyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 39) S.. N. As.

[0227] Y A

[0228] I39

[0229] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- o' yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0230] (compound 40)

[0231] \ / A

[0232] A [0

[0233] I \ |l 40 Cl

[0234] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- F yl)((1S,4S,5R)-5-((3-fluoro-5-F(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0235] (compound 41) \ zNs As

[0236] A a0

[0237] I I I 41 Cl

[0238]

[0239] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- F

[0240] yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0241] \ / N. Ax.

[0242] (compound 42)

[0243] V i0AA zz

[0244] Cl N^J42

[0245] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0246] (compound 43) \ / N. Ax.

[0247] V AA i / 0NX

[0248] I \ I] 43 Cl

[0249] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- F

[0250] F— / yl)((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0251] (compound 44)

[0252] \ Ax.

[0253] V if0

[0254] T T |l 44 Cl N<x^JJ

[0255] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0256] (compound 45) \ Aix

[0257] Y ii °

[0258] I \ ll 45CL N^A

[0259]

[0260] (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 46)

[0261] Y 1 °

[0262] a Xj462-(((1S,4S,5R)-2-(4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 47)

[0263] V II0

[0264] T T |l 47 Cl N<^>

[0265] (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((3-methyl-5-N. F HN— Z \ / (trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone N

[0266] (compound 48)

[0267] Y v0

[0268] N=V

[0269] (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- / N= / F yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0270] \ / N. As.

[0271] (compound 49)

[0272] A i °

[0273] W49

[0274]

[0275] (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- F yl)((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0276] (compound 50) \ Ax.

[0277] A V °

[0278] I

[0279] (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0280] (compound 51)

[0281] - \

[0282] (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- Az z- - yl)((1S,4S,5R)-5-((3-methyl-5-F(trifluoromethyl)pyridin-2-yl)amino)-2- ^ fz azabicyclo[2.1.1]hexan-2-yl)methanone rj L (compound 52) \ Ax. I On A i0

[0283] 1 ^ 1 52 1 N^ /

[0284] ((1S,4S,5R)-5-((3-(difluoromethyl)-5-

[0285] F— / (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3- HN— / \_ / F(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

[0286] (compound 53)

[0287] \ / N. Ax,

[0288] A i0WN> 531N= /

[0289]

[0290] (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0291] (compound 54) \ Ji

[0292] \ZZz—"

[0293] / ) z —

[0294] / /

[0295] (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- HN— / \ _ / Fyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-

[0296] yl)methanone (compound 55)

[0297] 1N= /

[0298] 2-(((1S,4S,5R)-2-(4,6-dimethyl-3-(2H-1,2,3-

[0299] triazol-2-yl)picolinoyl)-2- azabicyclo[2.1.1]hexan-5-yl)amino)-5- HN— - / \_ / F(trifluoromethyl)nicotinonitrile (compound 56)

[0300] 10

[0301] 1N= /

[0302] (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0303] (compound 57) \ / N. Ax.

[0304] A i °

[0305] V -jA> «1N=^ /

[0306]

[0307] (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0308] (compound 58) 0 ^ ((7S,4S,5F?)-5-((3-fluoro-5- r F (trifluoromethyl)pyridin-2-yl)amino)-2- HN— / / Fazabicyclo[2.1.1]hexan-2-yl)(4-(5- fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 59)

[0309] — I NZ

[0310] z

[0311] / J / % 59 / Z^

[0312] F

[0313] ^ 5r°

[0314] (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0315] (compound 60)

[0316]

[0317] ((7S,4S,5R)-5-((3-(difluoromethyl)-5- F

[0318] F— / (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(4-(5- HN— / 'k / Ffluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 61)

[0319] — NZ°

[0320] / Ji

[0321] N / 61F

[0322] (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0323] (compound 62) I z

[0324] \ / >< zi=z- y 4z^

[0325] (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-

[0326] M -n (trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0327] (compound 63)

[0328] -NZ

[0329] / T

[0330] 63 F

[0331]

[0332] 2-(((1S,4S,5R)-2-(4-(5-fluoropyrimidin-2-yl)- N 1,5-dimethyl-1 H-pyrazole-3-carbonyl)-2- azabicyclo[2.1.1]hexan-5-yl)amino)-5- HN— Z 'v /

[0333] ]0 ( 1 (trifluoromethyl)nicotinonitrile (compound 64)

[0334] N^^x

[0335] — N' / P °

[0336] \ ) LA / ==z

[0337] / T

[0338] 64 F

[0339] 1

[0340] (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H- "=( F pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone N

[0341] (compound 65) -Nz^ ^0

[0342] u -XF

[0343] ((1S,4S,5R)-5-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin- 2-yl)- 1,5-dimethyl-1 H-pyrazol-3-yl)methanone

[0344] (compound 66)

[0345]

[0346] (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5- HN— / / F(trifluoromethyl)pyridin-2-yl)amino)-2- 9 < / O azabicyclo[2.1.1]hexan-2-yl)methanone

[0347] (compound 67)

[0348] -NZ

[0349] / PX z^

[0350] 67 F

[0351] z^^

[0352] ((1S,4S,5R)-5-((3-(difluoromethyl)-5- 1

[0353] (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin- 2-yl)- 1,5-dimethyl-1 H-pyrazol-3-yl)methanone

[0354] (compound 68)

[0355] I z.

[0356] / ^\=

[0357] X o

[0358] " H - / \

[0359] ^ " H\^ Z\

[0360] (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H- CTmpyrazol-3-yl)((1S,4S,5R)-5-((3-methoxy-5- / O) (trifluoromethyl)pyridin-2-yl)amino)-2-00azabicyclo[2.1.1]hexan-2-yl)methanone

[0361] (compound 69)

[0362]

[0363] (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0364] (compound 70)

[0365] 2-(((1S,4S,5R)-2-(4-(5-fluoropyridin-2-yl)-1,5- N dimethyl-1H-pyrazole-3-carbonyl)-2- azabicyclo[2.1.1]hexan-5-yl)amino)-5- HN— / (trifluoromethyl)nicotinonitrile (compound 71)

[0366] I N^A^

[0367] - zNZ

[0368] y Xr-'N.

[0369] rA /

[0370] ^A vzZ.71F

[0371] (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5- HN— Z / N==^( \ _ / F(trifluoromethyl)pyrimidin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone N t3(compound 72)

[0372] Q

[0373] 0^

[0374]

[0375] ((1S,4S,5R)-5-((3-fluoro-5- F (trifluoromethyl)pyridin-2-yl)amino)-2- HN— Z \ / Fazabicyclo[2.1.1]hexan-2-yl)(4-(5- methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazol- N

[0376] 3-yl)methanone (compound 73)

[0377] - / -A

[0378] 730^

[0379] (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5- HN— Z \ / F(trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0380] (compound 74)

[0381] - / -A

[0382] 740^

[0383] (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H- HN— / / Fpyrazol-3-yl)((1S,4S,5R)-5-((5- (trifluoromethyl)pyridin-2-yl)amino)-2- N

[0384] azabicyclo[2.1.1]hexan-2-yl)methanone

[0385] (compound 75)

[0386] 750^

[0387] (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H- pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone

[0388] (compound 76)

[0389] - / -A

[0390] / A-NK

[0391] 76O-^

[0392]

[0393] (5-fluoro-2-(2-methyl-2H-tetrazol-5- HN— / \ / Fyl)phenyl)((7S,4S,5R)-5-((5- (trifluoromethyl)pyridin-2-yl)amino)-2- N azabicyclo[2.1.1]hexan-2-yl)methanone Jx.

[0394] (compound 77) 1 1 °

[0395] I >

[0396] N-N 77 \

[0397] (5-fluoro-2-(2-methyl-2H-tetrazol-5- yl)phenyl)((7S,4S,5R)-5-((3-methyl-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0398] (compound 78)

[0399] (5-fluoro-2-(2-methyl-2H-tetrazol-5- \('zz=~- F

[0400] yl)phenyl)((7S,4S,5R)-5-((4-methyl-5- > < H oN— Z \ / (trifluoromethyl)pyrimidin-2-yl)amino)-2- 1z

[0401] ^X^ / Z azabicyclo[2.1.1]hexan-2-yl)methanone v (compound 79) F\ Jx- T co 1 1 °

[0402] T >

[0403] N-NZ79 \

[0404] (5-fluoro-2-(2-methyl-2H-tetrazol-5- yl)phenyl)((7S,4S,5R)-5-((3-methyl-5- HN — < / =N\ \ / F (trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0405] (compound 80) F\ Jx

[0406] N U

[0407] N-NzO 80 \

[0408]

[0409] (5-fluoro-2-(2-methyl-2H-tetrazol-5- yl)phenyl)((7S,4S,5R)-5-((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)methanone

[0410] (compound 81)

[0411]

[0412] or a pharmaceutically acceptable salt, or derivative thereof.

[0413] According to another aspect of the present invention, a compound, or a pharmaceutically acceptable salt, or derivative thereof is provided, wherein the compound has the structure of Formula l-aa,

[0414]

[0415] Formula l-aa

[0416] wherein:

[0417] X is selected from the group consisting of: -CH, -C-CH3, -C-CH2CH3, -C-F, -C-CI, -C-CN, -C-CHF2, N and -C-OMe; and

[0418] R is a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or any derivative thereof. Preferably, R in Formula l-aa is selected from:

[0419]

[0420] wherein:

[0421] R2and R5are each independently hydrogen or -CH3; and

[0422] Het’ and Z are each independently selected from the group consisting of:

[0423]

[0424] Preferably, the compound of Formula l-aa is selected from the group consisting of:

[0425]

[0426]

[0427] The novel compounds provided by general Formula I are non-peptide antagonists of human orexin receptors, especially the orexin-1 receptor.

[0428] In accordance with the results shown in Table 1, it has surprisingly been found that compounds of the present invention demonstrate excellent (nanomolar) potency and selectivity for OX1R over OX2R. In particular, compounds of the present invention demonstrate a significantly improved potency over conventional OX1R antagonists when considering the IC50for OX1R.

[0429] OX1R and OX2R are at least partially involved in the regulation of different physiological pathways. OX1R, for example, is considered to be more involved in substance addiction, obesity, and other metabolic disorders, whereas OX2R is considered to be more closely related to arousal and wakefulness. The development of compounds of the present invention which demonstrate significant selectivity over OX1R therefore facilitate the use of such compounds for improved targeting of disease modulation whilst minimising the risk of adverse side effects (by minimising the interaction of the compounds with OX2R signalling pathways). Compounds disclosed in the present invention may therefore be excellent candidates for the treatment of metabolic disorders involving OX1R.

[0430] Additionally, it is shown from Table 1 that the compounds of the present invention demonstrate good metabolic stability (as measured via intrinsic clearance hCLint). Critically, the compounds also demonstrate excellent apparent permeability (Papp), suggesting that the compounds are suitably bioavailable and readily cross cell membranes. The compounds are particularly useful for the potential treatment or prevention of central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression. The compounds of the present invention may be useful to treat diseases or disorders relating to dysfunctions of the orexin-1 receptor.

[0431] Half-maximal inhibitory concentration (IC50) may be used in the present invention to demonstrate the efficiency of compounds provided by the present invention). The IC50 values provided in this disclosure indicates how much drug is needed to inhibit orexin receptors by half, thus providing a measure of compounds provided by the present invention.

[0432] Compounds provided by the present invention may have an IC50of at least 3 nM for OX1 receptors. Preferably, compounds provided by the present invention may have an IC50value between 2 nM to 300 nM for OX1 receptors. Compounds provided by Formula I may have an IC50value between 2 nM to 250 nM; between 2 nM to 150 nM; between 2 nM 100 nM; between 2 nM to 75 nM; or between 2 nM to 50 nM for OX1 receptors.

[0433] More preferably, compounds provided by the present invention may have an IC50value between 2 nM to 13 nM for OX1 receptors. Compounds provided by the present invention may have an IC50value between 2 nM to 8 nM; between 2 nM to 7 nM; between 3 nM to 13 nM; between 4 nM to 13 nM; between 6 nM to 13 nM; or between 8 nM to 13 nM for OX1 receptors.

[0434] Compounds provided by the present invention may have an IC50of about 1000 or more nM for OX2 receptors. Preferably, compounds provided by the present invention have an IC50of about 3000 or more nM for OX2 receptors.

[0435] Compounds provided by the present invention may have an IC50of at least 100 nM for OX2 receptors. Preferably, compounds provided by the present invention may have an IC50value between 200 nM to 1000 nM for OX2 receptors. Compounds provided by Formula I may have an IC50value between 1000 nM to 5000 nM; between 2000 nM to 5000 nM, or equal to or >5000 nM for OX2 receptors.

[0436] Preferably, OX2R / OX1R IC50(nM) ratio of the compounds of the present invention is in the range of 10 nM to 850 nM. In some examples, the IC50ratio is in the range of about 20 to 850nM. In some examples, the IC50ratio may in the range of about 30 nM to 850 nM. In some examples, the IC50ratio may in the range of about 40 nM to 400 nM. In some examples, the IC50ratio may in the range of about 50 nM to 350 nM. In some examples, the IC50ratio may in the range of about 75 nM to 600 nM. In some examples, the IC50ratio may in the range of about 100 nM to 850 nM. Preferably, OX2R / OX1R IC50(nM) ratio of the compounds of the present invention is in the range of about 250 nM to 850 nM. In some examples, the ratio may be in the range of about 300 nM to 675nM. In some examples, the ratio may be 340 nM to 550 nM. In some examples the ration may be 400 nM to 600 nM.

[0437] The compounds of the present invention may be in the form of a pharmaceutically acceptable salt or derivative. A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0438] Examples of “pharmaceutically acceptable salts” include, but not limited to, hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates such as trifluoroacetate, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates, phosphates or diphosphates and aluminates.

[0439] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, prodrugs or a mixture thereof. The “pharmaceutically acceptable derivatives” of the compounds of the present invention disclosed herein includes, but is not limited to, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isomers, isotopically or radio-labelled compounds or a mixture thereof. The isomers are preferably stereoisomers or diastereomers.

[0440] Isotopic Labelling in Described Compounds

[0441] The present application further includes all pharmaceutically acceptable isotopically labelled compound [e.g., of Formula I or la-le] An "isotopically" or "radio-labelled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in certain examples, in compounds [e.g., of Formula I or la-e], hydrogen atoms are replaced or substituted by one or more deuterium or tritium. Isotopically labelled compounds [e.g., of Formula I or la-e] or their corresponding prodrugs can generally be prepared by conventional techniques known in the art.

[0442] According to another aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of present invention described herein and one or more pharmaceutically acceptable excipients.

[0443] Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art.

[0444] The pharmaceutical composition or the compound provided by the present invention may be used as a medicament.

[0445] The pharmaceutical composition comprising the compounds of the present invention may be in the form of tablets, capsules, hard candies, powders, spansules, soft gels, liquid or aqueous suspensions. Preferably, the pharmaceutical composition provided by the present invention is in the form of tablets or capsules.

[0446] The pharmaceutical composition provided by the present invention may be administered through oral, parenteral, topical, ocular, pulmonary and / or other suitable routes. Preferably, the pharmaceutical composition provided by the present invention is administered orally.

[0447] According to yet another aspect of the present invention, a method of treating or preventing a disease or disorder associated with the orexin receptor activity, is provided. The method comprising administering to a subject in need of such treatment an effective amount of at least one compound in accordance with the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled derivatives and isomers thereof) or a pharmaceutical composition comprising of at least one compound in accordance with the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled compounds and isomers thereof).

[0448] The method, pharmaceutical composition or medicament provided by the present invention may be used for the treatment or for the prevention of diseases or disorders selected from but not limited to eating disorders, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.

[0449] Dosage regimens may be adjusted to provide the optimum desired response. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.

[0450] As used herein, the term “subject” includes a human or non-human animal. An exemplary human subject includes a human subject having a disease (such as one described herein) (referred to as a patient), or a normal subject. The term “non-human animal” as used herein includes all vertebrates, such as non-mammals. The present invention also provides the use of a compound or a pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity and may be used in the treatment or prevention of such diseases and disorders.

[0451] According to yet another aspect of the present invention, a method of modulating the activity of orexin receptors OX1, OX2, or both. The method comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of the present invention or a pharmaceutical composition comprising the compound. The method of contacting the cell may either be carried out in vivo, in vitro or ex vivo.

[0452] According to yet another aspect of the present invention, compounds of the present invention may be prepared by the synthetic pathway described in the examples below.

[0453] The abbreviations used in the present disclosure are summarised:

[0454] The abbreviations used in the present disclosure are summarised:

[0455] BOC tert-butyloxycarbonyl

[0456] DIEA N, N-Diisopropylethylamine

[0457] DMS dimethyl sulfide

[0458] DMSO dimethylsulfoxide

[0459] DMAP 4-dimethylaminopyridine

[0460] PG protecting group

[0461] TEA triethanolamine

[0462] THF tetrahydrofuran

[0463] Ts Tosyl

[0464] eq Equivalents

[0465] N Normality

[0466] V Volume

[0467] The present invention provides a method for synthesizing tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (intermediate b) as shown in the synthetic pathway below: o o o

[0468]

[0469] Tert-butyl allylcarbamate (a) is reacted with 4,4-dimethoxybutan-2-one in the presence of a catalyst to form tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (b). Preferably, the catalyst is an acid catalyst. 4,4-dimethoxybutan-2-one may be used in excess relative to the acid catalyst. Any suitable acid catalyst may be used. The acid catalyst may comprise p-Toluenesulfonic acid (TsOH), benzenesulfonic acid, methanesulfonic acid, or H2SO4. Preferably, the acid catalyst is p-Toluenesulfonic acid. The reaction may be carried out at a temperature in the range of about 30 °C and about 80 °C. Preferably, the reaction temperature is about 40 °C to about 50 °C. The reaction may be carried out for a duration of about 12 hours to about 24 hours, more preferably for about 14 hours to 16 hours.

[0470] The present invention provides a method for synthesizing tert-butyl rac-5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate c) as shown in the synthetic pathway below:

[0471]

[0472] Tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (b) undergoes photoredox-catalysed intramolecular cyclisation to form tert-butyl rac-5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (c). Preferably, the reaction is carried out in the presence of a polar aprotic solvent. The polar aprotic solvent may include DMSO, DMF, THF or acetonitrile. Preferably, the solvent comprises acetonitrile. Any suitable organometallic photocatalyst may be used, such as ruthenium (II) complexes, Eosin Y, iridium (III) hexafluorophosphate complexes, or cobalt polypyridyl complexes. Preferably, the photocatalyst comprises bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate. The reaction may be carried out at a temperature in the range of about 30 °C to about 80 °C. Preferably, the reaction temperature is about 40 °C to about 50 °C. The reaction may be carried out for a duration of about 0.1 hours to about 2 hours, more preferably for about 0.25 hours to about 1 hour. Direct thermal cyclisation may be an alternative method for the synthesis of tert-butyl rac-5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (c), however photoredox catalysis provides favourable control of selectivity and the use of milder reaction conditions.

[0473] The present invention provides a method for synthesizing rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (d). as shown in the synthetic pathway below:

[0474]

[0475] Tert-butyl rac-5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (c) undergoes oxidation to form rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (d). Any suitable oxidation reagent may be used, such as KMnO4, Jones reagent (CrO3in H2SO4), ozonolysis, or sodium hypochlorite, preferably in a solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out with sodium hypochlorite in THF. The reaction may be carried out at a temperature in the range of about 15 °C to about 50 °C. Preferably, the reaction temperature is about 25 °C to about 35°C. The reaction may be carried out for a duration of about 0.25 hours to about 4 hours, more preferably for about 0.5 hours to about 1 hour.

[0476] The present invention provides a method for synthesizing (1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate e) as shown in the synthetic pathway below:

[0477]

[0478] (1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (e) was isolated from rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (d) by undergoing a chemical resolution process in the presence of a resolving agent. Suitable resolving agents such as antimony potassium tartrate, camphorsulfonic acid or 1-phenylethylamine may be used. Preferably, (1S)-1-phenylethanamine is used. Alternative methods for isolating (1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (e) may use chromatographic techniques or enzymatic resolution. The reaction may be carried out at a temperature in the range of about 10 °C to about 30 °C. Preferably, the reaction temperature is about 15 °C to about 20 °C. The reaction may be carried out for a duration of about 12 hours to about 24 hours, more preferably for about 14 hours to about 16 hours.

[0479] The present invention provides a method for synthesizing tert-butyl (1S,4S,5R)-5- (((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate f) as shown in the synthetic pathway below:

[0480] 0

[0481]

[0482] BocBoc

[0483] e f

[0484] The carboxylic acid group of (1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (e) is subject to a protection step. Preferably, the protection step comprises converting the carboxylic acid group (1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (e) to a primary amine. The primary amine may then be reacted with a carboxybenzyl (Cbz) protecting group in the presence of a solvent to provide tert-butyl (1S,4S,5R)-5-(((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (f). The reaction may be a one-pot reaction. Suitable reagents that may be used in the reaction comprise Diphenylphosphoryl azide (DPPA), N, N-Diisopropylethylamine (DIEA) and BnOH. Suitable solvents may include toluene, THF, DCM or mixtures thereof. Preferably, toluene is used.

[0485] The reaction may be carried out at a temperature in the range of about 70 °C to about 130 °C. Preferably, the reaction temperature is about 85 °C to about 100 °C. The reaction may be carried out for a duration of about 12 hours to about 22 hours, more preferably for about 14 hours to about 16 hours.

[0486] The present invention provides a method for synthesizing tert-butyl (1 S,4S,5R)-5-am'\r\o-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) as shown in the synthetic pathway below: HN-Cbz NH2

[0487] — '

[0488] I I

[0489] Boc Boc

[0490] f g

[0491] Tert-butyl (1S,4S,5R)-5-(((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (f) is reacted with a reducing agent. Preferably, the reduction comprises catalytic dehydrogenation. Any standard method may be used for reducing the Cbz protecting group to form intermediate g. Suitable catalysts include Palladium on Carbon (Pd / C). The reaction may be carried out at a temperature in the range of about 10°C to about 30°C. Preferably, the reaction temperature is about 15°C to about 20°C. The reaction may be carried out for a duration of about 12 hours to about 22 hours, more preferably for between about 14 hours to about 16 hours.

[0492] The present invention also provides a compound which is:

[0493] tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (intermediate b);

[0494] tert-butyl rac- 5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate c);

[0495] rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate d); (7S,4R,5 / ?9-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate e);

[0496] tert-butyl (7S,4S,5R)-5-(((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate f); or

[0497] tert-butyl (7S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g).

[0498] Preferably, intermediate g can be prepared starting from compound (a) or from any one of the intermediates compounds (b-f).

[0499] The present invention provides a method for synthesizing compounds 1-81 as shown in the general synthetic pathway below: HN-Het HN-Het Het-Hal

[0500] Boc Boc

[0501] h1-h1O i1-i10

[0502] RCOOH HN-Het

[0503]

[0504] R O

[0505] 1 - 81

[0506] The structure of compounds 1-81 is as shown herein above.

[0507] The present invention also provides a method for preparing a compound of Formula I:

[0508]

[0509] Formula I

[0510] wherein Het and R may be each independently as defined herein above,

[0511] said method comprising the steps of:

[0512] (a) reacting tert-butyl (1S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate with a halo-substituted heteroaromatic compound in the presence of a base, to form a first intermediate;

[0513] (b) reacting the first intermediate with an acid to form a second intermediate compound;

[0514] and

[0515] (c) reacting the second intermediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I.

[0516] tert-butyl (7S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate is reacted with a halogen-substituted heteroaromatic compound (Het-Hal) in the presence of a base, to form a first intermediate (h1 – h10). Preferably, the base is non-nucleophilic. Examples of bases that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA, DIEA or mixtures thereof. More preferably, the base comprises / V, / V-Diisopropylethylamine (DIEA). The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMSO.

[0517] The reaction may be performed at a temperature in the range of about 90 °C to about 190 °C, more preferably about 120 °C to about 140 °C. The reaction time may be about 10 hours to about 24 hours, preferably about 13 hours to about 20 hours and more preferably about 16 hours.

[0518] In some examples, tert-butyl (1S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) is reacted with a halogen-substituted heteroaromatic compound to form an intermediate compound, which may be reacted with an acid to form the first intermediate. The acid may be an alkylboronic acids and alkylboronates. Preferably the alkylboronic acid is methylboronic acid. Preferably, the intermediate is tert-butyl (1S,4S,5R)-5-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh5). Preferably, the intermediate gh5 is reacted with the acid in the presence of a solvent and / or a base. Suitable solvents may include diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably, the reaction is carried out in dioxane. Suitable bases may include potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIEA. More preferably, the base is sodium carbonate. The reaction may be performed at a temperature in the range of about 10°C to about 30°C, more preferably about 15°C to about 20°C.

