HK1237348B - Therapeutic compounds as inhibitors of the orexin-1 receptor - Google Patents

Description

Therapeutic compounds as orexin-1 receptor inhibitors

introduction

The present invention relates to therapeutic compounds. More specifically, the present invention relates to compounds that are inhibitors of the orexin-1 receptor. The present invention also relates to methods for preparing these compounds, to pharmaceutical compositions containing them, and to their use in the treatment of diseases or disorders associated with orexin-1 receptor activity.

Background Art

The neuropeptides orexin-A (OxA) and orexin-B (OxB) (also known as hypocretin-1 and hypocretin-2) are derived from the same pro-propeptide, which is expressed exclusively in the hypothalamus (1). Cleavage of the pro-propeptide (pre-pro-orexin) produces OxA, a 33 amino acid polypeptide, that is extensively post-translationally modified (C-terminal amidation, N-terminal cyclization with a pyroglutamyl residue). OxA shares 46% sequence identity with OxB, a 28 amino acid, C-terminally amidated linear polypeptide that likely forms a helical secondary structure (3).

The fully functional mature peptide neurotransmitters act as agonists for the orexin-1 (OX ₁ ) and orexin-2 (OX ₂ ) 7-transmembrane G protein-coupled receptors (also known as HCRTR1 and HCRTR2), which (e.g., the orexin neuropeptides) share high sequence homology across species (2, 6). OX ₁ binds to both OxA and OxB, albeit with differential affinities (OxA has an affinity >10-fold higher than OxB). In contrast, OX _2, which shares 64% sequence identity with OX ₁ , binds to both polypeptides with nearly equal affinity (2). The primary G protein-mediated mechanism (acting through both receptors) is G _q/11 activation of phospholipase C, which catalyzes the release of inositol-1,4,5-trisphosphate (IP ₃ ), which in turn acts on the IP ₃ receptor to release calcium from intracellular stores. _OX2 has also been reported to regulate cAMP levels by activating _Gs and _Gi , and _OX1 also appears to be able to regulate cAMP levels through Gi _/o signaling (5, 8).The high sequence similarity in peptides and receptors across species translates into similar in vitro pharmacology (7).

The hypothalamus, where orexin is primarily expressed, regulates a wide range of physiological and behavioral activities. Orexin expression in this brain structure has been immunohistochemically mapped to only a very limited number of neurons that reside specifically in the peri-fornical region (50%), the lateral region, and the dorsomedial region (4). The projection fields of these neurons have been identified in many brain regions, including the cortex, thalamus, hypothalamus, brainstem, and spinal cord, but not the cerebellum (9). This broad coverage of the brain suggests that the orexin ligand/receptor system is directly or indirectly involved in the regulation of multiple brain functions. Notably, knockout experiments in mice have shown that the orexin system is a key regulator of behavioral arousal, sleep, and insomnia. Indeed, the phenotype observed in orexin knockout mice is very similar to that of human narcolepsy (10, 11). Human narcolepsy is a chronic and disabling disorder characterized by excessive daytime sleepiness, fragmented sleep, and cataplexy. Studies in dogs have linked the cause of the disorder to disruption of the _OX2 gene or loss of orexin peptide expression (12). Further supporting evidence (specifically, that disruption of _OX2 function and/or loss of mature OxB ligands are associated with narcolepsy) comes from studies in knockout mice (17). Subsequent clinical studies comparing OxA levels in the cerebrospinal fluid of narcoleptic patients with normal individuals confirmed that disruption of the orexin system shows a causal relationship with the development of human narcolepsy (13). Additional studies of unusual early-onset human narcolepsy identified mutations in the orexin gene that further strengthened the link between human narcolepsy and the orexin system (14). Recently, clinical data demonstrating the pharmacological relevance of orexins in CNS disorders have emerged. Most notably, clinical trials using small molecule dual _OX1 and _OX2 antagonists (DORAs) such as (Suvorexant) have clearly demonstrated the potential utility of these drugs in the treatment of sleep disorders (15, 16, 18). These data, together with the preclinical evidence provided above, clearly implicate _OX2 in sleep regulation.

The differential brain expression of _OX1 and _OX2 , coupled with the diversity of neurobiological effects attributed to orexins, strongly suggests that drugs that modulate _OX1 or _OX2 will elicit distinct biological effects. To this end, recent reports linking the _OX1 /OxA system specifically to feeding and behavioral disorders are important.

Given that pro-orexin mRNA levels are primarily found in the lateral and posterior hypothalamus, brain regions generally associated with the regulation of food intake and energy balance/body weight, the link between the orexin system and feeding behavior is not surprising (19). The role of the _OX1 /OxA system in these functions has been reinforced by a series of preclinical studies. Thus, it has been demonstrated that intracerebroventricular (icv) administration of OxA (20) induces feeding and that specific anti-orexin antibodies dose-dependently inhibit food intake (21). Specifically, the latter study suggests that orexin receptor antagonists should have a beneficial effect on orexin-stimulated feeding. This hypothesis is supported by independent in vivo studies that clearly identify _OX1 as the primary receptor of the orexin system in the regulation of food intake and energy balance. Thus, experiments with selective _OX1 and _OX2 receptor antagonists have shown that _OX1 selective compounds alter food intake and energy balance in the presence of simultaneous exposure to stress (22, 23). The primary role of _OX1 in regulating feeding behavior and energy balance is further supported by observations showing that _OX1 expression is selectively upregulated in response to fasting, while _OX2 expression is unaffected (24). Finally, studies with _OX1- specific antibodies strongly suggest that selective _OX1 antagonists should inhibit food intake and therefore have potential therapeutic utility for the treatment of eating-related disorders such as binge eating or obesity.

