Modulators of g protein-coupled receptor 88

Abstract

N-([1,1'-biaryl]-4-yl)-N-((1-hydroxycycloalkyl)methyl)-2-(aryl)cyclopropane-1-carboxamide compounds (I) and derivatives are G-protein coupled receptor (GPR) 88 modulators for use in the treatment of a disease mediated by GPR88. Indications include Tourette's Syndrome, Huntington's Disease (HD), Addiction, Parkinson's Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, tardive dyskinesia, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer's disease, basal ganglia disorders, and tardive dyskinesia.

Description

MODULATORS OF G PROTEIN-COUPLED RECEPTOR 88 RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 691,083, filed September 5, 2024, which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure is generally directed to compounds which can modulate G- protein coupled receptor 88, compositions comprising such compounds, methods for modulating G-protein coupled receptor 88 and compounds for use in such methods. BACKGROUND

[0003] GPR88 is an orphan member of the G protein coupled receptor (GPCR) superfamily and a member of the class A rhodopsin family of GPCRs. The receptor exhibits high expression in the central nervous system (CNS) with limited expression in the periphery.

[0004] Within the CNS, the mRNA for the GPR88 receptor is localised primarily to selective areas of the brain, namely the striatum (Mizushima et al., Genomics (2000) 69, 314-321; Vassilatis et al., Proc. Natl. Acad. Sci. (2003), 100, 4903-4908; Massart et al., Eur. J. Neurosci. (2009), 30, 397-414). It is also present at lower expression levels in the frontal cortex and thalamus (Thomson et al., Genes, Brain and Behavior (2021), 20, e12710). Striatal expression is on GABAergic medium spiny neurons (MSN). Data from rodents suggest that GPR88 displays the highest mRNA expression levels compared to other knowns GPCRs in the striatum (Komatsu et al., PLOS One (2014), 9(2), e90134).

[0005] The striatum regulates various aspects of cognition, motivation and reward as well as movement and motor learning and has been implicated in neuropsychiatric diseases such as Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD) (Ena et al., Frontiers Behav. Neurosci. (2011), 5, doi: 10.3389 / fnbeh.2011.00047). The selective GPR88 expression profile in striatal output neurons, led to the discovery that the GPR88 receptor modulates the function of several cortico-striato-thalamic loops via striatal MSNs influencing both direct and indirect pathways and subsequently influencing cortical transmission. The receptor also regulates monoamine neurotransmission (Quintana et al., Nat Neurosci. (2012), 15(11), 1547-1555; Meirsman et al., Biological Psychiatry (2016), 79, 917-927), influences neural connectivity (Arefin et al., Brain Connectivity (2017), 7, 526-540), and thus suggest its possible relevance as a target for motor symptoms in CNS diseases (van Waes et al., Basal Ganglia (2011), 1(2), 83- 89) as well as its previously suggested roles in cognitive and reward pathways.

[0006] In GPR88Cre / Creknockout (KO) mice, MSNs have increased glutamatergic excitation resulting from enhanced phosphorylation of the AMPA-type glutamate receptor subunit GluR1, reduced tonic GABAergic inhibition resulting from low level of b3 protein (a GABA-A subunit) that together promote enhanced firing rates in vivo, resulting in hyperactivity, poor motor- coordination, and impaired cue-based learning in mice (Quintana et al., 2012). Furthermore, GPR88- / -knockout mice display impaired striatal dependent behaviours (Meirsman et al., 2016). GPR88 deletion impaired motor coordination and motor learning in the accelerating rotarod test. GPR88 knockout mice travelled a longer distance in the open field as compared to controls and this hyperactivity failed to habituate over sessions. In a separate study (Thomson et al., 2021), GPR88 KO mice showed impaired correct responding in an N-back task, suggesting a role for GPR88 receptors in working memory. In a touchscreen task, performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen-based equivalent of the Iowa gambling task.

[0007] In post-mortem brains from HD patients, it has been shown that GPR88 mRNA is significantly downregulated (Hodges et al., Human Molecular Genetics (2006), 15, 965-977). Additionally, in aged BACHD and R6 / 1 murine models of HD, a significant decrease in GPR88 mRNA has also been detected (Desplats et al., J. Neurochem. (2006), 96, 743-757; Rocher et al., Neurobiology of Disease (2016), 86, 131-139).

[0008] Rare mutations in humans suggest a role in cognition and motor function. A recent molecular investigation of patients from a consanguineous family (non-HD patients) who presented in childhood with choreiform movements, speech delay, and learning disabilities indicated a GPR88 deficiency due to a homozygous deleterious mutation in GPR88 (Alkufri et al., Neurol Genet (2016), 2:e64; doi: 10.1212 / NXG.0000000000000064). This clinical data is consistent with the reported abundant expression of GPR88 in the striatum and the hyperkinetic activity and learning impairment observed in GPR88 knockout mice as highlighted previously.

[0009] The therapeutic potential of GPR88 modulators in PD has been demonstrated by studies showing that the knockdown of GPR88 in the striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease (Galet et al., 2019. hal-02361982; Galet et al., J Psychiatry Neurosci (2020), doi: 10.1503 / jpn.190171) and further studies showing that genetic deletion of GPR88 promotes L-DOPA-induced rotation and spontaneous locomotion yet suppresses the induction of LIDs and also reduces tremor (Mantas et al., Neuropharmacology (2020), 162, 107829). Transcriptional profiling studies have also revealed that GPR88 expression is altered by treatments or conditions related to bipolar disorder (Ogden et al., Molecular Psychiatry (2004), 9, 1007-1029) and depression (Brandish et al., Neuron (2005), 45, 861-872; Boehm et al., J. Neurochem. (2006), 97 (Suppl. 1), 44-49). Furthermore, GPR88receptors have been implicated in addiction (Hamida et al., Biological Psychiatry (2018), doi: 1016 / j.biopsych.2018.01.026) and affective disorders (Watkins & Orlandi, Genes (2020), 11, 694; doi: 10.3390 / genes11060694).

[0010] Based on these data, compounds that modulate GPR88 activity (agonists, antagonists, or modulators) are predicted to have therapeutic utility in the treatment of Huntington’s Disease (HD) and other hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, attention deficit hyperactivity disorders (ADHD), Tourette’s Syndrome, bipolar disorder, addiction, Alzheimer's disease (AD) Parkinson's disease (PD), and other basal ganglia disorders.

[0011] GPR88 demonstrates GPCR activity in several assays including GTPgS binding, calcium influx, and cAMP inhibition assays.

[0012] Two main series of GPR88 agonists have been described in the literature and detailed in a review by Ye, N et al., ACS Chem. Neurosci.10(1), 190-200, 2019. In the biarylaniline Series 1, Bi et al Bioorganic & Medicinal Chemistry Letters 25, 1443–1447, 2015; Jin et al, ACS Chem. Neurosci.,5(7), 576–587, 2014; Jin et al, ACS Chem Neurosci., 7(10):1418-1432, 2016; Jin et al, J. Med. Chem., 61, 6748–58, 2018; Jin et al, SFN Poster 175.08, Oct 2019; WO2011044212 describe extensive exploration of the Ar1, Ar2and R-groups and agonist potency. Some preferred groups at each position for potency are identified, but very little data is disclosed for important ADME properties such as hepatocyte metabolic stability, or off-target pharmacology such as inhibition of the DAT dopamine transporter. Indeed, the Jin et al SFN poster 175.08 shows all analogues tested to have very high clearance in mouse liver microsomes. WO2022 / 129933 describes additional biarylaniline GPR88 modulators.

[0013] In the phenylglycinol Series 2, Dzierba et al., BMCL, 25, 1448-52, 2015; Jin et al., Bioorg. Med. Chem., 25(2), 805-12, 2017; Rahman et al., J. Med. Chem., 63(23), 14989-15012, 2020; Rahman et al., J. Med. Chem., 64(16), 12397-12413, 2021; WO2011 / 044225; WO2011 / 044195 describe extensive exploration of the R1, R2and R3-groups and agonist potency. Some preferred groups at each position for potency are identified, but very little data is disclosed for important ADME properties such as hepatocyte metabolic stability, or off-target pharmacology such as inhibition of the DAT dopamine transporter.

[0014] It has now been found that the prior art GPR88 modulators exhibit one or more suboptimal pharmacokinetic properties, potency, brain exposure, and / or exhibit off target activity. SUMMARY

[0015] The present disclosure is directed towards the identification of a novel class of GPR88 modulators having improved pharmacokinetic properties and / or reduced off target activity relative to prior art GPR88 modulators.

[0016] It is an aim of certain embodiments of this disclosure to provide compounds having GPR88 modulating activitiy.

[0017] It is an aim of certain embodiments of this disclosure to provide compounds having GPR88 modulating activitiy and improved pharmacokinetic properties relative to prior art GPR88 modulators.

[0018] It is an aim of certain embodiments of this disclosure to provide compounds having GPR88 modulating activitiy and reduced off target activity relative to prior art GPR88 modulators.

[0019] It is an aim of certain embodiments of this disclosure to provide compounds having GPR88 modulating activitiy, improved pharmacokinetic properties relative to prior art GPR88 modulators and reduced off target activity relative to prior art GPR88 modulators.

[0020] Certain embodiments of the present disclosure satisfy some or all of the above aims.

[0021] In an aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:wherein: R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl, –O-C3-C4-cycloalkyl, C1-C4-alkyl, and –CH2–O-C1-C4-alkyl, each unsubstituted or substituted with one or more fluoro; Z1is N or CR1a;5 R1ais selected from the group consisting of H, F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; m is 0 or 1; R1bis selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl; n is 0, 1, or 2; R2, at each occurrence, is independently selected from the group consisting of F, Cl, cyano, C1-C4-alkyl, C1-C4-fluoroalkyl, –OR2a, –SR2a, –NR2bR2c, –N(R2d)C(O)R2e, and a C3-C6-cycloalkyl; R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C4-cycloalkyl, and –C1-3alkylene–C3-C4- cycloalkyl; wherein alternatively, R2band R2c, together with the nitrogen to which each attaches, form an optionally substituted 4- to 7-membered heterocyclyl, optionally containing a second heteroatom selected from the group consisting of O, N, and S; or wherein alternatively, R2band R2c, together with the nitrogen to which each attaches, form an optionally substituted 5-membered heteroaryl, optionally containing 1-2 additional nitrogen atoms; L isR3is a 6-membered aromatic ring, optionally containing 1-2 nitrogen atoms, and optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; and R4aand R4btogether with the atom to which each attaches form a C3-C5cycloalkane or a 4- to 5-membered heterocycle containing one oxygen atom.

[0022] In another aspect is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0023] In another aspect is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, tardive dyskinesia, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer’s disease and basal ganglia disorders.

[0024] In another aspect is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of tardive dyskinesia or a symptom thereof.6 DETAILED DESCRIPTION

[0025] According to a first aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R1b, R2, R3, R4a, R4b, Z1, L, m, n, and p are as defined herein.

[0026] In the following, numbered embodiments of the invention are disclosed (e.g., E1, E1.1, E1.2, E2, E3, E3.1, E3.2, E3.3, E3.4, E4, etc.). In the numbered embodiments, the reference to a range of preceding embodiments in multiple dependent format (e.g., "the compound of any one of E1-E4.3") is a reference, in the alternative, to each embodiment sequentially listed herein in the recited range. For example, the range "any one of E1-E4.3 means "any one of E1, E1.1, E1.2, E2, E3, E3.1, E3.2, E3.3, E3.4, E4, E4.1, E4.2, or E4.3."

[0027] E1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein: R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl, –O-C3-C4-cycloalkyl, C1-C4-alkyl, and –CH2–O-C1-C4-alkyl, each unsubstituted or substituted with one or more fluoro; Z1is N or CR1a; R1ais selected from the group consisting of H, F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; m is 0 or 1; R1bis selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl; n is 0, 1, or 2; R2, at each occurrence, is independently selected from the group consisting of F, Cl, cyano, C1-C4-alkyl, C1-C4-fluoroalkyl, –OR2a, –SR2a, –NR2bR2c, –N(R2d)C(O)R2e, and a C3-C6-cycloalkyl;R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C4-cycloalkyl, and –C1-3alkylene–C3-C4- cycloalkyl; wherein alternatively, R2band R2c, together with the nitrogen to which each attaches, form an optionally substituted 4- to 7-membered heterocyclyl, optionally containing a second heteroatom selected from the group consisting of O, N, and S, the heterocyclyl being optionally substituted; or wherein alternatively, R2band R2c, together with the nitrogen to which each attaches, form an optionally substituted 5-membered heteroaryl, optionally containing 1-2 additional nitrogen atoms; L isR3is a 6-membered aromatic ring, optionally containing 1-2 nitrogen atoms, and optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; and R4aand R4btogether with the atom to which each attaches form a C3-C5cycloalkane or a 4- to 5-membered heterocycle containing one oxygen atom.

[0028] E1.1. The compound of E1, or a pharmaceutically acceptable salt thereof wherein the optionally substituted 4- to 7-membered heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches, is optionally substituted with a first substituent selected from the group consisting of halo, cyano, C1-C4-alkyl, C1-C4-fluoroalkyl, oxo, OH, and –O-C1-C4-alkyl, and optionally further substituted with 1-3 substituents independently selected from the group consisting of halo and C1-C4-alkyl.

[0029] E1.2. The compound of E1 or E1.1, or a pharmaceutically acceptable salt thereof wherein the optionally substituted 5-membered heteroaryl formed by R2band R2c, together with the nitrogen to which each attaches, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, cyano, C1-C4-alkyl, and C1-C4-fluoroalkyl.

[0030] E2. A compound any one of E1-E1.2, of Formula (I) or a pharmaceutically acceptable salt thereof:wherein: R1is selected from the group consisting of –O-C1-C4-alkyl, –O-C3-C4-cycloalkyl, C1-C4-alkyl, andR1ais selected from the group consisting of H, F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; m is 0 or 1; R1bis selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl; n is 0, 1, or 2; R2, at each occurrence, is independently selected from the group consisting of F, Cl, C1-C2-alkyl, -alkyl;R3is a 6-membered aromatic ring, optionally containing 1-2 nitrogen atoms, and optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; and R4aand R4btogether with the atom to which each attaches form a C4-C5cycloalkane or a 4- to 5-membered heterocycle containing one oxygen atom.

[0031] E3. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a C3-C5cycloalkane, i.e., the compound has formula (II-A):

[0032] E3.1. The compound of E3, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a cyclopropane, i.e., p is 1.

[0033] E3.2. The compound of E3, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a cyclobutane, i.e., p is 2.

[0034] E3.3. The compound of E3, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a cyclopentane, i.e., p is 3.

[0035] E3.4. The compound of any one of E1-E3 or E3.2-E3.3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II):p is 1 or 2.

[0036] E4. The compound of E1 or E2, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a 4- to 5-membered heterocycle containing one oxygen atom

[0037] E4.1. The compound of E4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):

[0038] E4.2. The compound of E4.1, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0039] E4.3. The compound of E4.1, or a pharmaceutically acceptable salt thereof, wherein q is 2.

[0040] E5. The compound of any one of E1-E4.3, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl, C1-C4-alkyl, –O-C1-C4-fluoroalkyl, and –CH2–O-C1-C4-alkyl. The –O-C1-C4-alkyl, –S-C1-C4-alkyl, C1-C4-alkyl, and –CH2–O-C1-C4-alkyl in E5 are not substituted with fluoro.

[0041] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein R1is –S-C1-C4-alkyl.

[0042] E5.2. The compound of E5.1, or a pharmaceutically acceptable salt thereof, wherein R1is –S-CH2CH3.

[0043] E5.3. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C4-alkyl.

[0044] E5.4. The compound of E5.3, or a pharmaceutically acceptable salt thereof, wherein R1is –CH2CH2CH3.

[0045] E5.5. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein R1is –O-C1-C4-fluoroalkyl.

[0046] E5.6. The compound of E5.5, or a pharmaceutically acceptable salt thereof, wherein R1is –OCH(CH3)(CF3).

[0047] E5.7. The compound of E5.6, or a pharmaceutically acceptable salt thereof, wherein R1is –(S)-OCH(CH3)(CF3).

[0048] E6. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein R1is –O-C1-C4-alkyl or –CH2–O-C1-C4-alkyl.

[0049] E6.1. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein R1is –O-C1-C4-alkyl.

[0050] E6.2. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein R1is –CH2–O-C1-C4-alkyl.

[0051] E7. The compound of any one of E6-E6.2, or a pharmaceutically acceptable saltthereof, wherein R1is selected from the group consisting of –OCH2CH3, –OCH(CH3)2, and–CH2–O-CH3.

[0052] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R1is –OCH2CH3.

[0053] E7.2. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R1is –OCH(CH3)2.

[0054] E7.3. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R1is –CH2–O-CH3.

[0055] E8. The compound of any one of E1-E7.3, or a pharmaceutically acceptable salt thereof, wherein Z1is N.

[0056] E9. The compound of any one of E1-E7.3, or a pharmaceutically acceptable salt thereof, wherein Z1is CR1a.

[0057] E10. The compound of any one of E1-E7.3 or E9, or a pharmaceutically acceptable salt thereof, wherein R1ais H.

[0058] E11. The compound of any one of E1-E10, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0059] E12. The compound of any one of E1-E11, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0060] E13. The compound of any one of E1-E11, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0061] E14. The compound of any one of E1-E11 or E13, or a pharmaceutically acceptable salt thereof, wherein

[0062] E15. The compound of any one of E1-E11 or E13-E14, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is independently selected from the group consisting of F, cyano, C1-C4-alkyl, –OR2a, –SR2a, –NR2bR2c, and –N(R2d)C(O)R2e.

[0063] E16. The compound of E15, or a pharmaceutically acceptable salt thereof, wherein R2is –NR2bR2c, and R2band R2c, together with the nitrogen to which each attaches, form the 4- to 7-membered heterocyclyl, optionally substituted as defined in E1.

[0064] E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein the 4- to 7-membered heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches, is selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, and morpholino, each optionally substituted as defined in E1.

[0065] E16.2. The compound of E16.1, or a pharmaceutically acceptable salt thereof, wherein the 4- to 7-membered heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches, is azetidin-1-yl, optionally substituted as defined in E1.

[0066] E16.2.1 The compound of E16.1, or a pharmaceutically acceptable salt thereof, wherein the 4- to 7-membered heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches, is pyrrolidin-1-yl, optionally substituted as defined in E1.

[0067] E16.2.2 The compound of E16.1, or a pharmaceutically acceptable salt thereof, wherein the 4- to 7-membered heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches, is piperidin-1-yl, optionally substituted as defined in E1.

[0068] E16.2.3 The compound of E16.1, or a pharmaceutically acceptable salt thereof, wherein the 4- to 7-membered heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches, is morpholino, optionally substituted as defined in E1.

[0069] E16.3. The compound of any one of E1-E11 or E13-E16.2.3, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches is optionally substituted with a first substitutuent selected from the group consisting of C1-C4-alkyl and oxo, and optionally further substituted with 1-3 C1-C4- alkyl.13

[0070] E16.4. The compound of E16.3, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl formed by R2band R2c, together with the nitrogen to which each attaches is optionally substituted with a first substitutuent selected from the group consisting of methyl and oxo, and optionally further substituted with 1-3 methyl.

[0071] E16.5. The compound of any one of E16-E16.4, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of

[0072] E16.6. The compound of any one of E16-E16.5, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of

[0073] E16.7. The compound of E16.6, or a pharmaceutically acceptable salt thereof, wherein R2is

[0074] E17. The compound of any one of E1-E11 or E13-E15, or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C4- cycloalkyl, and –C1-3alkylene–C3-C4-cycloalkyl.

[0075] E17.1. The compound of E17, or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, C1-C4-alkyl, and C3-C4-cycloalkyl.

[0076] E17.2. The compound of E17.1, or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, methyl, isopropyl, and cyclopropyl.

[0077] E17.3. The compound of any one of E15 or E17-E17.2, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is independently selected from the group consisting of F, cyano, C1-C4-alkyl, –OC1-C4-alkyl,–OC3-C4-cycloalkyl, –SC1-C4-alkyl, –NH2, –NHC1-C4-alkyl, –N(C1-C4-alkyl)2, –N(H)C(O)C1-C4-alkyl, and –N(H)C(O)C3-C4-cycloalkyl. 5

[0078] E17.4. The compound of E17.3, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is independently selected from the group consisting of F, cyano,.

[0079] E18. The compound of E15, or a pharmaceutically acceptable salt thereof, 10 wherein R2is –NR2bR2c, and R2band R2c, together with the nitrogen to which each attaches, form the 5-membered heteroaryl, optionally substituted as defined in E1.

[0080] E18.1. The compound of E18, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroaryl formed by R2band R2c, together with the nitrogen to which each attaches, is selected from the group consisting of pyrazolyl, imidazolyl, and triazolyl, each 15 optionally substituted as defined in E1.

[0081] E18.2. The compound of E18 or E18.1, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroaryl formed by R2band R2c, together with the nitrogen to which each attaches, is unsubstituted.

[0082] E18.3. The compound of E18.2, or a pharmaceutically acceptable salt thereof, 20 wherein R2is selected from the group consisting of , and

[0083] E19. The compound of any one of E1-E11, E13-E15, or E17-E17.4, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is independently selected from the group consisting of CH3, F, and OCH3. 25

[0084] E19.1. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is CH3.

[0085] E19.2. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is F.

[0086] E19.3. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is OCH3. 5

[0087] E20. The compound of any one of E1-E19.3, or a pharmaceutically acceptable salt thereof, wherein L is

[0088] E21. The compound of any one of E1-E20, or a pharmaceutically acceptable salt thereof, wherein R3is a pyridinyl or pyrimidinyl, each optionally substituted as defined in E1.

[0089] E21.1. The compound of E21, or a pharmaceutically acceptable salt thereof, 10 wherein R3is a pyridinyl, optionally substituted as defined in E1.

[0090] E21.2. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R3is a pyrimidinyl, optionally substituted as defined in E1.

[0091] E22. The compound of any one of E21-E21.2, or a pharmaceutically acceptable salt thereof, wherein R3is a pyridin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, each optionally 15 substituted as defined in E1.

[0092] E22.1. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R3is pyridin-2-yl, optionally substituted as defined in E1.

[0093] E22.2. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R3is pyrimidin-2-yl, optionally substituted as defined in E1. 20

[0094] E22.3. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R3is pyrimidin-4-yl, optionally substituted as defined in E1.

[0095] E23. The compound of any one of E1-E22.3, or a pharmaceutically acceptable salt thereof, wherein each R3is optionally substituted with 1 substituent selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl. 25

[0096] E24. The compound of E23, or a pharmaceutically acceptable salt thereof, wherein each R3is optionally substituted with F.16

[0097] E25. The compound of E24, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of

[0098] E25.1. The compound of E25, or a pharmaceutically acceptable salt thereof, 5 wherein R3is

[0099] E25.2. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R3is

[0100] E25.3. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R3is10

[0101] E25.4. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R3is

[0102] E25.5. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R3is

[0103] E26. The compound of E1, or a pharmaceutically acceptable salt thereof, 15 wherein the compound has formula (II-B) or (III-A):p is 1, or 2; q is 0, 1 or 2; n is 0 or 1; Z1is N or CH; R2is azetidin-1-yl; and R5is selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl.

[0104] E27. The compound of E26, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0105] E28. The compound of E26, or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0106] E29. The compound of any one of E26-E28, or a pharmaceutically acceptable salt thereof, wherein R5is F.

[0107] E30. The compound of any one of E26-E29, or a pharmaceutically acceptable salt thereof, wherein n is 0. When n is 0, it is understood that hydrogen is present in place of R2.

[0108] E31. The compound of any one of E26-E29, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0109] E32. The compound of any one of E26-E31, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl,C1-C4-alkyl, –O-C1-C4-fluoroalkyl, and –CH2–O-C1-C4-alkyl. The –O-C1-C4-alkyl, –S-C1-C4-alkyl, C1-C4-alkyl, and –CH2–O-C1-C4-alkyl in E32 are not substituted with fluoro

[0110] E33. The compound of any one of E26-E31, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –O-C1-C4-alkyl.

[0111] E34. The compound of any one of E26-E33, or a pharmaceutically acceptable salt thereof, wherein Z1is CH.

[0112] E35. The compound of any one of E26-E33, or a pharmaceutically acceptablesalt thereof, wherein Z1is N.

[0113] E36. The compound of E1 or E2, selected from the group consisting of: (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-2-(pyridin- 2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(6-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide;(1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-(methoxymethyl)pyridin-3-yl)phenyl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6- (methoxymethyl)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-Ethoxypyridin-3-yl)phenyl)-N-((1-hydroxycyclobutyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-Ethoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-propyl-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-propylpyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-methyl- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-methoxy- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide;(1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin- 3-yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide;(1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-(methoxymethyl)pyridin-3-yl)phenyl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6- (methoxymethyl)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-2-(6-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyrimidin- 4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-propyl-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-propylpyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-N-(4'-isopropoxy- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-N-(4'-isopropoxy- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(6-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide;(1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-(pyrrolidin- 1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-(piperidin- 1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3- morpholino-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)- 2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((3-hydroxyoxetan-3- yl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3,4'-diisopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan- 3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-cyclopropoxy-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3- (methylamino)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(dimethylamino)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide;(1R,2R)-N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-N-((1- hydroxycyclobutyl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-N-((3-hydroxyoxetan-3- yl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)- 2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((3-hydroxyoxetan-3- yl)methyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(methylthio)-[1,1'-biphenyl]-4-yl)- 2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(1H- 1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(1H-imidazol-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N- ((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(1H- 1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-amino-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-acetamido-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide;(1R,2R)-N-(3-(cyclopropanecarboxamido)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin- 2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(2- oxoazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; 5 (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl) -N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1- 10 hydroxycyclopropyl)methyl) -2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1- hydroxycyclopropyl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; 15 (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl) methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- 20 hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclopropyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; 25 (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclopentyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide;(1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-(1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)phenyl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-((S)-2- methylazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-((R)-2- methylazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-(1H- 1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-((2R,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-((2S,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-((2R,4R)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; and (1R,2R)-N-(3-(3,3-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2- yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0114] E37.1. The compound of E36, selected from the group consisting of: (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide;(1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; 5 (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin- 10 3-yl)phenyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0115] E37.2. The compound of E36, selected from the group consisting of: (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; 15 (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- 20 biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; 25 (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide;(1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; and (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0116] E37.3. The compound of E37.2, selected from the group consisting of: (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; and (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0117] E38. A pharmaceutical formulation comprising a compound of any one of E1- E37.3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0118] E39. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of E1-E38, for use as a medicament.

[0119] E40. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of E1-E39, for use in the treatment of a disease or disorder, or a symptom thereof, wherein the disease or disorder is mediated by GPR88.

[0120] E41. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of E1-E40, for use in the treatment of a disease or disorder, or a symptom thereof, wherein the disease or disorder is selected from the group consisting of Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, tardive dyskinesia, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer’s disease and basal ganglia disorders.

[0121] E42. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of E1-E41, for use in the treatment of tardive dyskinesia, or a symptom thereof.

[0122] E43. A method of treating a disease or disorder mediated by GPR88, or a symptom thereof, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of E1 to E37.3, or a pharmaceutically acceptable salt thereof, or the pharmaceutical formulation of E38.

[0123] E44. The method of E43, wherein the disease or disorder is selected from the group consisting of Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, tardive dyskinesia, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer’s disease and basal ganglia disorders.

[0124] E45. The method of E44, wherein the disease or disorder is tardive dyskinesia.

[0125] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds disclosed herein, a chiral atom depicted or described without a specificstereochemical configuration (e.g., a straight bond, not wedged or dashed bond, HC(OH)(CH3)(CH2CH3)) encompasses any stereochemical configuration at the chiral atom.

[0126] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[0127] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium).

[0128] The present disclosure also includes isotopically-labeled compounds (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively.

[0129] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label).

[0130] Also provided is a compound selected from the compounds recited in the examples below or a pharmaceutically acceptable salt thereof. Definitions

[0131] Unless otherwise stated, the following terms used in the specification and claims have the meanings set out below.

[0132] It is to be appreciated that references to “treating“ or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of astate, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, 5 disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0133] A “therapeutically effective amount” includes the amount of a compound that, when 10 administered to a mammal for treating a disease, is sufficient to affect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0134] The term “halo” or “halogen” includes to one of the halogens, group 17 of the periodic table. In particular the term includes fluorine, chlorine, bromine and iodine. 15

[0135] The term “C1-C6 alkyl” includes a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, n-pentyl and n-hexyl. The term “C1-C4alkyl” includes such groups containing up to 4 carbon atoms. Alkylene groups include divalent alkyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, an 20 alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-C4alkoxy. Other substituents for the alkyl group may alternatively be used. Alkyl and alkylene groups are unsubstituted, unless 25 substituents are specified.

[0136] The abbreviation “Me” may be used for methyl and “OMe” for methoxy.

[0137] The term “C1-C6haloalkyl”, e.g. “C1-C4haloalkyl”, includes a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example, from fluorine, chlorine, bromine and iodine. The halogen atom may be present at any 30 position on the hydrocarbon chain. For example, C1-C6haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl or trifluoropropyl.

[0138] The term “heteroalkyl”, includes an alkyl group in which the hydrocarbon chain has at least one heteroatom selected from nitrogen, oxygen and / or sulfur atom interrupting the hydrocarbon chain. The heteroatom may be present at any position in the hydrocarbon chain. For example, C1-C6heteroalkyl may refer to an ether, thioether or amine compound such as CH3CH2OCH2CH3, CH3NHCH2CH3or CH3SCH3. A heteroalkylene group includes divalent heteroalkyl group having two points of attachment to the remainder of the molecule. The groups -CH2CH2OCH2CH2-, -CH2NHCH2CH2- or -CH2SCH2- are examples of heteroalkylene groups. The heteroalkyl and heteroalkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-C4alkoxy. Other substituents for the heteroalkyl group may alternatively be used.

[0139] The term “C2-C6alkenyl” includes a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the “C2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0140] The term “C2-C6alkynyl” includes a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the “C2-C6alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0141] The term “C3-C6cycloalkyl” includes a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, the “C3-C6cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0142] The term “5-10 membered cycloalkyl” includes a saturated hydrocarbon ring system containing 5, 6, 7, 8, 9, or 10 carbon atoms. The term “5-10 membered cycloalkyl” includes bicyclic saturated hydrocarbon ring systems, for example bicyclo-[1.1.1]-pentyl, bicyclo-[2.2.2]- octyl, bicyclo[2.1.1]hexyl or a residue of pentacyclo[4.2.0.02,5.03,8.04,7]octyl (namely a cubane).

[0143] The term “heterocyclyl”, “heterocyclic” or “heterocycle” includes a non-aromatic saturated or partially saturated monocyclic or fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings may contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur in the ring. Bicyclic heterocycles may contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles comprising at least one nitrogen in a ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl, 2,5-Diaza-bicyclo[2.2.1]heptanyl and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O), for example, 2 oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. For example, the term “piperidino” or “morpholino” refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0144] The term “bridged ring systems” includes ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0145] The term “spiro bi-cyclic ring systems” includes ring systems in which two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-Diaza-bicyclo[2.2.1]heptane, 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 6-oxa-2-azaspiro[3.4]octane, 2,7-diaza-spiro[4.4]nonane, 2-azaspiro[3.5]nonane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0146] The term “aromatic” when applied to a substituent as a whole includes a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated (pi) system within the ring or ring system where all atoms contributing to the conjugated (pi) system are in the same plane.

[0147] The term “aryl” includes an aromatic hydrocarbon ring system. The ring system has 4n + 2 electrons in a conjugated (pi) system within a ring where all atoms contributing to the conjugated (pi) system are in the same plane. For example, the “aryl” may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

[0148] The term “heteroaryl” includes an aromatic mono- or bicyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The ring or ring system has 4n + 2 electrons in a conjugated (pi) system where all atoms contributing to the conjugated (pi) system are in the same plane.

[0149] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0150] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl and imidazo[1,2-b][1,2,4]triazinyl. Examples of heteroaryl groups comprising at least one nitrogen in a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2- benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0151] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0152] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0153] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0154] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0155] The term "optionally substituted" includes either groups, structures, or molecules that are substituted and those that are not substituted.

[0156] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0157] The phrase “compound of the disclosure” means those compounds which are disclosed herein, both generically and specifically.

[0158] A bond terminating in a “ ” represents that the bond is connected to another atomthat is not shown in the structure. A bond terminating inside a cyclic structure and not terminatingat an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

[0159] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g.1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. In a moiety or atom defined as "unsubstituted" (e.g., cycloalkyl), hydrogen atoms occupy the available valency. The hydrogen atoms occupying available valency include protium and deuterium.

[0160] In accordance with established chemical drawing conventions, it is also understood that in chemical structures, hydrogen atoms are implied on carbon atoms where a substituent is not explicitly depicted, so as to fulfil the valency requirement of carbon for an octet of electrons (https: / / en.wikipedia.org / wiki / Skeletal_formula). For example,are equivalent depictions of an isopropyl group.

[0161] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without undue effort which substitutions are chemically possible and which are not.

[0162] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, “ortho” substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or otherportions of the molecule, as indicated by the bond ending in “”..

[0163] “Meta” substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e. with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent. For example the groups below are meta substituted..

[0164] “Para” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e. with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another 5 substituent. For example the groups below are para substituted.

[0165] The term “acyl” includes an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(O)-, where R may be selected from H, C1-6alkyl, C3-8cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or 0 C1-3alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl (also represented as Ac).

[0166] Where heterocyclic and heteroaromatic rings are defined to "contain" or as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the group consisting 5 of O, N, and S), any ring atoms of the heterocyclic and heteroaromatic rings that are not one of the specified heteroatoms are carbon atoms.