[0519] In some examples, tert-butyl (7S,4S,5?)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) is reacted with a halogen-substituted heteroaromatic compound to form an intermediate compound, which may be reacted with a methylating agent to form the first intermediate. Preferably, the methylating agent is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. Preferably, the intermediate is tert-butyl (7S,4S,5F?)-5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh9). Preferably, the intermediate gh9 is reacted with the methylating agent in the presence of a catalyst, and / or a base. Preferably, the catalyst is a palladium compound such as Pd(PPh3)2Cl2. The reaction may be carried out in the presence of a solvent e.g. dioxane or the like. Suitable bases may include potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIEA. More preferably, the base is potassium carbonate. The reaction may be performed at a temperature in the range of about 20°C to 150°C, more preferably in the range of about 50°C to about 100°C.

[0520] The first intermediate (h1-h10) may be deprotected by treatment with an acid to form the second intermediate (i1-i10).

[0521] Examples of acids that may be used for the deprotection include but are not limited to aqueous phosphoric acid, hydrochloric acid, or trifluoroacetic acid. Preferably, hydrochloric acid is used for the deprotection of the first intermediates h1-h10. The deprotection may be carried out in the presence of a solvent which may be a polar or a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably, the reaction is carried out in 1,4-dioxane. The reaction may be performed at a temperature in the range of about 12°C to about 40°C, preferably about 15°C to about 30°C, more preferably about 20°C. The reaction time may be in the range of about 0.25 hours to about 3 hours, preferably about 0.5 hours to about 2 hours, or about 1 hour.

[0522] The halo-substituted heteroaromatic compound may be selected from the group consisting of: halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo-substituted pyrimidine, halo-substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo-substituted imidazole, halo-substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole and any derivatives thereof, wherein said halo-substituted heteroaromatic group may be further substituted; wherein the further substituents of the halo-substituted heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4)-straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, unsubstituted (C1-C4)-alkoxy group, unsubstituted (C3-C8)-cycloalkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, substituted (C1-C4)-alkoxy group, substituted (C3-C8)-cycloalkyl, fluoroalkyl, a cyano group and halogen (such as F, Cl, Br). Preferably, the further substituents of the heteroaromatic group is Cl, F, CHF2, CF3, CH3, CH3CH2, methoxy, nitrile or cyclopropyl.

[0523] The halo-substituted heteroaromatic compound may be a fluoro-substituted heteroaromatic compound, chloro-substituted heteroaromatic compound, bromo-substituted heteroaromatic compound or iodo-substituted heteroaromatic compound. Preferably, the halo-substituted heteroaromatic compound may be a chloro-substituted heteroaromatic compound. The halo-substituted heteroaromatic compound is preferably selected from:

[0524] 2-fluoro-5-(trifluoromethyl)pyridine (Het-Hal1) (CAS 69045-82-5);

[0525] 2-chloro-5-(trifluoromethyl)pyrimidine (Het-Hal2) (CAS 69034-12-4);

[0526] 2-chloro-5-(trifluoromethyl)pyrazine (Het-Hal3) (CAS 799557-87-2);

[0527] 2,3-difluoro-5-(trifluoromethyl)pyridine (Het-Hal4) (CAS 89402-42-6);

[0528] 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine (Het-Hal5) (CAS 1031929-01-7);

[0529] 2-chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine (Het-Hal6) (CAS 1805009-33-9);

[0530] 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine (Het-Hal7) (CAS 1227563-67-8);

[0531] 2-chloro-5-(trifluoromethyl)nicotinonitrile (Het-Hal8) (CAS 624734-22-1);

[0532] 2,4-dichloro-5-(trifluoromethyl)pyrimidine (Het-Hal9) (CAS 3932-97-6); or

[0533] 5-(trifluoromethyl)pyrazin-2-ol (Het-Hal10) (CAS 134510-03-5).

[0534] The second intermediate (i1 - i10) may be reacted with a carboxylic acid having the general formula R-COOH to form a compound in accordance with Formula I.

[0535] In some examples, R in R-COOH may be selected from the group consisting of a five or a six membered aromatic or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents. Preferably, R in in R-COOH comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, an unsubstituted triazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine, a substituted triazine or a derivative thereof.

[0536] The reaction of the second intermediates (i1 - i10) with carboxylic acid R-COOH may be carried out in the presence of a coupling reagent. Suitable coupling reagents include but are not limited to DCC, DIC, EDC-HCI, BOP, PyBOP, PyAOP, PyBrOP, BOP-CI, HATU, HBTU, HCTU, TATU, TBTU, T3P, DEPBT or GDI. Preferably, (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) is used as the coupling reagent. The reaction may be carried out in the presence of a base. Any suitable base may be used for this reaction. Examples of suitable bases include but are not limited DI PEA or TEA. Preferably, DIEA is used as the base in the reaction. The reaction may be carried out in a polar aprotic solvent such as THF, dichloromethane, ethyl acetate, DMF or DMSO. Preferably the reaction is carried out in DMSO.

[0537] The reaction may be performed at a temperature in the range of about 10°C to about 40°C, more preferably in the range of about 15 °C to about 40°C. The reaction time may be in the range of about 10 hours to about 30 hours, more preferably about 15 hours to about 20 hours.

[0538] The intermediates h1 to h10 may be an isomer such as 1S,4S,5R stereoisomer.

[0539] Preferably, the intermediates h1 to h10 are selected from:

[0540] tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h1);

[0541] tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h2);

[0542] tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h3);

[0543] tert-butyl (1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h4);

[0544] tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h5);

[0545] tert-butyl (1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h6);

[0546] tert-butyl (1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h7);

[0547] tert-butyl (1S,4S,5R)-5-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h8)

[0548] tert-butyl (1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h9); or

[0549] tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h10).

[0550] The intermediates i1 to i10 may be an isomer such as 1S,4S,5R stereoisomer.

[0551] Preferably, the intermediates i1 to i10 are selected from:(1S,4S,5R)-N-(5-(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1);

[0552] (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2); (1S,4S,5R)-N-(5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i3);

[0553] (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4);

[0554] (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5);

[0555] (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6);

[0556] (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7);

[0557] 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8);

[0558] (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9); or

[0559] (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10).

[0560] Suitable carboxylic acid R-COOH used in the method may be selected from the group consisting of:

[0561] 3-fluoro-2-pyrimidin-2-yl-benzoic acid (RCOOH1) (CAS 1293285-04-7);

[0562] 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (RCOOH2);

[0563] 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) (CAS 2125741-56-0);

[0564] 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4);

[0565] 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5);

[0566] 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6);

[0567] 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (RCOOH7) (CAS 1861694-10-1);

[0568] 5-methyl-2-(pyrimidin-2-yl)benzoic acid (RCOOH8) (CAS 1088994-22-2);

[0569] 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) (CAS 1228431-05-7);

[0570] 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) (CAS 1228188-37-1);

[0571] 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) (CAS 1228188-18-8); and

[0572] 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH12). Synthesis of (RCOOH) carboxylic acids

[0573] The present invention provides a method for synthesizing 4-(5-fluoropyridin-2-yl)-1,5-dimethyl- 1H-pyrazole-3-carboxylic acid (RCOOH2) as shown in the synthetic pathway below.

[0574] OH

[0575]

[0576] In a first step, the carboxylic acid group of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid may be protected to form a first intermediate. Any suitable protecting group may be used. Examples of suitable protecting groups that may be used include Me, Boc or benzyl. Preferably, Boc is used as the protecting group. The Boc protection reagents and conditions may use standard BOC2O and DMAP chemistry. The reaction may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C.

[0577] The first intermediate may be converted into a boronic acid or a derivative thereof (for example boronic esters or organotrifluoroborate salts) to form a second intermediate. The first intermediate may be reacted with a tri(alkyl)borate such as trimethylborate, tributylborate or triisopropylborate to form the second intermediate. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction is carried out in the presence of a Lewis base. Preferably, the Lewis base used in the synthesis of the second intermediate is butyl lithium. The reaction may be carried out at a temperature b in the range of about -78°C to about 60°C. Preferably, the reaction is carried out at about -78°C to about 20°C.

[0578] The second intermediate may be reacted with may be reacted with 2-bromo-5-fluoro-pyrimidine or2-iodo-5-fluoro-pyrimidine or2-chloro-5-fluoro-pyrimidine, via Suzuki coupling to form a third intermediate. Alternatively, 2-bromo-5-fluoro-pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine may be reacted with (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling. The reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof; in a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, or any combination thereof. Preferably the reaction is carried out in a combination of DMF and water.

[0579] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compoundr More preferably, Pd(PPh3)4 is used as the catalyst. The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KO‘Bu, CS2CO3, K3PO4, NaOH, or NEts. Preferably, K2CO3 is used. The base may be used in excess with respect to the second intermediate.

[0580] The reaction may be carried out at a temperature in the range of about 50°C to about 153°C, preferably, at about 80°C. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0581] The third intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably hydrochloric acid is used. The deprotection may be carried out in the presence of a solvent which may be a polar or a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane. The deprotection may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0582] The carboxylic acid RCOOH2 may then be isolated. The isolation step may comprise an acidic workup. The acidic workup may comprise HCI as a reagent.

[0583] The present invention provides a method for synthesizing 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) as shown in the synthetic pathway below. OH

[0584]

[0585] RCOOH4

[0586] In a first step, the Br of 5-bromo-2,4-dimethylpyridine was substituted with an unsubstituted 1,2,3-triazole. Preferably, this first step takes place via a nucleophilic aromatic substitution reaction. Preferably, the reaction comprises reagents comprising an excess of 1H-1,2,3-triazole and (1R,2R)-N1, N2-dimethylcyclohexane-1,2-diamine. Preferably, the reaction additionally comprises K2CO3 and Cu in NMP The reaction may be carried out at a temperature in the range of about 80 °C to about 150 °C. Preferably, the reaction temperature is about 100 °C to about 140 °C.

[0587] The pyridine nitrogen may then be subject to oxidation. Preferably, the oxidising agent comprises m-CPBA. The use of m-CPBA facilitates the nucleophilic addition of a nitrile group into the pyridine ring. Preferably, incorporation of the nitrile group into the pyridine ring comprises using TMSCN in DCM. The reaction may be carried out at a temperature in the range of about 0 °C to about 50 °C. Preferably, the reaction temperature is about 0 °C to about 30 °C. The reaction may be carried out for a duration of about 0.5 hours to about 6 hours, more preferably for about 1 hour to about 4 hours.

[0588] The nitrile was then subject to hydrolysis. Preferably, the hydrolysis is base-catalysed. Basecatalysed hydrolysis of the nitrile forms the corresponding carboxylic acid RCOOH4.

[0589] Preferably, the base-catalysed hydrolysis comprises using NaOH. The reaction may be carried out at a temperature in the range of about 30 °C to about 100 °C. Preferably, the reaction temperature is about 45 °C to about 90 °C. The reaction may be carried out for a duration of about 24 hours to about 72 hours, more preferably for about 36 hours to about 60 hours. The present invention provides a method for synthesizing 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) as shown in the synthetic pathway below.

[0590]

[0591] In a first step, the Br of 5-bromo-2,4-dimethylpyridine is substituted with a pyrimidine moiety to form a first intermediate. Preferably, standard Stille reaction conditions and reagents may be used. Preferably, the coupling step comprises a suitable coupling agent such as a stannane. Preferably, the coupling step further comprises CsF, Pd(PPh3)4 and CuI.

[0592] The first intermediate (pyridine nitrogen) may then be subject to oxidation to obtain a second intermediate. The oxidation step may be carried out in the presence of a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably, the reaction is carried out in dichloromethane. Preferably, the oxidising agent comprises m-CPBA. The use of m-CPBA facilitates the nucleophilic addition of a nitrile group into the pyridine ring.

[0593] Trimethylsilyl cyanide may be added to the second intermediate in a solvent to form a nitrile. Examples of solvent may include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the solvent is dichloromethane.

[0594] The nitrile was then subject to hydrolysis. Preferably, the hydrolysis is base-catalysed. Basecatalysed hydrolysis of the nitrile forms the corresponding carboxylic acid RCOOH5. Preferably, the base-catalysed hydrolysis comprises using NaOH.

[0595] The present invention provides a method for synthesizing 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RC00H6) as shown in the synthetic pathway below. o

[0596]

[0597] RCOOH6

[0598] In a first step, the carboxylic acid moiety of 3-bromo-6-methylpicolinic acid was subject to esterification. Preferably, the esterification is acid-catalysed. Preferably, the acid-catalysed esterification comprises using an acid. Examples of acids include but are not limited to sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Preferably, the acid is sulfuric acid. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1,4-dioxane or mixtures thereof. Preferably, the solvent is methanol. The reaction may be carried out at a temperature in the range of about 40°C to about 100°C. Preferably, the reaction is carried out at about 70°C.

[0599] The resulting ester may then be coupled with a pyrimidine moiety to form a pyridine nitrogen. Preferably, the coupling is made via nucleophilic aromatic substitution reaction. Preferably, standard Stille reaction conditions and reagents may be used. Preferably, the coupling step comprises a suitable coupling agent such as a stannane. Preferably, the coupling step further comprises CsF, Pd(PPh3)4 and CuI.

[0600] The pyridine nitrogen may then be subject to oxidation. Preferably, the oxidising agent comprises m-CPBA or any other suitable agents. The use of m-CPBA facilitates the nucleophilic addition of a nitrile group into the pyridine ring. Preferably, incorporation of the nitrile group into the pyridine ring comprises using TMSCN in DCM. The reaction may be carried out at a temperature in the range of about 0 °C to about 50 °C. Preferably, the reaction temperature is about 0 °C to about 30 °C. The nitrile was then subject to ester hydrolysis. Preferably, the hydrolysis is base-catalysed. Base-catalysed hydrolysis of the ester forms the corresponding carboxylic acid (4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid). Preferably, the base-catalysed hydrolysis comprises using LiOH. Any suitable ester hydrolysis reagents and conditions may be used, for example, hydrated LiOH. The reaction may be carried out at a temperature in the range of about 10 °C to about 60 °C. Preferably, the reaction temperature is about 15 °C to about 40 °C.

[0601] The present invention provides a method for synthesizing 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) as shown in the synthetic pathway below.

[0602]

[0603] RCOOH11

[0604] In a first step, 3-bromo-6-methylpicolinonitrile may be converted to a boronate ester. The reaction may be a Pd-mediated cross-coupling reaction wherein the palladium catalyst may be PdCl2(dppf), PdCl2(PPh3)2, Pd(PPh3)4 or Pd(OAc)2. Preferably, the Pd-mediated crosscoupling reaction is performed under Miyaura borylation reaction conditions and suitable reagents may be used. Preferably, the borylation step comprises a suitable diboron agent such as a bis(pinacolato)diboron (Bpin)2. Preferably, the coupling step further comprises KOAc, Pd(OAc)2 and PPh3. The reaction may be carried out at a temperature in the range of about 40 °C to about 120 °C. Preferably, the reaction temperature is about 75 °C to about 85 °C.

[0605] In next stage, the boronate moiety of 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile is replaced with a heteroaromatic moiety. Preferably, a Suzuki coupling reaction is used to replace the boronate moiety with a heteroaromatic moiety. Preferably, the heteroatomatic moiety comprises pyrimidine. The reaction may be carried out at a temperature in the range of about 40 °C to about 120 °C. Preferably, the reaction temperature is about 75 °C to about 85 °C.

[0606] The nitrile was then subject to hydrolysis. The hydrolysis may be base-catalysed. Basecatalysed hydrolysis forms the corresponding carboxylate (6-methyl-3-(pyrimidin-2-yl)picolinate). Any suitable hydrolysis reagents and conditions may be used, for example, hydrated LiOH, NaOH or KOH. Preferably, the base-catalysed hydrolysis comprises using NaOH. The reaction may be carried out at a temperature in the range of about 40 °C to about 100 °C. Preferably, the reaction temperature is about 75 °C to about 85 °C.

[0607] RCOOH11 may then obtained via pH adjustment by acidification. Preferably, the pH adjustment is made under acidic conditions until pH 2 - 3. Preferably, the pH adjustment comprises using HCI (12% in EtOH) as a reagent. The reaction may be carried out at a temperature in the range of about 0 °C to about 50 °C. Preferably, the reaction temperature is about 20 °C to about 30 °C.

[0608] The present invention provides a method for synthesizing 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (RC00H12) as shown in the synthetic pathway below.

[0609]

[0610] In a first step, the boronic acid moiety of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yljboronic acid is replaced with a heteroaromatic moiety. Preferably, a Suzuki coupling reaction is used to replace the boronic acid moiety with a heteroaromatic moiety. Preferably, the heteroatomatic moiety comprises methoxypyridine. The reaction may be carried out at a temperature in the range of about 40 °C to about 120 °C. Preferably, the reaction temperature is about 60 °C to about 100 °C.

[0611] RCOOH12 was then obtained via Boc-deprotection. Preferably, the Boc-deprotection is made under acidic conditions. Preferably, the Boc-deprotection comprises using HCI as a reagent. The reaction may be carried out at a temperature in the range of about 10 °C to about 50 °C. Preferably, the reaction temperature is about 15 °C to about 40 °C.

[0612] EXAMPLES

[0613] The present invention is further described with reference to the following examples, which are not provided to limit the scope of the present invention.

[0614] I. General Synthetic Methods and Procedures o o [lr(DF(CF3)ppy)2(dtbbpy)]PF61.1 eq 600 W, 450 nm blue light TsOH (0.1 eq) MeCN (40 V) DCM (20 V) 50°C, RT=25 mins 50°C, 16 hrs flow chemistry

[0615] DPPA (1.5 eq) DIEA (2.2 eq) HN-Cbz 5 wt% NaOCI (7 eq) chemical resolution BnOH (3 eq) THF (5 V) toluene (20 V) 35°C, 1 hr 100°C, 16 hrs Boc e f

[0616] HN-Het HN-Het Pd / C, H2(15 Psi) Het-Hal HCI / dioxane EtOAc (20 V) DIEA (5 eq) i 20°C, 1 hr 20°C, 16 hrs Boc DMSO (20 V) Boc H 140°C, 16 hrs h1-h10 i1-i10

[0617] RCOOH

[0618] PyAOP (1.1 eq)

[0619]

[0620] DIEA (2 eq)

[0621] DCM (20 V)

[0622] 20°C, 2 hrs 1 -81

[0623] PREPARATION OF INTERMEDIATES (b) - (g)

[0624] Example 1: Synthesis of tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (intermediate b)

[0625] O O

[0626] 1.1 eq TsOH (0.1 eq)

[0627] DCM (20 V)

[0628]

[0629] 50°C, 16 hrs

[0630] To a solution of tert-butyl allylcarbamate (a) (50 g, 318.05 mmol, 1 eq) in DCM (1000 mL) was added TsOH.H₂O (6.05 g, 31.80 mmol, 0.1 eq) and 4,4-dimethoxybutan-2-one (46.24 g, 349.85 mmol, 46.42 mL, 1.1 eq) at 20°C and the reaction was stirred at 50°C for 16 hours. LCMS showed the product with desired mass was detected. The reaction solution was poured into water (2000 mL), extracted with dichloromethane (3 x 1000 mL), the combined organic layer was washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate= 3:1) to give tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (intermediate b) (47 g, 198.19 mmol, 62.32% yield, 95% purity) as a colorless oil.

[0631] 1H NMR (400 MHz, DMSO-d6): 6 = 8.00 (d, J=14.43 Hz, 1 H), 5.76 (ddt, J=17.18, 10.34, 5.07, 5.07 Hz, 1 H), 5.63 (d, J=14.43 Hz, 1 H), 4.98 - 5.22 (m, 2 H), 4.11 - 4.22 (m, 2 H), 2.14 (s, 3 H) 1.48 (s, 9 H).

[0632] Example 2: Synthesis of tert-butyl rac-5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate c)

[0633] [lr(DF(CF3)ppy)2(dtbbpy)]PF6

[0634] 600 W, 450 nm blue light MeCN (40 V) 50°C, RT=25 mins

[0635]

[0636] flow chemistry

[0637] To a solution of tert-butyl (E)-allyl(3-oxobut-1-en-1-yl)carbamate (intermediate b) (47 g, 198.19 mmol, 1 eq) in CH3CN (1880 mL) was added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1 +);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate (2.22 g, 1.98 mmol, 0.01 eq) at 25°C under N2. The reaction solution was flowed through reactor coil heated to 50°C at 2 mL / min (RT=25mins, hv=450 nm, 600 W). LCMS showed the product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate= 3:1) and concentrated under reduced pressure to give tert-butyl rac- 5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate c) (30 g, 119.85 mmol, 60.47% yield, 90% purity) as a yellow oil.

[0638] 1H NMR (400 MHz, DMSO-d6): 5 = 4.48 (brs, 1 H), 3.13 - 3.28 (m, 1 H), 3.09 (br s, 1 H), 2.89 - 3.01 (m, 2 H), 1.99 (s, 3 H), 1.67 - 1.80 (m, 1 H), 1.28 - 1.48 (m, 9 H), 1.09 - 1.22 (m, 1 H).

[0639] LCMS (ESI+): m / z = 170.1 (M-56), RT: 0.402 min (The column used for chromatography was a Halo C183.0 x 30 mm, 5 urn. Detection method is diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10-100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL / min.)

[0640] Example 3: Synthesis of rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate d) 5 wt% NaOCI (7 eq)

[0641] THF (5 V)

[0642] 35°C, 1 hr

[0643]

[0644] To a solution of tert-butyl rac- 5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate c) (30 g, 119.85 mmol, 1 eq) in THF (150 mL) was added NaOCI (1.25 kg, 838.94 mmol, 1.04 L, 5% w / w, 7 eq) at 25°C. The mixture was stirred at 35°C for 1 hour. LCMS showed the product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (200 mL) and adjusted to pH 3 with 1 N aq. HCI and the mixture was extracted with ethyl acetate (200 mL x 3), the combined organic layer was washed with brine (200 mLx 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether and ethyl acetate (300 ml, 5:1) at20°Cfor 16 hours. The mixture was filtered and filter cake was dried in vacuum to give rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate d) (22 g, 91.97 mmol, 76.74% yield, 95% purity) as a white solid.

[0645] 1H NMR (400 MHz, CHLOROFORM-d): 5 = 9.76 - 10.50 (m, 1 H), 4.58 (br s, 1 H), 3.59 (br d, J=8.76 Hz, 1 H), 3.26 (d, J=8.88 Hz, 1 H), 2.94 - 3.17 (m, 1 H), 2.80 (br s, 1 H), 1.80 (br d, J=7.25 Hz, 1 H), 1.46 (s, 9 H), 1.34 (d, J=7.38 Hz, 1 H).

[0646] LCMS (ESI+): m / z = 172.1 (M-56), RT: 0.358 min.

[0647] Example 4: Synthesis of fS,4 / ?,5 / ?9-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1] hexane-5-carboxylic acid (intermediate e)

[0648]

[0649] To a solution of rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate d) (22 g, 91.97 mmol, 1 eq) in THF (330 mL) was added (1S)-1-phenylethanamine (10.48 g, 86.45 mmol, 11.00 mL, 0.94 eq) at 20°C and the reaction was stirred at 20°C for 16 hours. A white slurry was gradually formed. The reaction was filtered and filter cake dried in vacuum to give the salt. The recrystallized salt was partitioned between ethyl acetate (400 mL) and H2O (400 mL). The mixture was adjusted to pH 2.5 with 1 N aq. HCI. The mixture was extracted with ethyl acetate (300 mLx 5), the combined organic layer was washed with brine (300 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give (7S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate e) (12.1 g, 50.58 mmol, 55.00% yield, 95% purity) as a white solid.

[0650] 1H NMR (400 MHz, CHLOROFORM-d): 5 = 4.44 - 4.86 (m, 2 H), 3.58 (br d, J=8.76 Hz, 1 H), 3.26 (d, J=8.88 Hz, 1 H), 2.97 - 3.13 (m, 1 H), 2.81 (br s, 1 H), 1.75 - 1.85 (m, 1 H), 1.46 (s, 9 H), 1.34 (d, J=7.50 Hz, 1 H).

[0651] LCMS (ESI+): m / z = 172.1 (M-56), RT: 0.362 min.

[0652] SFC RT: 1.825 min (The column used for chromatography was Chiralcel AD-3, 150x4.6mm, 3um. Detection method was diode array (DAD). Mobile phase A was CO2, and mobile phase B was 0.2%NH₃ (7M in MeOH) in 2-propanol, v / v. The gradient was a hold of 10% B for 0.50 min, 10% to 50% B in 3 min, a hold at 50% B for 1 min, 50% to 10% B in 0.5 min. The flow rate was 2.5 mL / min. The column temperature was 35°C.)