Elevated _OX1 levels are also associated with psychiatric disorders including schizophrenia, anxiety and mood disorders, panic attacks, reward seeking behavior, and addiction (25, 26, 27). Studies with selective _OX1 antagonists (SB334867, SB408124) clearly demonstrated beneficial effects in clinically relevant animal models of panic, suggesting that _OX1 antagonists may provide novel therapeutic approaches for the treatment of panic disorder (27).

Indirect evidence for the involvement of the orexin system in reward-seeking behavior comes from studies showing that orexinergic neurons project to reward-related brain regions such as the nucleus accumbens and the ventral tegmental area (28). Direct experimental evidence comes from studies involving intracerebroventricular (icv) infusions of orexin, which resulted in a dose-dependent reinstatement of cocaine seeking. Work by Boutrel et al. also linked stress pathways to the effects of orexin on addiction and reward (29). Notably, stress is considered a major stimulus for relapse in addicts (31). The link between stress, addiction, and orexin was further strengthened by pharmacological studies in the foot shock model. These showed activation of orexin neurons in specific areas of the posterior and dorsomedial hypothalamus (which are specifically associated with stress) but not in areas of the lateral hypothalamus (which have strong links with reward) (32). In addition, orexin has been shown to be a mediator of stress-induced reinstatement of addictive behavior in alcohol seeking (30). Importantly, stress-induced reinstatement of alcohol and cocaine seeking in animal models can be attenuated by the selective _OX1 antagonist SB334867, supporting the therapeutic use of _OX1 selective antagonists in these conditions (29, 30).

Finally, the orexin/ _OX1 pathway has been implicated in nicotine self-administration (33, 34) and reinstatement of nicotine seeking (35, 36). These data suggest that _OX1 antagonists may be useful as smoking cessation therapies.

In conclusion, the orexin system, particularly the _OX1 pathway, should be considered as a target for the treatment of reward-seeking behavior, addiction, and related disorders.

Therefore, there is a need for compounds that can attenuate the activity of orexin-1 (OX ₁ ). There is also a need for compounds that can selectively modulate the function of orexin-1 (OX ₁ ).

The invention has been described

In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition in which orexin- ₁ (OX1) activity is implicated.

In another aspect, the present invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which orexin-1 ( _OX1 ) activity is implicated.

In another aspect, the present invention relates to a method of treating a disease or condition in which orexin- ₁ (OX1) activity is implicated, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

Examples of disorders involving orexin- ₁ (OX1) activity include behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks), and/or anxiety.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for use in the treatment of behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks) and/or anxiety).

In another aspect, the present invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks) and/or anxiety).

In another aspect, the present invention provides a method for treating behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks) and/or anxiety), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition.

In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in producing an orexin-1 inhibitory effect.

In another aspect, the present invention provides use of a compound or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for producing an orexin-1 inhibitory effect.

In another aspect, the present invention provides a method for producing an orexin-1 inhibitory effect in vitro, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method for producing an orexin-1 inhibitory effect in vivo, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibiting orexin-1 (OX ₁ ) in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides a method for synthesizing a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound obtainable by, or by, or directly by a synthetic method as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention provides novel intermediates as defined herein suitable for use in any of the synthetic methods set out herein.

Preferred, suitable and optional features of any particular aspect of the invention are also preferred, suitable and optional features of any other aspect.

Detailed Description of the Invention

definition

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

It should be understood that references to "treating" or "treatment" include preventing as well as alleviating established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition that develops in a human being who is suffering from or susceptible to the condition, disorder, or condition but who does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the condition or its recurrence (in the case of maintenance therapy) or the development of at least one clinical or subclinical symptom thereof; or (3) alleviating or slowing the condition, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

"Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment of 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.

In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups such as "propyl" are specific only to the straight-chain version, and references to individual branched-chain alkyl groups such as "isopropyl" are specific only to the branched version. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

"Cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane and bicyclo[2.2.1]heptyl.

The term "heteroalkyl" refers to an alkyl chain comprising 1 to 8 carbon atoms, which additionally includes one, two or three heteroatoms selected from the group consisting of N, O, or S present within the alkyl chain.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "haloalkyl" or "haloalkoxy" is used herein to refer to an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms have been replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl and haloalkoxy groups include fluoroalkyl and fluoroalkoxy groups such as _-CHF2 , _-CH2CF3 , or perfluoroalkyl/ _alkoxy groups such as _-CF3 , _-CF2CF3 , or _{-OCF3 .}

The term "carbocyclyl," "carbocyclic," or "carbocycle" means one or more non-aromatic, saturated or partially saturated monocyclic or fused, bridged, or spirobicyclic carbocyclic ring systems. Monocyclic carbocycles contain about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 7 to 17 carbon atoms in the ring, suitably 7 to 12 carbon atoms in the ring. Bicyclic carbocycles may be fused, spiro, or bridged ring systems.

The term "heterocyclyl", "heterocyclic" or "heterocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring systems. Monocyclic heterocycles 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 or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. One or more bicyclic heterocycles can be fused, spiro or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetane, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxothiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or _SO2 groups are also included. Examples include tetrahydrothienyl and thiomorpholinyl in the form of sulfoxides and sulfones, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values for heterocyclic groups with 1 or 2 oxo (=O) or thio (=S) substituents are, for example, 2 oxopyrrolidinyls, 2 thiopyrrolidinyls, 2 oxoimidazolidinyls, 2 thioimidazolidinyls, 2 oxopiperidyls, 2,5 dioxopyrrolidinyls, 2,5 dioxoimidazolidinyls or 2,6 dioxopiperidyls. Specific heterocyclic groups are saturated monocyclic 3 to 7 membered heterocyclic groups comprising 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle can be connected to another group via any suitable atom, such as via a carbon or nitrogen atom. Suitably the term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a 4, 5, 6 or 7 membered monocyclic ring as defined above.

"Bridged ring system" means a ring system in which two rings share more than two atoms, see, e.g., Advanced Organic Chemistry, edited by Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclic 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.