[0167] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). 0 Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non- human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; 5 laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0168] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to 0 (and do not) exclude other moieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. 5

[0169] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process 10 so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The disclosure is not restricted to the details of any foregoing embodiments. The disclosure extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any 15 method or process so disclosed.

[0170] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. 20

[0171] The various functional groups and substituents making up the compounds of the present disclosure are typically chosen such that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525. 25

[0172] Suitable or preferred features of any compounds of the present disclosure may also be suitable features of any other aspect. Methods and uses of the compounds

[0173] In accordance with a second aspect, the present disclosure also provides a pharmaceutical formulation comprising a compound of the disclosure, or a pharmaceutically 30 acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0174] In accordance with a third aspect, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0175] In accordance with a fourth aspect, the present disclosure also provides the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by GPR88.

[0176] In a fifth aspect, the present disclosure provides a compound for use in the treatment of, Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, tardive dyskinesia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer’s disease and basal ganglia disorders.

[0177] In an embodiment, the disclosure provides a compound for use in the treatment of, Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, Alzheimer’s disease, and Attention Deficit Hyperactivity Disorder (ADHD).

[0178] In an embodiment, the disclosure provides a compound of the disclosure for use in the treatment of Huntington’s Disease (HD).

[0179] Tardive dyskinesia (TD) is a disorder characterized by involuntary, repetitive body movements and can result from treatment with dopamine receptor-blocking agents, in particular neuroleptics, such as dopamine D2 receptor antipsychotic agents (e.g., haloperidol), or so-called atypical antipsychotic agents (dopamine D3 or D4 receptor ligands such as clozapine or olanzepine). The principal site affected by classic TD is the face, particularly around the mouth, typically called oral-buccal-facial dyskinesia. The limbs and trunk may be affected less often than the mouth, but symptoms include diffuse movements, rhythmic swinging of the trunk, swaying, and stomping. The TD symptoms tend to appear late in the course of neuroleptic drug treatment, hence the term tardive. The symptoms can occur when the patient is taking these drugs or within a period of time after stopping the treatment.

[0180] The pathophysiology of drug-induced tardive dyskinesia has been hypothesized to result from a variety of underlying mechanisms, including prolonged blockade of postsynaptic dopamine receptors, gamma-aminobutyric acid (GABA) depletion, GABAergic neuron damage, cholinergic deficiency, oxidative stress, altered synaptic plasticity, neurotoxicity, and defective neuroadaptive signaling. Cornett et al., Ochsner Journal (2017) 162-174.

[0181] Tardive dyskinesia is primarily associated with use of antipsychotic agents, particularly first generation (typical) antipsychotic agents with dopamine D2 receptor antagonist activity. Other classes of drug agent that may induce or contribute to the development of tardive dyskinesia include so-called atypical (second generation) antipsychotic agents, anticholinergicagents, antidepressant agents, dopamine antagonist antiemetic agents, anticonvulsant agents, antihistamine agents, antimalarial agents, anxiolytic agents, stimulant agents, and lithium.

[0182] First generation antipsychotic agents include chlorpromazine, fluphenazine, haloperidol, perphenazine, prochlorperazine, thioridazine, loxapine, molindone, pimozide, thiothixene, trifluoperazine.

[0183] Second generation (atypical) antipsychotic agents include olanzapine, risperidone, clozapine, quetiapine, aripiprazole, asenapine, brexpiprazole, cariprazine, lumateperone, lurasidone, paliperidone, and pimavanserin.

[0184] Dopamine antagonist antiemetic agents include metoclopramide and prochlorperazine.

[0185] Antidepressant agents include selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline; monoamine oxidase inhibitors (MAOIs) such as phenelzine, rasagiline, and selegiline; tricyclic antidepressants such as amitriptyline, clomipramine, and doxepin; and trazodone (serotonin modulator).

[0186] Anticonvulsant agents include carbamazepine, lamotrigine, and phenytoin.

[0187] Antihistamine agents include hydroxyzine and phenothiazines.

[0188] Antimalarial agents include chloroquine and amodiaquine.

[0189] Anxiolytic agents include barbiturates and benzodiazepines like clonazepam, meprobamate.

[0190] Stimulant agents include amphetamine and methamphetamine.

[0191] The tardive dyskinesia treated with the GPR88 modulators of the present disclosure includes tardive dyskinesia resulting from use of any of the foregoing agents or classes of drug agent.

[0192] Treatment of tardive dyskinesia includes treatment of involuntary and repetitive body movement symptoms including involuntary movements of the face, lips, tongue, trunk, and extremities. Abnormal facial movements include blinking eyes rapidly, chewing motions, frowning, grimacing, grunting, puffing out cheeks, smaking lips, puckering lips, sticking out the tongue, poking the tongue into the inside of the cheek. Abnormal movement of the arms, legs, or torso include rocking the pelvis back and forth, swaying side to side, tapping the feet, wiggling or tapping fingers, waddling movement, and inability to sit still.

[0193] In a sixth aspect, the present disclosure provides a compound for use in the treatment of tardive dyskinesia, or a symptom thereof.

[0194] Thus, the disclosure contemplates a method of treating a disease mediated by GPR88, or any specific disease recited above, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the disclosure.

[0195] The embodiments relating to the first aspect are also applicable to all other aspects of the disclosure, including the second, third, fourth and fifth aspects above.

[0196] Compounds of the disclosure may possess agonist activitiy at GPR88, which may be determined by measuring compound effects on forskolin-stimulated cAMP concentrations in cells expressing GPR88, as described in the Examples below. In an embodiment, compounds have a GPR88 EC5020 μM, such as 5-20 μM, 1-5 μM, or 1 μM.

[0197] Compounds of the disclosure may selectively modulate GPR88 activitiy relative to inhibition of the dopamine uptake transporter. Dopamine uptake transporter inhibition may be determined at a concentration of 10μM of compound in rat striatum synaptosomes following [3H]dopamine scintillation counting (see Janowsky, A. et al. J. Neurochem., 46, 1272-1276, 1986). According to some embodiments compounds disclosed herein have % inhibition of less than 85, such as less than 70, such as less than 60, such as less than 50, such as less than 40, such as less than 30, such as less than 20, such as less than 10. Pharmaceutical compositions

[0198] A compound of the disclosure, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the disclosure, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0199] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0200] Depending on the mode of administration of the compounds of the disclosure, the pharmaceutical composition which is used to administer the compounds of the disclosure will preferably comprise from 0.05 to 99 % w / w compounds of the disclosure, more preferably from 0.05 to 80 % w / w compounds of the disclosure, still more preferably from 0.10 to 70 % w / w compounds of the disclosure, and even more preferably from 0.10 to 50 % w / w compounds of the disclosure (all percentages by weight being based on total composition).

[0201] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, ointments, gels, lotions, solutions, suspensions; or systemically, e.g. by oral administration in the form of tablets, lozenges, hard or soft capsules, aqueous or oilysuspensions, emulsions, dispersible powders or granules, syrups or elixirs; or by parenteral administration in the form of a sterile aqueous or oily solution, suspension or emulsion for injection (including intravenous, intracoronary, subcutaneous, intramyocardial, intraperitoneal, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories or enemas; by inhalation for example as a finely divided powder or a liquid aerosol; or for administration by insufflation (for example as a finely divided powder).

[0202] For oral administration the compounds of the disclosure may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and / or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0203] For the preparation of soft gelatine capsules, the compounds of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and / or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[0204] For intravenous (parenteral) administration the compounds of the disclosure may be administered as a sterile aqueous or oily solution.

[0205] The size of the dose for therapeutic or prophylactic purposes of a compound of the disclosure will naturally vary according to the nature and severity of the conditions, the concentration of the compound required for effectiveness in isolated cells, the concentration of the compound required for effectiveness in experimental animals, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0206] Dosage levels, dose frequency, and treatment durations of compounds of the disclosure are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.

[0207] An effective amount of a compound of the present disclosure for use in therapy of a condition is an amount sufficient to achieve symptomatic relief in a warm-blooded animal, particularly a human of the symptoms of the condition, to mitigate the physical manifestations of the condition, or to slow the progression of the condition.

[0208] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0209] For the above-mentioned compounds of the disclosure the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. In using a compound of the disclosure for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, a daily dose selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg or 5 mg / kg to 10 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Suitably the compound of the disclosure is admistered orally, for example in the form of a tablet, or capsule doasage form. The daily dose administered orally may be, for example a total daily dose selected from 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg or 25 mg to 500 mg. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this disclosure. Chemical Sythesis Abbreviations AIBN 2,2'-Azobis(2-methylpropionitrile); app apparent; Aq aqueous; B2Pin2Bis(pinacolato)diboron;45 51015 20 25

[0210] Other abbreviations are intended to convey their generally accepted meaning. General Experimental Conditions 30

[0211] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Reaction mixtures were magnetically stirred and reactions performed at room temperature (ca.20 °C) unless otherwise indicated.

[0212] Column chromatography was performed on an automated flash chromatography system, such as a Biotage Isolera Rf system, using pre-packed silica (40 μm) cartridges, unless otherwise indicated.

[0213] 1H NMR spectra were recorded using a Bruker AVANCE 400 MHz spectrometer. Data for1H are reported as chemical shift (ppm) and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, p = pentet, h = heptet)). Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. The spectra were recorded at 298 K unless otherwise indicated.

[0214] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC®H-Class system, equipped with ACQUITY PDA Detector and ACQUITY QDa Mass Detector, running one of the analytical methods described below.

[0215] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below.

[0216] Nomenclature of structures was generated using ‘Structure to Name’ conversion from ChemDraw®Professional 19 (PerkinElmer). Preparative TLC Generic Method:

[0217] The crude mixture or mixture of diastereoisomers was dissolved in DCM at a concentration of approximately 20 mg / 1 mL and applied to a preparative TLC silica gel plate. The plate was allowed to dry then was eluted in the appropriate solvent. The plate was visualised under UV light and the silica containing the product of interest collected, suspended in a mixture of DCM / MeCN (v / v=10 / 1) and sonicated. The suspension was filtered and the filter cake washed, the filtrate was concentrated under vacuum to give the desired product. Preparative HPLC Generic Methods:

[0218] HPLC Instruments: Shimadzu 20AP UV detector: SPD-20A. UV wavelength: 214 nm and 254 nm.

[0219] Conditions 1: Mobile phase A: water; Mobile phase B: acetonitrile.

[0220] Conditions 2: Mobile phase A: water with 0.1% trifluoroacetic acid; Mobile phase B: acetonitrile.

[0221] Conditions 3: Mobile phase A: water with 0.1% formic acid; Mobile phase B: acetonitrile.

[0222] Conditions 4: Mobile phase A: water with 0.1% ammonium hydroxide; Mobile phase B: acetonitrile.

[0223] Column: Agilent 10 Prep-C18250 x 21.2 mm. Column temperature: Ambient

[0224] LC gradient: 20% to 85% in 20 min; then 85% to 100% in 0.01 min; then hold 100% for 5 min; then 100 % to 20% in 0.01 min; hold at 20% for 5 min.

[0225] LC Flow rate: 20 mL / min binary pump. Preparative SFC Chiral Separation Generic Methods

[0226] Column: Daicel IC; Size: 30 mm I.D. × 50 cm L ,10 m

[0227] Mobilephase: CO2 / MeOH= 50 / 50

[0228] Flow rate: 50 ml / min

[0229] Back pressure: 100 bar

[0230] Wavelength: UV 254 nm, 214 nm

[0231] Temperature: 35 °C

[0232] Sample solution: 100mg compound in EtOH (5 mL)

[0233] Injection volume: 1.0 mL

[0234] SFC-150mgm (Waters) Analytical Methods as follows: Method 1. Acidic method (Shimadzu 3 min)

[0235] Column: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Agilent Poroshell 120 EC-C18, 2.7 m, 4.6×50 mm column

[0236] Detection: 2020, Quadrupole LC / MS, Ion Source: API-ESI, TIC: 100~900 m / z, Drying gas flow: 15 L / min, Nebulizer pressure: 1.5 L / min, Drying gas temperature: 250oC, Vcap: 4500V. Samples were dissolved in methanol at 1~10 g / mL, then filtered through a 0.22 m filter membrane. Injection volume: 1~10 L. Detection wavelength: 214 nm, 254 nm.

[0237] Solvents: A: 0.05% v / v Formic acid in water, B: 0.05% v / v Formic acid in MeCN (v / v) Gradient:

[0238] Method 2. Acidic 5 min method (Shimadzu 5 min) Column: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Agilent Poroshell 120 EC-C18, 2.7 m, 4.6×50 mm column.

[0239] Detection: 2020, Quadrupole LC / MS, Ion Source: API-ESI, TIC: 100~900 m / z, Drying gas flow: 15 L / min, Nebulizer pressure: 1.5 L / min, Drying gas temperature: 250oC, Vcap: 4500V. Samples were dissolved in methanol at 1~10 g / mL, then filtered through a 0.22 m filter membrane. Injection volume: 1~10 L. Detection wavelength: 214 nm, 254 nm.

[0240] Solvents: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v). Gradient:Method 3. Acidic method (Waters QDa 3 min)

[0241] Column: Waters QDa, Binary Pump, Diode Array Detector. Waters CORTECS UPLC, C18, 1.6 m, 2.1×50 mm column.

[0242] Detection: QDa, Quadrupole LC / MS, Ion Source: API-ES, TIC: 70~900 m / z, Fragmentor: 70, Drying gas flow: 12 L / min, Nebulizer pressure: 36 psi, Drying gas temperature: 350oC, Vcap: 3000V. Samples were dissolved in methanol at 1~10 g / mL, then filtered through a 0.22 m filter membrane. Injection volume: 1~10 L. Detector: 214 nm, 254 nm.

[0243] Solvents: A: 0.05% Formate in water (v / v), B: 0.05% Formate in MeCN (v / v). Gradient:Method 4. Acidic method (Agilent 3 min)

[0244] Column: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. AgilentEclipsePlus RRHD C18, 1.8 m, 3.0×50 mm.

[0245] Detection: G6120A, Quadrupole LC / MS, Ion Source: API-ES, TIC: 70~1000 m / z, Fragmentor: 70, Drying gas flow: 12 L / min, Nebulizer pressure: 36 psi, Drying gas temperature: 350oC, Vcap: 3000V. Samples were dissolved in methanol at 1~10 g / mL, then filtered through a 0.22 m filter membrane. Injection volume: 1~10 L. Detector: 214 nm, 254 nm.

[0246] Solvents: A: 0.05% Formate in water (v / v), B: 0.05% Formate in MeCN (v / v). Gradient:Chiral Analytical Method.

[0247] Column: CHIRALCEL®AD-H; Size: 4.6 mm I.D. ×25 cm L ,5 m

[0248] Mobilephase: Hexane / ETOH= 80 / 15(v / v)

[0249] Flow rate: 1.0 ml / min

[0250] Wavelength: UV 254 nm, 214 nm

[0251] Temperature: 35 °C

[0252] HPLC equipment: Shimadzu 2020

[0253] Compound Synthesis: The compounds of the invention may be prepared by methods well known to those skilled in the art and as described in the synthetic experimental procedures shown below.

[0254] Examples of the invention were prepared following the general Scheme 1 below, using the appropriate reagents for the target compound.Scheme 1; Reagents: (a) HATU, DIPEA, MeCN, RT or 50 °C

[0255] Carboxylic acids of the invention may be prepared as described in the preparation of representative intermediates 1-5. Anilines of the invention may be prepared as described in thepreparation of representative intermediates 6-61. Compounds of the invention may then be prepared by standard amide bond formation between acids (such as intermediates 1-5) and anilines (such as intermediates 6-61) using a coupling agent. Typically, a uronium reagent such as HATU is used, but many other coupling agents are common in the art for preparation of an amide.

[0256] In an alternative route, Examples of the invention were prepared following the general Scheme 2 below, using the appropriate reagents for the target compound.Scheme 2. (a) HATU, DIPEA, MeCN, RT or 50 °C (b) Epoxide, KOH, THF, sealed tube 50 °C

[0257] Carboxylic acids of the invention may be prepared as described in the preparation of representative intermediates 1-5. Anilines of the invention may be prepared as described in the preparation of representative intermediates 6-61. Intermediate secondary amides (62-87) may then be prepared by standard amide bond formation between acids (such as intermediates 1-5) and anilines (such as the primary anilines en route to the preparation of intermediate 6-61) using a coupling agent. Typically, a uronium reagent such as HATU is used, but many other couplingagents are common in the art for preparation of an amide. Compounds of the invention may then be prepared by reaction of intermediate secondary amides with an appropriate epoxide such as 1-oxaspiro[2.3]hexane (CAS 157-48-2), 1-oxaspiro[2.4]heptane (CAS 185-60-4), 1,5- dioxaspiro[2,3]hexane (CAS 15791-59-0), or 1,5-dioxaspiro[2.4]heptane (CAS 185-61-5). Typical conditions are to mix the amide and epoxide in THF with potassium hydroxide and heat in a sealed tube. Representative Carboxylic Acid Intermediates of the Invention

[0258] Representative intermediate acids (1-5) were prepared by two routes, illustrated in the schemes detailed for Intermediate 1. Cyclopropanation of a vinylic aryl substrate with ethyl 2- diazoacetate gave a mixture of racemic cis and trans arylcyclopropyl esters. The less polar trans racemate was isolated by column chromatography, saponified to the corresponding racemic carboxylic acid and separated by chiral HPLC into peak 1 and peak 2 products. For each intermediate acid, the chiral peak 1 and peak 2 product are coupled with an aniline intermediate such as 1-(((4'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol (Intermediate 8). The desired (R,R)-chiral acid was identified by GPR88 agonist potency screening since the trans-(R,R) is significantly more potent than the corresponding trans-(S,S) isomer. In an alternative route, the desired trans-(R,R) intermediate acids are prepared directly in high enantiomeric excess (ee) using chiral catalysis. The key chiral intermediate, potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate, is prepared from potassiumtrifluoro(vinyl)borate (CAS 13682-77-4) and ethyl 2-diazoacetate in high yield and enantiomeric excess through the use of Ru(II)-(S)-Pheox catalyst (CAS 1259070-80-8). Palladium catalysed cross-coupling of potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate and an arylhalide utilising the phosphine ligand cataCXium (CAS 321921-71-5) gives the ester of the desired trans-(R,R) intermediate carboxylic acids in high enantiomeric excess. Saponification of the esters then gives the desired trans-(R,R) acids. For each intermediate chiral acid, coupling with an aniline intermediate such as 1-(((4'-isopropoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclobutan-1-ol (Intermediate 8) gives a compound of the invention that is confirmed by GPR88 potency determination and cross-referenced to the same compound prepared by route 1 using chiral separation. Intermediate 1: (1R,2R)-2-(Pyridin-2-yl)cyclopropane-1-carboxylic acid Route 1: Chiral Separation

[0259] Step 1: Ethyl (trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylate: To a solution of 2- vinylpyridine (10.0 g, 95.2 mmol) in toluene (30 mL) was slowly added ethyl 2-diazoacetate (10 mL, 95.2 mmol). The reaction was heated at reflux for 16 h then the reaction was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (eluting with 1 / 60, EtOAc / PE) to give the trans racemate (9.0 g, 47.1 mmol, 50% yield) as a white solid.1H NMR (400 MHz, CDCl3) 8.43 (dt, J = 4.9, 1.2 Hz, 1H), 7.55 (td, J = 7.6, 1.8 Hz, 1H), 7.25 – 7.16 (m, 1H), 7.10 – 7.01 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.57 (ddd, J = 9.0, 6.1, 3.9 Hz, 1H), 2.33 – 2.13 (m, 1H), 1.66 – 1.54 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). Further elution (eluting with 1 / 20, EtOAc / PE) provided the cis racemate (2.9 g, 15.2 mmol, 16% yield) as a white solid.1H NMR (400 MHz, CDCl3) 8.49 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.58 (td, J = 7.7, 1.9 Hz, 1H), 7.24 (s, 1H), 7.10 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 3.90 (qd, J = 7.1, 1.2 Hz, 2H), 2.71 (q, J = 8.5 Hz, 1H), 2.16 (ddd, J = 9.3, 7.9, 5.8 Hz, 1H), 1.82 (dt, J = 7.5, 5.4 Hz, 1H), 1.41 (td, J = 8.3, 5.0 Hz, 1H), 1.01 (t, J = 7.1 Hz, 3H).

[0260] Step 2: (trans)-2-(Pyridin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (trans)-2-(pyridin-2-yl)cyclopropane-1-carboxylate (10.0 g, 53.3 mmol) and KOH (5.87 g, 104.6 mmol / L) in a mixture of MeOH (20 mL) and water (20 mL) was stirred at RT for 3 h. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 6~7 with 2M HCl. The mixture was extracted with EtOAc (200 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (5 g, 30.6 mmol, 57% yield).1H NMR (400 MHz, DMSO-d6) 8.42 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.67 (td, J = 7.6, 1.8 Hz, 1H), 7.41 (dt, J = 7.8, 1.1 Hz, 1H), 7.18 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 2.55 (ddd, J = 8.8, 6.0, 3.9 Hz, 1H), 1.99 (ddd, J = 8.3, 5.5, 3.9 Hz, 1H), 1.49 – 1.38 (m, 2H).

[0261] Step 3: (1R,2R)-2-(Pyridin-2-yl)cyclopropane-1-carboxylic acid: The racemic mixture (24.0 g, 147.0 mmol) was separated by chiral HPLC (column: CHIRALCEL®AD-H; Size: 21.1 mm I.D. ×250 mm ,10 m; Mobile phase : n-Hexane / EtOH= 85 / 15(v / v); Samples: In ethanol 20 mg / mL; Wave length : UV 254nm,214nm; Temperature: 35°C; HPLC equipment: Shimadzu 2020) to afford the two enantiomers. Enantiomer 1 (Peak 1 – S,S isomer, 9.2 g, 56.37 mmol, 38% yield ): chiral-HPLC: Rt=7.487 min; UPLC-MS (Method 1) m / z [M+H]+164.10 at 0.467 min.1H NMR (400 MHz, DMSO-d6) 8.48 (d, J = 4.4 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.32 – 7.26 (m, 1H), 2.65 – 2.58 (m, 1H), 2.09 – 2.02 (m, 1H), 1.49 (dtd, J = 18.5, 5.7, 2.7 Hz, 2H). Enantiomer 2 (Peak 2 – R,R isomer, 9.1 g, 55.76 mmol, 38% yield): Chiral- HPLC: Rt=10.251 min; UPLC-MS (Method 1) m / z 164.10 [M+H]+at 0.433 min.1H NMR (400 MHz, DMSO-d6) 12.33 (s, 1H), 8.42 (d, J = 4.3 Hz, 1H), 7.68 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (d,55 J = 7.8 Hz, 1H), 7.23 – 7.15 (m, 1H), 2.57 (dd, J = 5.6, 3.6 Hz, 1H), 2.06 – 1.96 (m, 1H), 1.45 (dddd, J = 12.6, 8.8, 5.7, 2.7 Hz, 2H). Route 2: Chiral Synthesis

[0262] Step 1: Potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate: To a solution of potassium trifluoro(vinyl)borate (25.0 g, 186.6 mmol) and Ru(II)-(S)-Pheox catalyst (1.18 g, 1.9 mmol) in EtOAc (175 mL) at 0-5 °C was slowly added a solution of ethyl 2- diazoacetate (42.5 g, 373.1 mmol) in EtOAc (25 mL) over 2 hours. After addition, the reaction was allowed to warm to RT and was stirred for 1 hour. Heptane (200 mL) was added and the solution cooled to 0- 5 °C and stirred for another 1 hour. The precipitate that formed was collected by filtration and washed with EtOAc / Heptane=1 / 1 (50 mL). The solid was dried under vacuum to give the title compound (33.0 g, 150.0 mmol, 80.4% yield) as a grey solid.1H NMR (400 MHz, DMSO-d6) 3.96 (q, J = 7.1 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H), 1.13 – 1.08 (m, 1H), 0.64 (d, J = 9.7 Hz, 1H), 0.48 (t, J = 7.4 Hz, 1H), -0.05 (s, 1H).

[0263] Step 2: Ethyl (1R,2R)-2-(pyridin-2-yl)cyclopropane-1-carboxylate: A mixture of potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (10.0 g, 45.5 mmol), 2- chloropyridine (10.3 g, 90.9 mmol), Pd(OAc)2(1.0 g, 4.5 mmol), cataCXium (3.3 g, 9.1 mmol) and Cs2CO3(37.0 g, 113.6 mmol) in a mixture of toluene (100 mL) and H2O (10 mL) was heated at 100 °C overnight under nitrogen in a sealed tube. The reaction was diluted with water (50 mL) and extracted with EtOAc (100 mL). The organic phase was concentrated in vacuo and purified by column chromatography on silica gel (eluting with 1 / 60 EtOAc / PE) to afford the title compound (4.0 g, 20.9 mmol, 46.0% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.45 – 8.40 (m,1H), 7.68 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (dt, J = 7.8, 1.1 Hz, 1H), 7.19 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.60 (ddd, J = 9.4, 6.0, 3.9 Hz, 1H), 2.13 – 2.06 (m, 1H), 1.48 (dddd, J = 17.6, 8.9, 5.7, 3.6 Hz, 2H), 1.20 (d, J = 7.1 Hz, 3H).

[0264] Step 3: (1R,2R)-2-(Pyridin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (1R,2R)-2-(pyridin-2-yl)cyclopropane-1-carboxylate (7.0 g, 36.6 mmol) and KOH (4.1 g, 73.2 mmol) in a mixture of MeOH (35 mL) and water (35 mL) was stirred at RT for 2 h. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 5~6 with 2M HCl. The mixture was extracted with CHCl3 / Isopropyl alcohol= 3 / 1 (3 x 100 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (3.8 g, 23.3 mmol, 63.7% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 12.24 (s, 1H), 8.46 – 8.36 (m, 1H), 7.72 – 7.64 (m, 1H), 7.41 (dd, J = 7.8, 1.2 Hz, 1H), 7.18 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.04 – 1.97 (m, 1H), 1.44 (dddd, J = 14.4, 12.3, 5.7, 3.5 Hz, 2H). Chiral-HPLC: Rt=7.575 min, %ee = 98. Intermediate 2: (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid Route 1: (Chiral Separation)57

[0265] Step 1: 5-Fluoro-2-vinylpyridine: A mixture of 2-chloro-5-fluoropyridine (15.0 g, 114.5 mmol), potassium trifluoro(vinyl)borate (30.6 g, 229.0 mmol), K3PO4(72.9 g, 343.5 mmol) and Pd(dppf)Cl2(4.2 g, 5.7 mmol) in a mixture of dioxane and water (v / v=10 / 1, 165 mL) was heated at 110 °C overnight in a sealed tube under nitrogen. The mixture was filtered through Celite® and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with 100% DCM) to afford the title compound (10 g, 81.2 mmol, 71% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.52 (d, J = 2.8 Hz, 1H), 7.71 (td, J = 8.7, 2.9 Hz, 1H), 7.59 (dd, J = 8.7, 4.6 Hz, 1H), 6.82 (dd, J = 17.5, 10.8 Hz, 1H), 6.20 – 6.11 (m, 1H), 5.45 (d, J = 10.8 Hz, 1H).

[0266] Step 2: Ethyl (trans)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylate: To a solution of 5-fluoro-2-vinylpyridine (10.0 g, 81.2 mmol) in toluene (100 mL) was added ethyl 2- diazoacetate (10.2 g, 89.3 mmol) and the solution heated at reflux for 4 h. The mixture was concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with 1 / 100, EtOAc / PE) to give the trans racemate (6.7 g, 32.0 mmol, 39% yield) as a yellow oil. UPLC-MS (Method 4) m / z 210.30 [M+H]+at 1.702 min.1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 2.8 Hz, 1H), 7.64 (td, J = 8.7, 2.9 Hz, 1H), 7.52 (dd, J = 8.6, 4.5 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.66 (ddd, J = 8.4, 6.4, 3.9 Hz, 1H), 2.05 (ddd, J = 8.2, 5.8, 4.0 Hz, 1H), 1.47 (ddd, J = 8.7, 6.0, 2.2 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). Further elution (eluting with 1 / 30, EtOAc / PE) provided the cis racemate (2.1 g, 10.0 mmol, 11% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.41 (d, J = 2.9 Hz, 1H), 7.61 (d, J = 3.0 Hz, 1H), 7.36 (dd, J = 8.7, 4.5 Hz, 1H), 3.81 (dd, J = 7.1, 1.4 Hz, 2H), 2.71 (d, J = 8.0 Hz, 1H), 2.12 (s, 1H), 1.70 – 1.59 (m, 1H), 1.38 (d, J = 4.7 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H).

[0267] Step 3: (trans)-2-(5-Fluoropyridin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (trans)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylate (8.0 g, 38.2 mmol) and KOH (4.3 g, 76.5 mmol) in a mixture of MeOH (50 mL) and water (50 mL) was stirred at RT for 2 h. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 6~7 with 2M HCl. The aqueous was extracted with EtOAc (200 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (6.0 g, 33.1 mmol, 87% yield) as a white solid.1H NMR (400 MHz, DMSO- d6) 8.41 (d, J = 2.8 Hz, 1H), 7.62 (td, J = 8.7, 2.9 Hz, 1H), 7.50 (dd, J = 8.7, 4.5 Hz, 1H), 2.63 – 2.57 (m, 1H), 1.98 – 1.93 (m, 1H), 1.45 – 1.36 (m, 2H).

[0268] Step 4: (1R,2R)-2-(5-Fluoropyridin-2-yl)cyclopropane-1-carboxylic acid: The trans racemic mixture (10.0 g, 55.23 mmol) was separated by chiral HPLC (column: CHIRALCEL®AD- H; Size: 21.1 mm I.D. ×250 mm ,10 m; Mobile phase : n-Hexane / EtOH= 85 / 15(v / v); Samples:In ethanol 20 mg / mL; Wave length : UV 254nm,214nm; Temperature: 35 °C HPLC equipment: Shimadzu 2020) to afford two enantiomers. Enantiomer 1 (Peak 1 – S,S isomer, 3.8 g, 21.00 mmol, 38% yield ): chiral-HPLC: Rt=11.572 min; UPLC-MS (Method 1) m / z 182.10 [M+H]+at 1.367 min.1H NMR (400 MHz, DMSO-d6) 12.35 (s, 1H), 8.42 (d, J = 2.9 Hz, 1H), 7.63 (dd, J = 8.7, 3.0 Hz, 1H), 7.52 (dd, J = 8.6, 4.5 Hz, 1H), 2.65 – 2.57 (m, 1H), 2.00 – 1.93 (m, 1H), 1.46 – 1.40 (m, 2H). Enantiomer 2 (Peak 2 – R,R isomer, 4.5 g, 24.86 mmol, 45% yield): chiral-HPLC: Rt=17.725 min; UPLC-MS (Method 1) m / z 182.10 [M+H]+at 1.367 min.1H NMR (400 MHz, DMSO-d6) 8.44 (d, J = 2.9 Hz, 1H), 7.66 (td, J = 8.7, 3.0 Hz, 1H), 7.54 (dd, J = 8.7, 4.5 Hz, 1H), 2.64 (ddd, J = 8.0, 6.6, 3.8 Hz, 1H), 2.01 – 1.96 (m, 1H), 1.47 – 1.42 (m, 2H). Route 2: (Chiral Synthesis)

[0269] Step 1: Ethyl (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylate: A mixture of potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (10.0 g, 45.5 mmol), 2-chloro- 5-fluoropyrimidine (12.0 g, 90.9 mmol), Pd(OAc)2(1.0 g, 4.5 mmol), cataCXium (3.3 g, 9.1 mmol) and Cs2CO3(37.0 g, 113.6 mmol) in a mixture of dioxane and water (v / v=10 / 1, 110 mL) was heated at 100 °C overnight in a sealed tube under nitrogen. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The organic phases were concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with 1 / 20 EtOAc / PE) to afford the title compound (3.8 g, 18.2 mmol, 40.0 % yield) as a yellow oil. UPLC-MS (Method 3) m / z 210.20 [M+H]+at 1.735 min.1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 2.9 Hz, 1H), 7.64 (td, J = 8.7, 2.9 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.66 (ddd, J = 8.5, 6.4, 3.9 Hz, 1H), 2.05 (ddd, J = 8.3, 5.8, 3.9 Hz, 1H), 1.47 (ddd, J = 8.7, 6.0, 2.3 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).

[0270] Step 2: (1R,2R)-2-(5-Fluoropyridin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylate (5.7 g, 27.3 mmol) and KOH (3.1 g, 54.6 mmol) in a mixture of MeOH (25 mL) and water (25 mL) was stirred at RT for 2 h. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 6~7 with 2M HCl. The mixture was extracted with EtOAc (200 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford title compound (4.5 g, 24.8 mmol, 95% yield) as a white solid. UPLC-MS (Method 3) m / z 182.10 [M+H]+at 0.993 min.1H NMR (400 MHz, DMSO-d6) 12.31 (s, 1H), 8.37 (d, J = 2.9 Hz, 1H),7.59 (td, J = 8.7, 3.0 Hz, 1H), 7.47 (dd, J = 8.7, 4.5 Hz, 1H), 2.57 (ddd, J = 8.0, 6.6, 3.8 Hz, 1H), 1.94 – 1.88 (m, 1H), 1.40 – 1.35 (m, 2H). Chiral-HPLC: Rt=10.306 min, %ee=97. Intermediate 3: (1R,2R)-2-(5-Fluoropyrimidin-2-yl)cyclopropane-1-carboxylic acid Route 1: (Chiral Separation)

[0271] Step 1: 5-Fluoro-2-vinylpyrimidine: A mixture of 2-chloro-5-fluoropyrimidine (10.0 g, 75.5 mmol), potassium trifluoro(vinyl)borate (20.2 g, 151.0 mmol), K3PO4(48.0 g, 226.4 mmol) and Pd(dppf)Cl2(2.8 g, 3.8 mmol) in a mixture of dioxane and water (v / v=10 / 1, 110 mL) was heated at 110 °C for 4 hours in a sealed tube under nitrogen. The reaction was filtered through Celite® and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with 100% DCM) to afford the title compound (7.0 g, 56.45 mmol, 75% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 8.85 (s, 2H), 6.84 (dd, J = 17.3, 10.6 Hz, 1H), 6.46 (dd, J = 17.4, 1.4 Hz, 1H), 5.77 – 5.74 (m, 1H).