[0653] Example 5: Synthesis of tert-butyl (7S,4S,5 / ?)-5-(((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate f)

[0654] DPPA (1.5 eq)

[0655] DIEA (2.2 eq) HN-Cbz

[0656] BnOH (3 eq)

[0657] toluene (20 V) i

[0658] Boc

[0659]

[0660] 100°C, 16 hrs

[0661] e f

[0662] To a solution of (7S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (intermediate e) (8.9 g, 37.20 mmol, 1 eq) in toluene (180 mL) was added DIEA (10.58 g, 81.85 mmol, 14.26 mL, 2.2 eq), DPPA (15.36 g, 55.81 mmol, 12.05 mL, 1.5 eq) and BnOH (12.07 g, 111.61 mmol, 11.56 mL, 3 eq) at 20°C. The mixture was stirred at 100°C for 16 hrs. LCMS showed the starting material was consumed and the product with desired mass was detected. The reaction solution was poured into water (200 mL), extracted with ethyl acetate (3 x 200 mL), the combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate= 3:1) and concentrated under reduced pressure to give tert-butyl (1S,4S,5R)-5-(((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate f) (5 g, 15.04 mmol, 40.43% yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6): 6 = 7.18 - 7.57 (m, 6 H), 4.84 - 5.14 (m, 2 H), 4.15 (br d, J=6.63 Hz, 1 H), 3.49 (br s, 1 H), 3.36 - 3.42 (m, 1 H), 3.05 (br s, 1 H), 2.61 - 2.83 (m, 1 H), 1.57 (br d, J=7.00 Hz, 1 H), 1.24 - 1.49 (m, 9 H), 1.13 (brs, 1 H).

[0663] Example 6: Synthesis of tert-butyl (lS,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g)

[0664] HN-Cbz NH2

[0665] Pd / C, H2(15 Psi)

[0666] N EtOAc (20 V) N

[0667]

[0668] Boc 20°C, 16 hrsBoc

[0669] f g

[0670] To a suspension of Pd / C (1.60 g, 1.50 mmol, 10% purity, 0.1 eq) in ethyl acetate (100 mL) was added tert-butyl ( 7S,4S,5R)-5-(((benzyloxy)carbonyl)amino)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate (intermediate f) (5 g, 15.04 mmol, 1 eq) at 20°C. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20°C for 16 hours. LCMS showed the starting material was consumed and the product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give tert-butyl (1S,4S, 5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) (2.5 g, 11.35 mmol, 75.44% yield, 90% purity) as a colorless oil.

[0671] 1H NMR (400 MHz, CHLOROFORM-d): 5 = 4.08 (q, J=7.15 Hz, 1 H), 3.18 (br s, 2 H), 3.04 (dd, J=2.64, 1.88 Hz, 1 H), 2.47 - 2.61 (m, 1 H), 1.41 - 1.49 (m, 9 H), 1.30 - 1.40 (m, 3 H), 1.09 (d, J=8.03 Hz, 1 H).

[0672] PREPARATION OF INTERMEDIATES h1-h10

[0673] HN— Het

[0674] Het-Hal

[0675] DIEA (5 eq)

[0676] Boc Boc

[0677] DMSO (20 V)

[0678]

[0679] 140°C, 16 hrs h1-h10

[0680] Example 7: Synthesis of tert-butyl (lS,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h1). General Procedure 1

[0681]

[0682] Boch1

[0683] To a solution of tert-butyl (7S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) (0.2 g, 958.33 pmol, 1 eq) in DMSO (4 mL) was added DIEA (619.28 mg, 4.79 mmol, 834.62 pL, 5 eq) and 2-fluoro-5-(trifluoromethyl)pyridine (Het-Hal1) (237.31 mg, 1.44 mmol, 1.5 eq) at 20°C and stirred at 140°C for 16 hours. LCMS showed the starting material was consumed and the product with desired mass was detected. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (3 x 20 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 30% to give tert-butyl ( 7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h1) (0.25 g, 655.32 pmol, 68.38% yield, 90% purity) as a yellow solid.

[0684] 1H NMR (400 MHz, CHLOROFORM-d): 5 = 8.34 (s, 1 H), 7.59 (dd, J=8.82, 2.31 Hz, 1 H), 6.42 (d, J=8.88 Hz, 1 H), 4.98 (brs, 1 H), 4.41 (brs, 1 H), 3.94 (brs, 1 H), 3.11 - 3.47 (m, 2 H), 2.84 - 3.03 (m, 1 H), 1.68 (dt, J=8.16, 1.42 Hz, 1 H), 1.44 (br s, 9 H), 1.32 (d, J=8.25 Hz, 1 H). LCMS (ESI+): m / z = 344.1 (M+1), RT: 0.485 min (The column used for chromatography was a Halo C18 3.0 x 30 mm, 5 urn. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10-100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL / min.)

[0685] Example 8: Synthesis of tert-butyl (7S,4S,5 / ?)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h2)

[0686]

[0687] Boch2

[0688] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2-chloro-5- (trifluoromethyl)pyrimidine (Het-Hal2) to give the title compound tert-butyl (7S,4S,5R)-5-((5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h2). Yield 69%, yellow solid.

[0689] 1H NMR (400 MHz, CHLOROFORM-d): 6 = 8.51 (br d, J=10.88 Hz, 2 H), 5.66 (br d, J=5.88 Hz, 1 H), 4.42 (br s, 1 H), 4.15 (br d, J=7.38 Hz, 1 H), 3.13 - 3.48 (m, 2 H), 2.86 - 3.02 (m, 1 H), 1.69 (br dd, J=8.25, 1.38 Hz, 1 H), 1.47 (br s, 9 H), 1.31 (d, J=8.25 Hz, 1 H).

[0690] Example 9: Synthesis of tert-butyl (lS,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h3)

[0691]

[0692] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2-chloro-5-(trifluoromethyl)pyrazine (Het-Hal3) to give the title compound tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h3). Yield 99%, red solid.

[0693] 1H NMR (400 MHz, CHLOROFORM-d): δ 8.34 (s, 1 H), 7.92 (d, J=0.88 Hz, 1 H), 5.18 (br d, J=5.50 Hz, 1 H), 4.36 - 4.49 (m, 1 H), 4.04 (br d, J=2.75 Hz, 1 H), 3.36 (br d, J=9.01 Hz, 1 H), 3.13 - 3.29 (m, 1 H), 2.93 - 3.04 (m, 1 H), 1.72 (dt, J=8.29, 1.55 Hz, 1 H), 1.46 (brs, 9 H), 1.36 (d, J=8.38 Hz, 1 H).

[0694] Example 10: Synthesis of tert-butyl (1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h4)

[0695]

[0696] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2,3-difluoro-5-(trifluoromethyl)pyridine (Het-Hal4) to give the title compound tert-butyl (1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h4). Yield 58%, yellow solid.1H NMR (400 MHz, DMSO-d6): 6 = 8.24 (br s, 1 H), 7.79 (br d, J=11.13 Hz, 1 H), 7.13 - 7.46 (m, 1 H), 4.26 - 4.48 (m, 1 H), 3.59 - 3.82 (m, 1 H), 3.53 (br d, J=8.63 Hz, 1 H), 3.00 - 3.21 (m, 1 H), 2.75 - 2.93 (m, 1 H), 1.71 (br d, J=6.75 Hz, 1 H), 0.95 - 1.36 (m, 10 H).

[0697] Example 11: Synthesis of tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h5)

[0698]

[0699] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S, 5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine (Het-Hal5) to give tert-butyl (7S,4S,5R)-5-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh5). Yield 63%, yellow solid.

[0700] 1H NMR (400 MHz, DMSO-d6): 5 = 8.42 (br s, 1 H), 8.13 (d, J=1.88 Hz, 1 H), 6.25 - 6.71 (m, 1 H), 4.38 (br d, J=6.63 Hz, 1 H), 3.58 - 3.89 (m, 1 H), 3.34 - 3.45 (m, 1 H), 3.03 - 3.23 (m, 1 H), 2.80 - 2.96 (m, 1 H), 1.71 (br d, J=7.50 Hz, 1 H), 0.96 - 1.42 (m, 10 H).

[0701] To a solution of tert-butyl (7S,4S,5R)-5-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh5) (0.45 g, 959.17 pmol, 1 eq) and methylboronic acid (172.25 mg, 2.88 mmol, 3 eq) in dioxane (8 mL) and H2O (2 mL) was added Na2COs (203.32 mg, 1.92 mmol, 2 eq) at 20°C. Then dichloropalladium triphenylphosphane (67.32 mg, 95.92 pmol, 0.1 eq) was added to the above mixture at 20°C under N2. The mixture was stirred at 100°C for 16 hours. LCMS showed the starting material was consumed and the product with desired mass was detected. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (3 x 20 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give a residue which was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate= 2:1) to give the title compound tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h5) (0.21 g, 528.86 pmol, 55.14% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6): 6 = 8.23 (br s, 1 H), 7.52 (s, 1 H), 6.31 (br s, 1 H), 4.36 (br d, J=6.02 Hz, 1 H), 3.65 (br s, 1 H), 3.52 (br d, J=8.53 Hz, 1 H), 3.01 - 3.23 (m, 1 H), 2.86 (br s, 1 H), 2.06 (br s, 3 H), 1.70 (br d, J=6.65 Hz, 1 H), 0.96 - 1.42 (m, 10 H).

[0702] LCMS (ESI+): m / z = 358.1 (M+1), RT: 0.482 min.

[0703] Example 12: Synthesis of tert-butyl (lS,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h6)

[0704] F

[0705]

[0706] Boch6

[0707] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S, 5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2-chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine (Het-Hal6) to give the title compound tert-butyl (1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h6). Yield 39%, yellow solid.

[0708] 1H NMR (400 MHz, DMSO- cfe): 6 = 8.56 (br s, 1 H), 7.91 (s, 1 H), 6.42 - 7.40 (m, 2 H), 4.40 (br d, J=4.88 Hz, 1 H), 3.63 - 3.94 (m, 1 H), 3.38 (br d, J=9.26 Hz, 1 H), 3.07 - 3.29 (m, 1 H), 2.89 (br d, J=2.13 Hz, 1 H), 1.71 (br d, J=6.75 Hz, 1 H), 0.98 - 1.39 (m, 9 H).

[0709] Example 13: Synthesis of tert-butyl {1 S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h7)

[0710]

[0711] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S, 5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine (Het-Hal7) to give the title compound tert-butyl (7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate (intermediate h7). Yield 54%, yellow solid.1H NMR (400 MHz, DMSO-d6): 5 = 7.87 - 8.05 (m, 1 H), 7.09 - 7.31 (m, 1 H), 4.18 - 4.48 (m, 1 H), 3.79 - 3.92 (m, 3 H), 3.73 (br d, J=8.25 Hz, 1 H), 3.38 - 3.60 (m, 1 H), 2.91 - 3.21 (m, 1 H), 2.71 - 2.90 (m, 1 H), 1.49 - 1.78 (m, 1 H), 1.01 - 1.41 (m, 11 H).

[0712] Example 14: Synthesis of tert-butyl (lS,4S,5R)-5-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h8)

[0713]

[0714] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S, 5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2-chloro-5-(trifluoromethyl)nicotinonitrile (Het-Hal8) to give the title compound tert-butyl (7S,4S,5R)-5-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate (intermediate h8). Yield 64%, yellow solid.

[0715] 1H NMR (400 MHz, DMSO-d6): 6 = 8.67 (br s, 1 H), 8.44 (br s, 1 H), 7.52 - 7.86 (m, 1 H), 4.40 (br s, 1 H), 3.57 - 3.79 (m, 1 H), 3.37 - 3.52 (m, 1 H), 3.02 - 3.24 (m, 1 H), 2.78 - 2.98 (m, 1 H), 1.71 (br d, J=6.38 Hz, 1 H), 0.95 - 1.42 (m, 10 H).

[0716] Example 15: Synthesis of tert-butyl (lS,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h9)

[0717]

[0718] General Procedure 1 (see Example 7) was repeated using tert-butyl (1 S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (Het-Hal9) to give the title compound tert-butyl (1S,4S,5R)-5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh9), yield 52%, white solid.1H NMR (400 MHz, CDCl3): δ ppm 8.31-8.56 (m, 1 H), 5.77 (br d, J = 4.8 Hz, 1 H), 4.06-4.49 (m, 2 H), 3.13-3.50 (m, 2 H), 2.96 (brs, 1 H), 1.53-1.75 (m, 4 H), 1.47 (brs, 9 H), 1.32 (brd, J = 8.3 Hz, 1 H).

[0719] A mixture of tert-butyl (1S,4S,5R)-5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh9) (100 mg, 264.01 pmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (165.71 mg, 1.32 mmol, 184.53 pL, 5 eq), Pd(PPh3)2Cl2(18.53 mg, 26.40 pmol, 0.1 eq) and K2CO3 (109.46 mg, 792.02 pmol, 3 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with argon for 3 times, and then the mixture was stirred at 100°C for 1 hour under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, Petroleum ether: EtOAc = 10:1) to give the title compound tert-butyl (1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h9) (90 mg, 251.15 pmol, 95.13% yield) as a white solid.

[0720] 1H NMR (400 MHz, CDCl3): δ ppm 8.24-8.54 (m, 1 H), 5.55 (br d, J = 6.3 Hz, 1 H), 4.40 (br s, 1 H), 4.17 (brd, J = 5.6 Hz, 1 H), 3.18-3.37 (m, 2 H), 2.83-3.02 (m, 1 H), 2.47 (brs, 3 H), 1.62-1.71 (m, 2 H), 1.22-1.34 (m, 10 H).

[0721] Example 16: Synthesis of tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h10)

[0722]

[0723] To a solution of 5-(trifluoromethyl)pyrazin-2-ol (Het-Hal10) (120 mg, 706.14 pmol, 1.4 eq) in DMF (2.4 mL) was added DBU (230.36 mg, 1.51 mmol, 228.08 pL, 3 eq), then BOP (334.62 mg, 756.58 pmol, 1.5 eq) was added in portions at 0°C. The mixture was stirred at 25°C for 0.5 hours. Then tert-butyl (7S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate g) (100 mg, 504.38 pmol, 1 eq) was added to the mixture at 25°C. The mixture was stirred at 25°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was purified by reversed phase HPLC (0.1% FA condition) to give a crude product (75% purity). The crude product was further purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 5% to 30% to give the title compound tertbutyl (7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2- azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h10) (80 mg, 223.24 pmol, 44.26% yield) as a yellow solid.

[0724] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.35 (s, 1 H), 7.06 (br s, 1 H), 4.39 (br d, J=6.63 Hz, 1 H), 3.47 - 3.72 (m, 2 H), 3.27 - 3.32 (m, 1 H), 3.08 - 3.20 (m, 1 H), 2.90 (br d, J=2.75 Hz, 1 H), 2.26 - 2.37 (m, 3 H), 1.74 (br d, J=6.63 Hz, 1 H), 1.22 - 1.45 (m, 3 H), 0.98 (s, 6 H).

[0725] PREPARATION OF INTERMEDIATES i1-i10

[0726] HN-Het HN-Het

[0727] HCI / dioxaner, — (

[0728] 20°C, 1 hr N

[0729]

[0730] Boc H

[0731] h

[0732] Example 17: Synthesis of (1S,4S, 5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1). General Procedure 2.

[0733]

[0734] H i1

[0735] A solution of tert-butyl (7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h1) (0.25 g, 655.32 pmol, 1 eq) in HCI / dioxane (2.5 mL) was stirred at 20°C for 1 hour. LCMS showed the starting material was consumed and the product with desired mass was detected. The residue was diluted with water (10 mL) and adjusted to pH 8 with saturated aqueous NaHCOs. The mixture was extracted with ethyl acetate (3 x 20 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give the title compound (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) (0.16 g, 592.04 pmol, 90.34% yield, 90% purity) as a yellow solid.

[0736] LCMS (ESI+): m / z = 244.1 (M+1), RT: 0.306 min (The column used for chromatography was a Halo C18 3.0 x 30 mm, 5 urn. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10-100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL / min.) Example 18: Synthesis of (1S,4S, 5 / ?)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2). General Procedure 3

[0737]

[0738] A solution of tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h2) (0.3 g, 784.13 pmol, 1 eq) in HCI / dioxane (3 mL) was stirred at 20°C for 1 hour. LCMS showed the starting material was consumed and the product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the title compound (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2) (0.2 g, 641.31 pmol, 81.79% yield) as a yellow solid.

[0739] 1H NMR (400 MHz, DMSO-d6): δ = 9.58 (br s, 1 H), 8.82 (br s, 1 H), 8.73 (s, 2 H), 8.35 (d, J=3.75 Hz, 1 H), 4.27 (d, J=5.88 Hz, 1 H), 3.33 - 3.46 (m, 1 H), 3.14 - 3.29 (m, 1 H), 2.97 (dt, J=5.82, 2.85 Hz, 1 H), 1.85 (br d, J=8.38 Hz, 1 H), 1.39 (d, J=9.26 Hz, 1 H).

[0740] Example 19: Synthesis of (7S,4S,5 / ?)-N-(5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i3)

[0741]

[0742] i3

[0743] General Procedure 2 (see Example 17) was repeated using tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h3) to give the title compound (7S,4S, 5R)-N-(5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i3). Yield 98%, yellow solid.

[0744] LCMS (ESI+): m / z =245.6 (M+1), RT: 0.294 min

[0745] Example 20: Synthesis of (7S,4S,5 / ?)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4)

[0746]

[0747] General Procedure 2 (see Example 17) was repeated using tert-butyl (1 S,4S, 5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h4) to give the title compound (7S,4S, 5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4). Yield 79%, yellow solid.

[0748] LCMS (ESI+): m / z = 262.0 (M+1), RT: 0.315 min.

[0749] Example 21: Synthesis of (7S,4S,5 / ?)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5)

[0750]

[0751] H i5

[0752] General Procedure 2 (see Example 17) was repeated using tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h5) to give the title compound (7S,4S, 5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5). Yield 99%, yellow solid.

[0753] LCMS (ESI+): m / z = 258.1 (M+1), RT: 0.316 min.

[0754] Example 22: Synthesis of (lS,4S,5 / ?)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6)

[0755]

[0756] General Procedure 2 (see Example 17) was repeated using tert-butyl (1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h6) to give the title compound (7S,4S,5R)-N-(3-(difluoromethyl)-5- (trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6). Yield 70%, yellow solid.

[0757] LCMS (ESI+): m / z = 294.0 (M+1), RT: 0.334 min.

[0758] Example 23: Synthesis of (lS,4S,5 / ?)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) oZ

[0759]

[0760] General Procedure 2 (see Example 17) was repeated using tert-butyl (7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate (intermediate h7) to give the title compound ( 7S,4S, 5R)-N-(3-methoxy-5- (trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7). Yield 44%, yellow solid.

[0761] LCMS (ESI+): m / z = 274.0 (M+1), RT: 0.314 min.

[0762] Example 24: Synthesis of 2-(((lS,4S,5 / ?)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8)

[0763]

[0764] General Procedure 2 (see Example 17) was repeated using tert-butyl (1 S,4S, 5R)-5-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h8) to give the title compound 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8). Yield 74%, yellow solid.

[0765] LCMS (ESI+): m / z = 269.1 (M+1), RT: 0.317 min.

[0766] Example 25: Synthesis of (lS,4S,5 / ?)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9)

[0767]

[0768] General Procedure 3 (see Example 18) was repeated using tert-butyl (7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate (intermediate h9) to give the title compound (1S,4S, 5R)-N-(4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9). Yield 89%, white solid.

[0769] LCMS (ESI+): m / z =259.1 (M+1), RT: 0.233 min.

[0770] Example 26: Synthesis of (lS,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10)

[0771]

[0772] General Procedure 3 (see Example 18) was repeated using tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h10) to give the title compound (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10). Yield 90%, white solid.

[0773] LCMS (ESI+): m / z =258.9 (M+1), RT: 0.270 min.

[0774] PREPARATION OF CARBOXYLIC ACIDS (RCOOH): EXPERIMENTAL PROCEDURES Example 27: Synthesis of 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2)

[0775]

[0776] To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (10 g, 46.65 mmol, 1 eq) in THF (50 mL) and t-BuOH (50 mL) was added DMAP (557.75 mg, 4.57 mmol, 0.1 eq) and tert-butoxycarbonyl tert-butyl carbonate (29.89 g, 136.96 mmol, 3 eq) at20°C, then the mixture was stirred at 20°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was diluted with water (300 mL) and extracted with dichloromethane (300 mLx 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, yield 27.86%) as a white solid.

[0777] 1H NMR (400 MHz, DMSO-d6): δ ppm 3.84 (s, 3.00 H) 2.25 (s, 3.00 H) 1.51 (s, 9.00 H). To a solution of tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, 12.72 mmol, 1 eq) and triisopropyl borate (3.59 g, 19.08 mmol, 4.39 mL, 1.5 eq) in THF (70 mL) was added n-BuLi (1.22 g, 19.08 mmol, 1.5 eq) dropwise at -78°C, then the mixture was stirred at -78°C for 1 hour. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched by addition saturated ammonium chloride solution (50 mL) at 0°C, and then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether: ethyl acetate (50 mL, 10:1) at 20°C for 30 minutes, the mixture was filtered and the filter cake was dried in high vacuum to give (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (2.52 g, yield 82.52%) as a white solid.

[0778] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.49 (s, 2.00 H) 3.79 (s, 3.00 H) 2.41 (s, 3.00 H) 1.53 (s, 9.00 H).

[0779] To a mixture of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (2.5 g, 10.41 mmol, 1 eq) in DMF (37.5 mL) was added 2-bromo-5-fluoro-pyridine (2.75 g, 15.62 mmol, 1.5 eq) and then a solution of K2CO3 (2.16 g, 15.62 mmol, 1.5 eq) in H2O (7.5 mL) was added at 20°C. The vessel was evacuated and backfilled with argon (this process was repeated three times), the palladiumtriphenylphosphane (601.70 mg, 520.70 pmol, 0.05 eq) was added into the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times), then the mixture was stirred at 80°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (2.51 g, yield 82.73%) as a light-yellow solid.

[0780] LCMS (ESI+): m / z =292.0 (M+1), RT: 0.417 min.

[0781] A solution of tert-butyl 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (2.5 g, 8.58 mmol, 1 eq) in HCI / dioxane (4 M, 50 mL) was stirred at 20°C for 12 hours. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the title compound 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) (2.3 g, yield 98.65%, HCI) as a white solid.

[0782] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.62 (d, J=2.88 Hz, 1.00 H) 7.79 (td, J=8.76, 3.00 Hz, 1.00 H) 7.58 (dd, J=8.82, 4.57 Hz, 1.00 H) 3.85 (s, 3.00 H) 2.27 (s, 3.00 H).

[0783] Example 28: Synthesis of 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4)

[0784] H N

[0785] H (0.25 eq) m-CPBA (1.5 eq) 1H-1,2,3-triazole (5 eq) DCM (20 V)

[0786]

[0787] K2CO3(1 eq) 0-20°C, 2 hrs Cu (1 eq)

[0788] NMP (10 V)

[0789] 120°C, 12 hrs

[0790] TMSCN (3 eq) OH

[0791] DMCI (1.5 eq) NaOH (3 eq)

[0792] DCM (10 V) MeOH (10 V)

[0793]

[0794] 20°C, 17 hrs

[0795]

[0796] H2O (10 V)

[0797]

[0798] 60°C, 48 hrs

[0799] RCOOH4

[0800] A mixture of 5-bromo-2,4-dimethylpyridine (6 g, 32.25 mmol, 1 eq), 1H-1,2,3-triazole (11.14 g, 161.25 mmol, 9.34 mL, 5 eq), (1R,2R)-N1, N2-dimethylcyclohexane-1,2-diamine (4.59 g, 32.25 mmol, 0.25 eq), Cu (512.33 mg, 8.06 mmol, 57.18 pL, 1 eq) and K2CO3 (4.46 g, 32.25 mmol, 1 eq) in NMP (60 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120°C for 12 hours under N2 atmosphere. The reaction was complete by TLC (Petroleum ether / Ethyl acetate= 10 / 1). The reaction mixture was diluted with H2O (500 mL), then extracted with EtOAc (500 mLx 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=1 / 0 to 20 / 1) to give 2,4-dimethyl-5-(2H-1,2,3-triazol-2-yl)pyridine (2.5 g, 13.63 mmol, 42.28% yield) as a yellow oil.

[0801] 1H NMR (400 MHz, CDCl3): δ ppm 8.68 (s, 1 H), 7.86 (s, 2 H), 7.13 (s, 1 H), 2.58 (s, 3 H), 2.37 (s, 3 H).