"Spiro bicyclic ring system" means that the two ring systems share a common spiro carbon atom, i.e., the heterocycle is connected to another carbocycle or heterocycle through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane and 2-oxa-6-azaspiro[3.3]heptane.

"Heterocyclyl(m-nC)alkyl" means a heterocyclyl group covalently attached to a (m-nC)alkylene group, both as defined herein.

The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring having one or more (e.g., 14, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more typically from 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by a fused five- and six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in a heteroaryl group (including any amino group substituent of the ring) will be less than 5. Suitably, the term "heteroaryl" or "heteroaromatic" refers to a 5 or 6 membered monocyclic heteroaryl ring as defined above.

Non-limiting examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5 triazinyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, Quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridine, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3b]furanyl, 2Hfuro[3,2b]pyranyl, 5Hpyrido[2,3d]oxazinyl, 1Hpyrazolo[4,3d]oxazolyl, 4Himidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, imidazo[2,1b]thiazolyl, imidazo[1,2b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothiophenyl, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindole, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3b]pyrazinyl, and 3,4-dihydro-2Hpyrido[3,2b][1,4]oxazinyl.

Non-limiting 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.

Non-limiting examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

The bicyclic heteroaryl group may be, for example, a group selected from:

a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

f) a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

g) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

h) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

i) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

j) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

k) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

1) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

m) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

n) a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and

o) a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms;

Specific non-limiting examples of bicyclic heteroaryl groups comprising a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

Specific non-limiting examples of bicyclic heteroaryl groups comprising 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.

"Heteroaryl(m-nC)alkyl" means a heteroaryl group covalently attached to a (m-nC)alkylene group, both of which are defined herein. Examples of heteroarylalkyl groups include pyridin-3-ylmethyl, 3(benzofuran-2-yl)propyl, and the like.

The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In this embodiment, aryl is phenyl or naphthyl, particularly phenyl.

The term "aryl(m-nC)alkyl" means an aryl group covalently attached to a (m-nC)alkylene group, both of which are defined herein. Examples of aryl-(m-nC)alkyl groups include benzyl, phenylethyl, and the like.

This specification also uses several composite terms to describe groups that include more than one functionality. These terms will be understood by those skilled in the art. For example, heterocyclyl (m-nC) alkyl includes (m-nC) alkyl substituted with a heterocyclyl.

The term "optionally substituted" refers to substituted groups, structures or molecules as well as unsubstituted groups, structures or molecules.

When optional substituents are selected from "one or more" groups, it is to be understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

The phrase "compounds of the invention" refers to those compounds disclosed both generally and specifically herein.

Compounds of the present invention

In a first aspect, the present invention provides a compound of formula I

in:

X is a group:

-(CR ^2a R ^3a ) _m -X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -N(R ¹ )-C(O)-, -C(O)-N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, -N(R ¹ )SO ₂ - or -CR ⁴ R ⁵ -;

m and n are each independently selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from the group consisting of fluoro, cyano, hydroxy, thiol, NR ^1a R ^1b , (1-4C)alkoxy, (1-4C)haloalkoxy, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl, (2-4C)alkanoyl, (2-4C)alkanoyloxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-4C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluoro or (1-4C)alkyl;

R ^2a , R ^3a , R ^2b , R ^3b , R ⁴ and R ⁵ are each independently selected from hydrogen, halogen, hydroxyl or a (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

or R ^2a and R ^3a , R ^2b and R ^3b , R ⁴ and R ⁵ are optionally joined together with the carbon atoms to which they are attached such that they form a (3-6C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluoro substituents;

Ar is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, or a group of the formula:

-L ¹ -X ¹ -R ⁶

in

L ¹ is absent or is a linker group of formula -[CR ⁷ R ⁸ ] _r -, wherein r is an integer selected from 1, 2, 3 or 4, and R ⁷ and R ⁸ are each independently selected from hydrogen, halogen, hydroxyl or a (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ⁷ and R ⁸ are optionally linked together with the carbon atom to which they are attached such that they form a (3-6C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

X ¹ is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ⁹ )-, -N(R ⁹ )-C(O)-, -C(O)-N(R ⁹ )-, -N(R ⁹ )-C(O)O-, -OC(O)-N(R ⁹ )-, -N(R ⁹ )C(O)N(R ¹⁰ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ⁹ )-, -N(R ⁹ )SO ₂ -, or -S(O)(═NR ¹⁰ )-, wherein R ⁹ and R ¹⁰ are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ^is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl,

and wherein R ⁶ is optionally further substituted by one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ² -X ² -R ¹¹

in

L ² is absent or is a linker group of formula -[CR ¹² R ¹³ ] _s -, wherein s is an integer selected from 1, 2, 3 or 4, and R ¹² and R ¹³ are each independently selected from hydrogen, or a (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ¹² and R ¹³ are optionally linked together with the carbon atom to which they are attached such that they form a (3-6C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

^X2 is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -N( ^R14 )-, -N( ^R14 )-C(O)-, -C(O)-N( ^R14 )-, -N( ^R14 )-C(O)O-, -OC(O)-N( ^R14 )-, -N( ^R14 )C(O)N( ^R15 )-, -S-, -SO-, -SO2-, -S(O) _{2N (} ^R14 )-, -N( ^R14 ) _SO2- , or -S(O)(= ^NR14 )-, wherein ^R14 and ^R15 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ¹¹ is hydrogen or a (1-6C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one or five) fluoro substituents;

Q is aryl or heteroaryl, each optionally substituted with one or more R ^z substituents, wherein R ^z is selected from the group consisting of halogen, cyano, nitro, or a group of the formula:

-L ³ -X ³ -R ³⁰

in

L ³ is absent or is a linker group of formula -[CR ³¹ R ³² ] _t -, wherein t is an integer selected from 1, 2, 3 or 4, and R ³¹ and R ³² are each independently selected from hydrogen, or a (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ³¹ and R ³² are optionally linked together with the carbon atom to which they are attached such that they form a (3-6C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