[0272] Step 2: Ethyl (trans)-2-(5-fluoropyrimidin-2-yl)cyclopropane-1-carboxylate: To a solution of 5-fluoro-2-vinylpyrimidine (9.4 g, 76.0 mmol) in toluene (80 mL) was added ethyl 2- diazoacetate (8.6 g, 76.0 mmol). The reaction was heated at reflux for 16 h, then concentratedunder reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with 1 / 50, EtOAc / PE) to give the trans racemate as the less polar spot (2.86 g, 13.6 mmol, 18% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.74 (s, 2H), 4.09 (q, J = 6.4 Hz, 2H), 2.70 – 2.60 (m, 1H), 2.11 (ddd, J = 7.5, 6.2, 3.9 Hz, 1H), 1.55 (t, J = 7.2 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H). Further elution (eluting with 1 / 10, EtOAc / PE) provided the cis racemate (1.5 g, 7.1 mmol, 9% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.74 (s, 2H), 3.81 (q, J = 7.1 Hz, 2H), 2.81 (q, J = 8.6 Hz, 1H), 2.22 – 2.15 (m, 1H), 1.75 – 1.68 (m, 1H), 1.42 (td, J = 8.3, 4.5 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H).

[0273] Step 3: (trans)-2-(5-Fluoropyrimidin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (trans)-2-(5-fluoropyrimidin-2-yl)cyclopropane-1-carboxylate (10.8 g, 51.4 mmol) and KOH (5.77 g, 102.8 mmol) in a mixture of MeOH (50 mL) and water (50 mL) was stirred at RT for 2 h. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 5~6 with 2M HCl. The mixture was extracted with EtOAc (200 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford title compound (9.0 g, 49.4 mmol, 96% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 12.49 (s, 1H), 8.77 (s, 2H), 2.62 (ddd, J = 8.8, 6.2, 3.9 Hz, 1H), 2.04 (ddt, J = 9.3, 5.8, 3.4 Hz, 1H), 1.57 – 1.47 (m, 2H).

[0274] Step 4: (1R,2R)-2-(5-Fluoropyrimidin-2-yl)cyclopropane-1-carboxylic acid: The racemic mixture (12.0 g, 65.92 mmol) was separated by chiral HPLC (column: CHIRALCEL®AD-H; Size: 21.1 mm I.D. ×250 mm ,10 m; Mobile phase : n-Hexane / EtOH= 85 / 15(v / v); Samples: In ethanol 20 mg / mL; Wave length : UV 254nm, 214nm; Temperature: 35 °C HPLC equipment: Shimadzu 2020) to afford two enantiomers. Enantiomer 1 (Peak 1 – S,S isomer, 6.0 g, 32.96 mmol, 50% yield): chiral-HPLC: Rt=9.043 min; UPLC-MS (Method 1) m / z 183.10 [M+H]+at 1.167 min.1H NMR (400 MHz, DMSO-d6) 12.49 (s, 1H), 8.77 (s, 2H), 2.62 (ddd, J = 8.8, 6.2, 3.9 Hz, 1H), 2.04 (ddd, J = 8.5, 5.7, 3.9 Hz, 1H), 1.51 (ddq, J = 9.9, 7.5, 3.7 Hz, 2H). Enantiomer 2 (Peak 2 – R,R isomer, 5.0 g, 27.46 mmol, 42% yield): chiral-HPLC: Rt=15.250 min; UPLC-MS (Method 1) m / z 183.10 [M+H]+at 1.167 min.1H NMR (400 MHz, DMSO-d6) 12.51 (s, 1H), 8.77 (s, 2H), 2.64 (s, 1H), 2.09 – 2.00 (m, 1H), 1.56 – 1.46 (m, 2H). Route 2: (Chiral Synthesis)

[0275] Step 1: Ethyl (1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclopropane-1-carboxylate: A solution of potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (10.0 g, 45.5 mmol), 2- chloro-5-fluoropyrimidine (12.0 g, 90.9 mmol), Pd(OAc)2(1.0 g, 4.5 mmol), cataCXium (3.3 g, 9.1 mmol) and Cs2CO3(37.0 g, 113.6 mmol) in a mixture of dioxane and water (v / v=10 / 1, 110 mL) was heated at 100 °C overnight in a sealed tube under nitrogen. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The organic phase was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with 1 / 20 EtOAc / PE) to afford the title compound (5.2 g, 24.8 mmol, 54.3 % yield) as a yellow solid. UPLC-MS (Method 1) m / z 211.20 [M+H]+at 1.484 min.1H NMR (400 MHz, DMSO-d6) 8.78 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.71 – 2.61 (m, 1H), 2.13 (ddd, J = 7.8, 6.1, 3.9 Hz, 1H), 1.60 – 1.51 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H).

[0276] Step 2: (1R,2R)-2-(5-Fluoropyrimidin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclopropane-1-carboxylate (10.4 g, 49.5 mmol) and KOH (5.6 g, 99.0 mmol) in a mixture of MeOH (50 mL) and water (50 mL) was stirred at RT for 2 hrs. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 5~6 with 2M HCl. The mixture was extracted with EtOAc (200 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford title compound (7.2 g, 39.6 mmol, 81% yield) as a yellow solid. UPLC-MS (Method 1) m / z [M+H]+180.90 at 0.357 min.1H NMR (400 MHz, DMSO-d6) 12.50 (s, 1H), 8.76 (s, 2H), 2.65 – 2.58 (m, 1H), 2.07 – 2.00 (m, 1H), 1.50 (dt, J = 8.4, 4.6 Hz, 2H). Chiral-HPLC: Rt=12.615 min, %ee=98. Intermediate 4: (1R,2R)-2-(6-Fluoropyridin-2-yl)cyclopropane-1-carboxylic acid

[0277] Step 1: Ethyl (1R,2R)-2-(6-fluoropyridin-2-yl)cyclopropane-1-carboxylate: A mixture of potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (5.0 g, 22.7 mmol), 2-bromo- 6-fluoropyridine (3.3 g, 18.94 mmol), Pd(OAc)2(424 mg, 1.89 mmol), cataCXium (1.4 g, 3.79 mmol) and Cs2CO3(15.4 g, 47.35 mmol) in a mixture of dioxane and water (v / v=10 / 1, 33 mL) was heated to 100 °C overnight in a sealed tube under nitrogen. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic phases were concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with 1 / 25 EtOAc / PE) to afford the title compound (1.5 g, 7.2 mmol, 38 % yield) as a yellow oil. UPLC-MS (Method 3) m / z 210.2 [M+H]+at 1.828 min.1H NMR (400 MHz, DMSO-d6) 7.87 (td, J = 8.4, 7.4 Hz, 1H), 7.40 (dd, J = 7.4, 2.6 Hz, 1H), 6.95 (dd, J = 8.2, 2.5 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.63 (dddd, J = 8.7, 6.2, 3.9, 1.0 Hz, 1H), 2.05 (ddd, J = 8.2, 5.7, 3.9 Hz, 1H), 1.47 (ddq, J = 7.5, 6.1, 3.8 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).

[0278] Step 2: (1R,2R)-2-(6-Fluoropyridin-2-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (1R,2R)-2-(6-fluoropyridin-2-yl)cyclopropane-1-carboxylate (1.5 g, 7.2 mmol) and KOH (0.8 g, 14.4 mmol) in a mixture of MeOH (10 mL) and water (10 mL) was stirred at RT overnight. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 5~6 with 2M HCl. The mixture was extracted with EtOAc (100 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford title compound (1.1 g, 6.07 mmol, 84% yield) as a white solid. UPLC-MS (Method 3) m / z 182.2 [M+H]+at 1.070 min.1H NMR (400 MHz, DMSO-d6) 12.43 (s, 1H), 7.87 (q, J = 8.1 Hz, 1H), 7.41 (dd, J = 7.4, 2.6 Hz, 1H), 6.96 (dd, J = 8.1, 2.6 Hz, 1H), 2.59 (ddd, J = 9.3, 6.0, 3.8 Hz, 1H), 1.97 (ddd, J = 8.4, 5.6, 3.8 Hz, 1H), 1.43 (tdd, J = 9.7, 5.8, 3.7 Hz, 2H). Chiral-HPLC: Rt=10.126 min, %ee=96.Intermediate 5: (1R,2R)-2-(Pyrimidin-4-yl)cyclopropane-1-carboxylic acid

[0279] Step 1: Ethyl (1R,2R)-2-(pyrimidin-4-yl)cyclopropane-1-carboxylate: A mixture of potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (2.0 g, 9.09 mmol), 4- chloropyrimidine hydrochloride (2.0 g, 13.64 mmol), Pd(OAc)2(204 mg, 0.91 mmol), cataCXium (653 mg, 1.82 mmol) and Cs2CO3(9.0 g, 27.27 mmol) in a mixture of dioxane and water (v / v=5 / 1, 24 mL) was heated at 100 °C overnight in a sealed tube under nitrogen. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organic phase was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with 1 / 4 EtOAc / PE) to afford the title compound (305 mg, 1.59 mmol, 18 % yield) as a yellow solid. UPLC-MS (Method 4) m / z 193.10 [M+H]+at 1.075 min.1H NMR (400 MHz, DMSO-d6) 9.03 (d, J = 1.4 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 7.63 (dd, J = 5.2, 1.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.67 (ddd, J = 8.7, 6.0, 3.8 Hz, 1H), 2.23 (ddd, J = 8.4, 5.8, 3.8 Hz, 1H), 1.62 – 1.56 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0280] Step 2: (1R,2R)-2-(Pyrimidin-4-yl)cyclopropane-1-carboxylic acid: A mixture of ethyl (1R,2R)-2-(pyrimidin-4-yl)cyclopropane-1-carboxylate (305 mg, 1.59 mmol) and KOH (178.1 mg, 3.18 mmol) in a mixture of MeOH (5 mL) and water (5 mL) was stirred at RT overnight. The organic solvent was removed under reduced pressure and the pH of the aqueous solution was adjusted to 3~4 with 2M HCl. The mixture was extracted with EtOAc (50 mL x 3), and the combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to afford title compound (201 mg, 1.22 mmol, 77% yield) as a white solid. UPLC-MS (Method 4) m / z 165.0 [M+H]+at 0.293 min.1H NMR (400 MHz, DMSO-d6) 12.54 (s, 1H), 9.02 (d, J = 1.3 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 7.62 (dd, J = 5.2, 1.4 Hz, 1H), 2.62 (ddd, J = 8.6, 6.0, 3.8 Hz, 1H), 2.18 – 2.11 (m, 1H), 1.55 (ddd, J = 10.9, 5.6, 3.4 Hz, 2H). Chiral-HPLC: Rt=13.021 min, %ee=96. Representative Aniline Intermediates of the Invention

[0281] Representative intermediate anilines (6-61) were prepared by several routes as detailed in the schemes for Intermediates 6 & 7. In route 1, 4-bromoaniline is first coupled withan appropriate 1-hydroxycycloalkyl-1-carboxylic acid to give the amide. The amide bond is reduced to the corresponding secondary aniline with for example borane in THF. Palladium- catalysed Suzuki cross-coupling of the bromide intermediate with the appropriate arylboronic acid (or Pinacol esters) gives aniline intermediates such as 5-17. In an alternative route, the order of reactions is changed. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline is first cross-coupled with known arylbromides to give intermediate biraylanilines. The biarylanilines are then coupled with an appropriate 1-hydroxycycloalkyl-1-carboxylic acid to give the corresponding amide. The amide bond is reduced to the corresponding secondary aniline with for example borane in THF to aniline intermediates such as 6-17. These main routes may be further modified with additional steps when required. The preparation of primary and secondary aniline intermediates 6-61 are detailed herein.Intermediate 6: 1-(((4'-Ethoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol

[0282] Step 1: N-(4-Bromophenyl)-1-hydroxycyclobutane-1-carboxamide: To a mixture of 4- bromoaniline (7.8 g, 45.45 mmol), 1-hydroxycyclobutane-1-carboxylic acid (5.0 g, 45.45 mmol) and DIPEA (17.6 g, 136.36 mmol) in DMF (50 mL) at RT was added PyBOP (35.5 g, 68.18 mmol). The reaction was heated at 50 °C overnight, then cooled to room temperature and diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic phases were combined and washed with brine (3 x 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with 1 / 3 EtOAc / PE) to afford the title compound (11.0 g, 40.7 mmol, 90 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 9.61 (s, 1H), 7.78 – 7.69 (m, 2H), 7.47 – 7.42 (m, 2H), 6.31 (s, 1H), 2.49 – 2.43 (m, 2H), 2.15 – 2.04 (m, 2H), 1.87 – 1.72 (m, 2H).

[0283] Step 2: 1-(((4-Bromophenyl)amino)methyl)cyclobutan-1-ol: A mixture of N-(4- bromophenyl)-1-hydroxycyclobutane-1-carboxamide (13.0 g, 48.33 mmol) and BH3(1M in THF, 96.65 mL, 96.65 mmol) was stirred at RT for 16 h. The mixture was quenched with NaOH (2 M) and diluted with water (200 mL). The aqueous was extracted with EtOAc (3 x 200 mL) and the organic layers were combined, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give the title compound (11.0 g, 43.13 mmol, 89% yield) as a yellow solid. UPLC-MS (Method 3) m / z 256.0, 258.0 [M+H]+at 1.799 min.1H NMR (400 MHz, DMSO- d6) 7.16 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 5.46 (t, J = 5.6 Hz, 1H), 5.13 (s, 1H), 3.05 (d, J = 5.5 Hz, 2H), 1.99 (dd, J = 5.6, 2.8 Hz, 2H), 1.94 (dt, J = 11.4, 7.3 Hz, 2H), 1.70 – 1.57 (m, 1H), 1.51 (dt, J = 10.9, 8.9 Hz, 1H).

[0284] Step 3: 1-(((4'-Ethoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: A mixture of 1- (((4-bromophenyl)amino)methyl)cyclobutan-1-ol (3.0 g, 11.7 mmol), (4-ethoxyphenyl)boronic acid (3.9 g, 23.4 mmol), K3PO4(5.0 g, 23.4 mmol) and Pd(dppf)Cl2(877.2 mg, 1.2 mmol) in a mixture of dioxane and water (v / v=10 / 1, 27.5 mL) was heated at 110 °C for 3 hrs under nitrogen. The mixture was filtered through Celite®, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with PE / EtOAc=2 / 1) to afford the title compound (2.2 g, 7.4 mmol, 63% yield) as a yellow solid. UPLC-MS (Method 4) m / z 298.30 [M+H]+at 2.226 min.1H NMR (400 MHz, MeOD) 7.46 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.07 (t, J = 7.0 Hz, 2H), 3.27 (s, 2H), 2.24 – 2.17 (m, 2H), 2.15 – 2.07 (m, 2H), 1.89 – 1.77 (m, 1H), 1.67 (dt, J = 11.0, 8.8 Hz, 1H), 1.43 (t, J = 7.0 Hz, 3H). Intermediate 7: 1-(((4-(6-Ethoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol Route 1:

[0285] Step 1: 2-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: A mixture of 5-bromo-2-ethoxypyridine (5.0 g, 24.88 mmol), bis(pinacolato)diboron (7.0 g, 27.36 mmol), KOAc (4.9 g, 49.75 mmol) and Pd(dppf)Cl2(1.82 g, 2.49 mmol) in dioxane (30 mL) heated at 100 °C overnight under nitrogen. The mixture was filtered through Celite®, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with PE / EtOAc=20 / 1) to afford the title compound (2.3 g, 9.0 mmol, 36% yield) as a yellow solid. UPLC-MS (Method 3) m / z 250.30 [M+H]+at 2.331 min.

[0286] Step 2: 1-(((4-(6-Ethoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol: A mixture of 1-(((4-bromophenyl)amino)methyl)cyclobutan-1-ol (2.3 g, 8.84 mmol), 2-ethoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.3 g, 13.25 mmol), K3PO4(3.7 g, 17.67 mmol) and XPhos Pd G3 (747.0 mg, 0.88 mmol) in a mixture of THF and water (v / v=4 / 1, 27.5 mL) washeated at 50 °C overnight under nitrogen. The mixture was filtered through Celite®, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with PE / EtOAc=3 / 1) to afford the title compound (2.1 g, 7.04 mmol, 80% yield) as a yellow solid. UPLC-MS (Method 3) m / z 299.19 [M+H]+at 1.997 min.1H NMR (400 MHz, CDCl3) 8.31 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.6, 2.5 Hz, 1H), 7.39 – 7.35 (m, 2H), 6.84 – 6.79 (m, 2H), 6.76 (d, J = 8.6 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.32 (s, 2H), 2.21 – 2.09 (m, 4H), 1.89 – 1.78 (m, 1H), 1.67 – 1.55 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H). Route 2:

[0287] Step 1: 4-(6-Ethoxypyridin-3-yl)aniline: A mixture of 5-bromo-2-ethoxypyridine (20.0 g, 99.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (21.6 g, 99.0 mmol), K3PO4(42.0 g, 198.0 mmol) and Pd(dppf)Cl2(3.6 g, 5.0 mmol) in a mixture of dioxane and water (v / v=10 / 1, 440 mL) was heated at 110 °C for 3 h under nitrogen. The mixture was filtered through Celite®, diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with PE / EtOAc=10 / 1) to afford the title compound (14.0 g, 65.4 mmol, 66% yield) as a yellow solid. UPLC-MS (Method 3) m / z 215.34 [M+H]+at 1.255 min.

[0288] Step 2: N-(4-(6-Ethoxypyridin-3-yl)phenyl)-1-hydroxycyclobutane-1-carboxamide: Using the procedure outlined in Step 1 of Intermediate 6 starting with 4-(6-ethoxypyridin-3- yl)aniline (5.0 g, 23.4 mmol). The title compound was obtained (5.7 g, 18.24 mmol, 78% yield) as a yellow oil. UPLC-MS (Method 3) m / z 313.1 [M+H]+at 1.820 min.

[0289] Step 3: 1-(((4-(6-Ethoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol: Using the procedure outlined in Step 2 of Intermediate 6 starting with N-(4-(6-ethoxypyridin-3-yl)phenyl)- 1-hydroxycyclobutane-1-carboxamide (5.7 g, 18.24 mmol). The title compound was obtained (4.0 g, 13.42 mmol, 74% yield) as a yellow oil. UPLC-MS (Method 3) m / z 299.19 [M+H]+at 5 1.997 min.1H NMR (400 MHz, CDCl3) 8.31 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.6, 2.5 Hz, 1H), 7.39 – 7.35 (m, 2H), 6.84 – 6.79 (m, 2H), 6.76 (d, J = 8.6 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.32 (s, 2H), 2.21 – 2.09 (m, 4H), 1.89 – 1.78 (m, 1H), 1.67 – 1.55 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H). Intermediate 8: 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol 10

[0290] Step 1: 4'-Isopropoxy-[1,1'-biphenyl]-4-amine: Using the procedure outlined in Step 3 Intermediate 6 starting with 4-bromoaniline (6.3 g, 35.0 mmol). The title compound was obtained (4.7 g, 20.70 mmol, 59% yield) as a yellow solid. UPLC-MS (Method 3) m / z 228.1 [M+H]+at 1.630 min. 15

[0291] Step 2: 1-Hydroxy-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)cyclobutane-1-carboxamide: Using the procedure outlined in Step 1 of Intermediate 6 starting with 4'-isopropoxy-[1,1'- biphenyl]-4-amine (4.7 g, 20.70 mmol). The title compound was obtained (3.6 g, 11.07 mmol, 53% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 9.48 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.58 – 7.50 (m, 4H), 6.96 (d, J = 8.7 Hz, 2H), 4.67 – 4.59 (m, 1H), 2.10 (dq, J = 15.7, 7.9 20 Hz, 2H), 1.75 (s, 3H), 1.72 (s, 1H), 1.28 (d, J = 6.0 Hz, 6H).

[0292] Step 3: 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: Using the procedure outlined in Step 2 of Intermediate 6 starting with 1-hydroxy-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclobutane-1-carboxamide (3.6 g, 11.07 mmol). The title compound was obtained (2.9 g, 9.32 mmol, 84% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 7.43 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 5.26 (s, 1H), 5.15 (s, 1H), 4.58 (d, J = 6.0 Hz, 1H), 3.11 (s, 2H), 1.99 (tq, J = 18.1, 8.0 Hz, 4H), 1.71 – 1.60 (m, 1H), 1.58 – 1.50 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 9: 1-(((4-(6-Isopropoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol

[0293] Step 1: 2-Isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: Using the procedure outlined in Step 1 of Intermediate 7, Route 1 starting with 5-bromo-2- isopropoxypyridine (5.0 g, 23.4 mmol). The title compound was obtained (3.07 g, 11.67 mmol, 50% yield) as a yellow oil. UPLC-MS (Method 3) m / z 264.1 [M+H]+at 2.108 min.

[0294] Step 2: 1-(((4-(6-Isopropoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol: Using the procedure outlined in Step 2 of Intermediate 7, Route 1 starting with 1-(((4'-bromo-[1,1'- biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol (3.0 g, 11.7 mmol). The title compound was obtained (2.2 g, 7.05 mmol, 60% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.32 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.6, 2.6 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 6.74 (dd, J = 8.6, 3.3 Hz, 3H), 5.38 (s, 1H), 5.28 – 5.21 (m, 1H), 5.14 (s, 1H), 3.12 (s, 2H), 2.06 – 1.96 (m, 4H), 1.65 (s, 1H), 1.58 – 1.49 (m, 1H), 1.29 (d, J = 6.2 Hz, 6H). Intermediate 10: 1-(((4'-Ethoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol

[0295] Step 1: N-(4-Bromophenyl)-1-hydroxycyclopentane-1-carboxamide: To a mixture of 4- bromoaniline (13.1 g, 76.8 mmol), 1-hydroxycyclopentane-1-carboxylic acid (11.3 g, 87.2 mmol) and DIPEA (22.5 g, 174.0 mmol) in DMF (100 mL) was added PyBOP (68.0 g, 131.0 mmol). The reaction was heated at 50 °C overnight, then cooled to room temperature, diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with 1 / 3 EtOAc / PE) to afford the title compound (19.2 g, 67.8 mmol, 88 % yield) as a yellow oil. UPLC- MS (Method 4) m / z 284.00, 286.0 [M+H]+at 1.744 min.1H NMR (400 MHz, DMSO-d6) 9.81 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 5.59 (s, 1H), 2.06 – 1.96 (m, 2H), 1.73 (ddt, J = 22.2, 14.0, 6.9 Hz, 6H).

[0296] Step 2: 1-(((4-Bromophenyl)amino)methyl)cyclopentan-1-ol: To a solution of N-(4- bromophenyl)-1-hydroxycyclopentane-1-carboxamide (19.2 g, 67.8 mmol) in THF (100 mL) at 0 °C was added BH3(1M in THF, 255.0 mL, 255.0 mmol) and the reaction stirred at RT for 72 h. The mixture was quenched with NaOH (2 M) and diluted with water (200 mL). The aqueous was extracted with EtOAc (3 x 200 mL) and the combined organic layers dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purifed by column chromatography on silica gel (eluting with 1 / 3 EtOAc / PE) to afford the title compound (16.0 g, 59.2 mmol, 87% yield) as a yellow solid. UPLC-MS (Method 4) m / z 270.10, 272.10 [M+H]+at 2.026 min.1H NMR (400 MHz, DMSO-d6) 7.16 (d, J = 8.7 Hz, 2H),6.58 (d, J = 8.8 Hz, 2H), 5.54 (s, 1H), 4.38 (s, 1H), 3.01 (d, J = 5.6 Hz, 2H), 1.73 – 1.68 (m, 2H), 1.59 – 1.50 (m, 6H).

[0297] Step 3: 1-(((4'-Ethoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol: A mixture of 1-(((4-bromophenyl)amino)methyl)cyclopentan-1-ol (4.0 g, 14.8 mmol), (4-ethoxyphenyl)boronic acid (3.7 g, 22.3 mmol), K3PO4(6.3 g, 30 mmol) and Pd(dppf)Cl2(1.1 g, 1.5 mmol) in a mixture of dioxane and water (v / v=10 / 1, 44.0 mL) was heated at 110 °C for 3 h under N2. The mixture was filtered through Celite®, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with PE / EtOAc=2 / 1) to afford the title compound (3.6 g, 11.78 mmol, 80% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 7.44 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 5.36 (t, J = 5.6 Hz, 1H), 4.38 (s, 1H), 4.02 (q, J = 6.9 Hz, 2H), 3.08 (d, J = 5.6 Hz, 2H), 1.75 – 1.68 (m, 2H), 1.62 – 1.53 (m, 6H), 1.33 (t, J = 6.9 Hz, 3H). Intermediate 11: 1-(((4-(6-Ethoxypyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol

[0298] Step 1: N-(4-(6-Ethoxypyridin-3-yl)phenyl)-1-hydroxycyclopentane-1-carboxamide: Using the procedure outlined in Step 1 of Intermediate 10 starting with 4-(6-ethoxypyridin-3- yl)aniline (3.5 g, 16.3 mmol). The title compound was obtained (3.08 g, 9.44 mmol, 58% yield) as a yellow solid.NMR (400 MHz, DMSO-d6) 9.73 (s, 1H), 8.44 (d, J = 2.5 Hz, 1H), 7.97 (dd, J = 8.7, 2.6 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 1H), 5.62 (s, 1H), 4.33 (d, J = 7.0 Hz, 2H), 2.10 – 1.97 (m, 2H), 1.73 (ddd, J = 11.0, 7.1, 3.9 Hz, 6H), 1.33 (t, J = 7.0 Hz, 3H).

[0299] Step 2: 1-(((4-(6-Ethoxypyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol: Using the procedure outlined in Step 2 of Intermediate 10 starting with N-(4-(6-ethoxypyridin-3-yl)phenyl)- 1-hydroxycyclopentane-1-carboxamide (3.08 g, 9.20 mmol). The title compound was obtained (1.28 g, 4.09 mmol, 44% yield) as a white solid.1NMR (400 MHz, DMSO-d6) 8.32 (d, J = 2.5 Hz, 1H), 7.85 (dd, J = 8.6, 2.6 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 5.47 (s, 1H), 4.30 (d, J = 7.0 Hz, 2H), 3.09 (s, 1H), 3.01 (d, J = 3.8 Hz, 2H), 1.75 – 1.71 (m, 2H), 1.62 – 1.53 (m, 6H), 1.32 (t, J = 7.0 Hz, 3H).80 Intermediate 12: 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol

[0300] Step 1: 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol: Using the procedure outlined in Step 3 of Intermediate 10 starting with 1-(((4- bromophenyl)amino)methyl)cyclopentan-1-ol (5.0 g, 18.59 mmol). The title compound was obtained (2.9 g, 8.90 mmol, 48% yield) as a yellow solid. UPLC-MS (Method 3) m / z 326.2 [M+H]+at 2.359 min.1H NMR (400 MHz, DMSO-d6) 7.45 – 7.40 (m, 2H), 7.35 – 7.30 (m, 2H), 6.94 – 6.87 (m, 2H), 6.70 – 6.65 (m, 2H), 5.36 (t, J = 5.6 Hz, 1H), 4.59 (m, J = 6.0 Hz, 1H), 4.39 (s, 1H), 3.08 (d, J = 5.6 Hz, 2H), 1.71 (dd, J = 11.4, 7.2 Hz, 2H), 1.58 (dt, J = 17.6, 5.7 Hz, 6H), 1.26 (d, J = 6.0 Hz, 6H). Intermediate 13: 1-(((4-(6-Isopropoxypyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol

[0301] Step 1: 1-(((4-(6-Isopropoxypyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol: Using the procedure outlined in Step 3 of Intermediate 10 starting with 1-(((4- bromophenyl)amino)methyl)cyclopentan-1-ol (2.05 g, 7.6 mmol). The title compound was obtained (1.9 g, 5.82 mmol, 76% yield) as a yellow solid. UPLC-MS (Method 3) m / z 326.2 [M+H]+at 2.359 min.1H NMR (400 MHz, DMSO-d6) 8.32 (d, J = 2.6 Hz, 1H), 7.83 (dd, J = 8.6, 2.6 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 6.72 (dd, J = 11.6, 8.5 Hz, 3H), 5.47 (t, J = 5.7 Hz, 1H), 4.39 (s, 1H), 3.08 (d, J = 5.6 Hz, 2H), 1.77 – 1.51 (m, 8H), 1.29 (d, J = 6.1 Hz, 6H). Intermediate 14: 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1- ol

[0302] Step 1: 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: Using the procedure outlined in Step 3 of Intermediate 6 starting with 1-(((4- bromophenyl)amino)methyl)cyclobutan-1-ol (3.0 g, 11.71 mmol). The title compound was obtained (2.2 g, 7.39 mmol, 63% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 7.54 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.41 (t, J = 5.6 Hz, 1H), 5.17 (s, 1H), 4.42 (s, 2H), 3.31 (s, 3H), 3.15 (d, J = 5.6 Hz, 2H), 2.02 (ddd, J = 23.7, 9.2, 2.8 Hz, 4H), 1.74 – 1.50 (m, 2H). Intermediate 15: 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan- 1-ol

[0303] Step 1: 4'-(Methoxymethyl)-[1,1'-biphenyl]-4-amine: Using the procedure outlined in Step 3 of Intermediate 6 starting with 4-bromoaniline (15.0 g, 87.2 mmol). The title compound was obtained (15.0 g, 70.39 mmol, 81% yield) as a yellow solid. UPLC-MS (Method 4) m / z 214.1 [M+H]+at 1.222 min.1H NMR (400 MHz, DMSO-d6) 7.51 (d, J = 8.1 Hz, 2H), 7.37 – 7.27 (m, 4H), 6.63 (d, J = 8.2 Hz, 2H), 5.21 (s, 2H), 4.39 (s, 2H), 3.28 (s, 3H).

[0304] Step 2: 1-Hydroxy-N-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)cyclopentane-1- carboxamide: Using the procedure outlined in Step 1 of Intermediate 10 starting with 4'- (methoxymethyl)-[1,1'-biphenyl]-4-amine (5.0 g, 23.44 mmol). The title compound was obtained(4.8 g, 14.75 mmol, 63% yield) as a grey solid. UPLC-MS (Method 4) m / z 326.2 [M+H]+at 1.973 min.1H NMR (400 MHz, DMSO-d6) 9.73 (s, 1H), 7.94 – 7.88 (m, 1H), 7.87 – 7.80 (m, 1H), 7.62 (dd, J = 8.4, 6.4 Hz, 4H), 7.44 (dd, J = 6.4, 3.1 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 4.44 (s, 2H), 3.30 (s, 3H), 2.03 (dd, J = 7.6, 5.0 Hz, 2H), 1.82 – 1.68 (m, 6H).

[0305] Step3: 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol: Using the procedure outlined in Step 2 of Intermediate 10 starting with 1-hydroxy-N-(4'- (methoxymethyl)-[1,1'-biphenyl]-4-yl)cyclopentane-1-carboxamide (1.9 g, 5.84 mmol). The title compound was obtained (1.55 g, 4.98 mmol, 85% yield) as a yellow solid. UPLC-MS (Method 4) m / z 312.2 [M+H]+at 2.205 min.1H NMR (400 MHz, DMSO-d6) 7.52 (d, J = 8.1 Hz, 2H), 7.44 – 7.36 (m, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.71 (d, J = 8.1 Hz, 2H), 5.48 (d, J = 5.3 Hz, 1H), 4.39 (d, J = 4.3 Hz, 3H), 3.32 (d, J = 2.6 Hz, 1H), 3.29 (d, J = 3.0 Hz, 2H), 3.09 (q, J = 5.3 Hz, 2H), 1.78 – 1.67 (m, 2H), 1.57 (dq, J = 16.6, 5.5 Hz, 6H).

[0306] Step 1: 5-Bromo-2-(bromomethyl)pyridine: To a mixture of 5-bromo-2-methylpyridine (30.0 g, 174.38 mmol) in CCl4(300 mL) at RT was added 2,2'-azobis(2-methylpropionitrile) (7.14 g, 44.0 mmol) and NBS (32.6 g, 181.1 mmol). The reaction was heated at 90 °C overnight, then was cooled to room temperature and concentrated under reduced pressure. The residue 5 obtained was purified by column chromatography on silica gel (eluting with 1 / 100 EtOAc / PE) to afford the title compound (22.3 g, 88.87 mmol, 51 % yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.68 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.3, 2.4 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 4.68 (s, 2H).

[0307] Step 2: 5-Bromo-2-(methoxymethyl)pyridine: To a solution of 5-bromo-2- 10 (bromomethyl)pyridine (22.3 g, 88.87 mmol) in MeOH (50 mL) at RT was added sodium methoxide ( 30% in MeOH, 200 mL). The reaction was stirred at RT for 4 h, then concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with 1 / 10 EtOAc / PE) to afford the title compound (12.0 g, 59.39 mmol, 67 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.64 (d, J = 2.1 Hz, 1H), 8.07 – 8.02 (m, 1H), 15 7.38 (d, J = 8.4 Hz, 1H), 4.46 (s, 2H), 3.36 (s, 3H).

[0308] Step 3: 4-(6-(Methoxymethyl)pyridin-3-yl)aniline: Using the procedure outlined in Step 3 of Intermediate 6 starting with 5-bromo-2-(methoxymethyl)pyridine (6.0 g, 29.7 mmol). The title compound was obtained (6.2 g, 28.93 mmol, 97% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.70 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.1, 2.3 Hz, 1H), 7.39 (t, J = 9.1 Hz, 3H), 6.66 20 (d, J = 8.5 Hz, 2H), 5.32 (s, 2H), 4.48 (s, 2H), 3.36 (s, 3H).