[0802] To a solution of 2,4-dimethyl-5-(2H-1,2,3-triazol-2-yl)pyridine (2.5 g, 13.63 mmol, 1 eq) in DCM (50 mL) was added m-CPBA (5.04 g, 20.45 mmol, 70% purity, 1.5 eq) in portions at 0°C. The mixture was stirred at 20°C for 2 hours. TLC showed the reaction was completed. The reaction mixture was quenched by addition Na2SO3 (20 mL) at 0°C and adjusted to pH=8 with sat. NaHCO3 at 0°C, then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2,4-dimethyl-5-(2H-1,2,3-triazol-2-yl)pyridine 1-oxide (2.1 g, 10.49 mmol, 76.93% yield) as a yellow solid.

[0803] 1H NMR (400 MHz, CDCl3): δ ppm 8.72 (s, 1 H), 7.88 (s, 2 H), 7.22 (s, 1 H), 2.56 (s, 3 H), 2.48 (s, 3 H).

[0804] To a solution of 2,4-dimethyl-5-(2H-1,2,3-triazol-2-yl)pyridine 1-oxide (2.1 g, 9.94 mmol, 1 eq) in DCM (21 mL) was added TMSCN (2.64 g, 26.61 mmol, 3.33 mL, 3 eq) dropwise at 20°C. After addition, the mixture was stirred at this temperature for 1 hour, then N, N-dimethylcarbamoyl chloride (1.60 g, 14.91 mmol, 1.37 mL, 1.5 eq) was added dropwise at 20°C. The resulting mixture was stirred at 20 °C for 16 hours. TLC (Petroleum ether: Ethyl acetate = 5:1) indicated reaction was completed. The reaction mixture was diluted with water (50 mL) and adjusted to pH = 8 with sat. NaHCOs at 0°C, the mixture was extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1) to give 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile (1.6 g, 7.63 mmol, 76.79% yield) as a yellow solid.

[0805] 1H NMR (400 MHz, DMSO-d6): δ ppm 7.99 (s, 2 H), 7.38 (s, 1 H), 2.66 (s, 3 H), 2.24 (s, 3 H). To a solution of 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile (600 mg, 2.86 mmol, 1 eq) in MeOH (6 mL) and H2O (6 mL) was added NaOH (343.33 mg, 8.58 mmol, 3 eq) in one portion at 25°C. The mixture was stirred at 60°C for 48 hours. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with water (10 mL) and adjusted to pH=5 with 1 N aq. HCI at 0°C, then the mixture was lyophilized to give a residue. The residue was washed with EtOAc (30 mL x 3), the combined EtOAc was concentrated under reduced pressure to give the title compound 4,6-dimethyl-3-(2H-1,2, 3-triazol-2-yl)picolinic acid (RCOOH4) (600 mg, 2.47 mmol, 86.49% yield) as a yellow solid.

[0806] 1H NMR (400 MHz, DMSO-d6): δ ppm 7.90 (s, 2 H), 7.13 (s, 1 H), 2.46 (s, 3 H), 1.89 (s, 3 H).

[0807] Example 29: Synthesis of 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5)

[0808] m-CPBA (1.5 eq) CsF (2 eq) DCM (20 V) Pd(PPh3)4(0.1 eq) 0-20°C, 2 hrs Cui (0.1 eq) Dioxane (20 V) 100°C, 16 hrs

[0809] TMSCN (3 eq) O DMCI (1.5 eq) NaOH (3 eq) DCM (10 V) MeOH (10 V)

[0810]

[0811] 20°C, 17 hrs H2O (10 V)

[0812] 60°C, 48 hrs

[0813] RCOOH5

[0814] A mixture of 5-bromo-2,4-dimethylpyridine (1.00 g, 5.37 mmol, 1 eq), tributyl(pyrimidin-2-yl)stannane (2.38 g, 6.45 mmol, 1.2 eq), CsF (1.63 g, 10.75 mmol, 2 eq), Pd(PPhs)4 (621.11 mg, 537.49 mol, 0.1 eq) and Cui (102.37 mg, 537.49 mol, 0.1 eq) in dioxane (20 mL) was degassed and purged with argon for 3 times, and then the mixture was stirred at 100°C for 16 hours under argon atmosphere. LCMS showed the reaction was completed. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 60% to afford 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 50.22% yield) as a white solid.

[0815] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=4.88 Hz, 2 H), 8.84 (s, 1 H), 7.49 (t, J=4.88 Hz, 1 H), 7.23 (s, 1 H), 2.52 (s, 3 H), 2.49 (s, 3 H).

[0816] To a solution of 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 2.70 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (822.05 mg, 4.05 mmol, 85% purity, 1.5 eq) in portions at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition Na2SO3 (20 mL) at 0°C, and then adjusted to pH=8 with NaHCO3 at 0°C, then diluted with DCM (10 mL) and extracted with DCM (10 mLx 3). The combined organic layers were washed with brine (10 mLx 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide (0.5 g, 92.05% yield) as a white solid.

[0817] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.97 (d, J=5.02 Hz, 2 H), 8.61 (s, 1 H), 7.55 (t, J=4.89 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3 H).

[0818] To a solution of 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide (0.5 g, 2.48 mmol, 1 eq) in DCM (10 mL) was added TMSCN (739.55 mg, 7.45 mmol, 932.60 pL, 3 eq), the mixture was stirred at 20°C for 1 hour, then N, N-dimethylcarbamoyl chloride (400.82 mg, 3.73 mmol, 341.99 pL, 1.5 eq) was added to the mixture, the mixture was stirred at 20°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and adjusted to pH=8 with aq. NaHCOs at 0°C, extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 30% to afford 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile (0.4 g, 76.57% yield) as a white solid.

[0819] 1H NMR (400 MHz, DMSO-d6): 5 ppm 9.06 (d, J=4.88 Hz, 2 H), 7.61 - 7.73 (m, 2 H), 2.56 (s, 3 H), 2.28 (s, 3 H).

[0820] To a solution of 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile (0.3 g, 1.43 mmol, 1 eq) in methanol (3 mL) and H2O (3 mL) was added NaOH (171.23 mg, 4.28 mmol, 3 eq), the mixture was stirred at 60°C for 48 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with water (10 mL) and adjusted to pH=5 with 1 N HCI at 0°C, then the mixture was lyophilized to give the title compound 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) (0.8 g, 85.60% yield) as a white solid.

[0821] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.89 (d, J=5.00 Hz, 2 H), 7.49 (t, J=4.88 Hz, 1 H), 7.45 (s, 1 H), 2.54 (s, 3 H), 2.20 (s, 3 H).

[0822] Example 30: Synthesis of 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) H2SO4(1 eq) m-CPBA (2 eq) MeOH (10 V) CsF (2 eq) DCM (20 V) 70°C, 16 hrs Pd(PPh3)4(0.1 eq) 0-30°C, 16 hrs Cui (0.1 eq) Dioxane (20 V) 100°C, 16 hrs

[0823] POCI3(10 V) LiOH. H2O (2 eq) 120°C, 2 hrs H2O (10 V)

[0824] MeOH (10 V) THF (10 V)

[0825]

[0826] 20°C, 16 hrs RCOOH6 To a solution of 3-bromo-6-methylpicolinic acid (5 g, 23.14 mmol, 1 eq) in MeOH (50 mL) was added H2SO4 (2.27 g, 23.14 mmol, 1.23 mL, 1 eq) at 20°C and stirred at 70°C for 16 hours. LCMS showed all the starting material was consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-bromo-6-methylpicolinate (5 g, 93.90% yield) as a yellow oil.

[0827] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 7.84 (d, J=8.25 Hz, 1 H), 7.14 (d, J=8.25 Hz, 1 H), 3.99 (s, 3 H), 2.56 (s, 3 H).

[0828] To a solution of methyl 3-bromo-6-methylpicolinate (4 g, 17.39 mmol, 1 eq), tributyl(pyrimidin-2-yl)stannane (7.70 g, 20.86 mmol, 1.2 eq) and cesium fluoride (5.28 g, 34.77 mmol, 2 eq) in dioxane (80 mL) was added iodocopper (331.13 mg, 1.74 mmol, 0.1 eq) and palladiumtriphenylphosphane (2.01 g, 1.74 mmol, 0.1 eq) at 20°C under N2. The mixture was stirred at 100°C for 16 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give methyl 6-methyl-3-(pyrimidin-2-yl)picolinate (4.1 g, 51.43% yield) as a yellow oil.

[0829] 1H NMR (400 MHz, DMSO-d6): 6 = ppm 8.91 (d, J=4.75 Hz, 2 H), 8.49 (d, J=8.13 Hz, 1 H), 7.53 - 7.55 (m, 1 H), 7.50 (br t, J=4.82 Hz, 1 H), 3.75 (s, 3 H), 2.57 (s, 3 H). To a solution of methyl 6-methyl-3-(pyrimidin-2-yl)picolinate (4.1 g, 8.94 mmol, 50% purity 1 eq) in DCM (40 mL) was added 3-chlorobenzenecarboperoxoic acid (3.63 g, 17.89 mmol, 85% purity, 2 eq) in portions at 0°C and stirred at 30°C for 16 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was quenched by addition saturated with sodium sulfite solution (50 mL) at 0°C and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate ether from 0% to 10%) to give 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1 -oxide (1.77 g, 80.71% yield) as a yellow solid.

[0830] 1H NMR (400 MHz, DMSO-d6): 5 = ppm 8.94 (d, J=4.88 Hz, 2 H), 8.23 (d, J=8.26 Hz, 1 H), 7.75 (d, J=8.38 Hz, 1 H), 7.56 (t, J=4.88 Hz, 1 H), 3.88 (s, 3 H), 2.44 (s, 3 H).

[0831] A solution of 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide (500 mg, 2.04 mmol, 1 eq) in POCh (5 mL) was stirred at 120°C for 2 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and adjusted to pH=8 at 0°C, then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate ether from 0% to 20%) to give methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate (430 mg, 79.98% yield) as yellow oil.

[0832] 1H NMR (400 MHz, DMSO-d6): 5 = ppm 8.94 (d, J=4.88 Hz, 2 H), 7.85 (s, 1 H), 7.57 (t, J=4.94 Hz, 1 H), 3.58 (s, 3 H), 2.59 (s, 3 H).

[0833] To a solution of methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate (400 mg, 758.50 pmol, 1 eq) in MeOH (4 mL) and THF (4 mL) was added a solution of LiOH. H2O (63.65 mg, 1.52 mmol, 2 eq) in H2O (4 mL) at 20°C and stirred at 20°C for 16 hours. LCMS showed all the starting materials were consumed and product desired mass was detected. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane and methanol (10 mL x 3, 5: 1). The combined organic layers were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) (154 mg, 81.33% yield) as a yellow solid.

[0834] LCMS (ESI+): m / z =250.1 (M+1), RT: 0.207 min.

[0835] Example 31: Synthesis of 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RC00H11)

[0836]

[0837] RC00H11 To a solution of 3-bromo-6-methylpicolinonitrile in 1,4-dioxane (12 V) under stirring, KOAc (2.29 eq), (Bpin)2 (1.50 eq) were added, followed by PPhs (0.031 eq) and Pd(OAc)2 (0.016 eq). The reaction mixture was warmed at 75 - 85 °C and stirred for about 6 h, until no further 3-bromo-6-methylpicolinonitrile was observed by LCMS and the desired mass of product was detected.

[0838] The reaction mixture was allowed to cool down to 20 - 30 °C and filtered to afford a first filtrate and the cake was washed with 1,4-dioxane (3 V) to afford a second filtrate. The combined filtrates afforded the product 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinonitrile (yield 100%; purity 93.0%).

[0839] To the solution of 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile, in a reaction vessel, 2-bromopyrimidine (1.05 eq), anhydrous K3PO4 (0.12 eq) and Pd(OAc)2 (0.012 eq) were added, followed by Ad2nBuP (0.03 eq), in 1,4-dioxane (13 V) andnPrOH (2 V). The reaction mixture was warmed to 75 - 85 °C and stirred for 3 hours, then cooled to 20 - 30 °C. The reaction mixture was quenched by adding water (4.5 V) and extracted with AcOEt (4.5 V). The extracted organic phase was filtered using a diatomite pad and concentrated to about 3 V. Heptane (12 V) was added to the organic concentrate to crystallize. The crystallized product was filtered, and dried to afford the product 6-methyl-3-(pyrimidin-2-yl)picolinonitrile (60% based on 3-bromo-6-methylpyridine-2-carbonitrile (100% purity by NMR)) as a yellow solid.

[0840] LCMS (ESI+): m / z = 197 (M+1), RT: 1.7 min.

[0841] To a solution of 6-methyl-3-(pyrimidin-2-yl)picolinonitrile in EtOH (15 V) under stirring, a solution of NaOH (2.5 eq) in H2O (2.5 V) at 20 - 30 °C was added. The reaction mixture was warmed to 75 - 85 °C and stirred for 18 h, and monitored by LCMS. The reaction mixture was slowly cooled to 0 - 10 °C, filtered and the wet cake was rinsed with THF (2.7 V). The cake was further purified upon dissolution in a mixture of water (3 V) and EtOH (1 V) at 40 - 50 °C. The hot solution was filtered through a filter, and the filter was rinsed with water (0.5 V) and EtOH (1 V).

[0842] The combined filtrates containing the sodium carboxylate intermediate was cooled to 20 - 30 °C and the pH was adjusted to 2 - 3 with 12% HCI solution in EtOH. To the solution, added further EtOH (2 V), cooled to 0 - 10 °C and allowed to crystallize. The product was isolated after filtration, rinsed with EtOH (2.4 V) and dried to afford the title compound 6-methyl-3-(pyrimidin-2-yl)picolinic acid (71% yield, 100 % purity by HPLC analysis) as an off-white solid.

[0843] 1H NMR (400 MHz, DMSO-d6): 5 = 8.80 (m, 2 H) 8.00 (m, 1H) 7.35 (m, 1H) 7.23 (m, 1H) 2.49 (m, 3H).

[0844] LCMS (ESI+): m / z = 172 (M+1-CO2), RT: 0.271 min.

[0845] Example 32: Synthesis of 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RC00H12)

[0846] K2CO3(1.5 eq) Pd(PPh3)4(0.05 eq) DMF / H2O (15 V / 3 V)

[0847]

[0848] 80°C, 12 hrs To a solution of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (1 g, 3.04 mmol, 1 eq) in DMF (7.2 mL) was added 2-bromo-5-methoxy-pyridine (571.75 mg, 3.04 mmol, 1 eq) and a solution of K2CO3 (630.42 mg, 4.56 mmol, 1.5 eq) in H2O (1.44 mL) at 20°C, the vessel was evacuated and backfilled with N2 (this process was repeated three times), then Pd(PPhs)4 (175.70 mg, 152.04 pmol, 0.05 eq) was added into the mixture under N2, the vessel was evacuated and backfilled with N2 (this process was repeated three times). Then the mixture was stirred at 80°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.5 g, 50.95% yield) as a white solid.

[0849] 1H NMR (400 MHz, DMSO-d6): 5 = 8.30 (d, J=2.88 Hz, 1 H) 7.41 (dd, J=8.63, 3.00 Hz, 1 H) 7.28 - 7.35 (m, 1 H) 3.84 (s, 3 H) 3.82 (s, 3 H) 2.73 (s, 3 H) 1.33 (s, 9 H).

[0850] LCMS (ESI+): m / z =304.0 (M+1), RT: 0.312 min.

[0851] A solution of tert-butyl 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.5 g, 1.55 mmol, 1 eq) in dioxane / HCI (4N) (10 mL) was stirred at 20°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was filtered, and the filter cake was dried in high vacuum to give the title compound 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (RCOOH12) (0.37 g, 76.79% yield) as a white solid.

[0852] 1H NMR (400 MHz, DMSO-d6): 5 = 8.62 (d, J=2.88 Hz, 1 H) 8.09 (dd, J=8.94, 2.81 Hz, 1 H) 7.87 (d, J=8.88 Hz, 1 H) 4.01 (s, 3 H) 3.90 (s, 3 H) 2.30 (s, 3 H).

[0853] LCMS (ESI+): m / z =248.2 (M+1), RT: 0.095 min.

[0854] PREPARATION OF OX1R-ANT COMPOUNDS 1-81

[0855] HN-Het RCOOH _ HN-Het

[0856] - - PyAOP (1.1 eq) N

[0857]

[0858] H DIEA (2 eq)RAQ

[0859] . DCM (20 V)

[0860] 20°C, 2 hrs1'81

[0861] Example 33: Synthesis of (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 1). General Procedure 4.

[0862]

[0863] To a solution of 3-fluoro-2-pyrimidin-2-yl-benzoic acid (RCOOH1) (53.82 mg, 246.68 pmol, 1.5 eq) and (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) (40 mg, 164.45 pmol, 1 eq) in ethyl acetate (0.3 mL) was added T3P (93.80 mg, 246.68 pmol, 1.5 eq) dropwise at 60°C. The reaction mixture was stirred at 60°C for 3 hrs. LC-MS showed the starting material was consumed completely. The mixture was diluted with H2O (3 mL) and extracted with ethyl acetate (3 mL x 3), the combined organic layer was washed with brine (3 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by prep-TLC (SiC>2, ethyl acetate: methanol = 4: 1) to give the crude product. The crude product was purified by prep-HPLC to give (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 1) (19.3 mg, 26.41% yield) as a white solid.

[0864] 1H NMR (400 MHz, DMSO-d6): δ 8.85 - 9.02 (m, 1.60 H), 8.23 - 8.37 (m, 0.80 H), 7.68 - 7.78 (m, 0.85 H), 7.59 - 7.67 (m, 0.30 H), 7.35 - 7.58 (m, 3.45H), 6.99 (br d, J=5.13 Hz, 0.55 H), 6.77 (dd, J=18.51, 8.88 Hz, 0.90 H), 4.60 (d, J=6.88 Hz, 0.30 H), 4.07 (br d, J=5.75 Hz, 0.90 H), 3.91 (br s, 0.55 H), 3.37 (br d, J=9.63 Hz, 0.85 H), 3.13 - 3.26 (m, 0.90 H), 2.83 - 2.98 (m, 0.90 H), 1.55 - 1.78 (m, 0.85 H), 1.32 (d, J=7.63 Hz, 0.35 H), 1.00 - 1.27 (m, 0.60 H).

[0865] LCMS (ESI+): m / z =444.2 (M+1), RT: 2.286 min (The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml / min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.)

[0866] Example 34: Synthesis of (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 2)

[0867]

[0868] General Procedure 4 (see Example 33) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i3) and 3-fluoro-2-pyrimidin-2-yl-benzoic acid (RCOOH1) to give the title compound (3-fluoro-2-(pyrimidin-2-yl)phenyl)(( 7S,4S, 5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 2). Yield 28%, white solid.

[0869] 1H NMR (400 MHz, DMSO-d6): δ 8.80 - 8.97 (m, 1.80 H), 8.43 (s, 0.35 H), 8.35 (s, 0.55 H), 8.13 - 8.22 (m, 0.95 H), 8.08 (br d, J=5.50 Hz, 0.40 H), 7.99 (br d, J=5.88 Hz, 0.60 H), 7.60 -7.69 (m, 0.40 H), 7.53 - 7.59 (m, 0.40 H), 7.34 - 7.53 (m, 2.55 H), 7.04 (d, J=7.00 Hz, 0.60 H), 4.62 (d, J=6.88 Hz, 0.35 H), 4.00- 4.13 (m, 1.00 H), 3.91 - 4.00 (m, 0.60 H), 3.41 (brd, J=10.01 Hz, 0.65 H), 3.24 - 3.31 (m, 0.75 H), 3.21 (d, J=10.01 Hz, 0.60 H), 2.86 - 3.02 (m, 1.00 H), 1.74 (br d, J=6.88 Hz, 0.40 H), 1.65 (br d, J=7.50 Hz, 0.60 H), 1.35 (d, J=7.75 Hz, 0.40 H), 1.14 (br d, J=7.88 Hz, 0.60 H).

[0870] LCMS (ESI+): m / z =445.1 (M+1), RT: 2.317 min (The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml / min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0 mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.)

[0871] Example 35: Synthesis of (5-methyl-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 3)

[0872]

[0873] General Procedure 4 (see Example 33) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 5-methyl-2-(pyrimidin-2-yl)benzoic acid (RCOOH8) to give the title compound (5-methyl-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 3). Yield 6%, white solid.

[0874] 1H NMR (400 MHz, DMSO-d6): δ 8.71 - 9.05 (m, 1.70 H), 8.23 - 8.40 (m, 0.85 H), 7.89 - 8.04 (m, 0.90 H), 7.65 - 7.81 (m, 0.95 H), 7.35 - 7.58 (m, 2.50 H), 7.31 (br d, J=8.13 Hz, 0.70 H), 6.79 (br dd, J=19.26, 8.50 Hz, 1.50 H), 4.74 (d, J=6.75 Hz, 0.30 H), 4.08 (br d, J=6.00 Hz, 0.30 H), 3.97 (br s, 0.60 H), 3.84 (br s, 0.65 H), 3.52 (br d, J=6.75 Hz, 0.65 H), 3.37 (d, J=9.63 Hz, 0.75 H), 3.11 - 3.23 (m, 0.70 H), 2.86 - 3.02 (m, 0.95 H), 2.42 (s, 1.05 H), 2.16 (br s, 1.85 H), 1.74 (br d, J=6.63 Hz, 0.35 H), 1.61 (br s, 0.60 H), 1.51 (d, J=7.75 Hz, 0.30 H), 1.22 - 1.41 (m, 0.80 H).

[0875] LCMS (ESI+): m / z =440.2 (M+1), RT: 2.417 min (The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml / min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0 mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.)

[0876] Example 36: Synthesis of (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 4). General Procedure 5

[0877]

[0878] To a solution of (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) (0.16 g, 592.04 pmol, 1 eq) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) (191.12 mg, 888.06 pmol, 1.5 eq) in dichloromethane (3 mL) was added DIEA (153.03 mg, 1.18 mmol, 206.24 pL, 2 eq) and PyAOP (339.54 mg, 651.24 pmol, 1.1 eq) at 20°C and stirred at 20°C for 2 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into water (5 mL), extracted with dichloromethane (3x 5 mL), the combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 4) (43.8 mg, 96.77 pmol, 16.34% yield) as a white solid.

[0879] 1H NMR (400 MHz, DMSO-d6): δ = 9.00 (br s, 1 H), 8.92 (d, J=4.88 Hz, 0.40 H), 8.19 - 8.43 (m, 1.60 H), 7.72 (br d, J=6.63 Hz, 1 H), 7.41 - 7.54 (m, 2 H), 7.24 - 7.40 (m, 1 H), 6.63 - 6.81 (m, 1 H), 4.80 (br d, J=6.75 Hz, 0.21 H), 4.10 (br d, J=5.50 Hz, 0.61 H), 3.98 - 4.06 (m, 0.28 H), 3.87 (br s, 0.72 H), 3.44 - 3.52 (m, 0.75 H), 3.34 - 3.44 (m, 1.45 H), 3.22 (br d, J=8.38 Hz, 0.43 H), 2.92 - 3.10 (m, 1 H), 2.58 (s, 1 H), 2.39 (s, 2 H), 1.62 - 1.86 (m, 1 H), 1.47 (br dd, J=19.26, 7.75 Hz, 1 H).

[0880] LCMS (ESI+): m / z = 441.18 (M+1), RT: 10.789 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 min; the flow rate was 1.0 ml / min. Mobile phase A was 10 mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. The column used for chromatography was a Xbridge C184.6 x 150 mm column (3.5 urn particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80°C.)

[0881] Example 37: Synthesis of (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 5). General Procedure 6.

[0882]

[0883] To a solution of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) (29.13 mg, 142.66 pmol, 1.2 eq) and DIEA (61.46 mg, 475.53 pmol, 82.83 pL, 4 eq) in DCM (0.7 mL) was added HATU (67.80 mg, 178.32 pmol, 1.5 eq) at 0°C and the mixture was stirred at 0°C for 1 hour. Then (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) (0.035 g, 118.88 pmol, 1 eq) was added into the reaction mixture at 0°C and stirred at 20°C for 11 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into water (5 mL), extracted with dichloromethane (3x5 mL), the combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 5) (6.1 mg, 14.16 pmol, 11.91% yield) as a white solid.

[0884] 1H NMR (400 MHz, DMSO-d6): δ = 8.24 - 8.40 (m, 1 H), 8.10 - 8.23 (m, 3 H), 7.65 - 7.77 (m, 1 H), 7.44 - 7.59 (m, 1 H), 7.10 - 7.38 (m, 1 H), 6.66 - 6.78 (m, 1 H), 4.78 (d, J=6.75 Hz, 0.27 H), 4.06 (br d, J=6.38 Hz, 0.69 H), 3.89 (br s, 1 H), 3.54 (br d, J=10.38 Hz, 0.71 H), 3.37 (d, J=9.88 Hz, 0.73 H), 3.21 - 3.31 (m, 0.68 H), 2.87 - 3.06 (m, 1 H), 2.59 (s, 1 H), 2.34 (s, 2 H), 1.63 - 1.84 (m, 1 H), 1.28 - 1.46 (m, 1 H).