^X3 is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -N( ^R33 )-, -N( ^R33 )-C(O)-, -C(O)-N( ^R33 )-, -N( ^R33 )-C(O)O-, -OC(O)-N( ^R33 )-, -N( ^R33 )C(O)N( ^R34 )-, -S-, -SO-, -SO2-, -S(O) _{2N (} ^R33 )-, -N( ^R33 ) _SO2- , or -S(O)(= ^NR33 )-, wherein ^R33 and ^R34 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ³⁰ is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ is absent or is a linker group of formula -[CR ³⁶ R ³⁷ ] _u -, wherein u is an integer selected from 1, 2, 3 or 4, and R ³⁶ and R ³⁷ are each independently selected from hydrogen, or a (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ³⁶ and R ³⁷ are optionally linked together with the carbon atom to which they are attached such that they form a (3-6C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

^X4 is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -N( ^R38 )-, -N( ^R38 )-C(O)-, -C(O)-N( ^R38 )-, -N( ^R38 )-C(O)O-, -OC(O)-N( ^R38 )-, -N( ^R38 )C(O)N( ^R39 )-, -S-, -SO-, _-SO2- , -S(O) _2N ( ^R38 )-, -N( ^R38 ) _SO2- , or -S(O)(= ^NR38 )-, wherein ^R38 and ^R39 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ³⁵ is hydrogen or a (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one or five) fluoro substituents;

R _a is selected from:

(i) (1-4C)alkyl optionally substituted with one or more R ^c ;

(ii) (1-4C)fluoroalkyl;

(iii) (3-6C)cycloalkyl optionally substituted with one or more R ^c ;

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted with one or more R ^c ;

(v) a 3- to 6-membered heterocyclic ring optionally substituted with one or more R ^c ;

(vi) 3- to 6-membered heterocyclyl(1-2C)alkyl optionally substituted by one or more R ^c ;

(vii) aryl optionally substituted with one or more R ^d ;

(viii) aryl(1-2C)alkyl optionally substituted with one or more R ^d ;

(ix) 5- or 6-membered heteroaryl optionally substituted with one or more R ^d ;

(x) 5- or 6-membered heteroaryl(1-2C)alkyl optionally substituted with one or more R ^d ;

R _b is selected from:

(i)Hydrogen;

(ii) (1-4C)alkyl optionally substituted by one or more fluorine groups;

(iii) (3-6C)cycloalkyl optionally substituted by one or more fluorine groups;

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted by one or more fluorine groups;

Each R ^c group present is independently selected from oxo, halogen, or a group having the following formula:

-X ⁵ -R ⁵⁰

in

X ⁵ is absent or selected from -O-, -N(R ⁵¹ )-, or -S-, wherein R ⁵¹ is selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ⁵⁰ is hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl;

each R ^d group present is selected from the group consisting of halogen, cyano, hydroxy, thiol, amino, carbamoyl, sulfamoyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkylthio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl, (1-2C)alkoxycarbonyl, N-(1-2C)alkylcarbamoyl, N,N-di-[(1-2C)alkyl]carbamoyl, (2C)alkanoyl, (2C)alkanoyloxy, (2C)alkanoylamino, N-(1-2C)alkylsulfamoyl, and N,N-di-[(1-2C)alkyl]sulfamoyl;

or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound having the above-shown chemical formula I, wherein:

_Ra is ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or cyclopropylmethyl, each of which is optionally substituted with one or more fluorine;

R _b is selected from:

(i)Hydrogen;

(ii) (1-4C)alkyl optionally substituted by one or more fluorine groups;

(iii) (3-6C)cycloalkyl optionally substituted by one or more fluorines; or

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted by one or more fluorine groups;

X is a group:

-(CR ^2a R ^3a ) _m -X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )-C(O)-, -C(O)-N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )-, or -S-;

m is 0;

n is 0 or 1;

R ¹ is selected from hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy, or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5-, or 6-membered heterocyclic ring;

R ^2a , R ^3a , R ^2b , and R ^3b are all hydrogen; and

Ar and Q are as defined above.

or a pharmaceutically acceptable salt or solvate thereof.

Specific compounds of the present invention include, for example, compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein, unless otherwise specified, X, ^X₀ , m, n, ^R₁ , ^R₁a , ^R₁b , ^R₂a , ^R₂b , ^R₃b , ^R₄ , ^R₄ , ^R₄ , Ar, ^L₁ , ^R₁ , ^R₁ , ^R₁ , ^R₁ , ^L₂ , ^X₂ , ^R₁ , ^R₁ , ^R₁ , Q, ^L₃ , ^X₃ , ^R₃3 , ^R₃4 , ^{R₃0 , L₄} , ^X₄ , ^R₁ , ^R₃5 , ^R₁ , ^R₂2 , ^Ra , ^R₂ , ^R₁ , ^{R₁ , R₁ ,} Each of , and R ^d has any of the meanings defined above or in any of paragraphs (1) to (70) below:

(1) X is a group:

-(CR ^2a R ^3a ) _m -X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -N(R ¹ )-C(O)-, -C(O)-N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, or -N(R ¹ )SO ₂ -;

m and n are each independently selected from 0 or 1;

^R is selected from hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, cyano, hydroxy, thiol, NR ^1a R ^1b , (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylthio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl, (1-2C)alkoxycarbonyl, (2C)alkanoyl, (2C)alkanoyloxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluoro or (1-2C)alkyl;

R ^2a , R ^3a , R ^2b , and R ^3b are each independently selected from hydrogen, halogen, hydroxy, or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

or R ^2a and R ^3a , and R ^2b and R ^3b are optionally joined together with the carbon atom to which they are attached such that they form a (3-4C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluoro substituents;

(2) X is a group:

-(CR ^2a R ^3a ) _m -X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -N(R ¹ )-C(O)-, -C(O)-N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, or -N(R ¹ )SO ₂ -;

m and n are each independently selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluorine;