[0309] Step 4: 1-Hydroxy-N-(4-(6-(methoxymethyl)pyridin-3-yl)phenyl)cyclobutane-1- carboxamide: Using the procedure outlined in Step 1 of Intermediate 6 starting with 4-(6- (methoxymethyl)pyridin-3-yl)aniline (6.2 g, 28.93 mmol). The title compound was obtained (7.1 g, 22.75 mmol, 79% yield) as a yellow solid. UPLC-MS (Method 4) m / z 313.20 [M+H]+at 0.714 25 min.1H NMR (400 MHz, DMSO-d6) 9.60 (s, 1H), 8.82 (d, J = 1.9 Hz, 1H), 8.07 (dd, J = 8.1, 2.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.1 Hz, 1H), 6.36 (s, 1H), 4.52 (s, 2H), 3.38 (s, 3H), 2.52 (d, J = 12.0 Hz, 1H), 2.47 (s, 1H), 2.12 (q, J = 9.6 Hz, 2H), 1.88 – 1.76 (m, 2H).

[0310] Step 5: 1-(((4-(6-(Methoxymethyl)pyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol:30 Using the procedure outlined in Step 2 of Intermediate 6 starting with 1-hydroxy-N-(4-(6- (methoxymethyl)pyridin-3-yl)phenyl)cyclobutane-1-carboxamide (10.2 g, 32.68 mmol). The title compound was obtained (5.0 g, 16.75 mmol, 51% yield) as a yellow solid. UPLC-MS (Method 4) m / z 299.10 [M+H]+at 2.036 min.1H NMR (400 MHz, DMSO-d6) 8.76 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.75 (t, J= 5.5 Hz, 1H), 5.17 (s, 1H), 4.75 (s, 2H), 3.49 (s, 3H), 3.16 (d, J = 5.6 Hz, 2H), 1.99 (dq, J = 21.0, 10.2 Hz, 4H), 1.71 – 1.51 (m, 2H). Intermediate 17: 1-(((4-(6-(Methoxymethyl)pyridin-3- yl)phenyl)amino)methyl)cyclopentan-1-ol

[0311] Step 1: 2-(Methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: Using the procedure outlined in Step 1 of the Intermediate 7, Route 1 starting with 5-bromo-2- (methoxymethyl)pyridine (4.15 g, 20.65 mmol). The title compound was obtained (5.14 g, 20.65 mmol, crude, 100% yield) as a yellow oil. UPLC-MS (Method 3) m / z 168.02 [M+H]+at 0.343 min.

[0312] Step 2: 1-(((4-(6-(Methoxymethyl)pyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol: Using the procedure outlined in Step 3 of Intermediate 10 starting with 1-(((4- bromophenyl)amino)methyl)cyclopentan-1-ol (3.7 g, 13.7 mmol). The title compound was obtained (1.6 g, 5.12 mmol, 37% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.72 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.2, 2.4 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 6.78 – 6.71 (m, 2H), 5.60 (t, J = 5.7 Hz, 1H), 4.48 (s, 2H), 3.36 (s, 3H), 3.10 (d, J = 5.6 Hz, 2H), 1.76 – 1.49 (m, 8H). Intermediate 18: 1-(((4'-propyl-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol

[0313] Step 1: 1-(((4'-propyl-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: A mixture of 1- (((4-bromophenyl)amino)methyl)cyclobutan-1-ol (Intermediate 6 Step 2, 13.0 g, 50.9 mmol), (4-propylphenyl)boronic acid (12.0 g, 73.2 mmol), K3PO4(21.0 g, 100.0 mmol) and Pd(dppf)Cl2(1.8 g, 2.5 mmol) in a mixture of dioxane and water (v / v= 10 / 1, 130 mL) was heated at 100 °C for 16 h under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc =3 / 1) to afford the title compound (7.0 g, 24 mmol, 47% yield) as a yellow solid. UPLC- MS (Method 2) m / z [M+H]+296.10 at 4.450 min.1H NMR (400 MHz, DMSO-d6) 7.44 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.33 (s, 1H), 5.15 (s, 1H), 3.12 (d, J = 5.6 Hz, 2H), 2.55 (d, J = 7.4 Hz, 2H), 2.08 – 1.92 (m, 4H), 1.59 (dt, J = 14.2, 7.2 Hz, 4H), 0.90 (t, J = 7.3 Hz, 3H). Intermediate 19: 1-(((4-(6-propylpyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol

[0314] Step 1: (E)-5-bromo-2-(prop-1-en-1-yl)pyridine: To a solution of ethyltriphenylphosphonium bromide (2.0 g, 5.376 mmol) in dry THF (10 mL) at -78 °C under an atmosphere of nitrogen was added sodium bis(trimethylsilyl)amide (2.0 M in THF, 2.7 mL, 5.376 mmol) and the reaction stirred at -78 °C for 1 h. After this time, 5-bromopicolinaldehyde (1.0 g, 5.376 mmol) was added and the reaction allowed to warm to room temperature and stirred overnight. The mixture was quenched with sat. NH4Cl (30 mL) and extracted with EtOAc (13 x 5 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc =6 / 1) to afford the title compound (578 mg, 2.93 mmol, 55% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+198.00, 200.00 at 0.871 min.

[0315] Step 2: Step 1 bromide (578.0 mg, 2.93 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (767.0 mg, 3.50 mmol), K3PO4(1.24 g, 5.837 mmol) and Pd(dppf)Cl2(214.0 mg, 0.29 mmol) in a mixture of dioxane and water (v / v= 10 / 1, 5.5 mL) was heated at 100 °C overnight under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 1) to afford the title compound (340 mg, 1.62 mmol, 55% yield) as a yellow solid. UPLC-MS (Method 4) m / z [M+H]+211.21 at 0.61 min.1H NMR (400 MHz, DMSO-d6) 8.68 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 1H), 6.75 – 6.63 (m, 3H), 6.49 (dd, J = 15.7, 1.9 Hz, 1H), 5.31 (s, 2H), 1.89 (dd, J = 6.7, 1.6 Hz, 3H).

[0316] Step 3: 4-(6-propylpyridin-3-yl)aniline. A mixture of Step 2 aniline (330 mg, 1.57 mmol) and Pd / C (10% wet, 66 mg) in MeOH (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration through Celite® and the filtrate concentrated to afford the title compound (288 mg, 1.36 mmol, 87% yield) as a yellow oil, which was used in the next step without further purification. UPLC-MS (Method 4) m / z [M+H]+213.2 at 0.584 min.1H NMR (400 MHz, DMSO-d6) 8.65 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.1, 2.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.2 Hz, 2H), 5.27 (s, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.69 (p, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0317] Step 4: 1-hydroxy-N-(4-(6-propylpyridin-3-yl)phenyl)cyclobutane-1-carboxamide: A mixture of 4-(6-propylpyridin-3-yl)aniline (1.0 g, 4.72 mmol), 1-hydroxycyclobutane-1-carboxylic acid (547 mg, 4.72 mmol), DIPEA (1.8 g, 14.15 mmol) and PyBOP (3.7 g, 7.08 mmol) in DMF (10 mL) was heated at 50 °C overnight. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over solid anhydrous Na2SO4filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc =3 / 1) to afford the title compound (1.3 g, 4.19 mmol, 89 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 9.58 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 2.72 (d, J = 8.8 Hz, 3H), 2.55 – 2.51 (m, 1H), 2.11 (dd, J = 11.5, 8.7 Hz, 2H), 1.82 (ddd, J = 17.7, 12.8, 7.1 Hz, 2H), 1.70 (p, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0318] Step 5: 1-(((4-(6-propylpyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol: To a solution of Step 4 amide (200 mg, 0.65 mmol) was added a solution of borane (1M in THF, 3.0 mmol, 3mL) and the reaction stirred at room temperature for 16 h. The reaction was quenched with NaOH (2 mL of 2 M) and diluted with water (30 mL). The aqueous was extracted with EtOAc (3 x 30 mL) and the combined organic layers were dried over solid anhydrous Na2SO4. filtered and concentrated to give the title compound (190 mg, 0.642 mmol, 98% yield) as a yellow solid. 5 UPLC-MS (Method 3) m / z [M+H]+297.4 at 2.270 min. Intermediate 20: 1-(((4'-propyl-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol

[0319] Step 1: 1-(((4'-propyl-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol: A mixture of 1-(((4-bromophenyl)amino)methyl)cyclopentan-1-ol (Intermediate 10 Step 2, 5.0 g, 18.6 mmol), 10 (4-propylphenyl)boronic acid (6.1 g, 37.2 mmol), K3PO4(7.9 g, 37.2 mmol) and Pd(dppf)Cl2(1.3 g, 1.8 mmol) in a mixture of dioxane and water (v / v= 10 / 1, 55 mL) was heated at 80 °C for 4 h under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by 15 chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 5) to afford the title compound (3.7 g, 12.0 mmol, 65% yield) as a yellow solid. UPLC-MS (Method 4) m / z [M+H]+310.20 at 2.971 min.1H NMR (400 MHz, DMSO-d6) 7.44 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 5.43 (t, J = 5.5 Hz, 1H), 4.40 (s, 1H), 3.09 (d, J = 5.5 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.76 – 1.69 (m, 2H), 1.58 (dt, J = 15.4, 7.2 Hz, 20 8H), 0.90 (t, J = 7.3 Hz, 3H). Intermediate 21: 1-(((4-(6-propylpyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol

[0320] Step 1: 1-hydroxy-N-(4-(6-propylpyridin-3-yl)phenyl)cyclopentane-1-carboxamide: A mixture of 4-(6-propylpyridin-3-yl)aniline (Intermediate 19 Step 3, 1.0 g, 4.72 mmol), 1- hydroxycyclopentane-1-carboxylic acid (613 mg, 4.72 mmol), DIPEA (1.8 g, 14.15 mmol) and PyBOP (3.7 g, 7.08 mmol) in DMF (10 mL) was heated at 50 °C overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over solid anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting product was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 3) to afford the title compound (0.5 g, 1.61 mmol, 34 % yield) as a white solid.1NMR (400 MHz, DMSO-d6) 9.77 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.1, 2.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 5.62 (s, 1H), 2.73 (t, J = 7.6 Hz, 2H), 2.07 - 2.00 (m, 2H), 1.76 - 1.60 (m, 8H), 0.92 (t, J = 7.3 Hz, 3H).

[0321] Step 2: 1-(((4-(6-propylpyridin-3-yl)phenyl)amino)methyl)cyclopentan-1-ol: A solution of Step 1 amide (100 mg, 0.31 mmol) in a solution of borane (1M in THF, 1.24 mmol, 1.24 mL) was stirred at room temperature for 16 h. The mixture was quenched with NaOH (2 mL x 2 M), diluted with water (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated to give the title compound (90 mg, 0.29 mmol, 94% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.67 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.1, 2.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 6.74 – 6.61 (m, 2H), 5.55 (t, J = 5.7 Hz, 1H), 4.40 (s, 1H), 3.10 (d, J = 6.1 Hz, 2H), 1.68 (d, J = 7.5 Hz, 2H), 1.62 - 1.50 (m, 10H), 0.91 (t, J = 7.3 Hz, 3H).

[0322] Step 1: 3-hydroxy-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)tetrahydrofuran-3- carboxamide: A mixture of 4'-isopropoxy-[1,1'-biphenyl]-4-amine (Intermediate 8 Step 1, 482 mg, 2.12 mmol), 3-hydroxytetrahydrofuran-3-carboxylic acid (280 mg, 2.12 mmol), DIPEA (547 mg, 4.24 mmol) and PyBOP (1.3 g, 2.54 mmol) in DMF (5 mL) was heated at 50 °C overnight. Themixture was cooled to room temperature, then diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 3) to afford the title compound (360 mg, 1.05 mmol, 50% yield) as a yellow solid. UPLC-MS (Method 4) m / z [M+H]+342.20 at 2.558 min.

[0323] Step 2: 3-(((4'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)tetrahydrofuran-3-ol: To a solution of Step 1 amide (360 mg, 1.05 mmol) in THF (1 mL) at 0 °C was added a solution of borane (1 M in THF, 3.15 mL, 3.15 mmol) and the reaction stirred at room temperature for 2 days. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel (eluting with Petroleum ether / EtOAc = 2 / 1) to afford the title compound (250 mg, 0.76 mmol, 72% yield) as a yellow oil. UPLC-MS (Method 4) m / z [M+H]+328.30 at 2.657 min.1H NMR (400 MHz, DMSO-d6) 7.43 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 5.49 (t, J = 5.8 Hz, 1H), 4.96 (s, 1H), 4.59 (p, J = 6.0 Hz, 1H), 3.90 – 3.72 (m, 2H), 3.63 (d, J = 8.9 Hz, 1H), 3.55 (d, J = 8.9 Hz, 1H), 3.18 (d, J = 5.8 Hz, 2H), 2.02 – 1.78 (m, 2H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 23: 1-(((4'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol

[0324] Step 1: 1-hydroxy-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: A mixture of 4'-isopropoxy-[1,1'-biphenyl]-4-amine (Intermediate 8 Step 1, 227 mg, 1.0 mmol), PyBOP (780 mg, 1.5 mmol), DIPEA (387 mg, 3.0 mmol) and 1-hydroxycyclopropane-1- carboxylic acid (153 mg, 1.5 mmol) in DMF (3 mL) was heated at 50 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic phases were washed with brine (3 x 20 mL), dried over solid anhydrous Na2SO4 filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluting with Petroleum ether / EtOAc = 10 / 1) to afford the title compound (300 mg, 0.96 mmol, 96% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 9.82 (s, 1H), 7.83 –7.78 (m, 2H), 7.59 – 7.51 (m, 4H), 6.99 – 6.92 (m, 2H), 6.56 (s, 1H), 4.64 (p, J = 6.0 Hz, 1H), 1.28 (d, J = 6.0 Hz, 6H), 1.17 (d, J = 3.2 Hz, 2H), 0.97 (d, J = 3.2 Hz, 2H).

[0325] Step 2: 1-(((4'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol: A solution of Step 1 amide (500 mg, 1.6 mmol) in a solution of borane (1M in THF, 8.0 mmol, 8 mL) was heated at 50 °C for 16 h. The reaction was quenched with NaOH (5 mL x 2 M) and diluted with water (10 mL). The aqueous was extracted with EtOAc (3 x 20 mL) and the organic layers combined, dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by chromatography on silica gel (eluting with Petroleum ether / EtOAc = 10 / 1) to obtain the title compound (300 mg, 1.0 mmol, 63 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 7.43 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 5.55 (d, J = 5.6 Hz, 1H), 5.35 (s, 1H), 4.65 – 4.54 (m, 1H), 3.17 (d, J = 5.6 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 0.63 – 0.48 (m, 4H). Intermediate 24: 1-(((4-(6-isopropoxypyridin-3-yl)phenyl)amino)methyl)cyclopropan-1-ol

[0326] Step 1: 4-(6-isopropoxypyridin-3-yl)aniline: A mixture of 5-bromo-2-isopropoxypyridine (1.00 g, 4.63 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.38 g, 6.02 mmol), Pd(dppf)Cl2(338 mg, 0.46 mmol) and K3PO4(2.94 g, 13.88 mmol) in a mixture of dioxane (9 mL) and water (1 mL) was heated at reflux overnight under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by chromatography onsilica gel (eluting with Petroleum ether / EtOAc = 5 / 1) to afford the title compound (880 mg, 3.86 mmol, 83% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.30 (dd, J = 2.8, 0.8 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.73 (dd, J = 8.4, 0.8 Hz, 1H), 6.63 (d, J = 8.4 Hz, 2H), 5.24 (p, J = 6.4 Hz, 1H), 5.19 (s, 2H), 1.29 (d, J = 6.2 Hz, 6H).

[0327] Step 2: 1-hydroxy-N-(4-(6-isopropoxypyridin-3-yl)phenyl)cyclopropane-1-carboxamide: A mixture of Step 1 aniline (880 mg, 3.86 mmol), PyBOP (3.0 g, 5.78 mmol), DIPEA (1.49 g, 11.6 mmol) and 1-hydroxycyclopropane-1-carboxylic acid (590 mg, 5.78 mmol) in DMF (10 mL) was heated at 50 °C overnight. The mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL) and the combined organic phases washed with brine (3 x 50 mL), dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 1) to afford the title compound (550 mg, 1.76 mmol, 45% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 9.88 (s, 1H), 8.44 (dd, J = 2.8, 0.8 Hz, 1H), 7.96 (dd, J = 8.4, 2.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 6.80 (dd, J = 8.8, 0.8 Hz, 1H), 6.57 (s, 1H), 5.28 (p, J = 6.4 Hz, 1H), 1.31 (d, J = 6.4 Hz, 6H), 1.17 (q, J = 4.4 Hz, 2H), 0.97 (q, J = 4.4 Hz, 2H).

[0328] Step 3: 1-(((4-(6-isopropoxypyridin-3-yl)phenyl)amino)methyl)cyclopropan-1-ol: A solution of Step 2 amide (250 mg, 0.80 mmol) in a solution of borane (1M in THF, 4.0 mmol, 4 mL) was stirred at room temperature for 16 h. The reaction was quenched with NaOH (3 mL x 2 M), diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by chromatography on silica gel (eluting with Petroleum ether / EtOAc = 2 / 1) to give the title compound (98 mg, 0.33 mmol, 41% yield) as a white solid. UPLC-MS (Method 3) m / z [M+H]+299.19 at 1.714 min. Intermediate 28: 3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-amine

[0329] Step 1: 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl: A mixture of 4-bromo-2-fluoro-1- nitrobenzene (5.0 g, 22.73 mmol), (4-isopropoxyphenyl)boronic acid (6.0 g, 34.09 mmol), K3PO4(9.6 g, 45.45 mmol) and Pd(dppf)Cl2(1.6 g, 2.27 mmol) in a mixture of dioxane (27 mL) and water (3 mL) was heated at 100 °C overnight under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with 100% Petroleum ether) to afford the title compound (3.4 g, 12.36 mmol, 54% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8.17 (t, J = 8.4 Hz, 1H), 7.86 (dd, J = 13.4, 2.0 Hz, 1H), 7.79 – 7.74 (m, 2H), 7.73 – 7.68 (m, 1H), 7.08 – 6.98 (m, 2H), 4.70 (hept, J = 6.0 Hz, 1H), 1.29 (d, J = 6.0 Hz, 6H).

[0330] Step 2: 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)azetidine: A mixture of 3-fluoro-4'- isopropoxy-4-nitro-1,1'-biphenyl (1.0 g, 3.64 mmol), azetidine (310.9 mg, 5.45 mmol) and K2CO3(1.0 g, 7.28 mmol) in MeCN (10 mL) was heated at 80 °C overnight. The solvent was removed and the residue diluted with water (60 mL) and extracted with EtOAc (3 x 60 mL) . The combined organic phases were washed with brine (3 x 60 mL), dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (1.1 g, 3.52 mmol, 96% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 7.83 (d, J = 8.7 Hz, 1H), 7.70 – 7.59 (m,2H), 7.06 – 6.96 (m, 3H), 6.83 (d, J = 1.9 Hz, 1H), 4.68 (p, J = 6.1 Hz, 1H), 3.97 (t, J = 7.5 Hz, 4H), 2.38 – 2.24 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H).

[0331] Step 3: 3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-amine: A mixture of 1-(4'- isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)azetidine (500.0 mg, 1.60 mmol), iron powder (447.8 mg, 8.01 mmol) and NH4Cl (128.4 mg, 2.40 mmol) in a mixture of EtOH (5 mL) and water (1 mL) was heated at 80 °C overnight. The reaction was cooled to room temperature, filtered through Celite®, diluted with water (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (3 x 60 mL), dried over solid anhydrous Na2SO4 filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (250.0 mg, 0.89 mmol, 55% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 7.44 – 7.39 (m, 2H), 6.92 – 6.87 (m, 2H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.64 – 6.57 (m, 2H), 4.59 (p, J = 6.0 Hz, 1H), 4.41 (s, 2H), 3.78 (t, J = 7.0 Hz, 4H), 2.16 (m, 2H), 1.26 (d, J = 6.0 Hz, 6H). Intermediate 29: 4'-isopropoxy-3-(pyrrolidin-1-yl)-[1,1'-biphenyl]-4-amine

[0332] Step 1: 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)pyrrolidine: A mixture of 3-fluoro-4'- isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 500 mg, 1.82 mmol), pyrrolidine (194 mg, 2.73 mmol) and K2CO3(502 mg, 3.64 mmol) in DMF (5 mL) was heated at 80 °C overnight. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (3 x 30 mL) and dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (592 mg, 1.82 mmol, 99% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+327.4 at 2.563 min.

[0333] Step 2: 4'-isopropoxy-3-(pyrrolidin-1-yl)-[1,1'-biphenyl]-4-amine: A mixture of 1-(4'- isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)pyrrolidine (739 mg, 2.27 mmol), iron powder (635 mg, 11.33 mmol) and NH4Cl (184 mg, 3.40 mmol) in a mixture of MeOH (8 mL) and water (2 mL) was heated at 70 °C overnight. The mixture was filtered through the Celite®, diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 10 / 1) to afford the title compound (563 mg, 1.94 mmol, 86% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+297.3 at 1.783 min.1H NMR (400 MHz, DMSO-d6) 7.45 – 7.39 (m, 2H), 7.06 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.1, 2.1 Hz, 1H), 6.92 – 6.88 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 4.67 (s, 2H), 4.59 (p, J = 6.0 Hz, 1H), 3.02 (td, J = 5.1, 4.2, 2.2 Hz, 4H), 1.86 (m, 4H), 1.26 (d, J = 6.0 Hz, 6H). Intermediate 30: 4'-isopropoxy-3-(piperidin-1-yl)-[1,1'-biphenyl]-4-amine

[0334] Step 1: 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)piperidine: A mixture of 3-fluoro-4'- isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 200 mg, 0.73 mmol), piperidine (93 mg, 1.1 mmol) and K2CO3(202 mg, 1.46 mmol) in DMF (3 mL) was heated at 80 °C overnight. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 100 / 1) to afford the title compound (230 mg, 0.68 mmol, 93% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+341.4 at 2.72 min.1H NMR (400MHz, DMSO-d6) 7.86 (d, J = 8.5 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 8.5, 1.9 Hz, 1H), 7.05 – 6.99 (m, 2H), 4.70 (p, J = 6.0 Hz, 1H), 3.04 (t, J = 5.2 Hz, 4H), 1.67 – 1.53 (m, 6H), 1.29 (d, J = 6.0 Hz, 6H).

[0335] Step 2: 4'-isopropoxy-3-(piperidin-1-yl)-[1,1'-biphenyl]-4-amine: A mixture of 1-(4'- isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)piperidine (400 mg, 1.18 mmol), iron powder (330 mg, 5.9 mmol) and NH4Cl (95 mg, 1.77 mmol) in a mixture of MeOH (10 mL) and water (2 mL) was heated at 80 °C for 3 h. The mixture was filtered, the filtrate was concentrated and the resulting residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 60 / 1) to give the title compound (340 mg, 1.1 mmol, 93% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+311.4 at 2.44 min.1H NMR (400 MHz, DMSO-d6) 7.43 – 7.39 (m, 2H), 7.08 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.1, 2.1 Hz, 1H), 6.93 – 6.89 (m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 4.75 (s, 2H), 4.59 (p, J = 6.0 Hz, 1H), 2.80 (s, 4H), 1.67 (p, J = 5.6 Hz, 4H), 1.53 (s, 2H), 1.26 (d, J = 6.0 Hz, 6H).

[0336] Step 1: 4-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)morpholine: A mixture of 3-fluoro- 4'-isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 200 mg, 0.73 mmol), morpholine (95 mg, 1.09 mmol) and K2CO3(201 mg, 1.45 mmol) in DMF (4 mL) was heated at 80 °C overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography on silica gel (eluting withPetroleum ether / EtOAc = 5 / 1) to afford the title compound (233 mg, 94%) as a yellow oil. UPLC- MS (Method 4) m / z [M+H]+343.60 at 2.851 min.1H NMR (400 MHz, DMSO-d6) 7.91 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.5, 1.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.73 – 4.65 (m, 1H), 3.75 – 3.69 (m, 4H), 3.11 – 3.05 (m, 4H), 1.29 (d, J = 6.0 Hz, 6H).

[0337] Step 2: 4'-isopropoxy-3-morpholino-[1,1'-biphenyl]-4-amine: A mixture of Step 1 morpholine (370 mg, 1.08 mmol), iron powder (302 mg, 5.41 mmol) and NH4Cl (87 mg, 1.62 mmol) in a mixture of MeOH (5 mL) and water (1 mL) was heated at 80 °C for 2 h. The mixture was filtered through Celite®, diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over solid anhydrous Na2SO4, filtered and concentrated to afford the title compound (300 mg, 89% yield) as a yellow solid. UPLC-MS (Method 4) m / z [M+H]+313.20 at 1.817 min.1H NMR (400 MHz, DMSO-d6) 7.43 (d, J = 8.7 Hz, 2H), 7.11 – 7.04 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.1 Hz, 1H), 4.84 (s, 2H), 4.60 (p, J = 6.0 Hz, 1H), 3.76 (d, J = 8.9 Hz, 4H), 2.89 – 2.81 (m, 4H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 32: 4-(((1-hydroxycyclobutyl)methyl)amino)-4'-isopropoxy-[1,1'-biphenyl]-3- carbonitrile

[0338] Step 1: 5-bromo-2-(((1-hydroxycyclobutyl)methyl)amino)benzonitrile: To a solution of 5- bromo-2-fluorobenzonitrile (500 mg, 2.5 mmol) in acetonitrile (8 mL) was added 1- (aminomethyl)cyclobutan-1-ol (253 mg, 2.5 mmol) and K2CO3(691 mg, 5.0 mmol) and the reaction heated at 80 °C for 18 h. The reaction was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL) and the combined organic dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (360 mg, 1.28 mmol, 50% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 7.68 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 9.1, 2.5 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 5.58 (t, J = 5.5 Hz, 1H), 5.42 (s, 1H), 3.25 (d, J = 5.5 Hz, 2H), 2.01 – 1.95 (m, 4H), 1.70 – 1.59 (m, 1H), 1.58 – 1.49 (m, 1H).

[0339] Step 2: 4-(((1-hydroxycyclobutyl)methyl)amino)-4'-isopropoxy-[1,1'-biphenyl]-3- carbonitrile: A mixture of Step 1 bromide (352 mg, 1.25 mmol), (4-isopropoxyphenyl)boronic acid (225 mg, 1.25 mmol), Pd(dppf)Cl2(92 mg, 0.125 mmol) and K3PO4(532 mg, 2.50 mmol) in dioxane and water (v / v= 10 / 1, 4.4 mL) was heated at 100 °C for 2 h under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated and the resulting residue purified by column chromatography (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (331 mg, 0.98 mmol, 78% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 7.75 – 7.66 (m, 2H), 7.56 – 7.47 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.98 – 6.90 (m, 2H), 5.45 (s, 1H), 5.40 (t, J = 5.4 Hz, 1H), 4.63 (p, J = 6.0 Hz, 1H), 3.31 (s, 2H), 2.06 – 1.96 (m, 4H), 1.67 (m, 1H), 1.63 – 1.50 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H).

[0340] Step 1: 5-(3-fluoro-4-nitrophenyl)-2-isopropoxypyridine: A mixture of 4-bromo-2-fluoro- 1-nitrobenzene (1.0 g, 4.54 mmol), 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (1.79 g, 6.81 mmol), K3PO4(1.93 g, 9.08mmol) and Pd(dppf)Cl2(329 mg, 0.45 mmol) in dioxane and water (v / v= 10 / 1, 10 mL) was heated at 100 °C overnight night under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (eluting with 100% Petroleum ether) to afford the titlecompound (0.86 g, 3.11 mmol, 69% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.66 (d, J = 2.7 Hz, 1H), 8.25 – 8.14 (m, 2H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 6.89 (m, 2H), 5.25 – 5.17 (m, 1H), 1.35 (d, J = 6.2 Hz, 6H).

[0341] Step 2: 5-(3-(azetidin-1-yl)-4-nitrophenyl)-2-isopropoxypyridine: A mixture of 5-(3- fluoro-4-nitrophenyl)-2-isopropoxypyridine (500 mg, 1.81 mmol), azetidine (155 mg, 2.72 mmol) and K2CO3(749 mg, 5.43 mmol) in DMF (10 mL) was stirred at room temperature for two days. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over solid anhydrous Na2SO4 filtered and concentrated under reduced pressure to afford the title compound (560 mg, 1.79 mmol, 99% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.56 (dd, J = 2.7, 0.7 Hz, 1H), 8.06 (dd, J = 8.7, 2.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.06 (dd, J = 8.7, 1.9 Hz, 1H), 6.91 – 6.83 (m, 2H), 5.35 – 5.27 (m, 1H), 2.37 – 2.29 (m, 4H), 2.04 (m, 1H), 1.34 (d, J = 6.2 Hz, 7H).

[0342] Step 3: 5-(3-(azetidin-1-yl)-4-nitrophenyl)-2-isopropoxypyridine: A mixture of 5-(3- (azetidin-1-yl)-4-nitrophenyl)-2-isopropoxypyridine (560 mg, 1.79mmol), iron powder (501mg, 8.95 mmol) and NH4Cl (144 mg, 2.69mmol) in a mixture of MeOH and water (10 mL, v / v=5 / 1) was heated at 80 °C for 1 h. The mixture was filtered through Celite®, diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 10 / 1) to afford the title compound (460 mg, 1.62mmol, 91% yield) as a yellow oil.1H NMR (400 MHz, DMSO- d6) 8.33 (dd, J = 2.7, 0.7 Hz, 1H), 7.85 (dd, J = 8.6, 2.7 Hz, 1H), 6.90 (dd, J = 8.0, 2.1 Hz, 1H), 6.75 (dd, J = 8.6, 0.7 Hz, 1H), 6.70 – 6.63 (m, 2H), 5.26 (hept, J = 6.2 Hz, 1H), 3.81 (m, 4H), 2.18 (m,, 2H), 2.00 (s, 1H), 1.31 (d, J = 6.1 Hz, 7H). Intermediate 34: 2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)aniline

[0343] Step 1: 2-ethoxy-5-(3-fluoro-4-nitrophenyl)pyridine: A mixture of 4-bromo-2-fluoro-1- nitrobenzene (500 mg, 2.27 mmol), 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (623 mg, 2.50 mmol), Pd(dppf)Cl2(168 mg, 0.23 mmol) and K3PO4(962.5 mg, 4.54 mmol) in a mixture of dioxane (10 mL) and water (1 mL) was heated at 100 °C overnight under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated and the resulting residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 10 / 1) to afford the title compound (560 mg, 2.13 mmol, 94% yield) as a yellow oil. UPLC-MS (Method 4) m / z [M+Na]+284.23 at 1.170 min.

[0344] Step 2: 5-(3-(azetidin-1-yl)-4-nitrophenyl)-2-ethoxypyridine: A mixture of Step 1 pyridine (700 mg, 2.67 mmol), azetidine (183 mg, 3.2 mmol) and K2CO3(737 mg, 5.34 mmol) in DMF (5 mL) was heated at 80 °C for 3 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over solid anhydrous Na2SO4filtered and concentrated under reduced pressure. The resulting residue was purified by column (eluting with Petroleum ether / EtOAc = 5 / 1) to afford the title compound (500 mg, 1.67 mmol, 63% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+300.24 at 1.779 min.1H NMR (400 MHz, DMSO-d6) 8.55 (dd, J = 2.7, 0.7 Hz, 1H), 8.07 (dd, J = 8.6, 2.6 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.6, 1.8 Hz, 1H), 6.93 – 6.86 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.98 (t, J = 7.5 Hz, 2H), 2.31 (dd, J = 8.3, 6.8 Hz, 4H), 1.34 (t, J = 7.0 Hz, 3H).

[0345] Step 3: 2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)aniline: A mixture of 5-(3-(azetidin-1- yl)-4-nitrophenyl)-2-ethoxypyridine (500 mg, 1.7 mmol), iron powder (476 mg, 8.5 mmol) and ammonium chloride (455 mg, 8.5 mmol) in a mixture of EtOH (10 mL) and water (2 mL) was heated at 80 °C for 4 h. The mixture was filtered through Celite®, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over solid anhydrous Na2SO4, filtered and concentrated to afford the title compound (434 mg, 1.61 mmol, 95% yield) as a brown solid. UPLC-MS (Method 3) m / z [M+H]+270.21 at 1.173 min. Intermediate 35: 3,4'-diisopropoxy-[1,1'-biphenyl]-4-amine

[0346] Step 1: 3,4'-diisopropoxy-4-nitro-1,1'-biphenyl: A mixture of 3-fluoro-4'-isopropoxy-4- nitro-1,1'-biphenyl (Intermediate 28 Step 1, 500 mg, 1.82 mmol) and KOH (204 mg, 3.64 mmol) in a mixture of 2-propanol (5 mL) and DMF (1 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (5 x 15 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 24 / 1) to afford the title compound (534 mg, 1.69 mmol, 93% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 7.88 (d, J = 8.5 Hz, 1H), 7.74 – 7.68 (m, 2H), 7.50 (d, J = 1.7 Hz, 1H), 7.31 (dd, J = 8.5, 1.7 Hz, 1H), 7.07 – 6.99 (m, 2H), 5.02 (p, J = 6.0 Hz, 1H), 4.70 (p, J = 6.0 Hz, 1H), 1.31 (dd, J = 10.4, 6.0 Hz, 12H).