[0885] LCMS (ESI+): m / z = 430.08 (M+1), RT: 6.590 min (The gradient was 30-90% B in 16.00 min, 90%-100% B in 4.00 min, 100-30% B in 0.01 min, and then hold at 30% for 3 min, the flow rate was 1.0 mL / min. Mobile phase A was 10mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. The column used for chromatography was a Xbridge C184.6 x 150 mm column (3.5 urn particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80°C.)

[0886] Example 38: Synthesis of (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 6)

[0887]

[0888] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 6). Yield 41%, white solid.1H NMR (400 MHz, DMSO-d6): δ = 8.89 - 8.98 (m, 2 H), 8.53 - 8.79 (m, 2 H), 7.56 - 7.90 (m, 1 H), 4.83 (d, J=6.75 Hz, 0.24 H), 4.22 (d, J=6.63 Hz, 0.67 H), 4.04 - 4.14 (m, 0.25 H), 3.82 (s, 0.77 H), 3.78 (br s, 0.78 H), 3.75 (s, 2 H), 3.52 (d, J=10.01 Hz, 0.70 H), 3.35 (d, J=10.01 Hz, 0.72 H), 3.22 - 3.29 (m, 0.28 H) 3.15 - 3.22 (m, 0.27 H) 2.85 - 3.05 (m, 1 H) 2.53 - 2.61 (m, 3 H) 1.70 - 1.83 (m, 1 H) 1.32 - 1.49 (m, 1 H).

[0889] LCMS (ESI+): m / z = 463.1 (M+1), RT: 3.018 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0890] Example 39: Synthesis of (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 7)

[0891]

[0892] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 7). Yield 24%, white solid.

[0893] 1H NMR (400 MHz, DMSO-d6): δ = 8.62 - 8.75 (m, 1 H), 8.46 - 8.61 (m, 2 H), 7.99 - 8.10 (m, 1 H), 7.39 - 7.62 (m, 1 H), 7.23 - 7.37 (m, 1 H), 4.49 - 4.87 (m, 1 H), 3.86 (br s, 0.30 H), 3.83 (s, 0.84 H), 3.74 (s, 2 H), 3.72 (br s, 1 H), 3.58 - 3.67 (m, 1 H), 3.47 (d, J=9.26 Hz, 0.31 H), 3.29 (s, 0.69 H), 2.85 - 3.00 (m, 1 H), 2.34 - 2.41 (m, 3 H), 1.75 (br d, J=7.25 Hz, 1 H), 1.26 -1.43 (m, 1 H).

[0894] LCMS (ESI+): m / z = 462.1 (M+1), RT: 2.979 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0895] Example 40: Synthesis of (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 8)

[0896]

[0897] General Procedure 4 (see Example 33) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 8). Yield 1.3%, white solid.

[0898] 1H NMR (400 MHz, DMSO-d6): δ = 9.00 - 9.13 (m, 2 H), 8.61 - 8.80 (m, 2 H), 8.26 - 8.39 (m, 1 H), 7.77 - 8.19 (m, 1 H), 7.41 - 7.58 (m, 2 H), 4.82 (d, J=6.50 Hz, 0.24 H), 4.26 (br d, J=6.63 Hz, 0.28 H), 4.21 (br d, J=6.50 Hz, 0.67 H), 3.86 - 3.96 (m, 0.74 H), 3.39 - 3.50 (m, 2 H), 3.38 (s, 0.70 H), 3.23 (br d, J=8.50 Hz, 0.32 H), 2.93 - 3.07 (m, 1 H), 2.59 (s, 1 H), 2.47 (s, 2 H), 1.74 - 1.90 (m, 1 H), 1.13 - 1.58 (m, 1 H).

[0899] LCMS (ESI+): m / z = 442.21 (M+1), RT: 10.407 min (The gradient was 30-90% B in 16.00 min, 90%-100% B in 4.00 min, 100-30% B in 0.01 min, and then hold at 30% for 3 min, the flow rate was 1.0 mL / min. Mobile phase A was 10mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. The column used for chromatography was a Xbridge C184.6 x 150 mm column (3.5 urn particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80°C.)

[0900] Example 41: Synthesis of (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 9)

[0901]

[0902] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) to give the title compound (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 9). Yield 45%, white solid.

[0903] 1H NMR (400 MHz, DMSO-d6): δ = 8.76 (s, 0.50 H), 8.55 - 8.74 (m, 1 H), 8.26 (s, 0.50 H), 8.17 - 8.25 (m, 1 H), 8.16 (s, 2 H), 7.76 (br d, J=7.25 Hz, 0.29 H), 7.46 - 7.61 (m, 0.89H), 4.81 (d, J=6.75 Hz, 0.27 H), 4.28 (br d, J=7.13 Hz, 0.31 H), 4.16 (br d, J=6.50 Hz, 0.64 H), 3.82 (br s,0.69 H), 3.53 (br d, J=9.88 Hz, 0.77 H), 3.33 - 3.39 (m,1.37 H), 2.91 - 3.07 (m, 1 H), 2.60 (s, 1 H), 2.41 (s, 2 H), 1.70 - 1.89 (m, 1 H), 1.34 - 1.48 (m, 1 H).

[0904] LCMS (ESI+): m / z = 431.36 (M+1), RT: 10.336 min (The gradient was 30-90% B in 16.00 min, 90%-100% B in 4.00 min, 100-30% B in 0.01 min, and then hold at 30% for 3 min, the flow rate was 1.0 mL / min. Mobile phase A was 10mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. The column used for chromatography was a Xbridge C184.6 x 150 mm column (3.5 urn particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80°C.)

[0905] Example 42: Synthesis of (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 10)

[0906]

[0907] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 10). Yield 44%, white solid.

[0908] 1H NMR (400 MHz, DMSO-d6): δ = 8.71 - 8.93 (m, 2 H), 8.16 - 8.41 (m, 1 H), 7.60 - 7.77 (m, 1 H), 7.08 - 7.24 (m, 1 H), 6.63 - 6.79 (m, 1 H), 4.80 (d, J=6.75 Hz, 0.28 H), 4.12 (br d, J=6.38 Hz, 0.70 H), 3.83 - 3.98 (m, 1 H), 3.82 (s, 1 H), 3.73 (s, 2 H), 3.46 - 3.62 (m, 0.73H), 3.39 (d, J=9.88 Hz, 0.73 H), 3.32 (s, 2 H), 3.24 (d, J=8.50 Hz, 0.30 H), 3.13 (d, J=8.51 Hz, 0.30 H), 2.82 - 3.01 (m, 1 H), 2.58 (s, 1 H), 2.54 (s, 2 H), 1.57 - 1.79 (m, 1 H), 1.21 - 1.42 (m, 1 H). LCMS (ESI+): m / z = 462.1 (M+1), RT: 3.008 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0909] Example 43: Synthesis of (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 11)

[0910]

[0911] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5- (trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 11). Yield 13%, white solid.1H NMR (400 MHz, DMSO-d6): δ = 8.43 - 8.60 (m, 1 H), 8.13 - 8.38 (m, 1 H), 7.58 - 7.75 (m, 1 H), 7.55 (td, J=8.76, 3.00 Hz, 0.60 H), 7.32 - 7.37 (m, 0.36 H), 7.23 - 7.32 (m, 2 H), 6.65 (dd, J=8.69, 6.19 Hz, 1 H), 4.80 (d, J=6.88 Hz, 0.33 H), 4.57 (d, J=6.50 Hz, 0.63 H), 3.87 (br s, 1 H), 3.83 (s, 1 H), 3.74 (s, 2 H), 3.51 - 3.66 (m, 1.36 H), 3.36 (s, 0.62 H), 2.85 - 2.98 (m, 1 H), 2.33 - 2.44 (m, 3 H), 1.64 - 1.81 (m, 1 H), 1.28 (t, J=7.63 Hz, 1 H).

[0912] LCMS (ESI+): m / z = 461.1 (M+1), RT: 2.977 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0913] Example 44: Synthesis of ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 12)

[0914]

[0915] General Procedure 5 (see Example 36) was repeated using (7S,4S, 5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 12). Yield 13%, white solid.

[0916] 1H NMR (400 MHz, DMSO-d6): δ = 8.79 - 8.89 (m, 2 H), 8.32 - 8.43 (m, 1 H), 8.06 - 8.29 (m, 1 H), 7.75 - 7.90 (m, 1 H), 7.40 - 7.51 (m, 2 H), 7.00 - 7.39 (m, 1 H), 4.85 (d, J=6.63 Hz, 0.23 H), 4.14 - 4.23 (m, 0.23 H), 4.11 (d, J=6.50 Hz, 0.70 H), 3.84 (br s, 0.71 H), 3.47 - 3.55 (m, 0.70 H), 3.41 (d, J=9.76 Hz, 0.72 H), 3.35 (s, 0.30H), 3.27 - 3.29 (m, 0.30 H), 2.91 - 3.12 (m, 1 H), 2.57 (s, 1 H), 2.37 (s, 2 H), 1.67 - 1.93 (m, 1 H), 1.36 - 1.56 (m, 1 H).

[0917] LCMS (ESI+): m / z = 459.1 (M+1), RT: 3.057 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0918] Example 45: Synthesis of (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 13)

[0919]

[0920] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 13). Yield 17%, white solid.

[0921] 1H NMR (400 MHz, DMSO-d6): δ = 8.74 - 8.91 (m, 2 H), 8.31 - 8.47 (m, 1 H), 8.06 - 8.29 (m, 1 H), 7.54 - 7.70 (m, 1 H), 7.33 - 7.52 (m, 2 H), 5.90 - 6.46 (m, 1 H), 4.80 (d, J=6.88 Hz, 0.31 H), 4.12 - 4.24 (m, 0.32 H), 4.06 (d, J=6.50 Hz, 0.66 H), 3.88 (br s, 0.67 H), 3.38 (s, 1 H), 3.17 - 3.31 (m, 1 H), 2.91 - 3.12 (m, 1 H), 2.56 (s, 1 H), 2.41 (s, 2 H), 2.17 (s, 3 H), 1.65 - 1.90 (m, 1 H), 1.38 - 1.52 (m, 1 H).

[0922] LCMS (ESI+): m / z = 455.1 (M+1), RT: 3.062 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0923] Example 46: Synthesis of ((lS,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 14)

[0924]

[0925] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 14). Yield 15%, white solid.

[0926] 1H NMR (400 MHz, DMSO-d6): δ = 8.79 - 8.89 (m, 2 H), 8.41 - 8.61 (m, 1 H), 8.29 - 8.40 (m, 1 H), 7.91 - 8.07 (m, 1 H), 7.37 - 7.53 (m, 2 H), 6.94 - 7.36 (m, 1 H), 6.56 - 6.92 (m, 1 H), 4.83 (d, J=6.88 Hz, 0.27 H), 4.19 (br s, 0.28 H), 4.15 (br d, J=6.38 Hz, 0.68 H), 3.92 (br s, 0.69 H), 3.34 - 3.45 (m, 1 H), 3.17 - 3.29 (m, 1 H), 2.93 - 3.14 (m, 1 H), 2.55 (s, 1 H), 2.40 (s, 2 H), 1.67 - 1.90 (m, 1 H), 1.38 - 1.61 (m, 1 H).

[0927] LCMS (ESI+): m / z = 491.1 (M+1), RT: 3.191 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0928] Example 47: Synthesis of {{1S, 4S, 5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 15)

[0929]

[0930] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound ((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 15). Yield 13%, white solid.

[0931] 1H NMR (400 MHz, DMSO-d6): 5 = 8.77 - 8.91 (m, 2 H), 8.04 - 8.44 (m, 1 H), 7.87 - 8.03 (m, 1 H), 7.37 - 7.54 (m, 2 H), 7.18 - 7.35 (m, 1 H), 6.28 - 6.96 (m, 1 H), 4.04 - 5.06 (m, 1 H), 3.89 - 3.95 (m, 1 H), 3.76 - 3.89 (m, 3 H), 3.40 - 3.62 (m, 1.60 H), 3.14 - 3.26 (m, 0.45 H), 2.86 -3.11 (m, 1 H), 2.59 (s, 0.54 H), 2.40 - 2.48 (m, 2.52 H), 1.62 - 1.88 (m, 1 H), 1.16 - 1.50 (m, 1 H).

[0932] LCMS (ESI+): m / z = 471.44 (M+1), RT: 11.231 min (The gradient was 30-90% B in 16.00 min, 90%-100% B in 4.00 min, 100-30% B in 0.01 min, and then hold at 30% for 3 min, the flow rate was 1.0 mL / min. Mobile phase A was 10mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. The column used for chromatography was a Xbridge C184.6 x 150 mm column (3.5 urn particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80°C.)

[0933] Example 48: Synthesis of 2-(((7S,4S,5R)-2-(6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1,1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 16)

[0934]

[0935] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound 2-(((7S,4S,5R)-2-(6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 16). Yield 28%, white solid.

[0936] 1H NMR (400 MHz, DMSO-d6): δ = 8.65 - 8.88 (m, 2 H), 8.32 - 8.52 (m, 2 H), 7.91 (br d, J=2.00 Hz, 1 H), 7.41 - 7.52 (m, 2 H), 4.15 - 4.96 (m, 1 H), 3.75 - 4.11 (m, 1 H), 3.42 (s, 1 H) 3.32 - 3.35 (m, 1 H), 3.24 (br d, J=8.63 Hz, 1 H), 2.97 - 3.12 (m, 1 H), 2.57 (s, 0.60 H), 2.43 (s, 2.40 H), 1.73 - 1.87 (m, 1 H), 1.42 - 1.56 (m, 1 H).

[0937] LCMS (ESI+): m / z = 466.1 (M+1), RT: 3.053 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0938] Example 49: Synthesis of ((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 17)

[0939]

[0940] General Procedure 6 (see Example 37) was repeated using (7S,4S, 5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) to give the title compound ((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 17). Yield 19%, white solid.

[0941] 1H NMR (400 MHz, DMSO-d6): δ = 7.97 - 8.40 (m, 4 H), 7.77 - 7.93 (m, 1 H), 7.47 - 7.60 (m, 1 H), 6.91 - 7.36 (m, 1 H), 4.09 - 4.92 (m, 1 H), 3.84 (br s, 1 H), 3.52 (br d, J=9.88 Hz, 1 H), 3.37 (br d, J=9.76 Hz, 1 H), 2.91 - 3.11 (m, 1 H), 2.58 (s, 1 H), 2.37 (s, 2 H), 1.69 - 1.94 (m, 1 H), 1.29 - 1.51 (m, 1 H).

[0942] LCMS (ESI+): m / z = 448.1 (M+1), RT: 3.084 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 50: Synthesis of (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((lS,4S,5R)-5- ((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 18)

[0943]

[0944] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinicacid (RCOOH10) to give the title compound (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 18). Yield 19%, white solid.

[0945] 1H NMR (400 MHz, DMSO-d6): δ = 7.98 - 8.34 (m, 4 H), 7.43 - 7.70 (m, 2 H), 5.95 - 6.40 (m, 1 H), 4.04 - 4.87 (m, 1 H), 3.88 (br s, 1 H), 3.33 - 3.45 (m, 1.69 H), 3.21 (d, J=8.63 Hz, 0.34 H), 2.93 - 3.09 (m, 1 H), 2.57 (s, 1 H), 2.40 (s, 2 H), 2.16 (s, 3 H), 1.67 - 1.89 (m, 1 H), 1.31 -1.44 (m, 1 H).

[0946] LCMS (ESI+): m / z = 444.1 (M+1), RT: 3.082 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0947] Example 51: Synthesis of ((lS,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 19)

[0948]

[0949] General Procedure 6 (see Example 37) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) to give the title compound ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 19). Yield 23%, white solid.

[0950] 1H NMR (400 MHz, DMSO-d6): δ = 8.34 - 8.62 (m, 1 H), 8.11 - 8.26 (m, 1 H), 7.93 - 8.09 (m, 3 H), 7.46 - 7.61 (m, 1 H), 6.62 - 7.36 (m, 2 H), 4.16 - 4.89 (m, 1 H), 3.85 - 4.15 (m, 1 H), 3.37 (s, 1.64 H), 3.19 (d, J=8.50 Hz, 0.30 H), 2.96 - 3.12 (m, 1 H), 2.56 (s, 1 H), 2.40 (s, 2 H), 1.70 - 1.89 (m, 1 H), 1.32 - 1.50 (m, 1 H).

[0951] LCMS (ESI+): m / z = 480.1 (M+1), RT: 3.203 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0952] Example 52: Synthesis of ((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 20)

[0953]

[0954] General Procedure 6 (see Example 37) was repeated using (1 S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) to give the title compound ((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 20). Yield 20%, white solid.

[0955] 1H NMR (400 MHz, DMSO-d6): 5 = 8.18 - 8.29 (m, 1 H), 8.05 - 8.14 (m, 2 H), 7.86 - 8.04 (m, 1 H), 7.47 - 7.66 (m, 1 H), 7.18 - 7.33 (m, 1 H), 6.22 - 6.92 (m, 1 H), 4.80 (d, J=6.88 Hz, 0.22 H), 4.30 (br d, J=7.13 Hz, 0.23 H), 4.13 (d, J=6.50 Hz, 0.77 H), 3.90 (s, 3 H), 3.86 (s, 0.73 H), 3.37 - 3.42 (m, 1 H), 3.19 - 3.29 (m, 1 H), 2.90 - 3.09 (m, 1 H), 2.60 (s, 0.73 H), 2.47 (s, 2.22 H), 1.70 - 1.87 (m, 1 H), 1.35 - 1.45 (m, 1 H).

[0956] LCMS (ESI+): m / z = 460.1 (M+1), RT: 3.080 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.)

[0957] Example 53: Synthesis of 2-(((7S,4S,5R)-2-(6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinoyl)-2-azabicyclo[2.1,1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 21)

[0958]

[0959] General Procedure 6 (see Example 37) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) to give the title compound 2-(((1S,4S,5R)-2-(6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 21). Yield 17%, white solid.

[0960] 1H NMR (400 MHz, DMSO-d6): δ = 8.37 - 8.70 (m, 2 H), 8.13 - 8.22 (m, 1 H), 8.01 - 8.08 (m, 2 H), 7.84 (br s, 1 H), 7.48 - 7.58 (m, 1 H), 4.15 - 4.97 (m, 1 H), 3.75 - 4.00 (m, 1 H), 3.34 -3.52 (m, 1.88 H), 3.22 (d, J=8.50 Hz, 0.29 H), 2.96 - 3.15 (m, 1 H), 2.58 (s, 0.60 H), 2.43 (s, 2.42 H), 1.69 - 1.92 (m, 1 H), 1.32 - 1.54 (m, 1 H).

[0961] LCMS (ESI+): m / z = 455.1 (M+1), RT: 3.065 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was a Xbridge-C18 2.1 x 50 mm, 5 urn. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 54: Synthesis of (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 22)

[0962]

[0963] General Procedure 5 (see Example 36) was repeated using ( 1 S,4S,5R)- N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH11) to give the title compound (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 22). Yield 26%, white solid.

[0964] 1H NMR (400 MHz, DMSO-d6): 5 ppm 9.10 (br dd, J = 14.7, 4.8 Hz, 2 H), 8.27-8.60 (m, 2 H), 7.43-8.07 (m, 3 H), 3.40-4.89 (m, 3 H), 3.17-3.31 (m, 1 H), 2.92-3.07 (m, 1 H), 2.59 (s, 1 H), 2.48 (s, 2 H), 2.31-2.45 (m, 3 H), 1.73-1.92 (m, 1 H), 1.38-1.58 (m, 1 H).

[0965] LCMS (ESI+): m / z = 456.2 (M+1), RT: 2.088 min (Mobile phase: Ramp from 30% ACN (0.02%TFA) in water (0.04%TFA) to 100% ACN in 3.5 min, flow rate is set at 0.7 mL / min; then hold at 100% ACN for 1.90 minutes, flow rate is set at 1.0 mL / min; return back to 30% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is of ZORBAX SB-C182.1x50 mm 1.8 pm.)

[0966] Example 55: Synthesis of (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 23)

[0967]

[0968] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 6-methyl-3-(pyrimidin-2-yl)picolinic acid (RC00H11) to give the title compound (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 23). Yield 14%, white solid.

[0969] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.75 - 8.86 (m, 2 H), 8.03 - 8.41 (m, 2 H), 7.35 - 7.51 (m, 2 H), 6.81 - 7.10 (m, 1 H), 4.07 - 4.91 (m, 1 H), 3.70 - 4.00 (m, 1 H), 3.54 (d, J = 9.9 Hz, 1 H), 3.35 - 3.58 (m, 1 H), 2.97 - 3.08 (m, 1 H), 2.55 (s, 1 H), 2.41 (s, 3 H), 2.34 (s, 2 H), 1.73 (br dd, J = 5.9, 2.5 Hz, 1 H), 1.41 (d, J = 7.9 Hz, 1 H).

[0970] LCMS (ESI+): m / z = 456.2 (M+1), RT: 3.327 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is of ZORBAX SB-C182.1*50mm 1.8 pm.)

[0971] Example 56: Synthesis of ((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3,-bipyridin]-2,-yl)methanone (compound 24)

[0972]

[0973] General Procedure 4 (see Example 33) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give compound ((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 24). Yield 6.4%, white solid.

[0974] 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.55 (br d, J = 4.0 Hz, 1 H), 8.09-8.35 (m, 1 H), 8.01-8.08 (m, 1 H), 7.63-7.81 (m, 1 H), 7.50-7.62 (m, 1 H), 7.37-7.47 (m, 1 H), 7.31 (dd, J = 7.1, 4.9 Hz, 1 H), 6.83-7.13 (m, 1 H), 4.00-4.92 (m, 1 H), 3.63-3.93 (m, 1 H), 3.53 (br d, J = 9.6 Hz, 1 H), 3.17-3.29 (m, 1 H), 2.93-3.05 (m, 1 H), 2.54 (s, 1 H), 2.36-2.44 (m, 3 H), 2.34 (s, 2 H), 1.64-1.86 (m, 1 H), 1.13-1.35 (m, 1 H). LCMS (ESI+): m / z =455.2 (M+1), RT: 3.143 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is of ZORBAX SB-C182.1*50mm 1.8 pm.)

[0975] Example 57: Synthesis of (6'-methyl-[2,3'-bipyridin]-2'-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 25)

[0976]

[0977] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound (6'-methyl-[2,3'-bipyridin]-2'-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 25). Yield 15%, white solid.

[0978] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.60 - 8.81 (m, 1 H), 8.24 - 8.38 (m, 1 H), 7.99 - 8.09 (m, 1 H), 7.67 (s, 3 H), 7.32 - 7.50 (m, 3 H), 6.66 - 6.72 (m, 1 H), 3.75 - 4.82 (m, 2 H), 3.49 (br d, J=10.76 Hz, 1 H), 3.18 - 3.29 (m, 1 H), 2.91 - 3.01 (m, 1 H), 2.57 (s, 1 H), 2.37 (s, 2 H), 1.62 - 1.80 (m, 1 H), 1.13 - 1.22 (m, 1 H).

[0979] LCMS (ESI+): m / z = 440.0 (M+1), RT: 2.548 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8min, flow rate is set at 0.6 mL / min, then hold at 80% ACN for 0.60 min, flow rate is set at 1.0mL / min, return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is of Kinetex EVO C18 2.1×50mm 1.7μm.)

[0980] Example 58: Synthesis of {{1S, 4S, 5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3,-bipyridin]-2,-yl)methanone (compound 26)

[0981]

[0982] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound ((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 26). Yield 12%, white solid.

[0983] 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.51-8.62 (m, 1 H), 8.02-8.29 (m, 2 H), 7.78-7.88 (m, 2 H), 7.57-7.73 (m, 1 H), 7.38-7.50 (m, 2 H), 7.15-7.37 (m, 1 H), 4.03-4.89 (m, 1 H), 3.77 (br s, 1 H), 3.50 (br d, J = 9.8 Hz, 1 H), 3.30 (br s, 1 H), 2.90-3.08 (m, 1 H), 2.55 (s, 1 H), 2.35 (s, 2 H), 1.65-1.87 (m, 1 H), 1.12-1.40 (m, 1 H).

[0984] LCMS (ESI+): m / z =458.1 (M+1), RT: 3.415 min (Mobile phase: Ramp from 10% ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2mL / min. Column temperature at 40°C. The column is of XBridge C18 2.1×50mm 5um.)

[0985] Example 59: Synthesis of ((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3,-bipyridin]-2,-yl)methanone (compound 27)

[0986]

[0987] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound (( 7S,4S, 5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 27). Yield 36%, white solid.