R ^2a , R ^3a , R ^2b , and R ^3b are each independently selected from hydrogen, or a (1-2C)alkyl group optionally substituted with one or more (eg, one to five) fluoro substituents;

(3) X is a group:

-(CR ^2a R ^3a ) _m -X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )-C(O)-, -C(O)-N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )-, or -S-;

m and n are each independently selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy, or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5-, or 6-membered heterocyclic ring;

R ^2a , R ^3a , R ^2b , and R ^3b are each independently selected from hydrogen, or a (1-2C)alkyl group optionally substituted with one or more (eg, one to five) fluoro substituents;

(4) X is a group:

-(CR ^2a R ^3a ) _m -X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )-C(O)-, -C(O)-N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )-, or -S-;

m is 0;

n is 0 or 1;

R ¹ is selected from hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy, or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5-, or 6-membered heterocyclic ring;

R ^2a , R ^3a , R ^2b , and R ^3b are all hydrogen;

(5) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -N(R ¹ )-C(O)-, -C(O)-N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, or -N(R ¹ )SO ₂ -;

n is selected from 0 or 1;

^R is selected from hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, cyano, hydroxy, thiol, NR ^1a R ^1b , (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylthio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl, (1-2C)alkoxycarbonyl, (2C)alkanoyl, (2C)alkanoyloxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluoro or (1-2C)alkyl;

R ^2b and R ^3b are each independently selected from hydrogen, halogen, hydroxy, or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

or R ^2b and R ^3b are optionally linked together with the carbon atom to which they are attached such that they form a (3-4C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluoro substituents;

(6) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -N(R ¹ )-C(O)-, -C(O)-N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, or -N(R ¹ )SO ₂ -;

n is selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluorine;

R ^2b and R ^3b are each independently selected from hydrogen, or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(7) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )-C(O)-, -C(O)-N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )-, or -S-;

n is selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy, or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5-, or 6-membered heterocyclic ring;

R ^2b and R ^3b are hydrogen;

(8) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )-C(O)-, -C(O)-N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )-, or -S-;

n is 0 or 1;

^R1 is selected from hydrogen or (1-2C)alkyl;

R ^2b and R ^3b are hydrogen;

(9) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -C(O)-N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, or -N(R ¹ )SO ₂ -;

n is selected from 0 or 1;

^R is selected from hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, cyano, hydroxy, thiol, NR ^1a R ^1b , (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylthio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl, (1-2C)alkoxycarbonyl, (2C)alkanoyl, (2C)alkanoyloxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluoro or (1-2C)alkyl;

R ^2b and R ^3b are each independently selected from hydrogen, halogen, hydroxy, or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

or R ^2b and R ^3b are optionally linked together with the carbon atom to which they are attached such that they form a (3-4C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluoro substituents;

(10) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

X ⁰ is selected from -O-, -N(R ¹ )-, -N(R ¹ )C(O)N(R ¹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ¹ )-, or -N(R ¹ )SO ₂ -;

n is selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5- or 6-membered heterocyclic ring optionally substituted with fluorine;

R ^2b and R ^3b are each independently selected from hydrogen, or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(11) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )- or -S-;

n is selected from 0 or 1;

R ¹ is selected from hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) substituents selected from fluoro, hydroxy, NR ^1a R ^1b , (1-2C)alkoxy, or (1-2C)haloalkoxy;

R ^1a and R ^1b are each independently selected from hydrogen or (1-2C)alkyl, or R ^1a and R ^1b are linked together with the nitrogen atom to which they are attached such that they form a 4-, 5-, or 6-membered heterocyclic ring;

R ^2b and R ^3b are hydrogen;

(12) X is a group:

-X ⁰ -(CR ^2b R ^3b ) _n -

in

^X0 is selected from -O-, -N( ^R1 )-, -N( ^R1 )-C(O)-, -C(O)-N( ^R1 )-, -N( ^R1 )C(O)N( ^R1 )-, or -S-;

n is 0 or 1;

^R1 is selected from hydrogen or (1-2C)alkyl;

(13) R ^2b and R ^3b are hydrogen; Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, or a group having the following chemical formula:

-L ¹ -X ¹ -R ⁶

in

L ¹ is absent or is a linker group of formula -[CR ⁷ R ⁸ ] _r -, wherein r is an integer selected from 1, 2 or 3, and R ⁷ and R ⁸ are each independently selected from: hydrogen, halogen, hydroxyl, or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ⁷ and R ⁸ are optionally linked together with the carbon atom to which they are attached such that they form a (3-4C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

X ¹ is absent or selected from -O-, -C(O)-, -N(R ⁹ )-, -N(R ⁹ )-C(O)-, -C(O)-N(R ⁹ )-, -N(R ⁹ )C(O)N(R ¹⁰ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ⁹ )-, -N(R ⁹ )SO ₂ -, or -S(O)(═NR ¹⁰ )-, wherein R ⁹ and R ¹⁰ are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-4C)cycloalkyl; and

^R6 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl,

and wherein R ⁶ is optionally further substituted by one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ² -X ² -R ¹¹

in

L ² is absent or is a linker group of formula -[CR ¹² R ¹³ ] _s -, wherein s is an integer selected from 1, 2 or 3, and R ¹² and R ¹³ are each independently selected from: hydrogen or a (1-4C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ¹² and R ¹³ are optionally linked together with the carbon atom to which they are attached such that they form a (3-6C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

^X2 is absent or selected from -O-, -C(O)-, -N( ^R14 )-, -N( ^R14 )-C(O)-, -C(O)-N( ^R14 )-, -N( ^R14 )-C(O)O-, -N( ^R14 )C(O)N( ^R15 )-, -S-, -SO-, -SO2-, -S(O) _2N ( ^R14 )-, -N( ^R14 ) _{SO2- ,} or -S(O)(= ^NR14 )-, wherein ^R14 and ^R15 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ¹¹ is hydrogen or a (1-6C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one or five) fluoro substituents;