[0347] Step 2: 3,4'-diisopropoxy-[1,1'-biphenyl]-4-amine: To a solution of 3,4'-diisopropoxy-4- nitro-1,1'-biphenyl (534 mg, 1.69 mmol) in EtOAc (8 mL) was added Pd / C (10% wt, 53 mg) at room temperature. The reaction was stirred at room temperature for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter pad washed with a mixture of DCM and MeOH (v / v=9 / 1, 50 mL). The filtrate was concentrated to afford thetitle compound (467 mg, 1.64 mmol, 97% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) 7.47 – 7.39 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.96 – 6.87 (m, 3H), 6.68 (d, J = 8.1 Hz, 1H), 4.68 (s, 2H), 4.60 (m, 2H), 1.28 (dd, J = 8.6, 6.0 Hz, 12H). Intermediate 36: 3-cyclopropoxy-4'-isopropoxy-[1,1'-biphenyl]-4-amine

[0348] Step 1: 3-cyclopropoxy-4'-isopropoxy-4-nitro-1,1'-biphenyl: A mixture of 3-fluoro-4'- isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 500 mg, 1.82 mmol), cyclopropanol (211 mg, 3.64 mmol) and KOH (204 mg, 3.64 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 20 / 1) to afford the title compound (569 mg, 1.81 mmol, 99 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 7.94 (d, J = 8.5 Hz, 1H), 7.78 – 7.69 (m, 3H), 7.38 (dd, J = 8.5, 1.8 Hz, 1H), 7.08 – 7.03 (m, 2H), 4.70 (p, J = 6.0 Hz, 1H), 4.25 (m, 1H), 1.30 (d, J = 6.0 Hz, 6H), 0.89 (dtd, J = 7.1, 5.2, 4.5, 0.9 Hz, 2H), 0.77 (pd, J = 5.0, 4.5, 1.9 Hz, 2H).

[0349] Step 2: 3-cyclopropoxy-4'-isopropoxy-[1,1'-biphenyl]-4-amine: A mixture of 3- cyclopropoxy-4'-isopropoxy-4-nitro-1,1'-biphenyl (569 mg, 1.82 mmol), iron powder (509 mg, 9.09 mmol) and NH4Cl (145 mg, 2.73 mmol) in a mixture of MeOH (8 mL) and water (2 mL) was heated at 80 °C for 2 h. The mixture was filtered through Celite® and the filtrate concentrated to give the title compound (500 mg, 1.76 mmol, 98% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 7.48 – 7.42 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 6.93 (td, J = 7.4, 6.7, 2.1 Hz, 3H), 6.66 (d, J = 8.0 Hz, 1H), 4.67 (s, 2H), 4.63 – 4.56 (m, 1H), 3.92 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H), 0.81 – 0.75 (m, 2H), 0.69 (p, J = 3.4 Hz, 2H). Intermediate 37; 4'-isopropoxy-N3-(4-methoxybenzyl)-[1,1'-biphenyl]-3,4-diamine

[0350] Step 1: 4'-isopropoxy-N-(4-methoxybenzyl)-4-nitro-[1,1'-biphenyl]-3-amine: To a solution of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 1 g, 3.6 mmol) in THF (10 mL) was added DIPEA (1.4 g, 11.0 mmol) and 4-methoxybenzylamine (0.75 g, 5.4 mmol) and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 12 / 1) to afford the title compound (1.3 g, 3.31 mmol, 92% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) 8.65 (t, J = 5.7 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.7 Hz, 3H), 4.69 (d, J = 6.0 Hz, 1H), 4.65 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H).

[0351] Step 2: 4'-isopropoxy-N3-(4-methoxybenzyl)-[1,1'-biphenyl]-3,4-diamine: A mixture of Step 1 nitro compound (1.3 g, 3.39 mmol), iron powder (950 mg, 16.96 mmol) and NH4Cl (270 mg, 5.09 mmol) in a mixture of MeOH (20 mL) and water (4 mL) was heated at 80 °C for 2 h. The mixture was filtered through Celite® and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 10 / 1) to afford a yellow solid (900 mg, 2.49 mmol, 73% yield). UPLC-MS (Method 3) m / z [M+H]+363.8 at 1.41 min.1H NMR (400 MHz, DMSO-d6) 7.32 (dd, J = 8.7, 3.4 Hz, 4H), 6.90 – 6.83 (m, 4H), 6.65 (dd, J = 7.9, 1.9 Hz, 1H), 6.61 – 6.56 (m, 2H), 5.07 (t, J = 5.8 Hz, 1H), 4.63 (s, 2H), 4.57 (p, J = 6.0 Hz, 1H), 4.29 (d, J = 5.6 Hz, 2H), 3.72 (s, 3H), 1.25 (d, J = 6.0 Hz, 6H). Intermediate 38: 4'-isopropoxy-N3-methyl-[1,1'-biphenyl]-3,4-diamine

[0352] Step 1: 4'-isopropoxy-N-methyl-4-nitro-[1,1'-biphenyl]-3-amine: A mixture of 3-fluoro-4'- isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 1.0 g, 3.6 mmol) and methylamine (2M in THF, 9 mL) in THF (10 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 20 / 1) to afford the title compound (1.0 g, 3.5 mmol 97% yield) as a yellow solid. UPLC-MS (Method 2) m / z [M+H]+287.05 at 3.767 min.1H NMR (400 MHz, DMSO-d6) 8.26 (d, J = 4.7 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.10 – 6.99 (m, 3H), 6.95 (dd, J = 9.0, 1.5 Hz, 1H), 4.73 – 4.65 (m, 1H), 3.05 (d, J = 4.9 Hz, 3H), 1.29 (d, J = 6.0 Hz, 6H).

[0353] Step 2: 4'-isopropoxy-N3-methyl-[1,1'-biphenyl]-3,4-diamine: To a solution of Step 1 nitro compound (1.0 g, 3.5 mmol) in MeOH (10 mL) was added Pd / C (10% wt, 200 mg). The reaction was stirred at room temperature overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filtrate concentrated to afford the title compound (860 mg, 3.3 mmol, 96% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+257.1 at 0.735 min.1H NMR (400 MHz, DMSO-d6) 7.43 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 1.9 Hz, 1H), 6.60 – 6.55 (m, 2H), 4.66 (s, 1H), 4.59 (s, 1H), 4.52 (s, 2H), 2.77 (d, 3H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 39: 4'-isopropoxy-N3,N3-dimethyl-[1,1'-biphenyl]-3,4-diamine

[0354] Step 1: 4'-isopropoxy-N,N-dimethyl-4-nitro-[1,1'-biphenyl]-3-amine: A mixture of 3- fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (Intermediate 28 Step 1, 500 mg, 1.8 mmol), dimethylamine (2M in THF, 4.5 mL) and DIPEA (704 mg, 5.4 mmol) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 5 / 1) to afford the title compound (550 mg, 1.8 mmol) as a brown solid. UPLC-MS (Method 3) m / z [M+H]+104 301.1 at 1.997 min.1H NMR (400 MHz, DMSO-d6) 7.84 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 1.7 Hz, 1H), 7.10 (dd, J = 8.6, 1.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.73 – 4.60 (m, 1H), 2.88 (s, 6H), 1.29 (d, J = 6.0 Hz, 6H).

[0355] Step 2: 4'-isopropoxy-N3,N3-dimethyl-[1,1'-biphenyl]-3,4-diamine: To a solution of Step 1 nitro compound, (250 mg, 0.83 mmol) in MeOH (10 mL) was added Pd / C (10% wt, 25 mg) and the reaction stirred at room temperature overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filtrate concentrated to afford the title compound (180 mg, 0.67 mmol, 80% yield) as a brown oil. UPLC-MS (Method 3) m / z [M+H]+271.2 at 1.983 min.1H NMR (400 MHz, DMSO-d6) 7.42 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H), 4.79 (s, 2H), 4.66 – 4.53 (m, 1H), 2.62 (s, 6H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 40: 3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-amine

[0356] Step 1: 4'-ethoxy-3-fluoro-4-nitro-1,1'-biphenyl: A mixture of 4-bromo-2-fluoro-1- nitrobenzene (2 g, 9.0 mmol), (4-ethoxyphenyl)boronic acid (1.51 g, 9.1 mmol), Pd(dppf)Cl2(665 mg, 0.91 mmol) and K3PO4(3.86 g, 18.2 mmol) in a mixture of dioxane (20 mL) and water (2 mL) was heated at 100 °C overnight under an atmosphere of nitrogen. The mixture was filtered through Celite® and partitioned between EtOAc (80 mL) and water (100 mL). The aqueous was extracted with EtOAc (3 x 40 mL) and the combined organic layers dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 9 / 1) to afford the title compound (1.36 g, 5.2 mmol, 57% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.19 (t, J = 8.4 Hz, 1H), 7.89(dd, J = 13.4, 2.0 Hz, 1H), 7.83 – 7.77 (m, 2H), 7.73 (dd, J = 8.7, 1.9 Hz, 1H), 7.11 – 7.03 (m, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[0357] Step 2: 1-(4'-ethoxy-4-nitro-[1,1'-biphenyl]-3-yl)azetidine: A mixture of 4'-ethoxy-3- fluoro-4-nitro-1,1'-biphenyl (500 mg, 1.91 mmol), azetidine (164 mg, 2.81 mmol) and K2CO3(529 mg, 3.83 mmol) in DMF (5 mL) was stirred at room temperature for 48 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 9 / 1) to afford the title compound (531 mg, 1.78 mmol, 93% yield) as a yellow solid.1H NMR (400 MHz, DMSO- d6) 7.83 (d, J = 8.7 Hz, 1H), 7.71 – 7.63 (m, 2H), 7.06 – 6.99 (m, 3H), 6.83 (d, J = 1.9 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.97 (t, J = 7.5 Hz, 4H), 2.36 – 2.26 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H).

[0358] Step 3: 3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-amine: To a solution of 1-(4'-ethoxy- 4-nitro-[1,1'-biphenyl]-3-yl)azetidine (531 mg, 1.78 mmol) in EtOAc (18 mL) was added Pd / C (10% wt, 106 mg) and the reaction stirred for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with a mixture of DCM and MeOH (v / v=9 / 1, 50 mL). The filtrate was concentrated and the resulting residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 1) to afford the title compound (410 mg, 1.53 mmol, 85% yield) as a grey solid.1H NMR (400 MHz, DMSO-d6) 7.48 – 7.40 (m, 2H), 6.97 – 6.88 (m, 2H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.61 (dd, J = 5.1, 3.0 Hz, 2H), 4.42 (s, 2H), 4.02 (q, J = 6.9 Hz, 2H), 3.79 (t, J = 7.0 Hz, 4H), 2.16 (p, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H). Intermediate 41: 1-(((3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclo propan-1-ol

[0359] Step 1: N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1-hydroxycyclopropane- 1-carboxamide: A mixture of 3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-amine (Intermediate 28, 500 mg, 1.77 mmol), 1-hydroxycyclopropane-1-carboxylic acid (543 mg, 5.32 mmol), PyBOP (2.8 g, 5.32 mmol) and DIPEA (1.4 g, 10.64 mmol) in DMF (10 mL) was heated at 60 °C overnight, then cooled to room temperature. The mixture was diluted with water (50 mL)and extracted with EtOAc (2 x 50 mL), dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (391 mg, 1.07 mmol, 60 % yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+367.3 at 1.897 min.1H NMR (400 MHz, DMSO- d6) 8.95 (s, 1H), 7.55 (t, J = 8.2 Hz, 3H), 7.02 – 6.94 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 4.64 (p, J = 6.0 Hz, 1H), 3.92 (t, J = 7.2 Hz, 4H), 2.25 (p, J = 7.1 Hz, 2H), 1.28 (d, J = 6.0 Hz, 6H), 1.14 (q, J = 4.2 Hz, 2H), 0.97 (q, J = 4.3 Hz, 2H).

[0360] Step 2: 1-(((3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol: To Step 1 amide (423 mg, 1.16 mmol) was added borane dimethylsulfide complex (10M in DMS, 2 mL) and the reaction stirred at room temperature overnight. The reaction was quenched with NaOH (2 mL x 2 M) and diluted with water (20 mL). The aqueous was extracted with EtOAc (3 x30 mL) and the combined organic layers dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (67 mg, 0.19 mmol, 16 % yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+353.4 at 2.194 min.1H NMR (400 MHz, DMSO-d6) 7.46 – 7.43 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.93 – 6.90 (m, 2H), 6.73 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 5.50 (s, 1H), 5.4 (m, 1H), 4.61 (m, 1H), 3.78 (t, J = 7.1 Hz, 4H), 3.13 (d, J = 5.3 Hz, 2H), 2.20 (p, J = 7.0 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 0.62 (d, J = 5.1 Hz, 2H), 0.53 (d, J = 5.0 Hz, 2H). Intermediate 42: 1-(((2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)amino)methyl) cyclopropan-1-ol

[0361] Step 1: N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-1- hydroxycyclopropane-1-carboxamide: A mixture of 2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3- yl)aniline (Intermediate 33, 400 mg, 1.41 mmol), 1-hydroxycyclopropane-1-carboxylic acid (431 mg, 4.23 mmol), DIPEA (1.09 g, 8.46 mmol) and HATU (1.6 g, 4.23 mmol) in DMF (5 mL) was heated at 50 °C for 16 h. The mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over solid anhydrous Na2SO4filtered and concentrated. The resulting residue was purified by Biotage Isolera One (C18 column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (500 mg, 1.36 mmol, 96% yield) as a green oil. UPLC-MS (Method 3) m / z [M+H]+368.0 at 1.213 min.1H NMR (400 MHz, DMSO-d6) 8.97 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 8.6, 2.7 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.04 (dd, J = 8.2, 1.9 Hz, 1H), 6.83 – 6.78 (m, 2H), 6.66 (s, 1H), 5.37 – 5.19 (m, 1H), 3.93 (t, J = 7.2 Hz, 4H), 2.30 – 2.20 (m, 2H), 1.31 (d, J = 6.2 Hz, 6H), 1.14 (d, J = 3.3 Hz, 2H), 0.97 (d, J = 3.3 Hz, 2H).

[0362] Step 2: 1-(((2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3- yl)phenyl)amino)methyl)cyclopropan-1-ol: To Step 1 amide (250 mg, 0.68 mmol) was added borane dimethylsulfide complex (10M in DMS, 5 mL) and the reaction stirred at room temperature 2 days. The reaction was quenched with NaOH (5 mL x 2 M), diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4filtered, concentrated and the resulting residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 1) to afford the title compound (40 mg, 0.11 mmol, 17% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+354.3 at 1.328 min. Intermediate 43: 1-(((3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclo propan-1-ol

[0363] Step 1: N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-1-hydroxycyclopropane-1- carboxamide: A mixture of 3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-amine (Intermediate 40, 818 mg, 3.05 mmol), 1-hydroxycyclopropane-1-carboxylic acid (3.11 g, 30.5 mmol), PyBOP (7.93 g, 15.24 mmol) and DIPEA (3.94 g, 30.5 mmol) in DMF (20 mL) was heated at 60 °C overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL).The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 4 / 1), further purification by Biotage Isolera One (C18 column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) provided the title compound (128 mg, 0.36 mmol, 11% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.95 (s, 1H), 7.59 – 7.52 (m, 3H), 7.04 – 6.94 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.92 (t, J = 7.2 Hz, 4H), 2.25 (p, J = 7.2 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.14 (q, J = 4.2 Hz, 2H), 0.97 (q, J = 4.2 Hz, 2H).

[0364] Step 2: 1-(((3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan- 1-ol: To a solution of Step 1 amide (123 mg, 0.349 mmol) in THF (1 mL) at 0 °C was added borane dimethylsulfide complex (10M in DMS, 5 mL). The reaction was allowed to warm to room temperature and stirred for 2 days. The reaction was quenched with 2M NaOH (6 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 1 / 1) to afford the title compound (24 mg, 0.07 mmol, 20% yield) as a white solid. UPLC-MS (Method 4) m / z [M+H]+339.3 at 1.848 min. Intermediate 44: 1-(((2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)amino)methyl)cyclo propan-1-ol

[0365] Step 1: N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-1-hydroxycyclopropane-1- carboxamide: A mixture of 2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)aniline (Intermediate 34, 300 mg, 1.12 mmol) 1-hydroxycyclopropane-1-carboxylic acid (341 mg, 3.34 mmol), PyBOP (1.7 g, 3.34 mmol) and DIPEA (432 mg, 3.34 mmol) in DMF (10 mL) was heated at 50 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 2 / 1) to afford the title compound (200 mg, 0.57 mmol, 51% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+354.0 at 1.481 min.

[0366] Step 2: 1-(((2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)amino)methyl)cyclopropan- 1-ol: To a solution of Step 1 amide (200 mg, 0.57 mmol) in THF (2 mL) at 0 °C was added borane dimethylsulfide complex (10M in DMS, 2 mL, 20 mmol). The reaction was stirred at room temperature overnight then was quenched with NaOH (2 M, 10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were concentrated and purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 2 / 1) to afford the title compound (50 mg, 0.15 mmol, 26% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+340.3 at 1.695 min.1H NMR (400 MHz, DMSO-d6) 8.34 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.6, 2.6 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.81 – 6.76 (m, 2H), 6.56 (d, J = 8.3 Hz, 1H), 5.51 (s, 1H), 4.38 (s, 1H), 4.31 (d, J = 7.1 Hz, 2H), 3.79 (t, J = 7.1 Hz, 4H), 3.14 (d, J = 5.2 Hz, 2H), 2.24 – 2.16 (m, 2H), 1.31 (d, J = 7.0 Hz, 3H), 0.64 – 0.60 (m, 2H), 0.52 (t, J = 5.6 Hz, 2H). Intermediate 45: 1-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol

[0367] Step 1: 4'-(ethylthio)-[1,1'-biphenyl]-4-amine: A mixture of (4- bromophenyl)(ethyl)sulfane (5.28 g, 24.34 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (6.4 g, 29.21 mmol), Pd(dppf)Cl2(1.76 g, 2.43 mmol) and K3PO4(10.33 g, 48.68 mmol) in a mixture of dioxane / water (v / v = 10 / 1, 88 mL) was heated at 100 °C for 3 h under an atmosphere of nitrogen. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was concentrated in vacuo and the resulting residuewas purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 5 / 1) to afford the title compound (4.9 g, 21.4 mmol, 88% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+230.1 at 1.744 min.1H NMR (400 MHz, DMSO-d6) 7.51 – 7.46 (m, 2H), 7.37 – 7.29 (m, 4H), 6.65 – 6.60 (m, 2H), 5.21 (s, 2H), 2.96 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).

[0368] Step 2: N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-1-hydroxycyclopropane-1-carboxamide: A mixture of Step 1 amine (200 mg, 0.87 mmol), 1-hydroxycyclopropane-1-carboxylic acid (98 mg, 0.96 mmol), PyBOP (679 mg, 1.31 mmol) and DIPEA (450 mg, 3.48 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=2 / 1) to afford the title compound (200 mg, 0.64 mmol, 73% yield) as a white solid. UPLC-MS (Method 3) m / z [M+H]+314.0 at 1.859 min.1H NMR (400 MHz, DMSO-d6) 9.87 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.63 – 7.58 (m, 4H), 7.37 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 3.01 (q, J = 7.3 Hz, 2H), 1.26 (d, J = 7.3 Hz, 3H), 1.17 (q, J = 4.2 Hz, 2H), 0.98 (t, J = 3.7 Hz, 2H).

[0369] Step 3: 1-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol: To a solution of Step 2 amide (200 mg, 0.64 mmol) in THF (1 mL) at 0 °C was added borane (1 M in THF, 2.56 mL, 2.56 mmol). The reaction was stirred at room temperature overnight then was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (80 mg, 0.27 mmol, 42% yield) as a white solid. UPLC-MS (Method 3) m / z [M+H]+300.0 at 1.967 min.1H NMR (400 MHz, DMSO-d6) 7.54 – 7.46 (m, 2H), 7.41 – 7.36 (m, 2H), 7.34 – 7.27 (m, 2H), 6.72 – 6.62 (m, 2H), 5.69 (s, 1H), 5.35 (s, 1H), 3.18 (d, J = 5.6 Hz, 2H), 2.96 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H), 0.58 (t, J = 2.9 Hz, 2H), 0.51 (t, J = 2.9 Hz, 2H). Intermediate 46: 1-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol

[0370] Step 1: 1-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: A mixture of 4'-(ethylthio)-[1,1'-biphenyl]-4-amine (Intermediate 45 Step 1, 229 mg, 1.0 mmol), 1- oxaspiro[2.3]hexane (421 mg, 5.0 mmol) and LiClO4(426 mg, 4 mmol) in THF (5 mL) was stirred at 50 °C overnight. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL). The combined organic phases were washed with brine (15 mL), dried over solid anhydrous Na2SO4and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 5 / 1) to afford the title compound (140 mg, 44.6% yield) as a white solid. UPLC-MS (Method 3) m / z [M+H]+314.21 at 2.630 min. Intermediate 47: 3-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)oxetan-3-ol

[0371] Step 1: 3-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)oxetan-3-ol: To a solution of 4'-(ethylthio)-[1,1'-biphenyl]-4-amine (Intermediate 45 Step 1, 100 mg, 0.44 mmol) in THF (3 mL) was added 1,5-dioxaspiro[2.3]hexane (57 mg, 0.66 mmol) and LiClO4(187 mg, 1.76 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 2 / 1) to afford the title compound (100 mg, 0.32 mmol, 72% yield) as a white solid. UPLC-MS (Method 3) m / z [M+H]+316.0 at 1.848 min.1H NMR (400 MHz, DMSO-d6) 7.51 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.88 (s, 1H), 5.66 (t, J = 5.9 Hz, 1H), 4.44 (s, 4H), 3.53 – 3.47 (m, 2H), 2.97 (q, J = 7.3 Hz, 2H), 1.24 (t, J = 7.3 Hz, 3H). Intermediate 48: 1-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol

[0372] Step 1: 1-(((4'-(ethylthio)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol: A mixture of 4'-(ethylthio)-[1,1'-biphenyl]-4-amine (Intermediate 45 Step 1, 229 mg, 1.0 mmol), 1- oxaspiro[2.4]heptane (490 mg, 5.0 mmol), LiClO4(426 mg, 4.0 mmol) in THF (3 mL) was stirred at 50 °C overnight. The mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine (3 x 15 mL), dried over solid anhydrous Na2SO4and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 3 / 1) to afford the title compound (240 mg, 0.73 mmol, 73% yield) as a white solid. UPLC-MS (Method 3) m / z [M+H]+328.22 at 2.258 min.1H NMR (400 MHz, DMSO-d6) 7.52 – 7.48 (m, 2H), 7.42 – 7.35 (m, 2H), 7.33 – 7.30 (m, 2H), 6.73 – 6.66 (m, 2H), 5.84 (s, 1H), 5.50 (t, J = 5.7 Hz, 1H), 3.09 (d, J = 5.6 Hz, 2H), 2.99 – 2.93 (m, 2H), 1.73 – 1.70 (m, 2H), 1.60 – 1.54 (m, 6H), 1.23 (t, J = 7.2 Hz, 3H). Intermediate 49: 4'-isopropoxy-3-(methylthio)-[1,1'-biphenyl]-4-amine

[0373] Step 1: Preparation of (4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)(methyl)sulfane. To a solution of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (2.84 g, 10.32 mmol) in DMF (57 mL) at 0 °C was added a solution of sodium methylthiolate (1.74 g, 24.76 mmol) in water (19 mL). The mixture was stirred at room temperature for 1 h. The precipitate that formed was collected by filtration and dried under vacuum to afford the title compound (3.1 g, 10.22 mmol, 99% yield) as a yellow solid. UPLC-MS (Method 4) m / z 304.1 [M+H]+at 1.402 min.1H NMR (400 MHz, DMSO- d6) 8.28 (d, J = 8.5 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.64 – 7.59 (m, 2H), 7.11 – 7.02 (m, 2H), 4.81 – 4.67 (m, 1H), 2.64 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H).

[0374] Step 2: Preparation of 4'-isopropoxy-3-(methylthio)-[1,1'-biphenyl]-4-amine. To a solution of Step 1 sulfane (3.1 g, 10.22 mmol) in EtOAc (50 mL) was added Pd / C (10% wet, 654 mg). The mixture was stirred at room temperature for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with a mixture of DCM / MeOH (v / v=10 / 1, 200 mL). The filtrate was concentrated under vacuum and the resultant residue purified by column chromatography (eluting with Petroleum ether / EtOAc=9 / 1) to afford the title compound (1.76 g, 6.44 mmol, 63% yield) as a yellow solid. UPLC-MS (Method 4) m / z 274.1 [M+H]+at 1.066 min.1H NMR (400 MHz, DMSO-d6) 7.47 – 7.43 (m, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.3, 2.2 Hz, 1H), 6.94 – 6.89 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 5.23 (s, 2H), 4.65 – 4.58 (m, 1H), 2.37 (s, 3H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 50: 1-(((4'-isopropoxy-3-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol

[0375] Step 1: Preparation of 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-1H-pyrazole. To a solution of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (1.00 g, 3.67 mmol) in acetonitrile (10 mL) at room temperature was added 1H-pyrazole (0.41 g, 6 mmol) and K2CO3(1.11 g, 8 mmol). The mixture was heated at 80 °C for 18 h then diluted with water (1 L) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resultant residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=4 / 1) to afford the title compound (880 mg, 2.72 mmol, 74 % yield) as a yellow solid. UPLC-MS (Method 4) m / z 324.2 [M+H]+at 1.208 min.1H NMR (400 MHz, DMSO-d6) 8.46 (d, J = 2.5 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 8.5, 1.9 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 1.7 Hz, 1H), 7.10 – 7.03 (m, 2H), 6.58 (t, J = 2.2 Hz, 1H), 4.72 (p, J = 6.0 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H).

[0376] Step 2: Preparation of 4'-isopropoxy-3-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-amine. A mixture of Step 1 pyrazole (880 mg, 2.72 mmol) and Pd / C (10% wet, 180 mg) in EtOAc (10 mL) was stirred at room temperature for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with a mixture of DCM / MeOH (v / v=10 / 1, 100 mL). The filtrate was concentrated and the residue obtained purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=4 / 1) to afford the title compound (786 mg, 2.68 mmol, 98% yield) as a yellow oil. UPLC-MS (Method 4) m / z 294.2 [M+H]+at 0.994 min.1H NMR (400 MHz, DMSO-d6) 8.26 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.47 (d, J = 2.1 Hz, 1H), 7.41 – 7.35 (m, 1H), 6.98 – 6.94 (m, 2H), 6.92 (d, J = 2.0 Hz, 1H), 6.52 (t, J = 2.1 Hz, 1H), 5.67 (s, 2H), 4.69 – 4.50 (m, 1H), 1.26 (d, J = 6.0 Hz, 6H). Step 3: Preparation of 1-hydroxy-N-(4'-isopropoxy-3-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- yl)cyclopropane-1-carboxamide. A mixture of Step 2 amine (600 mg, 2.04 mmol), 1- hydroxycyclopropane-1-carboxylic acid (2.08 g, 20.45 mmol), HATU (3.88 g, 10.22 mmol) and DIPEA (2.66 g, 20.53 mmol) in DMF (30 mL) was heated at 60 °C overnight. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=7 / 3) to afford the title compound (220 mg, 0.58 mmol, 28% yield) as a yellow solid. UPLC-MS (Method 4) m / z 378.2 [M+H]+at 0.902 min.1H NMR (400 MHz, DMSO-d6) 8.53 – 8.47 (m, 1H), 7.95 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.65 (dd, J = 8.6, 2.2 Hz, 1H), 7.03 – 6.93 (m, 2H), 6.70 – 6.62 (m, 2H), 4.67 (p, J = 6.0 Hz, 1H), 1.29 (d, J = 6.0 Hz, 6H), 1.08 (d, J = 3.3 Hz, 2H), 0.89 (d, J = 3.3 Hz, 2H).

[0377] Step 4: Preparation of 1-(((4'-isopropoxy-3-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol. To a solution of Step 3 amide (220 mg, 0.58 mmol) in THF (2 mL) was added borane (10M in dimethyl sulfide, 2 mL) at room temperature. The mixture was stirred at room temperature for 18 h then quenched with MeOH (30 mL) at 0 °C and concentrated. The residue was diluted with NaOH (2 M, 20 mL) and stirred at room temperature for 30 min then extracted with EtOAc (3 x20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=7 / 3) to afford the title compound (80 mg, 0.22 mmol, 38% yield) as a yellow oil. UPLC-MS (Method 4) m / z 364.3 [M+H]+at 1.055 min.1H NMR (400 MHz, DMSO-d6) 8.30 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.49 (d, J = 8.3 Hz, 2H), 6.99 – 6.94 (m, 2H), 6.89 (d, J = 8.3 Hz,1H), 6.57 (t, J = 2.2 Hz, 1H), 6.42 (t, J = 5.2 Hz, 1H), 5.43 (s, 1H), 4.65 (p, J = 6.0 Hz, 1H), 3.24 (d, J = 5.2 Hz, 2H), 1.30 (d, J = 6.0 Hz, 6H), 0.66 – 0.61 (m, 2H), 0.54 – 0.49 (m, 2H). Intermediate 51: (S)-1-(((2-(azetidin-1-yl)-4-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-

[0378] Step 1: Preparation of (S)-5-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine. To a solution of (S)-1,1,1-trifluoropropan-2-ol (15.60 g, 137.0 mmol) in N,N-dimethylacetamide (200 mL) at 0 °C was added sodium hydride (60% in mineral oil, 5.47 g, 137.0 mmol). The reaction was stirred at room temperature for 1 h then 5-bromo-2-fluoropyridine (20 g, 114.0 mol) was added. The mixture was stirred for 2 h then quenched with ice water (50 mL), diluted with water (1 L) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with 100% Petroleum ether) to afford the title compound (26.0 g, 96.67 mmol, 85% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 8.33 (dd, J = 2.6, 0.7 Hz, 1H), 8.00 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (dd, J = 8.8, 0.6 Hz, 1H), 5.81 (p, J = 6.7 Hz, 1H), 1.44 (d, 3H).

[0379] Step 2: Preparation of (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1- trifluoropropan-2-yl)oxy)pyridine. A mixture of Step 1 pyridine (5.0 g, 18.51 mmol),bis(pinacolato)diboron (9.4 g, 37.03 mmol), potassium acetate (3.63 g, 37.03 mmol) and Pd(dppf)Cl2(1.35 g, 2.31 mmol) in dioxane (50 mL) was heated at 90 °C for 3 h under an atmosphere of nitrogen. The mixture was filtered through Celite®, diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=4 / 1) to afford the title compound (7.56 g, 75% purity, 17.88 mmol, 96% yield) as a yellow solid. UPLC-MS (Method 4) m / z 318.2 [M+H]+at 1.759 min.

[0380] Step 3: Preparation of (S)-5-(3-fluoro-4-nitrophenyl)-2-((1,1,1-trifluoropropan-2- yl)oxy)pyridine. A mixture of Step 2 pyridine (75% purity, 7.0 g, 16.5 mmol), 4-bromo-2-fluoro-1- nitrobenzene (3.24 g, 14.72 mmol), Pd(dppf)Cl2(1.62 g, 2.77 mmol) and potassium carbonate (9.37 g, 67.80 mmol) in a mixture of dioxane / water (v / v=10 / 1, 110 mL) was heated at 100 °C for 3 h under an atmosphere of nitrogen. The mixture was filtered through Celite® and washed with EtOAc (150 mL), then diluted with water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=9 / 1) to afford the title compound (3.73 g, 11.30 mmol, 77% yield) as a yellow oil. UPLC-MS (Method 4) m / z 331.1 [M+H]+at 1.331 min.1H NMR (400 MHz, DMSO-d6) 8.70 (d, J = 2.7 Hz, 1H), 8.32 – 8.19 (m, 2H), 8.06 – 7.99 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.5, 2.7 Hz, 1H), 5.96 (p, J = 6.8 Hz, 1H), 1.49 (d, J = 6.4 Hz, 3H).

[0381] Step 4: Preparation of (S)-5-(3-(azetidin-1-yl)-4-nitrophenyl)-2-((1,1,1-trifluoropropan-2- yl)oxy)pyridine. To a solution of Step 3 pyridine (3.73 g, 11.29 mmol) in DMF (40 mL) was added azetidine (967 mg, 16.94 mmol) and potassium carbonate (3.12 g, 22.59 mmol). The mixture was stirred overnight then diluted with water (400 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=9 / 1) to afford the title compound (4.02 g, 10.95 mmol, 97% yield) as a yellow solid. UPLC-MS (Method 4) m / z 368.2 [M+H]+at 1.576 min.1H NMR (400 MHz, DMSO- d6) 8.59 (dd, J = 2.6, 0.7 Hz, 1H), 8.18 (dd, J = 8.6, 2.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.6, 1.1 Hz, 2H), 6.93 (d, J = 1.8 Hz, 1H), 5.95 (p, J = 6.7 Hz, 1H), 3.98 (t, J = 7.5 Hz, 4H), 2.32 (p, J = 7.5 Hz, 2H), 1.49 (d, J = 6.5 Hz, 3H).

[0382] Step 5: Preparation of (S)-2-(azetidin-1-yl)-4-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin- 3-yl)aniline. To a solution of Step 4 pyridine (4.02 g, 10.95 mol) in EtOAc (80 mL) was added Pd / C (10% wet, 800 mg). The reaction was stirred at room temperature for 18 hours under anatmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with a mixture of DCM / MeOH (v / v=10 / 1, 100 mL). The filtrate was concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=7 / 3) to afford the title compound (2.90 g, 8.6 mmol, 79% yield) as a yellow oil. UPLC-MS (Method 4) m / z 338.1 [M+H]+at 1.485 min.1H NMR (400 MHz, DMSO-d6) 8.36 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 8.6, 2.6 Hz, 1H), 6.96 – 6.89 (m, 2H), 6.69 – 6.62 (m, 2H), 5.89 (p, J = 6.8 Hz, 1H), 4.55 (s, 2H), 3.80 (t, J = 7.1 Hz, 4H), 2.16 (p, J = 7.1 Hz, 2H), 1.46 (d, J = 6.5 Hz, 3H).