[0988] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.81-9.07 (m, 1 H), 8.40-8.62 (m, 1 H), 7.36-8.18 (m, 6 H), 3.38-4.79 (m, 3 H), 3.21-3.31 (m, 1 H), 2.91-3.02 (m, 1 H), 2.57 (s, 1 H), 2.44 (s, 5 H), 1.66-1.87 (m, 1 H), 1.21-1.39 (m, 1 H).

[0989] LCMS (ESI+): m / z =455.2 (M+1), RT: 3.597 min (Mobile phase: Ramp from 10%ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2mL / min. Column temperature at 40°C. The column is of XBridge C18 2.1×50mm 5um.)

[0990] Example 60: Synthesis of ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin- 2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3,-bipyridin]-2,-yl)methanone (compound 28)

[0991]

[0992] General Procedure 5 (see Example 36) was repeated, using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound ((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 28). Yield 48%, white solid.

[0993] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.36 - 8.65 (m, 2 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.95 -8.01 (m, 1H), 7.71 - 7.82 (m, 1 H), 7.53 - 7.67 (m, 1 H), 7.40 - 7.45 (m, 1 H), 7.30 - 7.37 (m, 1 H), 6.63 - 7.23 (m, 2 H), 4.14 - 4.86 (m, 1 H), 3.83 - 4.12 (m, 1 H), 3.36 (br s, 1 H), 3.19 - 3.31 (m, 1 H), 2.92 - 3.11 (m, 1 H), 2.54 (s, 1 H), 2.40 (s, 2 H), 1.65 - 1.86 (m, 1 H), 1.20 - 1.39 (m, 1 H). LCMS (ESI+): m / z =490.1 (M+1), RT: 3.354 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0 mm, 2.6 um.)

[0994] Example 61: Synthesis of 2-(((lS,4S,5R)-2-(6'-methyl-[2,3,-bipyridine]-2,-carbonyl)-2-azabicyclo[2.1,1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 29)

[0995]

[0996] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound 2-(((1S,4S,5R)-2-(6'-methyl-[2,3'-bipyridine]-2'-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 29). Yield 53%, white solid.

[0997] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.59 (d, J = 4.1 Hz, 1 H), 8.49 (s, 1 H), 8.39 - 8.48 (m, 1 H), 8.03 - 8.10 (m, 1 H), 7.99 (s, 1 H), 7.69 - 7.87 (m, 1 H), 7.54 - 7.66 (m, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 4.14 - 4.88 (m, 1 H), 3.75 - 3.97 (m, 1 H), 3.34 - 3.41 (m, 2 H), 2.93- 3.10 (m, 1 H), 2.55 (s, 1 H), 2.42 (s, 2 H), 1.68 - 1.86 (m, 1 H), 1.22 - 1.40 (m, 1 H).

[0998] LCMS (ESI+): m / z = 465.2 (M+1), RT: 3.373 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8min, flow rate is set at 0.7mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0mL / min. Column temperature at 50°C. The column is of ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[0999] Example 62: Synthesis of {{1S, 4S, 5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3,-bipyridin]-2,-yl)methanone (compound 30) o

[1000]

[1001] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound ((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 30). Yield 21%, white solid.

[1002] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.61 (br d, J=4.63 Hz, 1 H), 8.09 (d, J=8.13 Hz, 1 H), 7.86 - 8.02 (m, 1 H), 7.70 - 7.85 (m, 1 H), 7.60 - 7.69 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.33 - 7.39 (m, 1 H), 7.19 - 7.29 (m, 1 H), 6.33 - 7.06 (m, 1 H), 4.21 - 4.77 (m, 1 H), 4.08 (br d, J=6.38 Hz, 1 H), 3.83 - 3.89 (m, 3 H), 3.21 - 3.27 (m, 1 H), 2.86 - 3.07 (m, 2 H), 2.57 (s, 1 H), 2.46 (s, 2 H), 1.67 - 1.86 (m, 1 H), 1.23 - 1.38 (m, 1 H).

[1003] LCMS (ESI+): m / z = 470.2 (M+1), RT: 3.156 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8min, flow rate is set at 0.7mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0mL / min. Column temperature at 50°C. The column is of ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1004] Example 63: Synthesis of ((7S,4S,5 / ?)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3,-bipyridin]-2,-yl)methanone (compound 31)

[1005]

[1006] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 6'- methyl-[2,3'-bipyridine]-2'-carboxylic acid (RCOOH9) to give the title compound ((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 31). Yield 30%, white solid.

[1007] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.53 - 8.63 (m, 1 H), 8.03 - 8.28 (m, 2 H), 7.52 - 7.81 (m, 3 H), 7.28 - 7.47 (m, 2 H), 6.01 - 6.55 (m, 1 H), 3.76 - 4.86 (m, 2 H), 3.36 - 3.41 (m, 1 H), 3.20 - 3.31 (m, 1 H), 2.88 - 3.07 (m, 1 H), 2.54 (s, 1 H), 2.41 (s, 2 H), 2.11 - 2.25 (m, 3 H), 1.66 - 1.84 (m, 1 H), 1.18 - 1.35 (m, 1 H).

[1008] LCMS (ESI+): m / z = 454.1(M+1), RT: 2.751 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1009] Example 64: Synthesis of ((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 32)

[1010]

[1011] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound ((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 32). Yield 41%, off-white solid.

[1012] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.77 - 8.87 (m, 2 H), 8.47 (s, 1 H), 7.99 (s, 1 H), 7.41 -7.47 (m, 1 H), 7.31 (s, 1 H), 7.00 - 7.24 (s, 1 H), 6.59 - 6.97 (m, 1 H), 4.30 - 4.71 (m, 1 H), 3.90 - 4.15 (m, 1 H), 3.33 - 3.48 (m, 1 H), 3.13 - 3.23 (m, 1 H), 2.96 - 3.09 (m, 1 H), 2.53 (s, 1 H), 2.37 (s, 2 H), 2.22 - 2.29 (m, 3 H), 1.72 - 1.81 (m, 1 H), 1.20 - 1.39 (m, 1 H). LCMS (ESI+): m / z =505.0 (M+1), RT: 3.731 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1013] Example 65: Synthesis of 2-(((lS,4S,5R)-2-(4,6-dimethyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1,1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 33)

[1014]

[1015] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound 2-(((1S,4S,5R)-2-(4,6-dimethyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 33). Yield 32%, white solid.

[1016] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.78 - 8.88 (m, 2 H), 8.49 - 8.65 (m, 1 H), 8.41 - 8.48 (m, 1 H), 7.98 (br s, 1 H), 7.43 - 7.55 (m, 1 H), 7.28 - 7.42 (m, 1 H), 4.34 - 4.75 (m, 1 H), 3.80 - 4.00 (m, 1 H), 3.17 - 3.30 (m, 2 H), 2.98 - 3.10 (m, 1 H), 2.51 - 2.52 (m, 1 H), 2.41 (s, 2 H), 2.20 - 2.31 (m, 3 H), 1.80 (br d, J = 7.8 Hz, 1 H), 1.33 - 1.44 (m, 1 H).

[1017] LCMS (ESI+): m / z =480.2 (M+1), RT: 3.636 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1018] Example 66: Synthesis of (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 34)

[1019]

[1020] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 7S,4S, 5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 34). Yield 17%, pink solid.

[1021] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.64-8.80 (m, 2 H), 7.94-8.31 (m, 1 H), 7.68-7.88 (m, 1 H), 6.99-7.14 (m, 1 H), 4.16-4.98 (m, 1 H), 3.80-3.99 (m, 1 H), 3.70 (s, 3 H), 3.36-3.67 (m, 2 H), 2.87-3.02 (m, 1 H), 2.53-2.59 (m, 3 H), 1.64-1.85 (m, 1 H), 1.30-1.42 (m, 1 H).

[1022] LCMS (ESI+): m / z =473.2 (M+1), RT: 3.631 min (Mobile phase: Ramp from 10%ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2 mL / min. Column temperature at 40°C. The column is XBridge C18 2.1×50mm 5um.)

[1023] Example 67: Synthesis of (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 35)

[1024]

[1025] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 35). Yield 38%, white solid.

[1026] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.97 - 9.20 (m, 2 H), 8.44 - 8.60 (m, 1 H), 7.31 - 8.00 (m, 3 H), 3.86 - 4.69 (m, 3 H), 3.24 (br s, 1 H), 2.92 - 3.02 (m, 1 H), 2.53 (s, 1 H), 2.28 - 2.46 (m, 8 H), 1.80 (br s, 1 H), 1.31 - 1.49 (m, 1 H).

[1027] LCMS (ESI+): m / z = 470.2 (M+1), RT: 3.801 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1028] Example 68: Synthesis of (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 36)

[1029]

[1030] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 36). Yield 65%, white solid.

[1031] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.75 - 8.91 (m, 2 H), 8.13 - 8.27 (m, 1 H), 7.56 - 7.66 (m, 1 H), 7.38 - 7.51 (m, 1 H), 7.31 (s, 1 H), 5.94 - 6.50 (m, 1 H), 4.17 - 4.68 (m, 1 H), 3.91 (br s, 1 H), 3.42 (br d, J=10.26 Hz, 1 H), 3.12 - 3.31 (m, 2 H), 2.91 - 3.08 (m, 1 H), 2.38 (s, 2 H), 2.23 - 2.29 (m, 4 H), 2.13 (s, 2 H), 1.76 (br d, J=7.13 Hz, 1 H), 1.33 (d, J=8.13 Hz, 1 H). LCMS (ESI+): m / z =469.1 (M+1), RT: 2.855 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1032] Example 69: Synthesis of (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 37)

[1033]

[1034] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 7S,4S, 5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 37). Yield 19%, white solid.

[1035] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.78 - 8.89 (m, 2 H), 7.89 - 8.01 (m, 1 H), 7.40 - 7.51 (m, 1 H), 7.20 - 7.37 (m, 2 H), 6.27 - 7.03 (m, 1 H), 3.90 - 4.66 (m, 2 H), 3.86 (s, 3 H), 3.10 -3.26 (m, 2 H), 2.90 - 3.05 (m, 1 H), 2.53 (br s, 1 H), 2.43 (s, 2 H), 2.27 - 2.34 (m, 3 H), 1.78 (br d, J=7.00 Hz, 1 H), 1.28 - 1.43 (m, 1 H).

[1036] LCMS (ESI+): m / z = 485.2 (M+1), RT: 3.296 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1037] Example 70: Synthesis of (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 38)

[1038]

[1039] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give compound (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 38). Yield 26%, yellow solid.

[1040] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.69 - 8.85 (m, 2 H), 8.11 - 8.32 (m, 1 H), 7.36 - 7.46 (m, 1 H), 7.24 - 7.33 (m, 1 H), 6.79 - 7.08 (m, 1 H), 4.28 - 4.72 (m, 1 H), 3.72 - 3.93 (m, 1 H), 3.37- 3.51 (m, 1 H), 2.90- 3.20 (m, 2 H), 2.26 - 2.47 (m, 5 H), 2.19- 2.25 (m, 3 H), 1.71 - 1.84 (m, 1 H), 1.25 - 1.38 (m, 1 H), 0.94 (d, J=6.63 Hz, 1 H).

[1041] LCMS (ESI+): m / z =470.2 (M+1), RT: 3.454 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1042] Example 71: Synthesis of (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 39)

[1043]

[1044] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH5) to give the title compound (4,6-dimethyl- 3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 39). Yield 39%, white solid.

[1045] 1H NMR (400 MHz, DMSO-d6): 5 ppm 9.00 (br d, J=3.13 Hz, 1 H), 8.87 (d, J=5.00 Hz, 1 H), 8.34 (br s, 1 H), 7.74 (br d, J=8.75 Hz, 1 H), 7.43 - 7.54 (m, 1 H), 7.32 - 7.40 (m, 1 H), 7.16 -7.31 (m, 1 H), 6.68 - 6.80 (m, 1 H), 4.21 - 4.65 (m, 1 H), 3.80 - 4.02 (m, 1 H), 3.34 - 3.54 (m, 1 H), 3.15 - 3.26 (m, 1 H), 2.92 - 3.02 (m, 1 H), 2.53 (s, 1 H), 2.32 - 2.39 (m, 2 H), 2.25 - 2.31 (m, 3 H), 1.68 (s, 1 H), 1.36 (br dd, J=12.32, 7.94 Hz, 1 H).

[1046] LCMS (ESI+): m / z =455.1 (M+1), RT: 2.743 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1047] Example 72: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5 / ?)- 5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 40)

[1048]

[1049] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 40). Yield 15%, white solid.

[1050] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.80 - 8.92 (m, 2 H), 7.89 - 7.99 (m, 1 H), 7.66 - 7.73 (m, 1 H), 7.46 - 7.57 (m, 1 H), 7.20 - 7.29 (m, 1 H), 6.25 - 6.81 (m, 1 H), 4.16 - 4.66 (m, 2 H), 3.86 - 3.88 (m, 3 H), 3.16 - 3.24 (m, 2 H), 2.92 - 3.02 (m, 1 H), 2.59 (s, 1 H), 2.44 - 2.44 (m, 1 H), 2.45 (s, 1 H), 1.79 (br d, J=7.50 Hz, 1 H), 1.24 - 1.35 (m, 1 H). LCMS (ESI+): m / z = 505.1 (M+1), RT: 3.518 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1051] Example 73: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 41)

[1052]

[1053] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 41). Yield 20%, white solid.

[1054] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.75-8.94 (m, 2 H), 8.06-8.27 (m, 1 H), 7.80-7.91 (m, 1 H), 7.59-7.74 (m, 1 H), 7.42-7.56 (m, 1 H), 7.06-7.31 (m, 1 H), 4.30-4.74 (m, 1 H), 3.78-4.04 (m, 1 H), 3.43-3.50 (m, 1 H), 3.17 (d, J = 9.9 Hz, 1 H), 2.97 (br dd, J = 6.1, 2.9 Hz, 1 H), 2.57 (s, 1 H), 2.33 (s, 2 H), 1.78 (br d, J = 7.9 Hz, 1 H), 1.25-1.33 (m, 1 H).

[1055] LCMS (ESI+): m / z =439.1 (M+1), RT: 3.830 min (Mobile phase: Ramp from 10% ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2 mL / min. Column temperature at 40°C. The column is XBridge C18 2.1×50mm 5um.)

[1056] Example 74: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((lS,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 42)

[1057]

[1058] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 42). Yield 13%, yellow solid.

[1059] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.97 - 9.16 (m, 2 H), 8.44 - 8.59 (m, 1 H), 7.42 - 7.96 (m, 3 H), 3.49 - 4.70 (m, 3 H), 3.18 - 3.25 (m, 1 H), 2.91 - 3.01 (m, 1 H), 2.59 (s, 1 H), 2.46 (br s, 4 H), 2.32 (br s, 1 H), 1.68 - 1.84 (m, 1 H), 1.28 - 1.42 (m, 1 H).

[1060] LCMS (ESI+): m / z = 490.1 (M+1), RT: 3.980 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1061] Example 75: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5 / ?)- 5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 43)

[1062]

[1063] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4- chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 43). Yield 59%, purple solid.

[1064] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.77 - 8.92 (m, 2 H), 8.10 - 8.24 (m, 1 H), 7.64 - 7.71 (m, 1 H), 7.57 - 7.63 (m, 1 H), 7.43 - 7.54 (m, 1 H), 6.02 - 6.30 (m, 1 H), 4.25 - 4.67 (m, 1 H), 3.84 - 4.06 (m, 1 H), 3.39 - 3.53 (m, 1 H), 3.14 (d, J=9.76 Hz, 1 H), 2.92 - 3.02 (m, 1 H), 2.57 (s, 1 H), 2.37 (s, 2 H), 2.24 (s, 1 H), 2.13 (s, 2 H), 1.77 (br d, J=6.75 Hz, 1 H), 1.20 - 1.32 (m, 1 H).

[1065] LCMS (ESI+): m / z =489.0 (M+1), RT: 3.065 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1066] Example 76: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5 / ?)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 44)

[1067] F

[1068] 44

[1069]

[1070] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 44). Yield 29%, white solid.

[1071] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.82 - 8.90 (m, 2 H), 8.45 (s, 1 H), 7.98 (s, 1 H), 7.63 -7.72 (m, 1 H), 7.45 - 7.54 (m, 1 H), 6.90 - 7.23 (m, 1 H), 6.66 - 6.86 (m, 1 H), 4.37 - 4.70 (m, 1 H), 3.86 - 4.08 (m, 1 H), 3.39 - 3.52 (m, 1 H), 3.16 - 3.24 (m, 1 H), 3.01 - 3.06 (m, 1 H), 2.55 (s, 1 H), 2.40 (s, 2 H), 1.77 - 1.82 (m, 1 H), 1.30 - 1.34 (m, 1 H).

[1072] LCMS (ESI+): m / z =525.0 (M+1), RT: 3.861 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1073] Example 77: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 45)

[1074]

[1075] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 45). Yield 20%, white solid.

[1076] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.70 - 8.86 (m, 2 H), 8.05 - 8.32 (m, 1 H), 7.60 - 7.72 (m, 1 H), 7.37 - 7.54 (m, 1 H), 6.89 - 7.00 (m, 1 H), 4.35 - 4.75 (m, 1 H), 3.68 - 3.88 (m, 1 H), 3.43 - 3.58 (m, 1 H), 3.09 - 3.30 (m, 1 H), 2.65 - 3.03 (m, 1 H), 2.51 - 2.61 (m, 3 H), 2.32 - 2.39 (m, 3 H), 1.78 (br d, J = 6.1 Hz, 1 H), 1.18 - 1.36 (m, 1 H).

[1077] LCMS (ESI+): m / z =490.0 (M+1), RT: 3.341 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.) Example 78: Synthesis of (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)- 5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 46)

[1078]

[1079] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 7S,4S, 5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 46). Yield 23%, white solid.

[1080] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.99 (br s, 1 H), 8.96 (br s, 1 H), 8.28 - 8.36 (m, 1 H), 7.68 - 7.77 (m, 1 H), 7.64 (s, 1 H), 7.45 - 7.57 (m, 1 H), 7.14 - 7.32 (m, 1 H), 6.66 - 6.79 (m, 1 H), 4.21 - 4.66 (m, 1 H), 3.79 - 3.98 (m, 1 H), 3.36 - 3.52 (m, 1 H), 3.16 - 3.23 (m, 1 H), 2.87 -3.03 (m, 1 H), 2.59 (s, 1 H), 2.32 - 2.39 (m, 2 H), 1.64 - 1.80 (m, 1 H), 1.22 - 1.35 (m, 1 H).

[1081] LCMS (ESI+): m / z =475.0 (M+1), RT: 2.899 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1082] Example 79: Synthesis of 2-(((7S,4S,5R)-2-(4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1,1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 47)

[1083]

[1084] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (RCOOH6) to give the title compound 2-(((1S,4S,5R)-2-(4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 47). Yield 47%, white solid.

[1085] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.78 - 8.93 (m, 2 H), 8.41 - 8.65 (m, 2 H), 7.56 - 7.83 (m, 2 H), 7.43 - 7.55 (m, 1 H), 4.44 - 4.77 (m, 1 H), 3.76 - 3.94 (m, 1 H), 3.35 - 3.53 (m, 1 H), 3.20 (d, J = 10.1 Hz, 1 H), 2.98 - 3.07 (m, 1 H), 2.58 (s, 1 H), 2.43 (s, 2 H), 1.81 (br d, J = 8.0 Hz, 1 H), 1.27 - 1.38 (m, 1 H).

[1086] LCMS (ESI+): m / z =500.1 (M+1), RT: 3.775 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8μm.)

[1087] Example 80: Synthesis of (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5- ((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 48)

[1088]

[1089] General Procedure 5 (see Example 36) was repeated using (7S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i 10) and 6-methyl-3-(2H-1,2, 3-triazol-2-yl) picolinic acid (RCOOH10) to give the title compound (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 48). Yield 18%, white solid.

[1090] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.06 - 8.35 (m, 2 H), 7.93 - 8.05 (m, 2 H), 7.41 - 7.62 (m, 1 H), 6.79 - 7.07 (m, 1 H), 4.11 - 4.90 (m, 1 H), 3.69 - 3.96 (m, 1 H), 3.39 - 3.63 (m, 1 H), 3.35 (br d, J=10.01 Hz, 1 H), 2.99 - 3.25 (m, 1 H), 2.57 (s, 1 H), 2.46 (s, 1 H), 2.32 - 2.43 (m, 4 H), 1.70 - 1.91 (m, 1 H), 1.32 - 1.46 (m, 1 H).

[1091] LCMS (ESI+): m / z =445.1 (M+1), RT: 3.519 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1092] Example 81: Synthesis of (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5- ((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 49)

[1093]

[1094] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH10) to give the title compound (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 49). Yield 38%, white solid.

[1095] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.48-8.63 (m, 1 H), 8.21-8.32 (m, 1 H), 7.60-8.21 (m, 3 H), 7.51-7.59 (m, 1 H), 3.37-4.85 (m, 3 H), 2.91-3.05 (m, 1 H), 2.61 (s, 1 H), 2.42-2.49 (m, 4 H), 2.26 (br s, 1H), 1.72-1.90 (m, 1 H), 1.35-1.46 (m, 1 H).

[1096] LCMS (ESI+): m / z = 445.2 (M+1), RT: 3.664 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1097] Example 82: Synthesis of (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 50)

[1098]

[1099] General Procedure 5 (see Example 36) was repeated using (7S,4S, 5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 50). Yield 38%, white solid.

[1100] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.10-8.26 (m, 1 H), 7.93-8.07 (m, 2 H), 7.83 (br d, J = 11.3 Hz, 1 H), 7.39-7.51 (m, 1 H), 6.93-7.29 (m, 1 H), 4.12-4.74 (m, 1 H), 3.78-4.06 (m, 1 H), 3.34-3.45 (m, 1 H), 3.11-3.21 (m, 1 H), 2.89-3.00 (m, 1 H), 2.55 (s, 1 H), 2.32 (s, 2 H), 2.08-2.19 (m, 3 H), 1.78 (br d, J = 5.5 Hz, 1 H), 1.22-1.33 (m, 1 H).

[1101] LCMS (ESI+): m / z = 462.2 (M+1), RT: 3.917 min (Mobile phase: Ramp from 10% ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2 mL / min. Column temperature at 40°C. The column is XBridge C18 2.1×50mm 5um.)

[1102] Example 83: Synthesis of (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 51)

[1103]

[1104] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 51). Yield 33%, white solid.

[1105] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.42-8.62 (m, 1 H), 7.35-8.23 (m, 4 H), 3.39-4.72 (m, 3 H), 3.18 (br d, J = 9.8 Hz, 1 H), 2.95 (br d, J = 2.3 Hz, 1 H), 2.57 (s, 1 H), 2.36-2.48 (m, 4 H), 2.27 (br s, 1 H), 2.22 (s, 1 H), 2.15 (s, 2 H), 1.77 (br s, 1 H), 1.32 (br d, J = 8.0 Hz, 1 H). LCMS (ESI+): m / z =459.2 (M+1), RT: 3.866 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1106] Example 84: Synthesis of (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)- 5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 52)

[1107]

[1108] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound (4,6- dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5 / ?)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 52). Yield 48%, white solid.

[1109] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.10 - 8.26 (m, 1 H), 7.96 - 8.08 (m, 2 H), 7.60 (br s, 1 H), 7.41 - 7.50 (m, 1 H), 5.98 - 6.29 (m, 1 H), 4.15 (d, J=6.50 Hz, 1 H), 3.87 (br s, 1 H), 3.37 (br d, J=10.38 Hz, 1 H), 3.15 (d, J=9.76 Hz, 1 H), 2.91 - 3.02 (m, 1 H), 2.54 (s, 1 H), 2.36 (s, 2 H), 2.25 (s, 1 H), 2.13 - 2.17 (m, 3 H), 2.11 (s, 2 H), 1.72 - 1.80 (m, 1 H), 1.19 - 1.32 (m, 1 H).

[1110] LCMS (ESI+): m / z = 458.1(M+1), RT: 3.111 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1111] Example 85: Synthesis of ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 53)

[1112]

[1113] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 53). Yield 20%, white solid.

[1114] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.39 - 8.60 (m, 1 H), 7.95 - 8.06 (m, 3 H), 7.40 - 7.49 (m, 1 H), 6.91 - 7.25 (m, 1 H), 6.64 - 6.89 (m, 1 H), 4.20 - 4.71 (m, 1 H), 3.86 - 4.06 (m, 1 H), 3.36 - 3.41 (m, 1 H), 3.19 - 3.26 (m, 1 H), 2.95 - 3.07 (m, 1 H), 2.53 (s, 1 H), 2.37 (s, 2 H), 2.08 - 2.16 (m, 3 H), 1.75 - 1.80 (m, 1 H), 1.23 - 1.33 (m, 1 H).