(14) Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, or a group having the following formula:

-L ¹ -X ¹ -R ⁶

in

L ¹ is absent or is a linker group of formula -[CR ⁷ R ⁸ ] _r -, wherein r is an integer selected from 1 or 2, and R ⁷ and R ⁸ are each independently selected from: hydrogen, halogen, or a (1-4C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

X ¹ is absent or selected from -O-, -C(O)-, -N(R ⁹ )-, -N(R ⁹ )-C(O)-, -C(O)-N(R ⁹ )-, -N(R ⁹ )C(O)N(R ¹⁰ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ⁹ )-, -N(R ⁹ )SO ₂ -, or -S(O)(═NR ¹⁰ )-, wherein R ⁹ and R ¹⁰ are selected from hydrogen, (1-4C)alkyl, or (1-4C)fluoroalkyl; and

^R6 is hydrogen, (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ⁶ is optionally further substituted by one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ² -X ² -R ¹¹

in

L ² is absent or is a linker group of formula -[CR ¹² R ¹³ ] _s -, wherein s is an integer selected from 1 or 2, and R ¹² and R ¹³ are each independently selected from: hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

^X2 is absent or selected from -O-, -N( ^R14 )-, -N( ^R14 )-C(O)-, -C(O)-N( ^R14 )-, -S-, -SO-, -SO2-, -S(O) _2N ( ^R14 )-, -N( ^R14 _{) SO2-} , or -S(O)(= ^NR14 )-, wherein ^R14 is selected from hydrogen or (1-2C)alkyl; and

R ¹¹ is hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one or five) fluoro substituents;

(15) Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, or a group having the following formula:

-L ¹ -X ¹ -R ⁶

in

L ¹ is absent or is a linker group of formula -[CR ⁷ R ⁸ ] _r -, wherein r is an integer selected from 1 or 2, and R ⁷ and R ⁸ are each independently selected from: hydrogen, halogen, or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

X ¹ is absent or selected from -O-, -N(R ⁹ )-, -S-, -SO-, or -SO ₂ -, wherein R ⁹ is selected from hydrogen or (1-2C)alkyl; and

^R6 is hydrogen, (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ⁶ is optionally further substituted by one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ² -X ² -R ¹¹

in

L ² is absent or is a linker group of formula -[CR ¹² R ¹³ ] _s -, wherein s is an integer selected from 1 or 2, and R ¹² and R ¹³ are each independently selected from: hydrogen or a (1-2C)alkyl group

X ² is absent or selected from -O-, -N(R ¹⁴ )-, -S-, -SO-, or -SO ₂ -, wherein R ¹⁴ is selected from hydrogen or (1-2C)alkyl; and

R ¹¹ is hydrogen or a (1-4C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(16) Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, or a group having the following formula:

-L ¹ -X ¹ -R ⁶

in

L ¹ does not exist;

X ¹ is absent or selected from -O-, -N(R ⁹ )-, -S-, -SO-, or -SO ₂ -, wherein R ⁹ is selected from hydrogen or (1-2C)alkyl; and

^R6 is hydrogen, (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ⁶ is optionally further substituted by one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ² -X ² -R ¹¹

in

L ² does not exist;

X ² is absent or selected from -O-, -N(R ¹⁴ )-, -S-, -SO-, or -SO ₂ -, wherein R ¹⁴ is selected from hydrogen or (1-2C)alkyl; and

R ¹¹ is hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(17) Ar is phenyl, naphthyl, or mono- or bicyclic heteroaryl, each of which is optionally substituted with a substituent group as defined in any of paragraphs (13) to (16) above;

(18) Ar is phenyl or mono- or bicyclic heteroaryl, each of which is optionally substituted with a substituent group as defined in any of paragraphs (13) to (16) above;

(19) Ar is phenyl or a single or 5 or 6 membered heteroaromatic ring, each of which is optionally substituted with a substituent group as defined in any of paragraphs (13) to (16) above;

(20) Q is aryl or heteroaryl, each of which is optionally substituted with one or more R ^z substituents, wherein R ^z is selected from the group consisting of halogen, cyano, nitro, or a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ is absent or is a linker group of formula -[CR ³¹ R ³² ] _t -, wherein t is an integer selected from 1, 2 or 3, and R ³¹ and R ³² are each independently selected from hydrogen, or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ³¹ and R ³² are optionally linked together with the carbon atom to which they are attached such that they form a (3-4C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

^X3 is absent or selected from -O-, -C(O)-, -N( ^R33 )-, -N( ^R33 )-C(O)-, -C(O)-N( ^R33 )-, -N( ^R33 )C(O)N( ^R34 )-, -S-, -SO-, -SO2-, _-S (O) _2N ( ^R33 )-, -N( ^R33 ) _SO2- , or -S(O)(= ^NR33 )-, wherein ^R33 and ^R34 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-4C)cycloalkyl; and

R ³⁰ is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ is absent or is a linker group of formula -[CR ³⁶ R ³⁷ ] _u -, wherein u is an integer selected from 1, 2 or 3, and R ³⁶ and R ³⁷ are each independently selected from: hydrogen or a (1-4C)alkyl group optionally substituted with one or more (e.g., one to five) fluorine substituents; or R ³⁶ and R ³⁷ are optionally linked together with the carbon atom to which they are attached such that they form a (3-4C)cycloalkyl ring optionally substituted with one or more (e.g., one to five) fluorine substituents;

X ⁴ is absent or selected from -O-, -C(O)-, -N(R ³⁸ )-, -N(R ³⁸ )-C(O)-, -C(O)-N(R ³⁸ )-, -N(R ³⁸ )C(O)N(R ³⁹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ³⁸ )-, -N(R ³⁸ )SO ₂ -, or -S(O)(═NR ³⁸ )-, wherein R ³⁸ and R ³⁹ are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, or (3-6C)cycloalkyl; and