[0383] Step 6: Preparation of (S)-N-(2-(azetidin-1-yl)-4-(6-((1,1,1-trifluoropropan-2- yl)oxy)pyridin-3-yl)phenyl)-1-hydroxycyclopropane-1-carboxamide. A mixture of Step 5 aniline (1.0 g, 2.96 mmol), 1-hydroxycyclopropane-1-carboxylic acid (1.51 g, 14.82 mmol), HATU (5.64 g, 14.82 mmol) and DIPEA (1.92 g, 14.82 mmol) in DMF (30 mL) was heated at 60 °C overnight. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (990 mg, 2.35 mmol, 79% yield) as a yellow solid. UPLC-MS (Method 4) m / z 422.2 [M+H]+at 0.872 min.1H NMR (400 MHz, DMSO-d6) 8.99 (s, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.07 (dd, J = 8.6, 2.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.1, 2.0 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.67 (s, 1H), 5.92 (p, J = 6.8 Hz, 1H), 3.94 (t, J = 7.2 Hz, 4H), 2.25 (p, J = 7.2 Hz, 2H), 1.48 (d, J = 6.6 Hz, 3H), 1.14 (q, J = 4.2 Hz, 2H), 0.98 (q, J = 4.3 Hz, 2H).

[0384] Step 7: Preparation of (S)-1-(((2-(azetidin-1-yl)-4-(6-((1,1,1-trifluoropropan-2- yl)oxy)pyridin-3-yl)phenyl)amino)methyl)cyclopropan-1-ol. To a solution of Step 6 carboxamide (490 mg, 1.16 mmol) in THF (5 mL) was added borane (10M in dimethyl sulfide, 5 mL) and the mixture was stirred for 72 h. The reaction was cooled to 0 °C and quenched with MeOH (30 mL) then concentrated under vacuum. The residue was diluted with NaOH (2M, 50 mL) and stirred for 30 min, then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (65 mg, 0.16 mmol, 14% yield) as a red oil. UPLC-MS (Method 4) m / z 408.2 [M+H]+at 1.086 min.1H NMR (400 MHz, DMSO-d6) 8.39 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.6, 2.6 Hz, 1H), 7.05 (dd, J = 8.1, 2.1 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 5.89 (p, J = 6.8 Hz, 1H), 5.51 (s, 1H), 4.42 (t, J = 5.4 Hz, 1H), 3.80 (t, J = 7.1 Hz, 4H), 3.15 (d, J = 5.3 Hz, 2H), 2.20 (p, J = 7.1 Hz, 2H), 1.47 (d, J = 6.5 Hz, 3H), 0.66 – 0.60 (m, 2H), 0.55 – 0.49 (m, 2H).Intermediate 52: (S)-1-(((4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol

[0385] Step 1: Preparation of (S)-1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-2- methylazetidine. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (1 g, 3.72 mmol), (S)- 2-methylazetidine hydrochloride (600 mg, 5.58 mmol) and potassium carbonate (1 g, 7.44 mmol) in DMF (8 mL) was stirred overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=10 / 1) to afford the title compound (1.2 g, 3.68 mmol, 99% yield) as an orange oil. UPLC-MS (Method 3) m / z 327.5 [M+H]+at 1.955 min.1H NMR (400 MHz, DMSO-d6) 7.87 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.05 – 7.00 (m, 3H), 6.88 (d, J = 1.8 Hz, 1H), 4.69 (p, J = 6.1 Hz, 1H), 4.58 – 4.48 (m, 1H), 4.19 – 4.09 (m, 1H), 3.52 (td, J = 8.9, 5.9 Hz, 1H), 2.58 – 2.52 (m, 1H), 1.93 (dq, J = 10.0, 5.3 Hz, 1H), 1.30 (d, J = 6.0 Hz, 9H).

[0386] Step 2: Preparation of (S)-4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'-biphenyl]-4- amine. A mixture of Step 1 azetidine (1.2 g, 3.68 mmol), and Pd / C (10% wet, 0.3 g) in MeOH (8 mL) was stirred at room temperature overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filtrate concentrated to afford the title compound (1 g, 3.38 mmol, 92% yield) as a black solid. UPLC-MS (Method 3) m / z 297.2 [M+H]+at 1.035 min.1H NMR (400 MHz, DMSO-d6) 7.44 – 7.39 (m, 2H), 6.93 – 6.86 (m, 3H), 6.69 (d,J = 1.9 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.59 (p, J = 6.0 Hz, 1H), 4.43 (s, 2H), 4.25 (q, J = 6.6 Hz, 1H), 4.10 – 4.05 (m, 1H), 3.26 – 3.16 (m, 1H), 2.25 (qd, J = 7.7, 3.5 Hz, 1H), 1.87 (dd, J = 9.8, 7.5 Hz, 1H), 1.27 (d, J = 6.0 Hz, 6H), 1.23 (d, J = 6.1 Hz, 3H).

[0387] Step 3: Preparation of (S)-1-hydroxy-N-(4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide. A mixture of Step 2 amine (600 mg, 2.03 mmol), 1- hydroxycyclopropane-1-carboxylic acid (621 mg, 6.09 mmol), DIPEA (786 mg, 6.09 mmol) and HATU (1.54 g, 4.06 mmol) in acetonitrile (5 mL) was heated at 60 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (300 mg, 0.79 mmol, 39% yield) as an orange oil. UPLC-MS (Method 3) m / z 381.2 [M+H]+at 1.266 min.1H NMR (400 MHz, DMSO-d6) 8.96 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.55 – 7.51 (m, 2H), 7.07 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 – 6.96 (m, 2H), 6.92 (d, J = 2.0 Hz, 1H), 6.75 (s, 1H), 4.69 – 4.61 (m, 1H), 4.37 (q, J = 6.6 Hz, 1H), 4.12 (td, J = 8.0, 4.3 Hz, 1H), 3.46 (t, J = 7.8 Hz, 1H), 2.34 (d, J = 10.5 Hz, 1H), 1.98 – 1.91 (m, 1H), 1.29 – 1.26 (m, 9H), 1.17 – 1.13 (m, 2H), 0.98 (d, J = 3.5 Hz, 2H).

[0388] Step 4: Preparation of (S)-1-(((4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol. A mixture of Step 3 carboxamide (120 mg, 0.31 mmol) and borane ( in dimethyl sulfide, 2 mL) was stirred at room temperature overnight. The mixture was cooled at 0 °C and the reaction quenched with MeOH (20 mL). The solution was concentrated and the residue obtained was diluted with NaOH (2M, 20 mL) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (80 mg, 0.22 mmol, 70% yield) as a yellow oil. UPLC-MS (Method 3) m / z 367.4 [M+H]+at 1.437 min.1H NMR (400 MHz, DMSO-d6) 7.43 (td, J = 8.7, 2.3 Hz, 2H), 6.91 (dd, J = 8.7, 4.1 Hz, 2H), 6.88 – 6.76 (m, 1H), 6.69 – 6.60 (m, 1H), 6.53 (dd, J = 8.2, 6.8 Hz, 1H), 5.50 (s, 1H), 4.65 – 4.56 (m, 1H), 4.51 – 4.36 (m, 2H), 4.27 (dd, J = 15.0, 6.9 Hz, 1H), 3.20 (d, J = 5.7 Hz, 1H), 3.08 (dt, J = 12.3, 6.1 Hz, 1H), 2.26 (s, 1H), 1.91 (dd, J = 17.2, 8.6 Hz, 1H), 1.27 (dd, J = 6.0, 1.1 Hz, 9H), 0.63 (d, J = 6.4 Hz, 2H), 0.58 – 0.48 (m, 2H). Intermediate 53: (R)-1-(((4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol

[0389] Step 1: Preparation of (R)-1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-2- methylazetidine. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (1.3 g, 4.7 mmol), (R)- 2-methylazetidine hydrochloride (500 mg, 4.7 mmol) and potassium carbonate (1.9 g, 14.0 mmol) in DMF (5 mL) was stirred overnight then diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=10 / 1) to afford the title compound (1.3 g, 4.0 mmol, 87% yield) as a yellow oil. UPLC-MS (Method 3) m / z 327.6 [M+H]+at 2.060 min.1H NMR (400 MHz, DMSO-d6) 7.89 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 3H), 6.90 (s, 1H), 4.76 – 4.65 (m, 1H), 4.54 (d, J = 7.9 Hz, 1H), 4.16 (d, J = 6.1 Hz, 1H), 3.58 – 3.48 (m, 1H), 2.57 (d, J = 5.7 Hz, 1H), 1.98 – 1.88 (m, 1H), 1.31 (d, J = 6.0 Hz, 9H).

[0390] Step 2: Preparation of (R)-4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'-biphenyl]-4- amine. A mixture of Step 1 azetidine (1.3 g, 4.0 mmol) and Pd / C (10% wet, 260 mg) in MeOH (26 mL) was stirred overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filtrate concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=4 / 1) to afford the title compound (910 mg, 3.1 mmol, 76% yield) as a black oil. UPLC-MS (Method 3) m / z 297.5 [M+H]+at 1.816 min.1H NMR (400 MHz, DMSO-d6) 7.41 (d, J = 8.7 Hz, 2H), 6.95 – 6.84 (m, 3H), 6.68 (d, J = 1.7 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 4.63 – 4.55 (m, 1H), 4.43 (s, 2H), 4.25 (d, J = 6.5 Hz, 1H), 4.05 (s, 1H), 3.22 (d, J = 7.1 Hz, 1H), 2.30 – 2.21 (m, 1H), 1.92 – 1.82 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H), 1.23 (d, J = 6.1 Hz, 3H).

[0391] Step 3: Preparation of (R)-1-hydroxy-N-(4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide. To a mixture of Step 2 amine (400 mg, 1.4 mmol), 1-hydroxycyclopropane-1-carboxylic acid (689 mg, 6.8 mmol) and DIPEA (1.7 g, 14 mmol) in acetonitrile (8 mL) was added HATU (2.6 g, 6.8 mmol). The reaction was heated at 50 °C overnight then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated and the residue obtained purified by Biotage Isolera One (C18 column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% formic acid) to afford the title compound (210 mg, 0.55 mmol, 41% yield) as a yellow solid. UPLC-MS (Method 3) m / z 381.4 [M+H]+at 1.278 min.1NMR (400 MHz, DMSO-d6) 8.96 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 7.01 – 6.90 (m, 3H), 6.74 (s, 1H), 4.64 (p, J = 6.0 Hz, 1H), 4.37 (q, J = 6.7 Hz, 1H), 4.11 (d, J = 7.9 Hz, 1H), 3.46 (d, J = 7.6 Hz, 1H), 2.33 (s, 1H), 2.02 – 1.89 (m, 1H), 1.28 (d, J = 6.0 Hz, 6H), 1.26 (d, J = 6.1 Hz, 3H), 1.18 – 1.12 (m, 2H), 0.98 (d, J = 3.3 Hz, 2H).

[0392] Step 4: Preparation of (R)-1-(((4'-isopropoxy-3-(2-methylazetidin-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol. To a solution of Step 3 carboxamide (210 mg, 0.55 mmol) in THF (2 mL) was added borane (10M in dimethyl sulfide, 2 mL) and the mixture stirred at room temperature overnight. The reaction cooled to 0 °C and quenched with MeOH (2 mL) then concentrated. The residue obtained was diluted with NaOH (1M, 20 mL) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by Biotage Isolera One (C18 column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% formic acid) to afford the title compound (85 mg, 0.23 mmol, 42% yield) as a yellow oil. UPLC-MS (Method 3) m / z 367.1 [M+H]+at 1.313 min.1H NMR (400 MHz, DMSO-d6) 7.44 (dd, J = 9.0, 2.5 Hz, 2H), 7.00 (dd, J = 8.1, 1.9 Hz, 1H), 6.92 (dd, J = 8.6, 4.2 Hz, 2H), 6.79 (d, J = 1.9 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.49 (s, 1H), 4.60 (dd, J = 7.3, 4.7 Hz, 1H), 4.43 – 4.36 (m, 1H), 4.29 (d, J = 6.5 Hz, 1H), 4.08 (d, J = 5.2 Hz, 1H), 3.24 – 3.14 (m, 1H), 3.07 (dd, J = 12.4, 6.8 Hz, 1H), 2.34 – 2.22 (m, 1H), 1.97 – 1.85 (m, 1H), 1.27 (m, 9H), 0.62 (d, J = 4.1 Hz, 2H), 0.56 – 0.50 (m, 2H). Intermediate 54: 4'-isopropoxy-3-(1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-amine

[0393] Step 1: Preparation of 3-azido-4'-isopropoxy-4-nitro-1,1'-biphenyl. To a solution of 3- fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (2.1 g, 7.64 mmol) in DMSO (20 mL) at 0 °C was added sodium azide (596 mg, 9.16 mmol). The reaction was stirred overnight, diluted with water (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated to afford the title compound (2.2 g, 7.38 mmol, 97% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.05 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.6, 1.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.74 – 4.68 (m, 1H), 1.30 (d, J = 6.0 Hz, 6H).

[0394] Step 2: 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-1H-1,2,3-triazole. To a solution of CuSO4.5H2O (268 mg, 1.07 mmol) in H2O (2 mL) was added sodium ascorbate (106 mg, 0.54 mmol) and the reaction stirred at room temperature for 30 min. This mixture was added into a mixture of 3-azido-4'-isopropoxy-4-nitro-1,1'-biphenyl (1.6 g, 5.37 mmol), ethynyltrimethylsilane (1.6 g, 16.11 mmol) and potassium carbonate (1.5 g, 10.74 mmol) in MeOH (20 mL) at 0 °C. The resulting solution was allowed to warm to room temperature and stirred overnight. The mixture was filtered through Celite® and the filter cake washed with EtOAc (20 mL). The filtrate was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=3 / 1) to afford the title compound (480 mg, 1.48 mmol, 28% yield) as a yellow solid. UPLC-MS (Method 3) m / z 325.5 [M+H]+at 2.181 min.1H NMR (400 MHz, DMSO-d6) 8.79 (d, J = 1.1 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.10 – 8.06 (m, 2H), 8.02 (d, J = 1.1 Hz, 1H), 7.86 – 7.81 (m, 2H), 7.07 (d, J = 8.9 Hz, 2H), 4.76 – 4.70 (m, 1H), 1.30 (d, J = 6.0 Hz, 6H).

[0395] Step 3: 4'-isopropoxy-3-(1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-amine. A mixture of Step 2 triazole (930 mg, 2.87 mmol), iron powder (804 mg, 14.35 mmol) and NH4Cl (456 mg,8.61 mmol) in a mixture of MeOH and water (v / v=5 / 1, 24 mL) was heated at 80 °C for 16 h. The mixture was filtered through Celite® and the filter cake washed with EtOAc (20 mL). The filtrate was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated to afford the title compound (830 mg, 2.82 mmol, 98% yield) as a yellow solid. UPLC-MS (Method 3) m / z 295.2 [M+H]+at 1.180 min.1H NMR (400 MHz, DMSO-d6) 8.57 (s, 1H), 7.97 (s, 1H), 7.59 – 7.46 (m, 4H), 6.94 (d, J = 8.0 Hz, 3H), 5.51 (s, 2H), 4.67 – 4.58 (m, 1H), 1.27 (d, J = 5.4 Hz, 6H). Intermediate 55: Preparation of 3-(1H-imidazol-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-amine

[0396] Step 1: Preparation of 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-1H-imidazole. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (1.0 g, 3.64 mmol), 1H-pyrazole (0.41 g, 6.0 mol) and potassium carbonate (1.11 g, 8.0 mol) in acetonitrile (10 mL) was heated at 80 °C for 18 h. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (1.17 g, 3.62 mmol, 98% yield) as a yellow oil. UPLC-MS (Method 4) m / z 324.2 [M+H]+at 1.491 min.1H NMR (400 MHz, DMSO-d6) 8.21 (d, J = 8.6 Hz, 1H), 8.01 – 7.97 (m, 1H), 7.97 – 7.94 (m, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.85 – 7.80 (m, 2H), 7.49 (t, J = 1.3 Hz, 1H), 7.11 (t, J = 1.1 Hz, 1H), 7.08 – 7.03 (m, 2H), 4.72 (hept, J = 6.0 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H).

[0397] Step 2: Preparation of 3-(1H-imidazol-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-amine. A mixture of Step 1 imidazole (1.17 g, 3.62 mmol) and Pd / C (10% wet, 240 mg) in EtOAc (12 mL) was stirred at room temperature for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with a mixture of DCM / MeOH (v / v=10 / 1, 100 mL). The filtrate was concentrated and the resultant residue purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (910 mg, 3.10 mmol, 86% yield) as a yellow solid. UPLC-MS (Method 4) m / z 294.2 [M+H]+at 1.298 min.1H NMR (400 MHz, DMSO-d6) 7.83 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.4, 2.2 Hz, 1H), 7.38 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.11 (t, J = 1.1 Hz,1H), 6.92 (dd, J = 8.6, 1.7 Hz, 3H), 5.01 (s, 2H), 4.60 (p, J = 6.1 Hz, 1H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 56: Preparation of 4'-isopropoxy-3-(1H-1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4- amine

[0398] Step 1: Preparation of 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-1H-1,2,4-triazole. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (1.0 g, 3.64 mmol), 1H-1,2,4-triazole (251 mg, 3.64 mmol) and potassium carbonate (1.0 g, 7.27 mmol) in DMF (10 mL) was stirred overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=3 / 1) to afford the title compound (1.0 g, 3.08 mmol, 85% yield) as a yellow oil. UPLC-MS (Method 3) m / z 325.5 [M+H]+at 1.134 min.1H NMR (400 MHz, DMSO-d6) 9.20 (s, 1H), 8.27 (s, 1H), 8.20 – 8.13 (m, 2H), 8.02 (dd, J = 8.5, 1.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.76 – 4.69 (m, 1H), 1.30 (d, J = 6.0 Hz, 6H).

[0399] Step 2: Preparation of 4'-isopropoxy-3-(1H-1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-amine. A mixture of Step 1 triazole (1.0 g, 3.09 mmol), iron powder (864 mg, 15.43 mmol) and NH4Cl (245 mg, 4.63 mmol) in a mixture of MeOH / water (v / v=5 / 1, 20 mL) was heated at 80 °C for 16 h. The mixture was filtered through Celite® and the filter cake washed with EtOAc (20 mL). The filtrate was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated to afford the title compound (320 mg, 1.09 mmol, 35% yield) as a yellow solid. UPLC-MS (Method 3) m / z 295.5 [M+H]+at 0.908 min.1H NMR (400 MHz, DMSO-d6) 8.97 (s, 1H), 8.26 (s, 1H), 7.56 – 7.50 (m, 3H), 7.46 (d, J = 8.5 Hz, 1H), 6.95 (t, J = 8.7 Hz, 3H), 5.50 (s, 2H), 4.66 – 4.59 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H). Intermediate 57: Preparation of 1-(((4'-isopropoxy-3-(1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]- 4-yl)amino)methyl)cyclopropan-1-ol

[0400] Step 1: Preparation of 1-hydroxy-N-(4'-isopropoxy-3-(1H-1,2,3-triazol-1-yl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide. To a solution of 4'-isopropoxy-3-(1H-1,2,3-triazol- 1-yl)-[1,1'-biphenyl]-4-amine (Intermediate 54; 1.3 g, 4.42 mmol), 1-hydroxycyclopropane-1- carboxylic acid (1.35 g, 13.26 mmol) and DIPEA (1.7 g, 13.26 mmol) in MeCN (20 mL) was added HATU (5.0 g, 13.26 mmol) and the reaction heated at 60 °C for 2 days. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=2 / 1). Further purification by Prep-TLC (eluting with Petroleum ether / EtOAc=1 / 1) afforded the title compound (410 mg, 1.08 mmol, 24% yield) as a yellow oil. UPLC-MS (Method 3) m / z 379.0 [M+H]+at 1.018 min.1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 8.80 (d, J = 1.0 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.85 – 7.77 (m, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 4.72 – 4.60 (m, 1H), 1.29 (d, J = 6.0 Hz, 6H), 1.12 (d, J = 3.2 Hz, 2H), 0.96 (d, J = 3.3 Hz, 2H).

[0401] Step 2: Preparation of 1-(((4'-isopropoxy-3-(1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol. To a solution of Step 1 carboxamide (410 mg, 1.08 mmol) in THF (4 mL) at 0 °C was added borane (10M in dimethyl sulfide, 4 mL) and the mixture stirred overnight. The reaction was cooled to 0 °C, quenched with MeOH (10 mL) and concentrated. The residue obtained was diluted with NaOH (2M, 10 mL) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 20 mL). The organic phase was concentrated and the residue obtained purified by column chromatography on silica gel (eluting with Petroleumether / EtOAc=1 / 1) to afford the title compound (320 mg, 0.85 mmol, 79% yield) as a yellow solid. UPLC-MS (Method 3) m / z 365.0 [M+H]+at 1.750 min.1H NMR (400 MHz, DMSO-d6) 8.64 (s, 1H), 8.02 (s, 1H), 7.61 – 7.54 (m, 4H), 6.96 (t, J = 9.5 Hz, 3H), 5.78 (bs, 1H), 5.45 (s, 1H), 4.66 – 4.60 (m, 1H), 3.24 (d, J = 5.2 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 0.62 – 0.58 (m, 2H), 0.53 – 0.47 (m, 2H). Intermediate 58: Preparation of 1-(((3-((2R,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-

[0402] Step 1: Preparation of (2R,4S)-1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-2,4- dimethylazetidine. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (568 mg, 2.0 mmol), cis-2,4-dimethylazetidine hydrochloride (250 mg, 2.0 mmol) and K2CO3(855 mg, 6.0 mmol) in MeCN (10 mL) was stirred overnight. The mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to afford the title compound (690 mg, 2.0 mmol, 98% yield) as a yellow solid. UPLC-MS (Method 1) m / z 341.10 [M+H]+at 2.300 min.1H NMR (400 MHz, DMSO-d6) 7.67 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.94 – 6.84 (m, 2H), 4.71 – 4.63 (m, 1H), 4.39 (ddd, J = 8.7, 6.2, 4.8 Hz, 2H), 2.83 (dt, J = 10.7, 8.7 Hz, 1H), 1.54 – 1.48 (m, 1H), 1.35 (d, J = 6.2 Hz, 6H), 1.30 (s, 3H), 1.28 (s, 3H).

[0403] Step 2: Preparation of 3-((2R,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-amine. A mixture of Step 1 azetidine (690 mg, 2.0 mmol) and Pd / C (10% wet, 69.0 mg) in EtOAc (7 mL) was stirred at room temperature overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed withEtOAc (10 mL). The filtrate was concentrated to afford the title compound (610 mg, 1.96 mmol, 98% yield) as a yellow solid. UPLC-MS (Method 1) m / z 311.10 [M+H]+at 1.133 min.1H NMR (400 MHz, DMSO-d6) 7.44 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.2 Hz, 1H), 4.82 (s, 2H), 4.60 (p, J = 6.0 Hz, 1H), 3.77 – 3.66 (m, 2H), 2.31 (dt, J = 9.5, 7.1 Hz, 1H), 1.46 (q, J = 8.6 Hz, 1H), 1.27 (d, J = 6.0 Hz, 6H), 1.20 (d, J = 6.0 Hz, 6H).

[0404] Step 3: Preparation of N-(3-((2R,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-yl)-1-hydroxycyclopropane-1-carboxamide. To a mixture of Step 2 amine (610 mg, 1.96 mmol), 1-hydroxycyclopropane-1-carboxylic acid (1.0 g, 10.0 mmol) and DIPEA (2.5 g, 20.0 mmol) in MeCN (20 mL) was added HATU (3.8 g, 10.0 mmol). The reaction was heated at 50 °C overnight then diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=3 / 1) to afford the title compound (510 mg, 1.29 mmol, 66% yield) as a yellow solid. UPLC-MS (Method 1) m / z 395.15 [M+H]+at 1.767 min.1H NMR (400 MHz, DMSO- d6) 10.32 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 3H), 7.33 (dd, J = 8.5, 1.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.65 (s, 1H), 4.69 – 4.61 (m, 1H), 3.84 (d, J = 6.7 Hz, 2H), 2.43 – 2.34 (m, 1H), 1.52 (d, J = 9.4 Hz, 1H), 1.29 (d, J = 6.0 Hz, 6H), 1.20 (d, J = 6.0 Hz, 6H), 1.15 (t, J = 3.4 Hz, 2H), 0.99 (q, J = 4.4 Hz, 2H).

[0405] Step 4: Preparation of 1-(((3-((2R,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol . To a solution of Step 3 carboxamide (510 mg, 1.29 mmol) in THF (5 mL) at 0 °C was added borane (10M in dimethyl sulfide, 5 mL) and the mixture stirred at room temperature overnight. The reaction was cooled to 0 °C, quenched with MeOH (10 mL) and concentrated under reduced pressure. The residue obtained was diluted with NaOH (1M, 50 mL) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=5 / 1) to afford the title compound (210 mg, 0.55 mmol, 43% yield) as a colorless oil. UPLC-MS (Method 1) m / z 381.15 [M+H]+at 1.467 min.1H NMR (400 MHz, DMSO-d6) 7.46 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.3, 1.8 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 8.4 Hz, 1H), 5.37 (d, J = 8.8 Hz, 2H), 4.61 (q, J = 6.0 Hz, 1H), 3.78 – 3.67 (m, 2H), 3.12 (d, J = 5.5 Hz, 2H), 2.38 – 2.27 (m, 1H), 1.53 – 1.44 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H), 1.21 (d, J = 6.0 Hz, 6H), 0.67 – 0.59 (m, 2H), 0.54 – 0.46 (m, 2H).Intermediate 59: Preparation of 1-(((3-((2S,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy- [1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol

[0406] Step 1: Preparation of (2S,4S)-1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-2,4- 5 dimethylazetidine. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (568 mg, 2.07 mmol), (2S,4S)-2,4-dimethylazetidine hydrochloride (250 mg, 2.07 mmol) and K2CO3 (855 mg, 6.20 mmol) in DMF (5 mL) was stirred overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over solid anhydrous Na2SO4,filtered and concentrated under vacuum to afford the 10 title compound (700 mg, 2.06, 99% yield) as a yellow oil. UPLC-MS (Method 3) m / z 341.2 [M+H]+at 1.018 min.1H NMR (400 MHz, DMSO-d6) 7.94 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.06 – 7.01 (m, 3H), 6.92 (d, J = 1.7 Hz, 1H), 4.71 – 4.65 (m, 1H), 4.54 (d, J = 6.3 Hz, 2H), 2.12 (t, J = 6.6 Hz, 2H), 1.29 (d, J = 6.0 Hz, 6H), 1.17 (s, 6H).

[0407] Step 2: Preparation of 3-((2S,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- 15 biphenyl]-4-amine. A mixture of Step 1 azetidine (700 mg, 2.06 mmol) and Pd / C (10% wet, 70 mg) in EtOH (10 mL) was stirred at room temperature for 16 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with EtOAc (10 mL). The filtrate was concentrated afford the title compound (630 mg, 2.03 mmol, 98% yield) as a yellow solid. UPLC-MS (Method 3) m / z 311.0 [M+H]+at 1.192 min.1H NMR (400 MHz, 20 DMSO-d6) 7.41 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.87 (dd, J = 8.0, 1.5 Hz, 1H), 6.69 – 6.65 (m, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.62 – 4.56 (m, 1H), 4.43 – 4.32 (m, 4H), 1.98 (d, J = 8.1 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 1.10 (d, J = 6.1 Hz, 6H).

[0408] Step 3: Preparation of N-(3-((2S,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-yl)-1-hydroxycyclopropane-1-carboxamide. To a mixture of Step 2 amine (630 mg, 2.03 mmol), 1-hydroxycyclopropane-1-carboxylic acid (1.3 g, 12.90 mmol) and DIPEA (1.0 g, 7.74 mmol) in MeCN (40 mL) was added HATU (4.9 g, 12.90 mmol). The reaction was heated at 50 °C for 16 h then was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=5 / 1) to afford the title compound (240 mg, 50% purity, 0.30 mmol, 15% yield) as a yellow oil. UPLC-MS (Method 3) m / z 395.0 [M+H]+at 1.475 min.

[0409] Step 4: Preparation of 1-(((3-((2S,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol. To a solution of Step 3 carboxamide (50% purity, 240 mg, 0.30 mmol) in THF (2 mL) at 0 °C was added borane (10M in dimethyl sulfide, 2 mL). The mixture was stirred at room temperature overnight then was cooled to 0 °C, quenched with MeOH (10 mL) and concentrated. The residue obtained was diluted with NaOH (2M, 10 mL) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 10 mL). The organic phase was dried over with solid anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by Prep-TLC (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (25 mg, 0.066 mmol, 22% yield) as a yellow oil. UPLC-MS (Method 3) m / z 381.0 [M+H]+at 1.990 min. Intermediate 60: Preparation of 1-(((3-((2R,4R)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy- [1,1'-biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol

[0410] Step 1: Preparation of (2R,4R)-1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-2,4- dimethylazetidine. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (746 mg, 2.71 mmol), (2R,4R)-2,4-dimethylazetidine hydrochloride (330 mg, 2.71 mmol) and K2CO3(749 mg, 5.43 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The mixture was diluted with 5 water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over solid anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=19 / 1) to afford the title compound (890 mg, 2.61 mmol, 97% yield) as a yellow oil. UPLC-MS (Method 4) m / z 341.2 [M+H]+at 1.852 min.1H NMR (400 10 MHz, DMSO-d6) 7.94 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.10 – 6.98 (m, 3H), 6.92 (d, J = 1.9 Hz, 1H), 4.69 (tt, J = 12.1, 6.0 Hz, 1H), 4.53 (q, J = 6.5 Hz, 2H), 2.11 (t, J = 6.7 Hz, 2H), 1.29 (dd, J = 6.0, 1.4 Hz, 6H), 1.22 – 1.11 (m, 6H).

[0411] Step 2: Preparation of 3-((2R,4R)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-amine. A mixture of Step 1 azetidine (890 mg, 2.61 mmol) and Pd / C (10% wet, 178 15 mg) in EtOAc (9 mL) was stirred at room temperature for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and the filter cake washed with a mixture of DCM / MeOH (v / v=10 / 1, 100 mL). The filtrate was concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=10 / 1) to afford the title compound (680 mg, 2.19 mmol, 84% yield) as a yellow 20 solid. UPLC-MS (Method 4) m / z 311.2 [M+H]+at 0.963 min.1H NMR (400 MHz, DMSO-d6) 7.45 – 7.38 (m, 2H), 6.95 – 6.84 (m, 3H), 6.67 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 4.63 – 4.55 (m, 1H), 4.43 – 4.34 (m, 4H), 1.98 (t, J = 6.4 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 1.10 (d, J = 6.1 Hz, 6H).

[0412] Step 3: Preparation of N-(3-((2R,4R)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- 25 biphenyl]-4-yl)-1-hydroxycyclopropane-1-carboxamide. To a mixture of Step 2 amine (680 mg, 2.19 mmol), 1-hydroxycyclopropane-1-carboxylic acid (1.12 g, 10.97 mmol) and DIPEA (1.42 g, 10.97 mmol) in DMF (10 mL) was added HATU (4.12 g, 10.97 mmol). The mixture was heated at 60 °C overnight then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over solid anhydrous Na2SO4, filtered and concentrated 30 under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=10 / 1) to afford the title compound (490 mg, 1.24 mmol, 56% yield) as a yellow solid. UPLC-MS (Method 4) m / z 395.3 [M+H]+at 1.331 min.1H NMR (400 MHz, DMSO-d6) 8.80 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.09 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 – 6.95 (m, 2H), 6.91 (d, J = 2.0 Hz, 1H), 6.79 (s, 1H), 4.68 – 4.60 (m, 1H), 4.50(q, J = 6.3 Hz, 2H), 2.07 (t, J = 6.4 Hz, 2H), 1.28 (d, J = 6.0 Hz, 6H), 1.19 – 1.15 (m, 2H), 1.12 (d, J = 6.1 Hz, 6H), 1.00 (d, J = 3.3 Hz, 2H).

[0413] Step 4: Preparation of 1-(((3-((2R,4R)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol. To a solution of Step 3 carboxamide (197 mg, 0.50 mmol) in THF (5 mL) at 0 °C was added borane (10M in dimethyl sulfide, 5 mL) and the mixture stirred for 18 h. The reaction was cooled to 0 °C, quenched with MeOH (20 mL) and concentrated. The resultant residue was diluted with NaOH (2M, 10 mL) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=3 / 1) to afford the title compound (54 mg, 0.14 mmol, 32% yield) as a yellow solid. UPLC-MS (Method 4) m / z 381.3 [M+H]+at 1.239 min.1H NMR (400 MHz, DMSO-d6) 7.43 (t, J = 8.4 Hz, 2H), 6.92 (dd, J = 8.8, 4.1 Hz, 2H), 6.74 (dd, J = 4.0, 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.40 (s, 1H), 4.59 (pd, J = 6.0, 2.4 Hz, 1H), 4.49 (t, J = 5.6 Hz, 1H), 4.20 (d, J = 7.6 Hz, 1H), 3.57 – 3.44 (m, 1H), 3.14 (d, J = 5.4 Hz, 2H), 1.27 (dd, J = 6.0, 1.0 Hz, 6H), 1.18 – 1.12 (m, 3H), 1.08 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 7.1 Hz, 2H), 0.66 – 0.58 (m, 2H), 0.57 – 0.48 (m, 2H). Intermediate 61: Preparation of 1-(((3-(3,3-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'- biphenyl]-4-yl)amino)methyl)cyclopropan-1-ol

[0414] Step 1: Preparation of 1-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)-3,3- dimethylazetidine. A mixture of 3-fluoro-4'-isopropoxy-4-nitro-1,1'-biphenyl (679 mg, 2.48 mmol),3,3-dimethylazetidine hydrochloride (300 mg, 2.48 mmol), K2CO3(682 mg, 4.93 mmol) in DMF (7 mL) was stirred overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over solid anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=9 / 1) to afford the title compound (819 mg, 2.41 mmol, 97% yield) as a yellow solid. UPLC-MS (Method 4) m / z 341.2 [M+H]+at 2.096 min.1H NMR (400 MHz, DMSO-d6) 7.83 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.04 – 6.98 (m, 3H), 6.82 (d, J = 1.8 Hz, 1H), 4.69 (p, J = 6.0 Hz, 1H), 3.68 (s, 4H), 1.31 – 1.27 (m, 12H).