[1115] LCMS (ESI+): m / z =494.1 (M+1), RT: 3.888 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1116] Example 86: Synthesis of (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)- 5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 54)

[1117]

[1118] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 54). Yield 13%, white solid.

[1119] 1H NMR (400 MHz, DMSO-d6): 6 ppm 7.99 - 8.08 (m, 2 H), 7.90 (s, 1 H), 7.44 - 7.50 (m, 1 H), 7.22 - 7.29 (m, 1 H), 6.81 (d, J=4.25 Hz, 1 H), 4.12 - 4.68 (m, 1 H), 3.84 - 3.93 (m, 4 H), 3.14 - 3.27 (m, 2 H), 2.91 - 3.03 (m, 1 H), 2.57 (s, 1 H), 2.43 (s, 2 H), 2.11 - 2.22 (m, 3 H), 1.72 -1.81 (m, 1 H), 1.21 - 1.36 (m, 1 H).

[1120] LCMS (ESI+): m / z = 474.2 (M+1), RT: 3.560 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8μm.) Example 87: Synthesis of (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)- 5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 55)

[1121]

[1122] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 55). Yield 18%, white solid.

[1123] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.26 - 8.37 (m, 1 H), 8.05 - 8.11 (m, 2 H), 7.67 - 7.76 (m, 1 H), 7.38 - 7.51 (m, 1 H), 7.05 - 7.29 (m, 1 H), 6.67 - 6.78 (m, 1 H), 4.09 - 4.64 (m, 1 H), 3.85 - 3.98 (m, 1 H), 3.42 (br d, J=9.88 Hz, 1 H), 3.15 - 3.21 (m, 1 H), 2.89 - 2.97 (m, 1 H), 2.56 (s, 1 H), 2.28 - 2.33 (m, 2 H), 2.08 - 2.18 (m, 3 H), 1.71 (br d, J=6.75 Hz, 1 H), 1.24 (dd, J=7.69, 2.56 Hz, 1 H).

[1124] LCMS (ESI+): m / z =444.1 (M+1), RT: 2.827 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1125] Example 88: Synthesis of 2-(((1S,4S,5R)-2-(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 56)

[1126]

[1127] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound 2-(((7S,4S,5R)-2-(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 56). Yield 48%, white solid.

[1128] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.40 - 8.65 (m, 2 H), 7.92 - 8.07 (m, 2 H), 7.52 - 7.84 (m, 1 H), 7.42 - 7.49 (m, 1 H), 4.24 - 4.80 (m, 1 H), 3.73 - 3.91 (m, 1 H), 3.35 - 3.41 (m, 1 H), 3.20 (d, J = 9.9 Hz, 1 H), 2.97 - 3.07 (m, 1 H), 2.30 - 2.46 (m, 3 H), 2.07 - 2.17 (m, 3 H), 1.75 - 1.82 (m, 1 H), 1.22 - 1.37 (m, 1 H).

[1129] LCMS (ESI+): m / z =469.2 (M+1), RT: 3.815 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8μm.)

[1130] Example 89: Synthesis of (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)- 5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 57)

[1131]

[1132] General Procedure 5 (see Example 36) was repeated using ( 7 S,4S,5R)- N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (RCOOH4) to give the title compound (4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 57). Yield 24%, white solid.

[1133] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.07 - 8.33 (m, 1 H), 7.82 - 8.04 (m, 2 H), 7.33 - 7.52 (m, 1 H), 6.82 - 7.01 (m, 1 H), 4.17 - 4.79 (m, 1 H), 3.66 - 3.90 (m, 1 H), 3.33 - 3.52 (m, 2 H), 3.11 - 3.16 (m, 1 H), 2.94 - 3.02 (m, 1 H), 2.54 (s, 1 H), 2.39 (s, 2 H), 2.29 (s, 2 H), 2.08 (s, 3 H), 1.73 - 1.84 (m, 1 H), 1.24 - 1.29 (m, 1 H).

[1134] LCMS (ESI+): m / z =459.1 (M+1), RT: 3.333 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1135] Example 90: Synthesis of (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 58)

[1136]

[1137] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 58). Yield 44%, white solid.

[1138] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.84-9.11 (m, 2 H), 8.37-8.65 (m, 1 H), 7.24-7.78 (m, 1 H), 3.73-4.87 (m, 5 H), 3.50 (br d, J = 9.9 Hz, 1 H), 3.18-3.32 (m, 1 H), 2.99 (br d, J = 3.1 Hz, 1 H), 2.55-2.62 (m, 3 H), 2.22-2.48 (m, 3 H), 1.69-1.85 (m, 1 H), 1.30-1.51 (m, 1 H). LCMS (ESI+): m / z =477.2 (M+1), RT: 3.786 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1139] Example 91: Synthesis of ((lS,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 59)

[1140]

[1141] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 59). Yield 30%, white solid.

[1142] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.64-8.80 (m, 2 H), 7.94-8.31 (m, 1 H), 7.68-7.88 (m, 1 H), 6.99-7.14 (m, 1 H), 4.16-4.98 (m, 1 H), 3.80-3.99 (m, 1 H), 3.70 (s, 3 H), 3.36-3.67 (m, 2 H), 2.87-3.02 (m, 1 H), 2.53-2.59 (m, 3 H), 1.64-1.85 (m, 1 H), 1.30-1.42 (m, 1 H).

[1143] LCMS (ESI+): m / z =480.2 (M+1), RT: 3.616 min (Mobile phase: Ramp from 10% ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2 mL / min. Column temperature at 40°C. The column is XBridge C18 2.1×50mm 5um.)

[1144] Example 92: Synthesis of (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((lS,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 60)

[1145]

[1146] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 60). Yield 41%, white solid.

[1147] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.64 - 8.80 (m, 2 H), 7.97 - 8.31 (m, 1 H), 7.44 - 7.62 (m, 1 H), 5.98 - 6.22 (m, 1 H), 4.17 - 4.88 (m, 1 H), 3.68 - 4.02 (m, 4 H), 3.35 - 3.56 (m, 2 H), 2.85 - 3.01 (m, 1 H), 2.53 - 2.58 (m, 3 H), 2.12 (s, 3 H), 1.63 - 1.85 (m, 1 H), 1.31 - 1.40 (m, 1 H).

[1148] LCMS (ESI+): m / z = 476.0(M+1), RT: 2.773 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1149] Example 93: Synthesis of ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 61)

[1150]

[1151] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 61). Yield 51%, white solid.

[1152] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.62 - 8.81 (m, 2 H), 8.24 - 8.60 (m, 1 H), 7.79 - 8.03 (m, 1 H), 6.92 - 7.31 (m, 1 H), 6.53 - 6.82 (m, 1 H), 4.25 - 4.91 (m, 1 H), 3.68 - 4.05 (m, 4 H), 3.42 (br s, 2 H), 2.90 - 3.05 (m, 1 H), 2.54 - 2.59 (m, 3 H), 1.66 - 1.84 (m, 1 H), 1.32 - 1.46 (m, 1 H).

[1153] LCMS (ESI+): m / z =512.0 (M+1), RT: 3.632 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1154] Example 94: Synthesis of (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 62)

[1155]

[1156] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 62). Yield 27%, white solid.

[1157] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.62 - 8.86 (m, 2 H), 7.70 - 8.07 (m, 1 H), 7.11 - 7.28 (m, 1 H), 6.11 - 6.40 (m, 1 H), 4.03 - 4.89 (m, 1 H), 3.71 - 3.98 (m, 6 H), 3.40 (s, 1 H), 3.13 -3.22 (m, 1 H), 2.84 - 3.02 (m, 1 H), 2.53 - 2.60 (m, 3 H), 1.61 - 1.81 (m, 1 H), 1.27 - 1.40 (m, 1 H).

[1158] LCMS (ESI+): m / z = 492.2 (M+1), RT: 3.302 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1159] Example 95: Synthesis of (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 63)

[1160]

[1161] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RC00H3) to give the title compound (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 63). Yield 27%, white solid.

[1162] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.48 - 8.80 (m, 2 H), 7.87 - 8.40 (m, 1 H), 6.85 - 6.99 (m, 1 H), 4.31 - 4.94 (m, 1 H), 3.68 - 3.82 (m, 3 H), 3.40 - 3.66 (m, 2 H), 3.36 (br d, J=9.63 Hz, 1 H), 2.92 - 3.02 (m, 1 H), 2.51 - 2.53 (m, 3 H), 2.37 (s, 3 H), 1.69 - 1.83 (m, 1 H), 1.34 - 1.44 (m, 1 H).

[1163] LCMS (ESI+): m / z =477.2 (M+1), RT: 3.394 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1164] Example 96: Synthesis of 2-(((1S,4S,5R)-2-(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 64)

[1165]

[1166] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH3) to give the title compound 2-(((1S,4S,5R)-2-(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 64). Yield 19%, white solid.

[1167] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.68 - 8.78 (m, 2 H), 8.34 (s, 2 H), 7.66 (s, 1 H), 4.39 (br d, J = 6.1 Hz, 1 H), 3.81 (s, 1 H), 3.64 - 3.73 (m, 3 H), 3.52 (br d, J = 9.8 Hz, 1 H), 3.38 (br d, J = 10.0 Hz, 1 H), 2.92 - 3.04 (m, 1 H), 2.52 (brs, 3 H), 1.67 - 1.82 (m, 1 H), 1.32 - 1.44 (m, 1 H).

[1168] LCMS (ESI+): m / z =487.2 (M+1), RT: 3.521 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1169] Example 97: Synthesis of (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 65)

[1170]

[1171] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RC00H2) to give the title compound (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 65). Yield 41%, white solid.

[1172] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.20-8.80 (m, 2 H), 7.94 (br d, J = 3.4 Hz, 1 H), 7.04-7.66 (m, 2 H), 3.53-4.90 (m, 6 H), 3.26-3.31 (m, 1 H), 2.82-2.98 (m, 1 H), 2.10-2.47 (m, 5 H), 1.77 (brs, 1 H), 1.25-1.46 (m, 1 H).

[1173] LCMS (ESI+): m / z =476.1 (M+1), RT: 3.442 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1174] Example 98: Synthesis of ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 66)

[1175]

[1176] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 66). Yield 35%, white solid.

[1177] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.37-8.55 (m, 1 H), 7.94-8.28 (m, 1 H), 7.60-7.87 (m, 1 H), 7.14-7.55 (m, 3 H), 4.56-4.92 (m, 1 H), 3.67-3.85 (m, 5 H), 3.41-3.66 (m, 1 H), 2.85-3.01 (m, 1 H), 2.37 (s, 3 H), 1.72-1.83 (m, 1 H), 1.29-1.41 (m, 1 H).

[1178] LCMS (ESI+): m / z =479.2 (M+1), RT: 3.543 min (Mobile phase: Ramp from 10% ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2 mL / min. Column temperature at 40°C. The column is XBridge C18 2.1×50mm 5um.)

[1179] Example 99: Synthesis of (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 67)

[1180]

[1181] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 67). Yield 38%, white solid.

[1182] 1H NMR (400 MHz, DMSO-d6): δ ppm 8.35 - 8.56 (m, 1 H), 7.94 - 8.26 (m, 1 H), 7.46 - 7.56 (m, 1 H), 7.13 - 7.45 (m, 2 H), 6.13 - 6.31 (m, 1 H), 4.61 - 4.91 (m, 1 H), 3.68 - 3.85 (m, 4 H), 3.34 - 3.61 (m, 2 H), 2.89 - 3.02 (m, 1 H), 2.35 - 2.43 (m, 3 H), 1.92 - 2.09 (m, 3 H), 1.76 (br d, J=8.88 Hz, 1 H), 1.31 - 1.41 (m, 1 H).

[1183] LCMS (ESI+): m / z =475.1 (M+1), RT: 2.882 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1184] Example 100: Synthesis of ((1S,4S, 5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 68)

[1185]

[1186] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound ((7S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 68). Yield 44%, white solid.

[1187] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.21 - 8.61 (m, 2H), 7.75 - 7.98 (m, 1H), 7.19 - 7.52 (m, 2H), 6.87 - 7.18 (m, 1H), 6.62 - 6.85 (m, 1H), 4.68 - 4.96 (m, 1H), 3.80 - 3.95 (m, 1H), 3.75 (s, 3H), 3.37 - 3.54 (m, 2H), 2.95 - 3.05 (m, 1H), 2.34 - 2.42 (m, 3H), 1.78 (br d, J = 5.4 Hz, 1H), 1.29 - 1.43 (m, 1H).

[1188] LCMS (ESI+): m / z =511.0 (M+1), RT: 3.511 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1189] Example 101: Synthesis of (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 69)

[1190]

[1191] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 69). Yield 38%, white solid.

[1192] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.38 - 8.54 (m, 1 H), 7.69 - 8.03 (m, 1 H), 7.08 - 7.58 (m, 3 H), 6.29 - 6.46 (m, 1 H), 4.55 - 4.89 (m, 1 H), 3.68 - 3.93 (m, 7 H), 3.48 (br d, J=12.26 Hz, 2 H), 2.86 - 3.00 (m, 1 H), 2.38 (s, 3 H), 1.68 - 1.81 (m, 1 H), 1.24 - 1.37 (m, 1 H).

[1193] LCMS (ESI+): m / z = 491.2 (M+1), RT: 3.254 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8μm.)

[1194] Example 102: Synthesis of (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 70)

[1195]

[1196] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RC00H2) to give the title compound (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 70). Yield 17%, white solid.

[1197] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.35 - 8.49 (m, 1 H), 7.95 - 8.34 (m, 1 H), 7.12 - 7.54 (m, 2 H), 6.91 - 6.99 (m, 1 H), 4.63 - 4.95 (m, 1 H), 3.70 - 3.83 (m, 3 H), 3.53 - 3.69 (m, 2 H), 3.34- 3.47 (m, 1 H), 2.93 - 3.03 (m, 1 H), 2.35 - 2.41 (m, 3 H), 2.17 - 2.31 (m, 3 H), 1.72 - 1.87 (m, 1 H), 1.33 - 1.43 (m, 1 H).

[1198] LCMS (ESI+): m / z =476.2 (M+1), RT: 3.387 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1199] Example 103: Synthesis of 2-(((7S,4S,5R)-2-(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 71)

[1200]

[1201] General Procedure 5 (see Example 36) was repeated using 2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8) and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH2) to give the title compound 2-(((7S,4S,5R)-2-(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 71). Yield 46%, white solid.

[1202] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.25 - 8.67 (m, 3 H), 7.63 - 7.79 (m, 1 H), 7.34 - 7.61 (m, 1 H), 7.23 - 7.34 (m, 1 H), 4.69 - 4.97 (m, 1 H), 3.82 (s, 1 H), 3.65 - 3.77 (m, 3 H), 3.51 -3.56 (m, 1 H), 3.36 (br s, 1 H), 2.96 - 3.06 (m, 1 H), 2.33 - 2.42 (m, 3 H), 1.74 - 1.84 (m, 1 H), 1.32 - 1.44 (m, 1 H).

[1203] LCMS (ESI+): m / z = 486.1 (M+1), RT: 3.509 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1204] Example 104: Synthesis of (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 72)

[1205]

[1206] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH12) to give the title compound (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 72). Yield 43%, white solid.

[1207] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.27 - 8.68 (m, 2 H), 7.78 - 8.00 (m, 1 H), 6.98 - 7.35 (m, 2 H), 3.64 - 4.90 (m, 8 H), 3.41 - 3.58 (m, 1 H), 3.29 (d, J=10.01 Hz, 1 H), 2.84 - 3.01 (m, 1 H), 2.09 - 2.48 (m, 6 H), 1.76 (br s, 1 H), 1.23 - 1.45 (m, 1 H).

[1208] LCMS (ESI+): m / z =488.2 (M+1), RT: 2.873 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8μm.)

[1209] Example 105: Synthesis of ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 73)

[1210]

[1211] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4) and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH12) to give the title compound ((7S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 73). Yield 40%, white solid.

[1212] 1H NMR (400 MHz, DMSO-d6): 5 ppm 7.94-8.32 (m, 2 H), 7.52-7.91 (m, 1 H), 6.90-7.34 (m, 3 H), 4.51-4.95 (m, 1 H), 3.42-3.85 (m, 9 H), 2.88-2.99 (m, 1 H), 2.30-2.42 (m, 3 H), 1.67-1.85 (m, 1 H), 1.26-1.37 (m, 1 H).

[1213] LCMS (ESI+): m / z =491.1 (M+1), RT: 2.876 min (Mobile phase: Ramp from 10% ACN in water (10mM NH4HCO3) to 80% ACN in 5.00 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.70 minutes, flow rate is set from 0.7 mL / min to 1.2 mL / min; return back to 10% ACN in water and hold for 0.30 min, flow rate is set at 1.2 mL / min. Column temperature at 40°C. The column is XBridge C18 2.1×50mm 5um.)

[1214] Example 106: Synthesis of (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 74)

[1215]

[1216] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH12) to give the title compound (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 74). Yield 25%, white solid.

[1217] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.17 - 8.25 (m, 1 H), 7.42 - 8.06 (m, 2 H), 6.87 - 7.23 (m, 2 H), 6.12 - 6.28 (m, 1 H), 4.53 - 4.93 (m, 1 H), 3.68 - 3.86 (m, 7 H), 3.33 - 3.59 (m, 2 H), 2.86 - 3.05 (m, 1 H), 2.32 - 2.43 (m, 3 H), 1.93 - 2.10 (m, 3 H), 1.70 - 1.85 (m, 1 H), 1.29 - 1.39 (m, 1 H).

[1218] LCMS (ESI+): m / z =487.1 (M+1), RT: 2.310 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1219] Example 107: Synthesis of (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 75)

[1220]

[1221] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH12) to give the title compound (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 75). Yield 22%, white solid.

[1222] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.13 - 8.42 (m, 2 H), 7.58 - 7.76 (m, 1 H), 6.93 - 7.34 (m, 3 H), 6.67 (dd, J=8.88, 2.63 Hz, 1 H), 4.45 - 4.85 (m, 1 H), 3.84 - 3.94 (m, 1 H), 3.69 - 3.84 (m, 6 H), 3.44 - 3.62 (m, 2 H), 2.84 - 2.97 (m, 1 H), 2.31 - 2.40 (m, 3 H), 1.62 - 1.81 (m, 1 H), 1.26 (dd, J=18.39, 7.75 Hz, 1 H).

[1223] LCMS (ESI+): m / z =473.2 (M+1), RT: 2.531 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.) Example 108: Synthesis of (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((lS,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 76)

[1224]

[1225] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (RCOOH12) to give the title compound (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 76). Yield 40%, white solid.

[1226] 1H NMR (400 MHz, DMSO-d6): 6 ppm 7.99 - 8.41 (m, 2 H), 6.84 - 7.25 (m, 3 H), 4.53 - 4.99 (m, 1 H), 3.60 - 3.86 (m, 8 H), 3.43 - 3.53 (m, 1 H), 2.91 - 3.03 (m, 1 H), 2.15 - 2.40 (m, 6 H), 1.68 - 1.87 (m, 1 H), 1.30 - 1.40 (m, 1 H).

[1227] LCMS (ESI+): m / z =488.1 (M+1), RT: 2.389 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1228] Example 109: Synthesis of (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 77)

[1229]

[1230] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1) and 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (RCOOH7) to give the title compound (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 77). Yield 34%, white solid.

[1231] 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.21 - 8.37 (m, 1 H), 7.92 - 8.04 (m, 1 H), 7.72 (dd, J=8.94, 2.19 Hz, 1 H), 6.88 - 7.64 (m, 3 H), 6.73 - 6.87 (m, 1 H), 3.85 - 4.80 (m, 5 H), 3.38 -3.51 (m, 1 H), 2.88 - 3.18 (m, 2 H), 1.58 - 1.77 (m, 1 H), 1.27 - 1.53 (m, 1 H).

[1232] LCMS (ESI+): m / z =448.1 (M+1), RT: 2.557 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1233] Example 110: Synthesis of (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5- ((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 78)

[1234]

[1235] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5) and 5- fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (RCOOH7) to give the title compound (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 78). Yield 24%, white solid.

[1236] 1H NMR (400 MHz, DMSO-d6): δ ppm 7.90 - 8.25 (m, 2 H), 7.29 - 7.63 (m, 3 H), 6.43 - 6.51 (m, 1 H), 4.32 - 4.85 (m, 4 H), 3.94 - 4.04 (m, 1 H), 3.62 - 3.69 (m, 1 H), 2.93 - 3.21 (m, 2 H), 2.19 (s, 3 H), 1.61 - 1.77 (m, 1 H), 1.22 - 1.55 (m, 1 H).

[1237] LCMS (ESI+): m / z =462.1 (M+1), RT: 3.274 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in water in 4.80 min, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.01 minutes, flow rate is set at 0.6 mL / min; then hold at 80% ACN for 0.59 min, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is Kinetex EVO C18 50×3.0mm, 2.6 um.)

[1238] Example 111: Synthesis of (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 79)

[1239]

[1240] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9) and 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (RCOOH7) to give the title compound (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 79). Yield 24%, white solid.

[1241] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.27 - 8.58 (m, 1 H), 7.85 - 8.23 (m, 2 H), 6.73 - 7.72 (m, 2 H), 3.55 - 4.79 (m, 6 H), 3.09 (br d, J=8.13 Hz, 1 H), 2.86 - 2.96 (m, 1 H), 2.14 - 2.45 (m, 3 H), 1.59 - 1.86 (m, 1 H), 1.20 - 1.54 (m, 1 H). LCMS (ESI+): m / z =463.2 (M+1), RT: 3.839 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1242] Example 112: Synthesis of (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((lS,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 80)

[1243]

[1244] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10) and 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (RCOOH7) to give the title compound (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 80). Yield 48%, white solid.

[1245] 1H NMR (400 MHz, DMSO-d6): 6 ppm 7.85 - 8.38 (m, 2 H), 6.11 - 7.51 (m, 3 H), 4.36 (d, J = 5.25 Hz, 3 H), 3.89 - 4.11 (m, 1 H), 3.37 - 3.68 (m, 2 H), 3.03 - 3.28 (m, 1 H), 2.95 - 3.03 (m, 1 H), 2.38 - 2.48 (m, 3 H), 1.62 - 1.88 (m, 1 H), 1.16 - 1.61 (m, 1 H).

[1246] LCMS (ESI+): m / z =463.1 (M+1), RT: 3.348 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1247] Example 113: Synthesis of (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((lS,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 81)

[1248]

[1249] General Procedure 5 (see Example 36) was repeated using (1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7) and 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (RCOOH7) to give the title compound (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((7S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 81). Yield 23%, purple solid.

[1250] 1H NMR (400 MHz, DMSO-d6): δ ppm 7.72 - 8.07 (m, 2 H) 6.56 - 7.53 (m, 4 H) 3.96 (br s, 8 H) 3.50 (br d, J=9.26 Hz, 1 H) 3.06 - 3.19 (m, 1 H) 2.88 - 2.99 (m, 1 H) 1.59 - 1.82 (m, 1 H) 1.22 - 1.49 (m, 1 H)

[1251] LCMS (ESI+): m / z = 478.1 (M+1), RT: 3.715 min (Mobile phase: Ramp from 10% ACN (0.02%TFA) in water (0.04%TFA) to 80% ACN in 4.8 min, flow rate is set at 0.7 mL / min; then hold at 80% ACN for 0.60 minutes, flow rate is set at 1.0 mL / min; return back to 10% ACN in water and hold for 0.60 min, flow rate is set at 1.0 mL / min. Column temperature at 50°C. The column is ZORBAX SB-C18 2.1x50mm 1.8 μm.)

[1252] BIOLOGICAL ASSAY

[1253] Example 114: IC50 values of compounds with respect to OX1 R and OX2R receptors -In vitro assay: Intracellular calcium measurement

[1254] Antagonistic activity on both human orexin receptors OX1 R and OX2R has been measured using the following procedure:

[1255] HEK cells expressing the human orexin-1 receptor (OX1 R) and the human orexin-2 receptor (OX2R), were seeded at 20000 cells I well into 384-well plates.

[1256] On the day of the assay, after removal of the medium, 40 and 32pL of staining buffer (HBSS / HEPES, probenecid and fluorescent calcium 6 assay dye) was added to IC50 wells, respectively, and the cells were incubated for 90 min at room temperature. Antagonists test compounds were prepared as 10 mM stock solution in DMSO, then diluted with staining buffer. Then, the test compound solution (8 pL) was added to each respective well of the plate, followed by 30 min incubation at room temperature before measurement. For the IC50 compound determination (the concentration of compound needed to inhibit 50 % of the agonistic response), human Orexin-A was diluted in HBSS / HEPES buffer (5x working solution) and within FLIPR 10 pL / well was added and fluorescence measured. The test results are shown in Table 1 below.