R ³⁵ is hydrogen or a (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one or five) fluoro substituents;

(21) Q is aryl or heteroaryl, each of which is optionally substituted with one or more ^R substituents, wherein ^R is selected from the group consisting of halogen, cyano, nitro, or a group having the following formula:

-L ³ -X ³ -R ³⁰

in

L ³ is absent or is a linker group of formula -[CR ³¹ R ³² ] _t -, wherein t is an integer selected from 1 or 2, and R ³¹ and R ³² are each independently selected from: hydrogen or a (1-4C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

^X3 is absent or selected from -O-, -C(O)-, -N( ^R33 )-, -N( ^R33 )-C(O)-, -C(O)-N( ^R33 )-, -N( ^R33 )C(O)N( ^R34 )-, -S-, -SO-, -SO2-, -S(O) _2N ( ^R33 )-, -N( ^R33 _{) SO2-} , or -S(O)(= ^NR33 )-, wherein ^R33 and ^R34 are selected from hydrogen or (1-4C)alkyl; and

R ³⁰ is hydrogen, (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ is absent or is a linker group of formula -[CR ³⁶ R ³⁷ ] _u -, wherein u is an integer selected from 1 or 2, and R ³⁶ and R ³⁷ are each independently selected from: hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

X ⁴ is absent or selected from -O-, -N(R ³⁸ )-, -N(R ³⁸ )-C(O)-, -C(O)-N(R ³⁸ )-, -N(R ³⁸ )C(O)N(R ³⁹ )-, -S-, -SO-, -SO ₂ -, -S(O) ₂ N(R ³⁸ )-, -N(R ³⁸ )SO ₂ -, or -S(O)(═NR ³⁸ )-, wherein R ³⁸ and R ³⁹ are selected from hydrogen or (1-4C)alkyl; and

R ³⁵ is hydrogen or a (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl group optionally substituted with one or more (e.g., one or five) fluoro substituents;

(22) Q is aryl or heteroaryl, each of which is optionally substituted with one or more ^R substituents, wherein ^R is selected from the group consisting of halogen, cyano, nitro, or a group having the following formula:

-L ³ -X ³ -R ³⁰

in

L ³ is absent or is a linker group having the formula -[CR ³¹ R ³² ] _t -, wherein t is an integer selected from 1 or 2, and R ³¹ and R ³² are each independently selected from: hydrogen or a (1-4C)alkyl group;

X ³ is absent or selected from -O-, -N(R ³³ )-, -N(R ³³ )-C(O)-, -C(O)-N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is hydrogen, (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ is absent or is a linker group of formula -[CR ³⁶ R ³⁷ ] _u -, wherein u is an integer selected from 1 or 2, and R ³⁶ and R ³⁷ are each independently selected from: hydrogen or a (1-2C)alkyl group;

X ⁴ is absent or selected from -O-, -N(R ³⁸ )-, -S-, -SO-, or -SO ₂ -, wherein R ³⁸ is selected from hydrogen or (1-2C)alkyl; and

R ³⁵ is hydrogen or a (1-4C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(23) Q is aryl or heteroaryl, each of which is optionally substituted with one or more R ^z substituents, wherein R ^z is selected from the group consisting of halogen, cyano, nitro, or a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ is absent or selected from -O-, -N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is hydrogen, (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more substituent groups independently selected from the group consisting of oxo, halogen, cyano, nitro, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ does not exist;

X ⁴ is absent or selected from -O-, -N(R ³⁸ )-, -S-, -SO-, or -SO ₂ -, wherein R ³⁸ is selected from hydrogen or (1-2C)alkyl; and

R ³⁵ is hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(24) Q is aryl or heteroaryl, each of which is substituted with one or more R ^z substituents, wherein R ^z is halogen or a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ is absent or selected from -O-, -N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is (1-4C)alkyl, phenyl or a 5-6 membered heteroaromatic ring,

and wherein R ³⁰ is optionally further substituted by one or more substituent groups independently selected from the group consisting of halogen, cyano, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ does not exist;

X ⁴ is absent or selected from -O-, -N(R ³⁸ )-, -S-, -SO-, or -SO ₂ -, wherein R ³⁸ is selected from hydrogen or (1-2C)alkyl; and

R ³⁵ is hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(25) Q is aryl or heteroaryl, each of which is substituted with one or more R ^z substituents, wherein R ^z is a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ does not exist; and

R ³⁰ is a phenyl group or a 5-6 membered heteroaromatic ring,

and wherein R ³⁰ is optionally further substituted by one or more substituent groups independently selected from the group consisting of halogen, cyano, or a group having the following formula:

-L ⁴ -X ⁴ -R ³⁵

in

L ⁴ does not exist;

X ⁴ does not exist; and

R ³⁵ is hydrogen or a (1-2C)alkyl group optionally substituted with one or more (e.g., one to five) fluoro substituents;

(26) Q is phenyl, naphthyl, or mono- or bicyclic heteroaryl, each of which is optionally substituted with one or more ^R substituents as defined in any of paragraphs (20) to (25) above;

(27) Q is phenyl, or mono- or bicyclic heteroaryl, each of which is optionally substituted with one or more ^R substituents as defined in any of paragraphs (20) to (25) above;

(28) Q is phenyl, naphthyl, or mono- or bicyclic heteroaryl, each of which is substituted with one or more R ^z substituents as defined in any of paragraphs (20) to (25) above;

(29) Q is phenyl, or mono- or bicyclic heteroaryl, each of which is substituted with one or more R ^z substituents as defined in any of paragraphs (20) to (25) above;

(30) Q is selected from phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, or 9-10 membered bicyclic heteroaryl, each of which is optionally substituted in the ortho position relative to the point of attachment of the -C(O)-N(R _b )- motif with an R ^z substituent group as defined in any of paragraphs (20) to (25) above (particularly paragraph (25) above), and optionally further substituted in any other position with one or more R ^z substituent groups as defined in any of paragraphs (20) to (25) above;