[0415] Step 2: Preparation of 3-(3,3-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4- amine. A mixture of Step 1 azetidine (819 mg, 2.41 mmol) and Pd / C (10% wet, 163 mg) in EtOAc (20 mL) was stirred at room temperature for 18 h under an atmosphere of hydrogen. The catalyst was removed by filtration through Celite® and washed with a mixture of DCM / MeOH (v / v=10 / 1, 100 mL). The filtrate was concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=5 / 1) to afford the title compound (700 mg, 2.25 mmol, 93% yield) as a blue oil. UPLC-MS (Method 4) m / z 311.2 [M+H]+at 1.226 min.1H NMR (400 MHz, DMSO-d6) 7.45 – 7.38 (m, 2H), 6.94 – 6.88 (m, 2H), 6.83 (dd, J = 8.0, 2.0 Hz, 1H), 6.65 – 6.56 (m, 2H), 4.59 (p, J = 6.0 Hz, 1H), 4.37 (s, 2H), 3.52 (s, 4H), 1.29 – 1.25 (m, 12H).

[0416] Step 3: Preparation of N-(3-(3,3-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4- yl)-1-hydroxycyclopropane-1-carboxamide. To a mixture of Step 2 amine (700 mg, 2.25 mmol), 1-hydroxycyclopropane-1-carboxylic acid (1.25 g, 12.27 mmol) and DIPEA (1.59 g, 12.27 mmol) in DMF (20 mL) was added HATU (4.67 g, 12.27 mmol). The reaction was heated at 60 °C overnight then diluted with water (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (800 mg, 2.03 mmol, 90% yield) as a yellow solid. UPLC-MS (Method 4) m / z 395.3 [M+H]+at 1.300 min.1H NMR (400 MHz, DMSO-d6) 8.98 (s, 1H), 7.61 – 7.50 (m, 3H), 7.04 – 6.92 (m, 3H), 6.75 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 4.64 (p, J = 6.1 Hz, 1H), 3.65 (s, 4H), 1.31 – 1.26 (m, 12H), 1.13 (q, J = 4.3 Hz, 2H), 0.97 (q, J = 4.2 Hz, 2H).

[0417] Step 4: Preparation of 1-(((3-(3,3-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopropan-1-ol. To a solution of Step 3 carboxamide (400 mg, 1.01 mmol) in THF (6 mL) at 0 °C was added borane (10M in dimethyl sulfide, 6 mL). The reaction was warmedto room temperature and stirred for 18 h then cooled to 0 °C, quenched with MeOH (40 mL) and concentrated under reduced pressure. The residue obtained was diluted with NaOH (2M, 50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over solid anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=2 / 1) to afford the title compound (205 mg, 0.54 mmol, 53% yield) as a yellow oil. UPLC-MS (Method 4) m / z 381.3 [M+H]+at 1.545 min.1H NMR (400 MHz, DMSO-d6) 7.45 (d, J = 8.6 Hz, 2H), 6.96 (dd, J = 8.1, 2.0 Hz, 1H), 6.93 – 6.89 (m, 2H), 6.68 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.47 (s, 1H), 4.60 (p, J = 6.0 Hz, 1H), 4.24 (t, J = 5.5 Hz, 1H), 3.53 (s, 4H), 3.14 (d, J = 5.4 Hz, 2H), 1.30 – 1.26 (m, 12H), 0.65 – 0.59 (m, 2H), 0.55 – 0.49 (m, 2H).

[0418] Intermediate secondary amides (62-87) can be prepared by standard amide bond formation between acids (such as intermediates 1-5) and anilines (such as the primary anilines used in the preparation of intermediates 6-61) using a coupling agent. Typically, a uronium reagent such as HATU is used, but many other coupling agents are common in the art for preparation of an amide. A typical procedure is described in Intermediate 62 step 1. Intermediate 62: (1R,2R)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide

[0419] Step 1: (1R,2R)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1- carboxamide: To a solution of (1R,2R)-2-(pyridin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 1, 215 mg, 1.32 mmol) in acetonitrile (10 mL) at room temperature was added DIPEA (512 mg, 3.96 mmol) and HATU (753 mg, 1.98 mmol). The reaction was stirred at room temperature for 30 mins then 4'-isopropoxy-[1,1'-biphenyl]-4-amine (300 mg, 1.32 mmol) was added. The resulting solution was heated at 50 °C overnight, then cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over solid anhydrous Na2SO4 filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc = 5 / 1) to afford the title compound (440 mg, 1.18 mmol, 89 % yield) as a white solid. UPLC- MS (Method 1) m / z 373.05 (M+H)+at 2.18 min.1H NMR (400 MHz, DMSO-d6) 10.32 (s, 1H), 8.45 (m, 1H), 7.72 – 7.63 (m, 3H), 7.53 (d, J = 8.4 Hz, 4H), 7.45 (d, J = 9.0 Hz, 1H), 7.20 (m, 1H), ,6.94 (d, J = 8.7 Hz, 2H), 4.62 (p, J = 6.0 Hz, 1H), 2.58 (m,1H), 2.40 (m, 1H), 1.48 (dt, J = 8.1, 5.3 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H).

[0420] Other secondary amides were prepared by an analogous method unless otherwise stated. Table of secondary amides

[0421] Examples of the invention can be prepared by several routes, utilising anilines such 6- 61, carboxylic acids such as intermediates 1-5 and secondary amides such as inermediates 62- 87. In one route, an aniline is coupled to a carboxylic acid using a uronium reagent such as 5 HATU, but many other coupling agents are common in the art for preparation of an amide. A typical procedure is described in Example 1 step 1. Example 1: (1R,2R)-N-((1-Hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0422] Step 1: (1R,2R)-N-((1-Hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide: To a solution of (1R,2R)-2-(pyridin- 2-yl)cyclopropane-1-carboxylic acid (Intermediate 1, 31.3 mg, 0.19 mmol) and DIPEA (61.9 mg, 0.48 mmol) in MeCN (5 mL) at RT was added HATU (91.2 mg, 0.24 mmol) and the reaction stirred for 30 mins. 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol (Int-14, 47.5 mg, 0.16 mmol) was added and the reaction heated at 50 °C overnight. The reaction was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using a Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (20 mg, 0.045 mmol, 28% yield) as a white solid. UPLC-MS (Method 1) m / z 443.20 [M+H]+at 1.733 min.1H NMR (400 MHz, DMSO-d6) 8.26 (d, J = 4.9 Hz, 1H), 7.67 – 7.56 (m, 5H), 7.38 (t, J = 8.1 Hz, 5H), 7.14 (d, J = 6.1 Hz, 1H), 4.44 (s, 2H), 3.93 (t, J = 11.9 Hz, 2H), 3.31 (s, 3H), 2.56 (dd, J = 6.2, 3.1 Hz, 1H), 1.90 (s, 3H), 1.82 (d, J = 10.4 Hz, 2H), 1.58 (d, J = 9.1 Hz, 1H), 1.48 (tt, J = 8.1, 3.9 Hz, 2H), 1.32 (s, 1H). Example 2: (1R,2R)-N-(4-(6-Ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide

[0423] Step 1: (1R,2R)-N-(4-(6-Ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(5- fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 2, 1.82 g, 10.04 mmol) and DIPEA (3.9 g, 30.13 mmol) in MeCN (30 mL) at RT was added HATU (5.7 g, 15.06 mmol) and the reaction stirred for 30 min.1-(((4-(6-Ethoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1-ol (Int-7 Route 1, 3.0 g, 10.04 mmol) was added and stirring continued overnight. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure and the residue obtained purified by column chromatography on silica gel (EtOAc in PE=1 / 1) and then using a Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (3.78 g, 8.19 mmol, 81% yield) as a yellow solid. UPLC-MS (Method 2) m / z 462.15 [M+H]+at 3.067 min.1H NMR (400 MHz, DMSO-d6) 8.43 (d, J = 2.6 Hz, 1H), 8.23 (d, J = 2.9 Hz, 1H), 7.97 (dd, J = 8.6, 2.6 Hz, 1H), 7.58 (dq, J = 8.2, 4.4 Hz, 3H), 7.46 (dd, J = 8.7, 4.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 6.89 – 6.84 (m, 1H), 4.94 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.95 – 3.85 (m, 2H), 2.60 (ddd, J = 9.1, 5.8, 4.0 Hz, 1H), 1.91 (s, 2H), 1.81 (d, J = 9.9 Hz, 3H), 1.58 (d, J = 9.7 Hz, 1H), 1.47 (ddd, J = 8.6, 5.5, 3.5 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.26 (s, 1H). Alternative Synthesis of Example 2.

[0424] Step 1: Preparation of ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl) trifluoroborate. To a solution of potassium trifluoro(vinyl)borate (50.0 g, 373 mmol) and Ru(II)-(S)-Pheox Catalyst (2.36 g, 3.7 mmol) in EtOAc (350 mL) was slowly added a solution of ethyl 2-diazoacetate (85.1 g, 746.3 mmol) in EtOAc (50 mL) at 0-5 °C over 3 hours. After addition was complete, the reaction was allowed to warm to RT and stirred for 1 hour. Heptane (400 mL) was added dropwise and the mixture was cooled to 0-5 °C and stirred for 1 hour. The precipitate was collected by filtration and washed with EtOAc / Heptane=1 / 1 (100 mL). The solid was dried under vacuum to give the title compound (171g, 777.3 mmol, 69.5% yield) as a grey solid.1H NMR (400 MHz, DMSO-d6) 3.96 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H), 1.12 – 1.08 (m, 1H),0.67- 0.59 (m, 1H), 0.48 (t, J = 7.2 Hz, 1H), 0.00 – -0.12 (m, 1H).19F NMR (400 MHz, DMSO- d6) -141.46.

[0425] Step 2: Ethyl (1R,2R)-2-(pyridin-2-yl)cyclopropane-1-carboxylate. A mixture of Step 1 trifluoroborate (75.0 g, 341 mmol), 2-chloro-5-fluoropyridine (89.7 g, 681.8 mmol), Pd(OAc)2(3.8 g, 17.0 mmol), cataCXium (12.1 g, 34.1 mmol) and Cs2CO3(277.7 g, 852.3 mmol) in a mixture of 1,4-dioxane (550 mL) and water (55 mL) was heated at 100 °C overnight under nitrogen. The reaction was cooled to room temperature, diluted with water (1.5 L) and extracted with EtOAc (2 x 1 L). The combined organic phases were concentrated under reduced pressure and the residue obtained purified by column chromatography (eluting with EtOAc / PE=1 / 60) to afford title compound (56.4 g, 270 mmol, 79 % yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6)1H NMR (400 MHz, DMSO-d6) 8.41 (d, J =3.0 Hz, 1H), 7.63 (td, J = 8.8, 3.0 Hz, 1H), 7.52 (dd, J = 8.8, 4.4 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 2.69 – 2.63 (m, 1H), 2.08 – 2.03 (m, 1H), 1.49 – 1.44 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[0426] Step 3: (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid. To a solution of Step 2 ester (56.4 g, 270 mmol) in a mixture of MeOH (200 mL) and water (200 mL) was added KOH (30.2 g, 539.1 mmol) and the reaction stirred at room temperature for 2 h. Most of the MeOH was removed under reduced pressure and the pH was adjusted to 3-4 with 2M HCl. The mixture was extracted with chloroform / Isopropyl alcohol (3 / 1, 3 x 800 mL) and the combined organic layers dried over solid anhydrous Na2SO4, filtered and concentrated to afford the title compound (42.0 g, 231.8 mmol, 86.0% yield, 93.7% ee) as a white solid. LCMS: m / z 182.10 (M+H)+at 0.936 min.1H NMR (400 MHz, DMSO-d6) 12.33 (s, 1H), 8.42 (d, J = 3.0 Hz, 1H), 7.63 (dd, J = 8.8, 3.0 Hz, 1H), 7.52 (dd, J = 8.8, 4.4 Hz, 1H), 2.66 – 2.57 (m, 1H), 1.99 – 1.94 (m, 1H), 1.45 – 1.40 (m, 2H).

[0427] Step 4: Preparation of (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carbonyl chloride. To a solution of Step 3 acid (100.0 g, 552 mmol) in a mixture of DCM (1 L) and DMF (cat) at 0 °C was added oxalylchloride (105.1 g, 828.0 mmol) dropwise and the reaction was stirred at rt for 1 h. The mixture was concentrated and redissolved in DCM (500 mL) and this mixture used directly in the coupling step 7.

[0428] Step 5: Preparation of 1-hydroxycyclobutane-1-carbonitrile. To a solution of cyclobutanone (200.0 g, 2.85 mol) and ZnI2(91.1 g, 0.285 mol) in dichloroethane at 0 °C (2 L, 10 Vol) was added trimethylsilylcyanide (339.7 g, 3.42 mol, 1.2 eq) dropwise. The reaction was stirred at room temperature overnight then was diluted with saturated NaHCO3aq (2 L) and extracted with DCM (3 x 2 L). The combined organic layers were washed with brine (3 x 2 L), dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo to give title nitrile useddirectly in the next step 6. TLC: Rf=0.7 (Petroleum ether / Ethyl acetate =20 / 1 bromocresol green stain).

[0429] Step 6: Preparation of 1-hydroxycyclobutane-1-carboxylic acid. A solution of Step 5 carbonitrile (280g, 2.88 mol), in a mixture of HCI (12 M, 400 mL, 2 Vol) and acetic acid (400 ml, 2 Vol) was heated at 100oC for 2 h. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc (3 x 1 L). The combined organic phases were washed with brine (2 x 1 L), dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH) =50:1 to 10:1 (v / v) to afford title acid (142.8 g, 1.23 mol, 43 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 6.52 – 4.74 (m, 1H), 2.37 (ddt, J = 12.7, 8.8, 3.5 Hz, 2H), 2.10 – 1.97 (m, 2H), 1.83 – 1.64 (m, 2H). TLC: Rf=0.2 (DCM / MeOH=10 / 1, bromocresol green stain).

[0430] Step 7: Preparation of 4-(6-ethoxypyridin-3-yl)aniline. A mixture of 5-bromo-2- ethoxypyridine (200 g, 990 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (216 g, 990 mmol), K3PO4(420 g, 1.98 mol) and Pd(dppf)Cl2(36 g, 49.5 mmol) in a mixture of 1,4- dioxane (2.4 L) and water (800 mL) was heated at 110 °C for 2 h. The mixture was cooled to room temperature, filtered, diluted with water (1 L) and extracted with EtOAc (3 x 800 mL). The combined organic phases were washed with brine (1500 mL), dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (eluting with Petroleum ether / EtOAc 10 / 1) to afford title aniline(195 g , 910. mmol, 91.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.30 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 8.8, 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H), 4.30 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H).

[0431] Step 8; Preparation of N-(4-(6-ethoxypyridin-3-yl)phenyl)-1-hydroxycyclobutane-1- carboxamide. To a solution of 4-(6-ethoxypyridin-3-yl)aniline (310 g, 1.45 mol), 1- hydroxycyclobutane-1-carboxylic acid (201.6 g, 1.74 mol) and PyBOP (1129.3 g, 2.17 mol) in DMF (2.4 L) was added DIPEA (776.3 g, 6.01 mol) and the reaction heated at 50 °C for 2 days. The mixture was cooled to rt, diluted with water (12 L) and extracted with EtOAc (3 x 3 L). The combined organic phases were washed with water (3 L) and brine (3 L), dried over dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (eluting with EtOAc / Petroleum ether =1 / 3 to 1 / 1) to afford title amide (341.0 g, 75.5 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 9.55 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.6, 2.6 Hz, 1H), 7.39 – 7.35 (m, 2H), 6.84 – 6.79 (m, 2H), 6.76 (d, J = 8.6 Hz, 1H), 6.34 (s, 1H), 4.33 (q, J = 7.0 Hz, 2H), 2.55 – 2.51 (m, 1H), 2.49 – 2.46 (m, 1H), 2.18 – 2.06 (m, 2H), 1.89 – 1.76 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H).

[0432] Step 9: Preparation of 1-(((4-(6-ethoxypyridin-3-yl)phenyl)amino)methyl)cyclobutan-1- ol. Step 8 amide (210.0 g, 672.3 mmol) was dissolved in a solution of BH3(1.0 M in THF, 3.360 L) and the reaction stirred at rt for 2 days. The mixture was quenched with NaOH aq (1.0 mol / L, 3.4 L), diluted with water (5 L) and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (4 L) dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (eluting with EtOAc / petroleum ether =1 / 5 to 1 / 3). The solid obtained was triturated with EtOAc (1.5 L) to afford title compound (122.3 g, 409 mmol, 61.0% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.32 (d, J = 2.8 Hz, 1H), 7.86 (dd, J = 8.6, 2.6 Hz, 1H), 7.41 – 7.32 (m, 2H), 6.85 – 6.69 (m, 3H), 5.39 (t, J = 5.6 Hz, 1H), 5.15 (s, 1H), 4.30 (q, J = 7.0 Hz, 2H), 3.12 (d, J = 5.6 Hz, 2H), 2.09 – 1.98 (m, 2H), 2.01 – 1.82 (m, 2H), 1.74 – 1.60 (m, 1H), 1.62 – 1.45 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H).

[0433] Step 10: Preparation of Example 2; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide. A solution of Step 4 acylchloride in DCM (500 mL, 552 mmol) was added dropwise to a solution of Step 9 aniline (164.7 g, 552.0 mmol) and DIPEA (142.7 g, 1.10 mol) in DCM (800 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h then diluted with water (2 L) and extracted with DCM (2 x 800 mL). The combined organic phases were washed with brine (1.5 L) dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (eluting with Petroleum ether / EtOAC=6 / 1) to afford title amide (193.4 g, 418.9 mmol, 75.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.43 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.96 (dd, J = 8.8, 2.8 Hz, 1H), 7.63 – 7.53 (m, 3H), 7.46 (dd, J = 8.8, 4.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.95 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 3.97 – 3.82 (m, 2H), 2.63 – 2.57 (m, 1H), 1.96 – 1.87 (m, 2H), 1.86 – 1.76 (m, 3H), 1.63 – 1.53 (m, 1H), 1.51 – 1.42 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.30 – 1.21 (m, 1H).

[0434] Step 11: Procedure for Residual Metal Scavenging Purge. To a solution of Step 10 amide (400 g, 867 mmol) in MeOH (1 L) at room temperature was added SiliaMetS Triaminetetraacetate, sodium salt (SiliaMetS®TAAcONa; 400 g) and the reaction stirred for 16 h. The metal scavenger was removed by filtration and the filtrate concentrated in vacuo. The residue obtained was dissolved in diethyl ether (5 V) and hexane (8V) was added dropwise and stirred at rt for 16 h. The precipitate that formed was collected by filtration and dried in vacuo to afford (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide (302 g, 650 mmol, 75.5 % yield, 95.2% ee) as a white solid.Example 3: (1R,2R)-N-(4-(6-Ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide

[0435] Step 1: (1R,2R)-N-(4-(6-Ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(5- fluoropyrimidin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 3, Route 1, 24 mg, 0.13 mmol) and DIPEA (35 mg, 0.27 mmol) in MeCN (1 mL) at RT was added HATU (76 mg, 0.20 mmol) and the reaction stirred for 30 mins. 1-(((4-(6-Ethoxypyridin-3- yl)phenyl)amino)methyl)cyclobutan-1-ol (Int-7, 40 mg, 0.13 mmol) was added and stirring continued overnight, then the reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure and the residue obtained purified by prep-TLC (MeOH in DCM=1 / 15) to afford the title compound (30 mg, 0.065 mmol, 50% yield) as a yellow oil. UPLC-MS (Method 1) m / z 463.15 [M+H]+at 2.100 min.1H NMR (400 MHz, DMSO- d6) 8.65 (s, 2H), 8.45 (d, J = 2.5 Hz, 1H), 7.98 (dd, J = 8.6, 2.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 4.92 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.99 – 3.83 (m, 2H), 2.62 (ddd, J = 9.0, 5.6, 3.9 Hz, 1H), 1.96 – 1.76 (m, 5H), 1.63 – 1.53 (m, 2H), 1.48 (t, J = 9.2 Hz, 1H), 1.34 (t, J = 7.0 Hz, 4H). Example 4: (1R,2R)-2-(6-Fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'- (methoxymethyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide

[0436] Step 1: (1R,2R)-2-(6-Fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'- (methoxymethyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2- (6-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 4, 61 mg, 0.34 mmol) and DIPEA (130 mg, 1.01 mmol) in MeCN (5 mL) at RT was added HATU (192 mg, 0.51 mmol) and the reaction stirred for 30 mins. 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4- yl)amino)methyl)cyclobutan-1-ol (Int-6, 100 mg, 0.34 mmol) was added and the reaction heated at 50 °C overnight. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure and the residue obtained purified by prep-TLC (EtOAc in PE=1 / 1) to afford the title compound (150 mg, 0.32 mmol, 94% yield) as a yellow solid. UPLC-MS (Method 1) m / z 461.15 [M+H]+at 2.267 min.1H NMR (400 MHz, DMSO-d6) 7.82 (q, J = 8.0 Hz, 1H), 7.59 (t, J = 8.9 Hz, 4H), 7.38 (t, J = 8.9 Hz, 5H), 6.85 (dd, J = 8.2, 2.4 Hz, 1H), 4.44 (s, 2H), 3.98 – 3.85 (m, 2H), 3.31 (s, 3H), 2.56 (dt, J = 9.0, 5.1 Hz, 1H), 1.95 – 1.77 (m, 5H), 1.58 (d, J = 9.3 Hz, 1H), 1.53 – 1.43 (m, 2H), 1.25 (s, 1H).

[0437] The following examples were prepared by methods analogous to Examples 1 - 4, substituting appropriate starting materials and intermediates where necessary:

[0438] Step 1: 4'-Isopropoxy-3-methyl-[1,1'-biphenyl]-4-amine: Using the procedure outlined in Step 3 of Intermediate 6 starting with 4-bromo-2-methylaniline (620 mg, 3.3 mmol). The title compound was obtained (454 mg, 1.88 mmol, 57% yield) as a grey solid. UPLC-MS (Method 3) m / z 242.3 [M+H]+at 2.027 min.

[0439] Step 2: 1-Hydroxy-N-(4'-isopropoxy-3-methyl-[1,1'-biphenyl]-4-yl)cyclobutane-1- carboxamide: Using the procedure outlined in Step 1 of Intermediate 6 starting 4'-isopropoxy- 3-methyl-[1,1'-biphenyl]-4-amine (280 mg, 1.16 mmol). The title compound was obtained (160 mg, 0.47 mmol, 41% yield) as a grey solid. UPLC-MS (Method 3) m / z 339.3, [M+H]+at 2.204 min.

[0440] Step 3: 1-(((4'-Isopropoxy-3-methyl-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: Using the procedure outlined in Step 2 of Intermediate 6 starting with 1-hydroxy-N-(4'- isopropoxy-3-methyl-[1,1'-biphenyl]-4-yl)cyclobutane-1-carboxamide (160 mg, 0.47 mmol). The title compound was obtained (80 mg, 0.25 mmol, 53% yield) as a colorless oil. UPLC-MS (Method 3) m / z 326.2, [M+H]+at 2.506 min.

[0441] Step 4: (1R,2R)-2-(5-Fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'- isopropoxy-3-methyl-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: Using the procedure outlined in Step 1 of Example 1 starting with 1-hydroxy-N-(4'-isopropoxy-3-methyl-[1,1'- biphenyl]-4-yl)cyclobutane-1-carboxamide (75 mg, 0.23 mmol). The title compound was obtained (62.9 mg, 0.13 mmol, 56% yield) as a white solid. UPLC-MS (Method 2) m / z 489.40 [M+H]+at 3.767 min.1H NMR (400 MHz, DMSO-d6) 8.21 (dd, J = 7.4, 2.9 Hz, 1H), 7.58 – 7.42 (m, 5H), 7.38 – 7.20 (m, 2H), 6.97 (dd, J = 8.9, 2.4 Hz, 2H), 4.91 (d, J = 6.5 Hz, 1H), 4.65 (td, J = 6.0, 2.0 Hz, 1H), 3.99 – 3.69 (m, 2H), 2.64 – 2.52 (m, 1H), 2.31 (s, 1H), 2.04 (s, 2H), 1.89 (dd, J = 36.3, 10.1 Hz, 4H), 1.76 – 1.69 (m, 1H), 1.59 – 1.38 (m, 3H), 1.28 (dd, J = 6.1, 1.1 Hz, 7H). Example 18: (1R,2R)-N-(3-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2- yl)-N-((1-hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide

[0442] Step 1: 3-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-amine: Using the procedure outlined in Step 3 of Intermediate 6 starting with 4-bromo-2-fluoroaniline (870 mg, 4.6 mmol). The titlecompound was obtained (860 mg, 3.51 mmol, 76% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 7.52 – 7.41 (m, 2H), 7.25 (dd, J = 13.2, 2.1 Hz, 1H), 7.15 (dd, J = 8.3, 2.1 Hz, 1H), 6.95 – 6.86 (m, 2H), 6.80 (dd, J = 9.6, 8.2 Hz, 1H), 5.15 (s, 2H), 4.61 (hept, J = 6.1 Hz, 1H), 1.26 (d, J = 6.0 Hz, 6H).

[0443] Step 2: N-(3-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1-hydroxycyclobutane-1- carboxamide: To a mixture of (1-hydroxycyclobutane-1-carboxylic acid (280 mg, 2.4 mmol) and DIPEA (948 mg, 7.2 mmol) in DCM (3 mL) was added HATU (931.0 mg, 2.4 mmol) and the reaction stirred for 30 mins.3-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-amine (600 mg, 2.4 mmol) was added and stirring continued overnight. The solvent was removed under reduced pressure and the residue obtained purified by column chromatography on silica gel (eluting with 1 / 10 EtOAc / PE) to afford the title compound (90 mg, 0.26 mmol, 11 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 9.11 (d, J = 1.9 Hz, 1H), 8.06 (s, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 12.6, 2.0 Hz, 1H), 7.45 (dd, J = 8.4, 2.1 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.57 (s, 1H), 4.66 (s, 1H), 2.53 (s, 1H), 2.48 (d, J = 7.6 Hz, 1H), 2.22 – 2.08 (m, 2H), 1.84 (d, J = 8.4 Hz, 2H), 1.28 (d, J = 6.0 Hz, 6H).

[0444] Step 3: 1-(((3-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol: A mixture of N-(3-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-1-hydroxycyclobutane-1- carboxamide (90 mg, 0.26 mmol) and BH3(1M in THF, 10.0 mL, 2.6 mmol) was heated at 60 °C for 3 h in a sealed tube. The reaction was quenched with NaOH (2 M) and diluted with water (20 mL). The aqueous was extracted with EtOAc (3 x 20 mL) and the combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (80mg, 0.24 mmol, 92% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 7.52 – 7.46 (m,2H), 7.35 – 7.22 (m, 2H), 6.95 – 6.85 (m, 3H), 5.30 (s, 1H), 4.80 (d, J = 2.5 Hz, 1H), 4.69 – 4.52 (m, 1H), 3.19 (d, J = 5.5 Hz, 2H), 2.10 – 1.91 (m, 4H), 1.66 (s, 1H), 1.60 – 1.50 (m, 1H), 1.27 (d, J = 6.1 Hz, 6H).

[0445] Step 4: 2,5-Dioxopyrrolidin-1-yl (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1- carboxylate: A mixture of (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 2, Route 2, 200 mg, 1.1 mmol), N,N'-diisopropylcarbodiimide (139 mg, 1.1 mmol), N-hydroxysuccinimide (127 mg, 1.1 mmol) and DMAP (13.0 mg, 0.11 mmol) in DCM (5 mL) was stirred at RT for 2 h. The mixture was diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 20 mL), dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with 1 / 20 MeOH / DCM) to afford the title compound (80 mg, 0.29 mmol, 26% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.48 (d, J = 2.8 Hz, 1H), 7.67 (dd, J =25.9, 3.7 Hz, 2H), 2.93 (ddd, J = 9.4, 6.4, 3.9 Hz, 1H), 2.82 (s, 4H), 2.43 (dd, J = 6.0, 2.4 Hz, 1H), 1.77 (ddd, J = 8.4, 5.4, 3.2 Hz, 1H), 1.67 (dd, J = 9.2, 5.1 Hz, 1H).

[0446] Step 5: (1R,2R)-N-(3-Fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)- N-((1-hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide: To a solution of 1-(((3-fluoro-4'- isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1-ol (55 mg, 0.17 mmol) in THF (3 mL) at 0 °C was added NaHMDS (2M in THF, 0.17 mL, 0.33 mmol) and the reaction stirred for 30 mins. Then 2,5-dioxopyrrolidin-1-yl (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylate (56 mg, 0.2 mmol) was added and the reaction allowed to warm to RT and stirred for 3 h. The solvent was removed under reduced pressure and the residue was purified by prep-TLC (eluting with 1 / 5 EtOAc / PE) to afford the title compound (15.0 mg, 0.031 mmol, 21 % yield) as a white solid. UPLC-MS (Method 2) m / z 493.40 [M+H]+at 4.417 min.1H NMR (400 MHz, DMSO-d6) 8.21 (dd, J = 11.0, 2.9 Hz, 1H), 7.55 (d, J = 9.0 Hz, 4H), 7.45-7.29 (m, 3H), 6.98 (d, J = 3.5 Hz, 2H), 4.86 (d, J = 2.8 Hz, 1H), 4.73 – 4.59 (m, 1H), 3.91 (d, J = 15.6 Hz, 1H), 3.79 (d, J = 17.1 Hz, 1H), 2.60 (s, 1H), 1.99 (s, 2H), 1.83 (s, 3H), 1.59 (d, J = 10.2 Hz, 1H), 1.51 – 1.42 (m, 2H), 1.32 – 1.25 (m, 7H). Example 19: (1R,2R)-2-(5-Fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'- isopropoxy-3-methoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide

[0447] Step 1: 4'-Isopropoxy-3-methoxy-[1,1'-biphenyl]-4-amine: Using the procedure outlined in Step 3 of Intermediate 6 starting with 4-bromo-2-methoxyaniline (935 mg, 4.6 mmol). The title compound was obtained (800 mg, 3.1 mmol, 67% yield) as a yellow oil. UPLC-MS (Method 4) m / z 258.10 [M+H]+at 0.52 min.1H NMR (400 MHz, DMSO-d6) 7.47 (d, J = 8.7 Hz, 2H), 7.01(d, J = 1.6 Hz, 1H), 6.92 (t, J = 7.9 Hz, 3H), 6.67 (d, J = 8.0 Hz, 1H), 4.74 (s, 2H), 4.60 (p, J = 6.0 Hz, 1H), 3.83 (s, 3H), 1.27 (d, J = 6.0 Hz, 6H).

[0448] Step 2: 1-Hydroxy-N-(4'-isopropoxy-3-methoxy-[1,1'-biphenyl]-4-yl)cyclobutane-1- carboxamide: Using the procedure outlined in Step 1 of Intermediate 6 starting with 4'- isopropoxy-3-methoxy-[1,1'-biphenyl]-4-amine (550 mg, 2.14 mmol). The title compound was obtained (550 mg, 1.54 mmol, 72% yield) as a yellow solid. UPLC-MS (Method 4) m / z 356.50 [M+H]+at 1.165 min.1H NMR (400 MHz, DMSO-d6) 9.18 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.25 (s, 1H), 7.20 – 7.16 (m, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.60 (s, 1H), 4.65 (m, J = 6.0 Hz, 1H), 3.95 (s, 3H), 2.47 (d, J = 7.2 Hz, 2H), 2.14 (q, J = 9.5 Hz, 2H), 1.86 (q, J = 7.9 Hz, 2H), 1.28 (d, J = 6.0 Hz, 6H).

[0449] Step 3: 1-(((4'-Isopropoxy-3-methoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclobutan-1- ol: Using the procedure outlined in Step 2 of Intermediate 6 starting with 1-hydroxy-N-(4'- isopropoxy-3-methoxy-[1,1'-biphenyl]-4-yl)cyclobutane-1-carboxamide (600 mg, 1.7 mmol). The title compound was obtained (450 mg, 1.32 mmol, 78% yield) as a yellow solid. UPLC-MS (Method 4) m / z 342.20 [M+H]+at 1.297 min.1H NMR (400 MHz, DMSO-d6) 7.49 (d, J = 8.6 Hz, 2H), 7.03 (s, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.6 Hz, 1H), 5.31 (s, 1H), 4.60 (dd, J = 10.3, 4.1 Hz, 2H), 3.87 (s, 3H), 3.13 (d, J = 5.2 Hz, 2H), 2.00 (s, 4H), 1.72 – 1.52 (m, 2H), 1.27 (d, J = 6.0 Hz, 6H).