[1257] Example 115: Metabolic Stability and Intrinsic Clearance in Human Liver Hepatocytes Stock solutions of test compounds and the positive control were prepared at 10 mM and 30 mM, respectively, in dimethyl sulfoxide (DMSO). The stock solutions of test compounds and positive control, were diluted, respectively with Acetonitrile into a 100 pM and 300 pM (dosing solution), to get a final concentration of 1 pM and 3 pM in the incubation 96-well plates with 0.90% of Acetonitrile and 0.1% of DMSO.

[1258] The cryopreserved hepatocyte cells were thawed in Williams’ Medium E containing 5% fetal bovine serum and 30% Percoll solution and other supplements, isolated and suspended in Incubation Medium (Williams’ Medium E (no phenol red) containing 2 mM L-Glutamine and 25 mM HEPES.). The cell suspension was then diluted with pre-warmed incubation Medium to 0.5 x 106cells / mL and 198 pL pre-warmed suspension were added in 96-well plates. The dosing solution (2 pL) with test compounds were spiked in each well of the 96-well plates in duplicates.

[1259] The samples to evaluate the metabolic clearance in presence of cryopreserved hepatocytes were incubated for 90 min (T90) with the incubation mixture (i.e. cells with incubation medium). At time zero (TO), samples, containing test compounds together with cell suspension diluted to 0.5 x 106cells / mL were mixed to achieve a homogenous suspension for about 1 min, then 25 pL of each sample was immediately transferred into the well of the 96-well plates containing 125 pL of ice-cold stop solution (acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards) followed by mixing. The plates were incubated at 37°C in a 95% humidified incubator at 5% CO2 to start the reactions with constant shaking at about 650 rpm. At 15, 30, 60 and 90 min, samples were mixed and then 25 pL of each sample, at each time point, were transferred to the well containing 125 pL of ice-cold stop solution in a set of pre-labelled 96-well plates, followed by mixing.

[1260] Medium Control (MC) sample plates (labelled as T0-MC and T90-MC) were prepared by adding the incubation medium, except cell suspensions to each well. Samples were collected at time zero (TO) and after 90 min incubation (T90). At each corresponding time point, the reaction was stop by removing the plates from incubator and mixing with 125 pL of ice-cold stop solution. The plates were vortex immediately on a plate shaker at 600 rpm for 10 minutes. Then, all sample plates were centrifuged at 3220 x g for 20 min at 4°C. After centrifugation, 80 pL / well of supernatant in the sample plates were transferred to another set of pre-labelled 96-well plates which containing 240 pL of ultra-pure water according to the plate map. Analytical plates are sealed and store at 4°C until LC-MS / MS analysis. Peak areas were determined from the extracted chromatograms and in vitro half-life of parent compound was determined by regression analysis in the Ln percent parent disappearance vs. time curve. The in vitro Intrinsic Clearance (in vitro Clint, in pL / min / 106cells) was determined from the slope value using the following equation: in vitro CLint=KV / N (V=incubation volume (0.2 mL); N= number of hepatocytes per well.

[1261] Compounds with hCLint LV.hep values ranging from 20 to 35 indicate moderate metabolic stability, while compounds with hCLint LV.hep values below 20, indicate good metabolic stability. The limit of quantification in the assay is 6.4. The test results are shown in Table 1 below.

[1262] Example 116: Caco-2 Cells Assay

[1263] Information of Cell

[1264] Caco-2 cells purchased from ATCC were seeded onto 0.4 pm pore polycarbonate membranes (PC) in 96-well Corning Insert plates at 3.5 x 104 cells / cm2, and refreshed medium every 4~5 days until to the 21stto 28thday for confluent cell monolayer formation.

[1265] Transport Buffer

[1266] The transport buffer in the study was HBSS (Hanks Balanced Salt Solution) containing 10.0 mM HEPES (2-[4-(2-Hydroxyethyl)-1-piperazinyl] ethanesulfonic acid) at pH 7.40 ± 0.05. Methods

[1267] Test compounds were tested at 2.00 pM bi-directionally in duplicate. Digoxin was tested at 10.0 pM bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 pM in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1.0%. The plate was incubated for 2 hours in CO2 incubator at 37.0°C, with 5% CO2 at saturated humidity without shaking. And all samples after mixed with stop solution were centrifuged at 3220 g for 10 minutes. Concentrations of test and control compounds in all samples were semi-quantitatively determined by LC-MS / MS methodologies, using area ratio of analyte / internal standard. After transport assay, the lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity.

[1268] Data Analysis

[1269] The apparent permeability coefficient Papp (cm / s) was calculated using the equation:

[1270] Papp = (dCr / dt) x Vr / (A x Co)

[1271] Where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time; Vris the solution volume in the receiver chamber (0.0750 mL on the apical side, 0.250 mL on the basolateral side); A is the surface area for the transport, i.e. 0.143 cm2for the area of the monolayer; Co is the initial concentration in the donor chamber.

[1272] The efflux ratio was calculated using the equation:

[1273] Efflux Ratio (ER) = Papp (B-A) I Papp (A-B)

[1274] Assay Criteria

[1275] The binning criteria of permeability are proposed based on Caco-2 permeability assay conditions (2.00 pM dosing concentration and 120 minutes incubation). The boundaries for low and high permeability binning are equivalent to 50.0% and 85.0% of the "calculated Fa" in human. The apparent permeability was considered low for Papp < 0.600 (*10-6 cm / s), moderate for 0.600 < Papp < 6.00 (*10-6 cm / s) and high for Papp > 6.00 (*10-6 cm / s).

[1276] The efflux transporter substrate potential was considered likely for ER > 2.00 and poor substrate or non- substrate for ER < 2.00. Most of the tested exemplified compounds show excellent permeability and are not substrates of the efflux transporters.

[1277] Table 1. Bioactivity of exemplary compounds with respect to 0X1 R and 0X2R and Intrinsic Clearance in Human Liver Hepatocytes, Permeability and Efflux ratio in Caco-2 cell line of exemplary compounds in Human Liver Hepatocytes

[1278] Compound # OX1 R OX2R hCLint Papp Efflux ratio

[1279] IC50(nM) IC50 (nM) LV.hep (Caco-2 (Caco-2)

[1280] (ul / min / x10A-6

[1281] 10A6) cm / s)

[1282] 1 25.2 3373 11.4 9.3 3.6

[1283] 2 35.6 2496

[1284] 3 5.5 602.8 25.4 14.8 1.3

[1285] 4 8.6 2986.5 <6.4 20.3 1.2

[1286] 5 5.3 2141 <6.4 19.5 0.9

[1287] 6 80.1 >5000

[1288]

[1289] 7 49.8 >5000 227.8 >5000

[1290] 65.7 >5000

[1291] 4.2 2280 <6.4 10.1 3.2 6.4 4269 8.4 8.1 4.4 12.8 3915 <6.4 23.2 0.8 5.3 2051 <6.4 25.3 0.9 14.2 >5000 13.8 19.6 1 5.3 373.7 <6.4 14.8 1.9 18.5 >5000 6.5 20.1 1.9 6.2 2400 <6.4 25.4 0.7 4 1017 25.8 22.3 0.8 8.2 2452 19.1 17 0.9 2.3 198.8 <6.4 19.9 1.1 10.3 4876 11.3 19.4 1.2 15.5 1050

[1292] 21.9 >5000

[1293] 43 4185

[1294] 14.2 >5000

[1295] 90.5 >5000

[1296] 12.6 568.9

[1297] 51.2 >5000

[1298] 135.4 >5000

[1299] 3.8 526.2

[1300] 36 >5000

[1301] 39.6 4063

[1302] 75.4 >5000

[1303] 24.6 >5000

[1304] 18.9 248.1

[1305] 13.5 1736

[1306] 5.8 183.1

[1307] 39.7 1132

[1308] 8.3 1306 <6.4 13 2 4.8 100.9

[1309] 50.5 2382

[1310] 10.7 112.8

[1311] 16.5 3042

[1312] 38.1 4648

[1313] 22 2183

[1314] 5.3 717.8

[1315] 282 >5000

[1316] 14.3 2309 7.0 18.3 1.2 11.8 1315

[1317] 42.9 4979

[1318] 14.4 266.8

[1319] 20.8 3920

[1320] 61.7 >5000

[1321] 5 237.9

[1322] 8.9 2147 14.3 20 1.1 238.9 >5000

[1323] 47.9 1699

[1324]

[1325] 10.3 789.4 59 19.1 >5000

[1326] 60 15.8 >5000

[1327] 61 34.5 >5000

[1328] 62 15.5 >5000

[1329] 63 16.7 4231 <6.4 2.9 9.7

[1330] 64 51.2 >5000

[1331] 65 15.4 1478

[1332] 66 29.8 >5000

[1333] 67 28.9 >5000

[1334] 68 47.8 >5000

[1335] 69 3.1 2571 7.7 9.2 4

[1336] 70 23.2 >5000

[1337] 71 52.3 >5000

[1338] 72 37.5 1084

[1339] 73 55.1 >5000

[1340] 74 20.3 1999

[1341] 75 26.7 1742

[1342] 76 36.1 2873

[1343] 77 73.7 >5000

[1344] 78 25.3 >5000

[1345] 79 46.4 1242

[1346] 80 240.8 >5000

[1347]

[1348] 81 43.5 2232

[1349] The tested compounds 1-81 showed good binding efficiency for 0X1 receptor; and showed excellent selectively for 0X1 receptors over 0X2 receptors.

[1350] The majority of the tested compounds showed good metabolic stability in human liver hepatocytes. The compounds provided by the present invention are more selective towards 0X1 receptors and have better / similar metabolic stability in human liver hepatocytes.

[1351] Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. CLAIMS:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,3.HN— Het5.

6. Formula I7.wherein:8.Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein said heteroaromatic group is unsubstituted, mono-substituted, di-substituted, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4) straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, fluoroalkyl, cycloalkyl, cyano, alkoxy and halogen; and9.R is selected from a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.

2. The compound as claimed in claim 1 wherein the substituent of the heteroaromatic group in Het is (Ci-C4)-alkyl, (Ci-C4)-fluoroalkyl, (C3-C8)-cycloalkyl, a cyano group, (C1-C4)-alkoxy or a halogen.

3. The compound as claimed in claim 1 or 2, wherein the substituent of the heteroaromatic group in Het is F, Cl, CHF2, CF3, methyl, ethyl, methoxy or nitrile.

4. The compound as claimed in claim 1, 2 or 3, wherein R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof.

5. The compound as claimed in claim 1, 2 or 3, wherein R in the compound of Formula I comprises a six membered aromatic group which is an unsubstituted aryl, or substituted aryl, or any derivatives thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, unsubstituted pyrazine, unsubstituted pyridazine, unsubstituted pyrimidine, unsubstituted triazine, substituted pyridine, substituted pyrazine, substituted pyridazine, substituted pyrimidine, substituted triazine or a derivative thereof.

6. The compound as claimed in claim 4 or 5, wherein the substituent of the R group is independently selected from: a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the substituent is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the substituents of the aromatic or heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-straight chain or branched alkyl group, unsubstituted or substituted (C1-C4)-alkoxy group, and halogen; preferably, the halogen is F, Cl, or Br.

7. The compound as claimed in any one of claims 1 to 6, wherein Het in the compound of Formula I has the following structure:

16. 18.wherein: X and Y are each independently N or C-R6, where R6is H, F, Cl, CHF2, CF3, methyl, ethyl, methoxy or nitrile.

8. The compound as claimed in any one of claims 1 to 7, wherein Het is selected from21.

22.

9. The compound as claimed in any one of claims 1 to 4 and 6 to 8, wherein R is23. 25.wherein Z represents an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the Z is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, and any derivative thereof, wherein the substituents are independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-alkyl group, unsubstituted or substituted (C1-C4)-alkoxy group, and halogen; preferably, the halogen is F, Cl, or Br.

10. The compound according to claim 9, wherein the aromatic group or heteroaromatic group of Z is substituted with F or -O-alkyl, wherein the alkyl group comprises 1-4 carbon atoms, preferably O-alkyl is -OCH3.

11. The compound as claimed in claim 9 or 10 wherein Z is selected from29.

12. The compound as claimed in any one of claims 1 to 11, wherein R is selected from:

33.

34.

13. The compound as claimed in any one of claims 1 to 6, wherein R is selected from:

36. 38.wherein:39.Ri, R2, R3 and R4 are each independently selected from the group consisting of: hydrogen, unsubstituted (Ci-Ce)-straight chain alkyl, unsubstituted (Ci-Ce)-branched alkyl, substituted (Ci-Ce)-straight chain alkyl, substituted (Ci-Ce)-branched alkyl, and halogen; and40.Het’ is selected from the group consisting of: a heteroaromatic group selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein said heteroaromatic group is unsubstituted, mono-substituted, disubstituted, tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: (Ci-C4)-straight chain or branched alkyl, substituted straight chain or branched (Ci-C4)-alkyl, and halogen, preferably the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: F, Cl, and CH3.

14. The compound according to claim 13, wherein R1, R2, R3 and R4 are each independently selected from the group consisting of: H, Cl, F, CF3, methyl and methoxy.

15. The compound as claimed in claim 13 or 14, wherein Het’ is selected from43.

16. The compound as claimed in any one of claims 1 to 8 or 13 to 15, wherein R is selected from:

47.

48.

17. The compound as claimed in any one of claims 1 to 16, wherein the compound has the structure of Formula la, lb, Ic, Id or le:49.F50.

51. ormula la Formula Ic Formula Id53.

54. Formula le55.wherein R1, R2, R3, R4, Het’, X, Y and Z are each independently as defined in any preceding claim.

18. The compound as claimed in claim 1, wherein the compound is selected from:57.(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 1)58. 60.(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 2)62. 64.(5-methyl-2-(pyrimidin-2-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 3)66. 68.(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)- 2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 4)69. 71.(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 5)73. 75.(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 6)77.

78. (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 7)80. 82.(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 8)84. 86.(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 9)88.

89. (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((7S,4S,5R)-5-((5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 10)91. 93.(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazol-3-yl)(( 1S,4S, 5R)-5-((5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 11)95. 97.((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 12)98. 100.(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 13)102. 104.((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo [2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 14)106.

107. ((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 15)109. 111.2-(((1S,4S,5R)-2-(6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 16)113. 115.((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 17)116. 118.(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 18)120. 122.((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1] hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 19)124. 126.((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 20)127. 129.2-(((1S,4S,5R)-2-(6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 21)131. 133.(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 22)135. 137.(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 23)138. 140.((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 24)142. 144.(6'-methyl-[2,3'-bipyridin]-2'-yl)(( 1S,4S, 5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 25)146. 148.((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 26)149. 151.((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 27)153. 155.((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 28)157.

158. 2-(((1S,4S,5R)-2-(6'-methyl-[2,3'-bipyridine]-2'-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 29)160. 162.((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 30)164. 166.((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone (compound 31)168.

169. ((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (compound 32)171. 173.2-(((1S,4S,5R)-2-(4,6-dimethyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 33)175. 177.(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 34)178. 180.(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((4-methyl-5-(trifluoromethyl) pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 35)182. 184.(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 36)186.

187. (4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((3-methoxy-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 37)189. 191.(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 38)193. 195.(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 39)197.

198. (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoro methyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 40)200. 202.(4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 41)204. 206.(4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl) pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 42)208.

209. (4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 43)211. 213.(4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((3-(difluoromethyl)-5-(trifluoro methyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 44)215. 217.(4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 45)218. 220.(4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 46)222. 224.2-(((1S,4S,5R)-2-(4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 47)226. 228.(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 48)229. 231.(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl) pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 49)233. 235.(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((3-fluoro-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 50)236. 238.(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((4-methyl-5-(trifluoromethyl) pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 51 )240. 242.(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 52)244.

245. ((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1] hexan-2-yl)(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 53)247. 249.(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(( 1S,4S, 5R)-5-((3-methoxy-5-(trifluoro methyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 54)251. 253.(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 55)254. 256.2-(((1S,4S,5R)-2-(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinoyl)-2-azabicyclo[2.1.1]hexan- 5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 56)258. 260.(4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 57)262.

263. (4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoro methyl) pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 58)265. 267.((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1 H-pyrazol-3-yl)methanone (compound 59)269. 271.(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoro methyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 60)272. 274.((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo [2.1.1]hexan-2-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 61)276. 278.(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methoxy-5-(tri fluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 62)279. 281.(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoro methyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 63)283. 285.2-(((1S,4S,5R)-2-(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 64)286. 288.(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoro methyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 65)290. 292.((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazol-3-yl)methanone (compound 66)293. 295.(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazol-3-yl)(( 1S,4S, 5R)-5-((3-methyl-5-(trifluoro methyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 67)297. 299.((1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1] hexan-2-yl)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazol-3-yl)methanone (compound 68)301.

302. (4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoro methyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 69)304. 306.(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazol-3-yl)(( 1S,4S, 5R)-5-((3-methyl-5-(trifluoro methyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 70)308. 310.2-(((1S,4S,5R)-2-(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-azabicyclo [2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (compound 71)311. 313.(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((4-methyl-5-(trifluoro methyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 72)315. 317.((1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone (compound 73)318. 320.(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoro methyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 74)322. 324.(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 75)326.

327. (4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)((1S,4S,5R)-5-((3-methyl-5-(trifluoro methyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 76)329. 331.(5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((1S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl) amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 77)333. 335.(5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 78)336. 338.(5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl) pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 79)340. 342.(5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl) pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 80)344.

345. (5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl) pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)methanone (compound 81)347.

348. or a pharmaceutically acceptable salt thereof.

19. A compound of Formula l-aa, or a pharmaceutically acceptable salt thereof:

351.

352. Formula l-aa353.wherein:354.X is selected from the group consisting of: -CH, -C-CH3, -C-CH2CH3, -C-F, -C-CI, -C-CN, -C-CHF2, N and -C-OMe; and355.R is a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or any derivative thereof.

20. The compound as claimed in claim 19, wherein R is selected from:

358. 360.wherein:361.R2and R5are each independently hydrogen or -CH3; and362.Het’ and Z are each independently selected from:

364.

21. The compound according to claim 19 or 20, wherein the compound is selected from:

368.

370.

22. The compound according to any preceding claims, wherein the compound of Formula I is a stereoisomer:

374. 376.preferably, the stereoisomer is a 1S,4S,5R stereoisomer.

23. The compound according to any preceding claim, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, trifluoroacetate, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates,phosphates or diphosphates, aluminates, stereoisomers, enantiomers, diastereomers, solvates, adducts, polymorphs, hydrates, tautomers, isomers, prodrugs, isotopically or radio-labelled compounds, and mixtures thereof.

24. A pharmaceutical composition comprising (a) a compound according to any of claims 1 to 23; and (b) one or more pharmaceutically acceptable excipients; preferably the pharmaceutical composition is in the form of a tablet or a capsule.

25. A compound according to claims 1 to 23 or a pharmaceutical composition according to claim 24 for use as a medicament.

26. A compound according to claims 1 to 23 or a pharmaceutical composition according to claim 24 for use in treating or preventing a disease or disorder at least partially mediated by orexin receptor activity.

27. A method of treating or preventing a disease or disorder at least partially mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of claims 1 to 23 or a pharmaceutical composition according to claim 24.

28. The compound or pharmaceutical composition according to claim 25 or the method according to claim 27, wherein the disease or disorder is selected from the group consisting of: an eating disorder, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, opioid dependence, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behavior disorder and mood disorder depression.

29. Use of a compound according to any of claims 1 to 23 or a pharmaceutical composition according to claim 24, in the preparation of a medicament for the treatment or prevention of diseases or disorders associated with orexin receptor activity.

30. A method of modulating the activity of an orexin receptor OX1, OX2, or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound according to any one of claims 1 to 23, or a pharmaceutical composition according to claim 24.

31. A method for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof:

386.

387. Formula I388.wherein Het and R are each independently as defined in any of claims 1 to 23,389.said method comprising the steps of:390.(a) reacting tert-butyl (1S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate;391.(b) reacting the first intermediate with an acid to form a second intermediate compound;392.and393.(c) reacting the second intermediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I.

32. The method as claimed in claim 1, wherein the step (a) is carried out in the presence of a solvent, preferably the solvent is a polar aprotic solvent selected from the group consisting of: THF, DMF, DMSO and mixtures thereof, more preferably the solvent is DMSO.

33. The method as claimed in claims 31 or 32, wherein the method further comprises at least one of the following features:395.wherein the step (a) is carried out at a temperature in the range of about 90°C to about 190°C, preferably at a temperature about 140°C;396.wherein the step (a) is carried out for a duration of about 10 to about 24 hours, preferably for a duration of about 16 hours.

34. The method as claimed in any preceding claim 31 to 33, wherein the acid is selected from the group consisting of: aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid and mixtures thereof, preferably the acid is hydrochloric acid.

35. The method as claimed in any preceding claim 31 to 34, wherein the step (b) is carried out in the presence of a solvent selected from the group consisting of: diethyl ether, benzene, toluene, chloroform, 1,4-dioxane and mixtures thereof, preferably the solvent is 1,4-dioxane.

36. The method as claimed in any preceding claim 31 to 35, wherein the method further comprises at least one of the following features:400.wherein the step (b) is carried out at a temperature in the range of about 12°C to about 40°C, preferably at about 20°C.401.wherein the step (b) is carried out for a duration of about 30 mins to about 3 hours, preferably for a duration of about 1 hours.

37. The method as claimed in any preceding claim 31 to 36, wherein the halo-substituted heteroaromatic compound is selected from: 2-fluoro-5-(trifluoromethyl)pyridine; 2-chloro-5-(trifluoromethyl)pyrimidine; 2-chloro-5-(trifluoromethyl)pyrazine; 2,3-difluoro-5- (trifluoromethyl)pyridine; 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine; 2-chloro-3- (difluoromethyl)-5-(trifluoromethyl)pyridine; 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine; 2-chloro-5-(trifluoromethyl)nicotinonitrile; 2,4-dichloro-5-(trifluoromethyl)pyrimidine; or 5-(trifluoromethyl)pyrazin-2-ol.

38. The method as claimed in any preceding claim 31 to 37, wherein R in R-COOH group is selected from: a five or a six membered aromatic or heteroaromatic group, wherein thearomatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents, preferably, R comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, oxazole, thiazole, imidazole, a substituted pyrazole oxazole, thiazole, imidazole or a derivative thereof; a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, pyrimidine, pyridazine, pyrazine, or pyridine, pyrimidine, pyridazine, pyrazine or a derivative thereof.

39. The method as claimed in any preceding claim 31 to 38, wherein the carboxylic acid R-COOH is selected from the group consisting of:405.3-fluoro-2-pyrimidin-2-yl-benzoic acid; 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid; 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid;406.4,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid; 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid; 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid; 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid; 5-methyl-2-(pyrimidin-2-yl)benzoic acid; 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid; 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid; 6-methyl-3-(pyrimidin-2-yl)picolinic acid; and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

40. The method as claimed in any preceding claim 31 to 39, wherein tert-butyl (1S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate is reacted with the halogen-substituted heteroaromatic compound to form an intermediate compound, which is reacted with an acid to form the first intermediate; preferably the acid is an alkylboronic acid or alkylboronate such as methylboronic acid.

41. The method as claimed in any preceding claim 31 to 39, wherein tert-butyl (1S,4S,5R)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate is reacted with the halogen-substituted heteroaromatic compound to form an intermediate compound, which is reacted with a methylating agent to form the first intermediate; preferably the methylating agent is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane.

42. The method as claimed in the claim 40 or 41, wherein the intermediate is tert-butyl (7S,4S,5R)-5-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh5) or tert-butyl (1S,4S,5R)-5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate gh9).

43. The method as claimed in any preceding claim 31 to 42, wherein the first intermediate compound is:411.tert-butyl (7S,4S,5R)-5-((5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h1);412.tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h2);413.tert-butyl (1S,4S,5R)-5-((5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h3);414.tert-butyl (1S,4S,5R)-5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h4);415.tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h5);416.tert-butyl (1S,4S,5R)-5-((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h6);417.tert-butyl (1S,4S,5R)-5-((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h7);418.tert-butyl (1S,4S,5R)-5-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h8)419.tert-butyl (1S,4S,5R)-5-((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h9); or420.tert-butyl (1S,4S,5R)-5-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (intermediate h10).

44. The method as claimed in any preceding claim 31 to 43, wherein the second intermediate compound is:422.(1S,4S,5R)-N-(5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i1); (1S,4S,5R)-N-(5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i2);423.(1S,4S,5R)-N-(5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i3);424.(1S,4S,5R)-N-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i4);425.(1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i5);426.(1S,4S,5R)-N-(3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i6);427.(1S,4S,5R)-N-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine (intermediate i7);428.2-(((1S,4S,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-5-(trifluoromethyl)nicotinonitrile (intermediate i8);429.(1S,4S,5R)-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i9); or430.(1S,4S,5R)-N-(3-methyl-5-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[2.1.1]hexan-5-amine hydrochloride (intermediate i10).

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