[0450] Step 4: (1R,2R)-2-(5-Fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'- isopropoxy-3-methoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: Using the procedure outlined in Step 1 of Example 1 starting with 1-(((4'-isopropoxy-3-methoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclobutan-1-ol (80 mg, 0.23 mmol). The title compound was obtained (70 mg, 0.14 mmol, 61% yield) as a white solid. UPLC-MS (Method 1) m / z 505.20 [M+H]+at 2.467 min.1H NMR (400 MHz, DMSO-d6) 8.22 (dd, J = 5.0, 3.0 Hz, 1H), 7.62 – 7.53 (m, 3H), 7.47 – 7.37 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.04 – 6.95 (m, 3H), 4.87 (d, J = 2.5 Hz, 1H), 4.66 (td, J = 6.0, 2.4 Hz, 1H), 4.13 (dd, J = 46.9, 14.1 Hz, 1H), 3.93 (s, 1H), 3.52 (s, 2H), 3.45 (d, J = 13.9 Hz, 1H), 2.48 (s, 1H), 2.01 (d, J = 4.1 Hz, 1H), 1.89 – 1.74 (m, 4H), 1.58 (d, J = 9.5 Hz, 1H), 1.48 – 1.37 (m, 2H), 1.30 – 1.27 (m, 6H), 1.19 (d, J = 5.4 Hz, 1H). Example 20: (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0451] Step 1: (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(pyridin- 2-yl)cyclopropane-1-carboxylic acid (Intermediate 1, Route 1, 43 mg, 0.26 mmol) and DIPEA (50 mg, 0.39 mmol) in MeCN (2 mL) at RT was added HATU (74 mg, 0.19 mmol) and the reaction stirred for 30 mins. 1-(((4'-(Methoxymethyl)-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol (Int-15, 40 mg, 0.13 mmol) was added and the reaction heated at 50 °C overnight. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 20 mL), dried over Na2SO4, filtred, and concentrated under reduced pressure and the residue obtained was purified by column chromatograph using a Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (8 mg, 0.018 mmol, 14% yield) as a white solid. UPLC-MS (Method 1) m / z 457.20 [M+H]+at 1.800 min.1H NMR (400 MHz, DMSO-d6) 8.23 (d, J = 4.8 Hz, 1H), 7.60 (dd, J = 13.0, 7.9 Hz, 5H), 7.41 – 7.36 (m, 5H), 7.12 – 7.06 (m, 1H), 4.45 (s, 2H), 4.30 (s, 1H), 3.91 (q, J = 13.9 Hz, 2H), 3.31 (s, 3H), 2.57 – 2.52 (m, 1H), 1.89 (d, J = 5.9 Hz, 1H), 1.62 (s, 2H), 1.46 (s, 7H), 1.30 (s, 1H).4-yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide

[0452] Step 1: (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4- yl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(pyridin-2- yl)cyclopropane-1-carboxylic acid (Intermediate 1, Route 1, 50 mg, 0.31 mmol) and DIPEA (119mg, 0.93 mmol) in MeCN (3 mL) at RT was added HATU (117 mg, 0.31 mmol) and the reaction stirred for 30 mins. 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol (Int- 12, 100 mg, 0.31 mmol) was added and stirring continued overnight. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (EtOAc in PE=1 / 3) to afford the title compound (50 mg, 0.106 mmol, 34% yield) as a colorless oil. UPLC-MS (Method 2) m / z 471.45 [M+H]+at 4.050 min.1H NMR (400 MHz, DMSO-d6) 8.43 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.56 – 7.34 (m, 8H), 7.00 – 6.95 (m, 2H), 4.68 – 4.64 (m, 1H), 3.97 – 3.85 (m, 2H), 2.64 (t, J = 4.7 Hz, 1H), 2.00 – 1.88 (m, 1H), 1.66 – 1.56 (m, 3H), 1.45 (m, J = 5.7 Hz, 7H), 1.28 (d, J = 6.0 Hz, 6H). Example 22: (1R,2R)-2-(5-Fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide

[0453] Step 1: (1R,2R)-2-(5-Fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(5- fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 2, Route 1, 56 mg, 0.31 mmol) and DIPEA (119 mg, 0.93 mmol) in MeCN (3 mL) at RT was added HATU (117 mg, 0.31 mmol) and the reaction stirred for 30 mins. 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopentan-1-ol (Int-12, 100 mg, 0.31 mmol) was added and stirring was continued overnight. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by prep- HPLC (eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (30 mg, 0.061 mmol, 20% yield) as a white solid. UPLC-MS (Method 2) m / z 489.40 [M+H]+at 3.900 min.1H NMR (400 MHz, DMSO-d6) 8.23 (d, J = 2.9 Hz, 1H), 7.61 – 7.45 (m, 6H), 7.35 (d, J = 8.0 Hz, 2H), 7.00 – 6.95 (m, 2H), 4.65 (m, J = 6.0 Hz, 1H), 4.29 (s, 1H), 3.89(q, J = 14.0 Hz, 2H), 2.59 (ddd, J = 9.1, 5.7, 3.9 Hz, 1H), 1.85 (dt, J = 9.1, 4.9 Hz, 1H), 1.62 (s, 2H), 1.52 – 1.38 (m, 7H), 1.28 (d, J = 6.0 Hz, 6H), 1.25 (s, 1H). Example 29: (1R,2R)-2-(5-Fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide

[0454] Step 1: (1R,2R)-2-(5-Fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'- isopropoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(5- fluoropyrimidin-2-yl)cyclopropane-1-carboxylic acid (Intermediate 3, Route 1, 45 mg, 0.25 mmol) and DIPEA (95 mg, 0.75 mmol) in MeCN (3 mL) at RT was added HATU (93 mg, 0.25 mmol) and the reaction stirred for 30 mins. 1-(((4'-Isopropoxy-[1,1'-biphenyl]-4- yl)amino)methyl)cyclopentan-1-ol (Int-12, 80 mg, 0.25 mmol) was added and stirring continued overnight. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (eluting with EtOAc in PE=1 / 3) and Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (20.0 mg, 0.041 mmol, 16% yield) as a colorless oil. UPLC-MS (Method 2) m / z 490.40 [M+H]+at 3.567 min.1H NMR (400 MHz, DMSO-d6) 8.65 (s, 2H), 7.60 – 7.51 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H), 7.01 – 6.96 (m, 2H), 4.65 (m, J = 6.0 Hz, 1H), 4.26 (s, 1H), 3.97 – 3.82 (m, 2H), 2.62 (ddd, J = 9.2, 5.8, 4.0 Hz, 1H), 1.97 – 1.89 (m, 1H), 1.62 (s, 2H), 1.57 – 1.53 (m, 1H), 1.44 (d, J = 8.0 Hz, 6H), 1.28 (d, J = 6.0 Hz, 7H). Example 36: (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]- 4-yl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide

[0455] Step 1: (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4- yl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide: To a mixture of (1R,2R)-2-(pyrimidin-4- yl)cyclopropane-1-carboxylic acid (Int-5, 75 mg, 0.46 mmol) and DIPEA (178 mg, 1.38 mmol) in MeCN (5 mL) at RT was added HATU (262 mg, 0.69 mmol) and the reaction stirred for 30 mins. 1-(((4'-Isopropoxy-[1,1’-biphenyl]-4-yl)amino)methyl)cyclopentan-1-ol (Int-12, 148 mg, 0.46 mmol) was added and the reaction heated at 50 °C overnight. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (eluting with EtOAc in PE=1 / 1) and then using Biotage Isolera One (C18column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (30.0 mg, 0.064 mmol, 14% yield) as a yellow solid. UPLC-MS (Method 2) m / z 472.15 [M+H]+at 2.367 min.1H NMR (400 MHz, DMSO-d6) 8.82 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.55 (q, J = 6.1 Hz, 5H), 7.38 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 4.67 (m, J = 6.0 Hz, 1H), 4.29 (s, 1H), 3.97 – 3.85 (m, 2H), 2.58 (dt, J = 9.1, 4.8 Hz, 1H), 2.00 (dt, J = 9.3, 4.8 Hz, 1H), 1.66 – 1.56 (m, 3H), 1.51 – 1.43 (m, 6H), 1.38 (q, J = 4.2 Hz, 1H), 1.30 (d, J = 5.9 Hz, 6H).

[0456] The following examples were prepared by methods analogous to Examples 20 – 22, 29 and 36, substituting appropriate starting materials and intermediates where necessary:

[0457] When the central substituent in compounds of the invention is a 4 or 5-membered ring, with or without an oxygen atom present, compounds of the invention may be prepared by reacting the secondary amides such as 62-87 with the appropriate spiro epoxide reagent. For instance, Example 46 is prepared by reaction of secondary amide intermediate 66 with 1,5- dioxaspiro[2,3]hexane (CAS 15791-59-0), Typical conditions are to mix the amide and epoxide in THF with potassium hydroxide and heat in a sealed tube. Example 46: (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4- yl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide

[0458] Step 1: (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4- yl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide: A mixture of (1R,2R)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide (Intermediate 66, 100 mg, 0.27 mmol), 1,5-dioxaspiro[2.3]hexane (46 mg, 0.54 mmol) and KOH (23 mg, 0.40 mmol) in THF (1 mL) was stirred at room temperature for 6 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) to afford the title compound (6 mg, 0.05 mmol, 18% yield) as a white solid. UPLC-MS (Method 2) m / z 460.30 [M+H]+at 3.347 min.1H NMR (400 MHz, DMSO-d6) 8.79 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.55 (q, J = 6.8 Hz, 5H), 7.36 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 5.80 (b, 1H), 4.57 (m, J = 6.0 Hz, 1H), 4.29 – 4.20 (m, 4H), 4.07 (s, 2H), 2.58 (m, 1H), 2.00 (m, 1H), 1.60 – 1.56 (m, 1H), 1.40 – 1.32 (m, 1H), 1.30 (d, J = 4.8 Hz, 6H).

[0459] The following examples were prepared by methods analogous to Example 46 substituting appropriate starting materials and intermediates where necessary:Example 55: (1R,2R)-N-(3-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-

[0460] Step 1: (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carbonyl chloride: To a solution of (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (90 mg, 0.497 mmol) in DCM (2 mL) at 0 °C was added oxalylchloride (126 mg, 0.994 mmol) and DMF (1 drop). The mixture was stirred at room temperature for 2 h and used in the next step without workup.

[0461] Step 2: (1R,2R)-N-(3-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)- N-((1-hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide: To a solution of 4-(((1- hydroxycyclobutyl)methyl)amino)-4'-isopropoxy-[1,1'-biphenyl]-3-carbonitrile (Intermediate 32, 50 mg, 0.149 mmol), DIPEA (96 mg, 0.743 mmol) and DMAP (2 mg, 0.015 mmol) was added a solution of (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carbonyl chloride in DCM as prepared above. The mixture was stirred at room temperature for 18 h then diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by prep-TLC (eluting with Petroleum ether / EtOAc = 1 / 1) to afford the title compound (56 mg, 0.11 mmol, 74% yield) as a yellow solid. UPLC-MS (Method 2) m / z 500.30 [M+H]+at 3.386 min.1H NMR (400 MHz, DMSO- d6) 8.19 (m, 1.5H), 7.97 (m, 0.5H), 7.88 – 7.82 (m, 1H), 7.67 (m, 1.5H), 7.62 – 7.50 (m, 2.5H), 7.2 (bm, 1H), 7.00 – 6.90 (m.2H), 4.87 (s, 1H), 4.68 – 4.60 (m, 1H), 4.06 – 4.00 (m, 1H), 3.90 – 3.76 (m, 1H), 2.68 – 2.62 (m, 0.5H), 2.54 – 2.50 (m, 0.5H), 2.16 – 2.05 (m, 1H), 2.04 – 1.98 (m, 1H), 1.94 – 1.84 (m, 2H), 1.74 – 1.70 (m, 1H), 1.68 – 1.49 (m, 3H), 1.32 (d, J = 8.8 Hz, 7H). Example 64: (1R,2R)-N-(3-amino-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2- yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide

[0462] Step 1: (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'- isopropoxy-3-((4-methoxybenzyl)amino)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide: To a solution of (1R,2R)-2-(5-fluoropyridin-2-yl)-N-(4'-isopropoxy-3-((4-methoxybenzyl)amino)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide (Intermediate 76, 508 mg, 0.97 mmol) in THF (5 mL) was added 1,5-dioxaspiro[2.3]hexane (100 mg, 1.16 mmol) and KOH (55 mg, 0.97 mmol) and the reaction stirred at room temperature for 4 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by Prep-TLC (eluting with MeOH / DCM = 1 / 80) to afford the title compound (300 mg, 0.49 mmol, 51% yield) as a brown solid. UPLC-MS (Method 3) m / z 612.0 [M+H]+at 1.54 min.

[0463] Step 2: (1R,2R)-N-(3-amino-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)- N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide: To a solution of (Step 1 amide (43 mg, 0.07 mmol) in a mixture of MeCN and water (v / v = 5 / 1, 1.2 mL) was added 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone (34 mg, 0.15 mmol) and the mixture stirred at room temperature for 30 min. The reaction was quenched with sodium bicarbonate solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over solid anhydrous Na2SO4and filtered. The resulting residue was purified by Prep-TLC (eluting with MeOH / DCM = 1 / 40) to afford the title compound (11 mg, 0.022 mmol, 32% yield) as a brown solid. UPLC-MS (Method 2) m / z 492.10 [M+H]+at 2.232 min.1H NMR (400 MHz, DMSO-d6) 8.27 (dd, J = 2.8, 18.4 Hz, 1H), 7.59 – 7.39 (m, 4H), 7.14 (d, J = 8.0 Hz, 0.5H), 7.00 – 6.95 (m.3H), 6.90 (m, 0.5H), 6.83 (m.0.5H), 6.55 (m, 0.5H), 5.92 (ds, 1H), 5.31 (s, 1H), 5.20 (s, 1H), 4.68 – 4.60 (m, 1H), 4.32 – 4.22 (m, 2H), 4.24 – 4.20 (m, 2H), 3.98 – 3.90 (m, 2H), 2.64 – 2.60 (m, 0.5H), 2.45 – 2.41 (m, 0.5H), 1.90 – 1.85 (m, 1H), 1.51 – 1.46 (m, 1H), 1.38 – 1.34 (m, 1H), 1.30 (d, J = 8.8 Hz, 6H). Example 66: (1R,2R)-N-(3-acetamido-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide

[0464] Step 1: 4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-amine: A mixture of 5-bromo-2- nitroaniline (9.62 g, 44.3 mmol), (4-isopropoxyphenyl)boronic acid (8.71 g, 48.0 mmol), Pd(dppf)Cl2(1.61 g, 2.0 mmol) and K3PO4(18.68 g, 88.0 mmol) in a mixture of dioxane / water (v / v=11 / 1, 108 mL) was heated at 100 °C for 2 h under an atmosphere of nitrogen. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (10.9 g, 40.05 mmol, 90% yield) as a yellow solid. UPLC-MS (Method 4) m / z [M+H]+273.2 at 1.117 min.1H NMR (400 MHz, DMSO-d6) 8.00 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.43 (s, 2H), 7.24 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.91 (dd, J = 9.0, 1.8 Hz, 1H), 4.73 – 4.64 (m, 1H), 1.29 (d, J = 6.0 Hz, 6H).

[0465] Step 2; N-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)acetamide: To a solution of Step 1 amine (200 mg, 0.74 mmol) in THF (3 mL) at 0 °C was added NaH (60% wt, 36 mg, 0.90 mmol). The mixture was stirred at room temperature for 30 min, then cooled down to 0 °C and acetyl chloride (58 mg, 0.74 mmol) was added. The resulting solution was stirred at room temperature overnight. The mixture was quenched with ice water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with Petroleum ether / EtOAc=5 / 1) to afford the title compound (230 mg, 0.73 mmol, 99% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+315.0 at 1.533 min.1H NMR (400 MHz, DMSO-d6) 10.29 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.67 – 7.61 (m,2H), 7.59 (dd, J = 8.7, 2.0 Hz, 1H), 7.08 – 7.03 (m, 2H), 4.70 (dq, J = 12.0, 6.0, 5.6 Hz, 1H), 2.11 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H).

[0466] Step 3: A mixture of Step 2 amide (230 mg, 0.73 mmol), Fe powder (204 mg, 3.65 mmol), NH4Cl (58 mg, 1.095 mmol) in a mixture of MeOH / water (v / v=5 / 1, 6 mL) was heated at 80 °C for 2 h. The mixture was filtered through the Celite® and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title compound (200 mg, 0.70 mmol, 97% yield) as a black solid. UPLC-MS (Method 3) m / z [M+H]+285.0 at 0.952 min.

[0467] Step 4: N-(4-(((3-hydroxyoxetan-3-yl)methyl)amino)-4'-isopropoxy-[1,1'-biphenyl]-3- yl)acetamide: A mixture of Step 3 aniline (160 mg, 0.56 mmol), 1,5-dioxaspiro[2.3]hexane (48 mg, 0.56 mmol), LiClO4(238 mg, 2.24 mmol) in THF (3 mL) was stirred overnight at room temperature in a sealed tube. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep- TLC (eluting with eluting with Petroleum ether / EtOAc=10 / 1) to afford the title compound (50 mg, 0.14 mmol, 24% yield) as a yellow oil. UPLC-MS (Method 3) m / z [M+H]+371.0 at 1.439 min.

[0468] Step 5: (1R,2R)-N-(3-acetamido-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin- 2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide: To a solution of (1R,2R)-2- (5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (38 mg, 0.21 mmol) in MeCN (2 mL) at room temperature was added DIPEA (54 mg, 0.42 mmol) and HATU (80 mg, 0.21 mmol). The reaction was stirred at room temperature for 30 min, then Step 4 acetamide (50 mg, 0.14 mmol) was added. The resulting solution was heated at 50 °C overnight. The mixture was cooled down to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over solid anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (eluting with eluting with Petroleum ether / EtOAc=1 / 5) and prep-HPLC to afford the title compound (11 mg, 0.021 mmol, 15 % yield) as a white solid. UPLC-MS (Method 2) m / z 534.10 [M+H]+at 1.578 min.1H NMR (400 MHz, DMSO-d6) 9.62 (s, 0.5H), 9.35 (s, 0.5H), 8.25 – 8.19 (m, 2H), 7.59 – 7.34 (m, 5H), 7.28 (bd, 0.5H), 7.14 (bd, 0.5H), 7.02 – 6.96 (m.2H), 6.70 (d, J = 8.0 Hz,1H), 4.68 – 4.60 (m, 1H), 4.48 – 4.40 (m, 2H), 4.33 – 4.20 (m, 2H), 4.12 (d, 0.5H), 4.05 (d, 0.5H), 3.81 – 3.72 (m, 1H), 2.63 – 2.58 (m, 1H), 2.10 (s, 1.5H), 1.87 (s,1.5H), 1.81 – 1.78 (m, 0.5H), 1.68 – 1.60 (m, 0.5H), 1.72 – 1.38 (m, 2H), 1.30 (dd, J = 8.8 Hz, 6H). Example 67: (1R,2R)-N-(3-(cyclopropanecarboxamido)-4'-isopropoxy-[1,1'-biphenyl]-4- yl)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1- carboxamide

[0469] Step 1: N-(4'-isopropoxy-4-nitro-[1,1'-biphenyl]-3-yl)cyclopropanecarboxamide: To a solution of Example 66 Step 1 amine (200 mg, 0.74 mmol) and triethylamine (371 mg, 3.68 mmol) in DCM (2 mL) at 0 °C was added cyclopropanecarbonyl chloride (229 mg, 2.21 mmol). 5The mixture was stirred at room temperature overnight then diluted with water (5 mL) andextracted with EtOAc (3 x 5 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo and the resulting residue was purified by prep-TLC (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (80 mg, 0.23 mmol, 31% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+341.0 at 1.834 min.1H NMR (400 10 MHz, DMSO-d6) 10.55 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.67 – 7.63 (m, 2H), 7.58 (dd, J = 8.6, 2.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.73 – 4.67 (m, 1H), 1.88 (s, 1H), 1.30 (d, J = 6.0 Hz, 6H), 0.83 (d, J = 10.0 Hz, 4H).

[0470] Step 2: N-(4-amino-4'-isopropoxy-[1,1'-biphenyl]-3-yl)cyclopropanecarboxamide: A mixture of Step 1 carboxamide (80 mg, 0.24 mmol), Fe powder (66 mg, 1.18 mmol), NH4Cl (19 15 mg, 0.35 mmol) in a mixture of MeOH / water (v / v=5 / 1, 6 mL) was heated at 80 °C for 2 h. The mixture was filtered through Celite® and washed with EtOAc (5 mL), then diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (70 mg, 96% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+311.2 at 0.972 min.1H NMR (400 20 MHz, DMSO-d6) 9.45 (s, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 6.8 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 4.93 (s, 2H), 4.63 – 4.56 (m, 1H), 1.85 (s, 1H), 1.27 (d, J = 6.0 Hz, 6H), 0.80 (d, J = 4.6 Hz, 4H).

[0471] Step 3: N-(4-(((3-hydroxyoxetan-3-yl)methyl)amino)-4'-isopropoxy-[1,1'-biphenyl]-3- yl)cyclopropanecarboxamide: To a solution of Step 2 carboxamide (70 mg, 0.23 mmol) and 1,5- dioxaspiro[2.3]hexane (19 mg, 0.23 mmol) in THF (1 mL) at room temperature was added LiClO4(24 mg, 0.23 mmol). The mixture was stirred at room temperature overnight, then quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by prep-TLC (eluting with Petroleum ether / EtOAc=1 / 1) to afford the title compound (50 mg, 0.13 mmol, 56% yield) as a yellow solid. UPLC-MS (Method 3) m / z [M+H]+396.7 at 0.879 min.1H NMR (400 MHz, DMSO-d6) 9.63 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.39 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.5 Hz, 1H), 5.99 (s, 1H), 4.84 (t, J = 5.4 Hz, 1H), 4.64 – 4.58 (m, 1H), 4.49 – 4.41 (m, 4H), 3.36 (d, J = 5.5 Hz, 2H), 1.84 (s, 1H), 1.27 (d, J = 6.0 Hz, 6H), 0.80 (s, 4H).

[0472] Step 4: (1R,2R)-N-(3-(cyclopropanecarboxamido)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2- (5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide To a solution of Step 3 carboxamide (50 mg, 0.13 mmol) in MeCN (2 mL) at room temperature was added (1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid (27 mg, 0.15 mmol), HATU (72 mg, 0.19 mmol) and DIPEA (33 mg, 0.25 mmol). The mixture was heated at 50 °C overnight. The reaction was cooled down to room temperature, then diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over solid anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Biotage Isolera One (C18 column, eluting with 10 % to 90 % MeCN / H2O, containing 0.1% HCOOH) followed by prep-HPLC to afford the title compound (12 mg, 0.021 mmol, 17% yield) as a yellow solid. UPLC-MS (Method 2) m / z 560.10 [M+H]+at 2.167 min.1H NMR (400 MHz, DMSO-d6) 9.81 (s, 0.5H), 9.57 (s, 0.5H), 8.25 – 8.19 (m, 2H), 7.59 – 7.34 (m, 5H), 7.31 (bd, 0.5H), 7.17 (bd, 0.5H), 7.02 – 6.96 (m.2H), 6.70 (d, 1H), 4.68 – 4.60 (m, 1H), 4.48 – 4.40 (m, 2H), 4.35 (d, J = 14 Hz, 0.5H), 4.30 – 4.25 (m, 1.5H), 4.09 – 4.03 (m, 1H), 3.81 – 3.76 (m, 1H), 2.63 – 2.58 (m, 1H), 1.81 – 1.78 (m, 1H), 1.68 – 1.60 (m, 1H), 1.42 – 1.38 (m, 1H), 1.30 (dd, J = 8.8 Hz, 6H).1.28 – 1.20 (m, 1H), 0.90 – 0.83 (m, 2H), 0.74 – 0.68 (m, 2H). Example 68: (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'- isopropoxy-3-(2-oxoazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide

[0473] Step 1: 3-bromo-4'-isopropoxy-[1,1'-biphenyl]-4-amine: A mixture of 2-bromo-4- iodoaniline (5.0 g, 16.78 mmol), (4-isopropoxyphenyl)boronic aci...

Claims

1. Claims:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein: R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl, –O-C3-C4-cycloalkyl, C1-C4-alkyl, and –CH2–O-C1-C4-alkyl, each unsubstituted or substituted with one or more fluoro; Z1is N or CR1a; R1ais selected from the group consisting of H, F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; m is 0 or 1; R1bis selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl; n is 0, 1, or 2; R2, at each occurrence, is independently selected from the group consisting of F, Cl, cyano, C1-C4-alkyl, C1-C4-fluoroalkyl, –OR2a, –SR2a, –NR2bR2c, –N(R2d)C(O)R2e, and a C3-C6-cycloalkyl; R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C4-cycloalkyl, and –C1-3alkylene–C3-C4- cycloalkyl; wherein alternatively, R2band R2c, together with the nitrogen to which each attaches, form an optionally substituted 4- to 7-membered heterocyclyl, optionally containing a second heteroatom selected from the group consisting of O, N, and S; or wherein alternatively, R2band R2c, together with the nitrogen to which each attaches, form an optionally substituted 5-membered heteroaryl, optionally containing 1-2 additional nitrogen atoms;R3is a 6-membered aromatic ring, optionally containing 1-2 nitrogen atoms, and optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; and R4aand R4btogether with the atom to which each attaches form a C3-C5cycloalkane or a 4- to 5-membered heterocycle containing one oxygen atom.

2. A compound of claim 1 of Formula (I) or a pharmaceutically acceptable salt thereof:wherein: R1is selected from the group consisting of –O-C1-C4-alkyl, –O-C3-C4-cycloalkyl, C1-C4-alkyl, and –CH2–O-C1-C4-alkyl; Z1is N or CR1a; R1ais selected from the group consisting of H, F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; m is 0 or 1; R1bis selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl; n is 0, 1, or 2; R2, at each occurrence, is independently selected from the group consisting of F, Cl, C1-C2- alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; L isR3is a 6-membered aromatic ring, optionally containing 1-2 nitrogen atoms, and optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl; andR4aand R4btogether with the atom to which each attaches form a C4-C5cycloalkane or a 4- to 5-membered heterocycle containing one oxygen atom.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a C3-C5cycloalkane.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4aand R4btogether with the atom to which each attaches form a 4- to 5-membered heterocycle containing one oxygen atom.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl, C1-C4-alkyl, –O-C1-C4-fluoroalkyl, and –CH2–O-C1-C4-alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R1is –O-C1-C4-alkyl or –CH2–O-C1-C4-alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –OCH2CH3, –OCH(CH3)2, and –CH2–O-CH3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z1is N.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z1is CR1a.

10. The compound of any one of claims 1-7 or 9, or a pharmaceutically acceptable salt thereof, wherein R1ais H.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein m is 0.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein n is 0.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. The compound of any one of claims 1-11 or 13, or a pharmaceutically acceptable salt thereof, wherein15. The compound of any one of claims 1-11 or 13-14, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is independently selected from the group consisting of F, cyano, C1-C4-alkyl, –OR2a, –SR2a, –NR2bR2c, and –N(R2d)C(O)R2e.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R2is –NR2bR2c, and R2band R2c, together with the nitrogen to which each attaches, form the 4- to 7-membered heterocyclyl, optionally substituted as defined in clam 1.

17. The compound of any one of claims 1-11 or 13-15, or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, R2c, R2d, and R2e, at each occurrence, are independently selected from the group consisting of H, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C4-cycloalkyl, and – C1-3alkylene–C3-C4-cycloalkyl.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R2is –NR2bR2c, and R2band R2c, together with the nitrogen to which each attaches, form the 5- membered heteroaryl, optionally substituted as defined in claim 1.

19. The compound of any one of claims 1-11, 13-15, or 17, or a pharmaceutically acceptable salt thereof, wherein R2, at each occurrence, is independently selected from the group consisting of CH3, F, and OCH3.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein L is21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R3is a pyridinyl or pyrimidinyl, each optionally substituted as defined in claim 1 or 2.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R3is a pyridine-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, each optionally substituted as defined in claim 1 or 2.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein each R3is optionally substituted with 1 substituent selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2-alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein each R3is optionally substituted with F.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting ofand26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-B) or (III-A):p is 1, or 2; q is 0, 1 or 2; n is 0 or 1; Z1is N or CH; R2is azetidin-1-yl; and R5is selected from the group consisting of F, Cl, C1-C2-alkyl, C1-C2-fluoroalkyl, and –O-C1-C2- alkyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein p is 1.

28. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein p is 2.

29. The compound of any one of claims 26-28, or a pharmaceutically acceptable salt thereof, wherein R5is F.

30. The compound of any one of claims 26-29, or a pharmaceutically acceptable salt thereof, wherein n is 0.

31. The compound of any one of claims 26-29, or a pharmaceutically acceptable salt thereof, wherein n is 1.

32. The compound of any one of claims 26-31, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –O-C1-C4-alkyl, –S-C1-C4-alkyl, C1-C4-alkyl, –O-C1-C4-fluoroalkyl, and –CH2–O-C1-C4-alkyl.

33. The compound of any one of claims 26-31, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of –O-C1-C4-alkyl.

34. The compound of any one of claims 26-33, or a pharmaceutically acceptable salt thereof, wherein Z1is CH.

35. The compound of any one of claims 26-33, or a pharmaceutically acceptable salt thereof, wherein Z1is N.

36. The compound of claim 1 or 2, selected from the group consisting of: (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-2-(pyridin- 2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(6-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide;(1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-(methoxymethyl)pyridin-3-yl)phenyl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6- (methoxymethyl)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-Ethoxypyridin-3-yl)phenyl)-N-((1-hydroxycyclobutyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-Ethoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-propyl-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-propylpyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-methyl- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-fluoro-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-methoxy- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide;(1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin- 3-yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-(methoxymethyl)pyridin-3-yl)phenyl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6- (methoxymethyl)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide;(1R,2R)-2-(6-fluoropyridin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-Hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin-3-yl)phenyl)-2-(pyrimidin- 4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-propyl-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-propylpyridin-3-yl)phenyl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-N-(4'-isopropoxy- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-N-(4'-isopropoxy- [1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(pyridin-2- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(6-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-(pyrrolidin- 1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3-(piperidin- 1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-isopropoxy-3- morpholino-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)- 2-(pyrimidin-4-yl)cyclopropane-1-carboxamide;(1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((3-hydroxyoxetan-3- yl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3,4'-diisopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan- 3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-cyclopropoxy-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3- (methylamino)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(dimethylamino)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-N-((1- hydroxycyclobutyl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-N-((3-hydroxyoxetan-3- yl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)- 2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((3-hydroxyoxetan-3- yl)methyl)-2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)-2- (pyridin-2-yl)cyclopropane-1-carboxamide;(1R,2R)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(methylthio)-[1,1'-biphenyl]-4-yl)- 2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(1H- 1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(1H-imidazol-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N- ((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(1H- 1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-cyano-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-amino-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-acetamido-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(cyclopropanecarboxamido)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin- 2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-N-(4'-isopropoxy-3-(2- oxoazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl) -N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1- hydroxycyclopropyl)methyl) -2-(pyridin-2-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-N-((1- hydroxycyclopropyl)methyl)-2-(pyrimidin-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide;(1R,2R)-N-(3-(azetidin-1-yl)-4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl) methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclopropyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclobutyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-(ethylthio)-[1,1'-biphenyl]-4-yl)-N-((1-hydroxycyclopentyl)methyl)-2-(pyrimidin-4- yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-(1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)phenyl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-((S)-2- methylazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-((R)-2- methylazetidin-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)-N-(4'-isopropoxy-3-(1H- 1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-((2R,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-((2S,4S)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-((2R,4R)-2,4-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5- fluoropyridin-2-yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; and (1R,2R)-N-(3-(3,3-dimethylazetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2- yl)-N-((1-hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

37. The compound of claim 36, selected from the group consisting of: (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyrimidin-2-yl)-N-((1- hydroxycyclopentyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4'-(methoxymethyl)-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4-(6-isopropoxypyridin- 3-yl)phenyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof; or a compound selected from the group consisting of: (1R,2R)-N-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(4-(6-ethoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyridin-2-yl)-N-((1-hydroxycyclobutyl)methyl)-N-(4-(6-isopropoxypyridin-3- yl)phenyl)cyclopropane-1-carboxamide; (1R,2R)-2-(5-fluoropyrimidin-2-yl)-N-((1-hydroxycyclopentyl)methyl)-N-(4'-isopropoxy-[1,1'- biphenyl]-4-yl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide;(1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)cyclopropane-1-carboxamide; (1R,2R)-N-(3-(azetidin-1-yl)-4'-isopropoxy-[1,1'-biphenyl]-4-yl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; and (1R,2R)-N-(2-(azetidin-1-yl)-4-(6-isopropoxypyridin-3-yl)phenyl)-2-(5-fluoropyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)cyclopropane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical formulation comprising a compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of claims 1-38, for use as a medicament.

40. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of claims 1-39, for use in the treatment of a disease or disorder, or a symptom thereof, wherein the disease or disorder is mediated by GPR88.

41. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of claims 1-40, for use in the treatment of a disease or disorder, or a symptom thereof, wherein the disease or disorder is selected from the group consisting of Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, tardive dyskinesia, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer’s disease, and basal ganglia disorders.

42. A compound, or pharmaceutically acceptable salt or pharmaceutical formulation thereof, of any one of claims 1-41, for use in the treatment of tardive dyskinesia, or a symptom thereof.

43. A method of treating a disease or disorder mediated by GPR88, or a symptom thereof, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, or the pharmaceutical formulation of claim 38.

44. The method of claim 43, wherein the disease or disorder is selected from the group consisting of Tourette’s Syndrome, Huntington’s Disease (HD), Addiction, Parkinson’s Disease (PD), Schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD), choreiform movements, tardive dyskinesia, speech delay, learning disabilities, depression, hyperkinetic movement disorders characterised by chorea and / or dystonia, psychosis, cognitive deficits in schizophrenia, affective disorders, bipolar disorder, Alzheimer’s disease and basal ganglia disorders.

45. The method of claim 44, wherein the disease or disorder is tardive dyskinesia.

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