(31) Q is selected from phenyl, 5-6 membered monocyclic heteroaryl, or 9-10 membered bicyclic heteroaryl, each of which is substituted in the ortho position relative to the point of attachment of the -C(O)-N(R _b )- motif with a substituent group as defined in any one of paragraphs (20) to (25) above (particularly paragraph (25) above), and is optionally further substituted in any other position with one or more substituent groups as defined in any one of paragraphs (20) to (25) above;

(32) Q is a group having the following structure:

wherein ring Q is selected from phenyl, 5-6 membered monocyclic heteroaryl, or 9-10 membered bicyclic heteroaryl; a is an integer from 0 to 1; and b is an integer from 0 to 5; and R ^z1 and R ^z2 are substituent groups R ^z on Q as defined in any of paragraphs (20) to (25) above, or R ^z1 is defined in any of paragraphs (37), (38) or (39) below, and R ^z2 is defined in any of paragraphs (40), (41) or (42) below;

(33) Q is a group having any of the following structures W1-W7:

wherein X ¹ , X ² and X ³ are each a heteroatom selected from O, N or S; a is an integer from 0 to 1; and b is an integer from 0 to 5; and R ^z1 and R ^z2 are substituent groups R ^z on Q as defined in any of paragraphs (20) to (25) above, or R ^z1 is defined in any of paragraphs (37), (38) or (39) below, and R ^z2 is defined in any of paragraphs (40), (41) or (42) below;

(34) Q is a group as defined in paragraph (32) or (33) above, wherein a is 1; and b is an integer of 0 or 1;

(35) Q is a group selected from any one of the following structures:

wherein a and b are each independently an integer from 0 to 1; and R ^z1 and R ^z2 are substituent groups R ^z on Q as defined in any of paragraphs (20) to (25) above, or R ^z1 is defined in any of paragraphs (37), (38) or (39) below, and R ^z2 is defined in any of paragraphs (40), (41) or (42) below;

(36) Q is a group selected from any one of the following structures:

wherein R ^z1 and R ^z2 are substituent groups R ^z on Q as defined in any of paragraphs (20) to (25) above, or R ^z1 is as defined in any of paragraphs (37), (38) or (39) below, and R ^z2 is as defined in any of paragraphs (40), (41) or (42) below;

(37) R ^z1 is a substituent group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ is absent or selected from -O-, -N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is hydrogen, (1-4C)alkyl, phenyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted as defined in any of paragraphs (20) to (25) above;

(38) R ^z1 is a substituent group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ does not exist; and

R ³⁰ is phenyl or a C- or N-linked 5-6 membered heteroaryl group,

and wherein R ³⁰ is optionally further substituted as defined in any of paragraphs (20) to (25) above;

(39) R ^z1 is a substituent group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ does not exist; and

R ³⁰ is phenyl or N-linked 1,2,3-triazolyl,

and wherein R ³⁰ is optionally further substituted as defined in any of paragraphs (20) to (25) above;

(40) R ^z2 is a substituent group R ^z as defined in any of paragraphs (20) to (25) above;

(41) R ^z2 is selected from the group consisting of halogen, cyano, nitro, or a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ is absent or selected from -O-, -N(R ³³ )-, -N(R ³³ )-C(O)-, -C(O)-N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more substituent groups as defined in any of paragraphs (20) to (25) above;

(42) R ^z2 is selected from the group consisting of halogen, cyano, or a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ is absent or selected from -O-, -N(R ³³ )-, -N(R ³³ )-C(O)-, -C(O)-N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is hydrogen or (1-4C)alkyl,

and wherein R ³⁰ is optionally further substituted with one or more fluorine atoms;

(43) _Ra is selected from:

(i) (1-4C)alkyl optionally substituted with one or more R ^c ;

(ii) (1-4C)fluoroalkyl;

(iii) (3-6C)cycloalkyl optionally substituted with one or more R ^c ;

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted with one or more R ^c ;

(v) a 3- to 6-membered heterocyclic ring optionally substituted with one or more R ^c ;

(vi) 3- to 6-membered heterocyclyl(1-2C)alkyl optionally substituted by one or more R ^c ;

(vii) phenyl optionally substituted with one or more R ^d ;

(viii) phenyl(1-2C)alkyl optionally substituted with one or more R ^d ;

(ix) 5- or 6-membered heteroaryl optionally substituted with one or more R ^d ;

(x) 5- or 6-membered heteroaryl(1-2C)alkyl optionally substituted with one or more R ^d ;

(44) _Ra is selected from:

(i) (1-4C)alkyl optionally substituted with one or more R ^c ;

(ii) (1-4C)fluoroalkyl;

(iii) (3-6C)cycloalkyl optionally substituted with one or more R ^c ; or

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted with one or more R ^c ;

(45) _Ra is selected from:

(i) (1-4C)alkyl optionally substituted with one or more R ^c ;

(ii) (1-4C)fluoroalkyl;

(iii) (3-4C)cycloalkyl optionally substituted with one or more R ^c ; or

(iv) (3-4C)cycloalkyl(1-2C)alkyl optionally substituted with one or more R ^c ;

(46) _Ra is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or cyclopropylmethyl, each of which is optionally substituted with one or more ^Rc ;

(47) _Ra is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, or cyclopropylmethyl, each of which is optionally substituted with one or more fluorines;

(48) _Ra is methyl, ethyl, isopropyl, cyclopropyl, isobutyl or tert-butyl, each of which is optionally substituted with one or more fluorine groups;

(49) _Ra is methyl, ethyl, isopropyl, cyclopropyl, or isobutyl, each of which is optionally substituted with one or more fluorine groups;

(50) _Ra is methyl, ethyl, isopropyl, or cyclopropyl, each of which is optionally substituted with one or more fluorine groups;

(51) _Ra is selected from:

(i) (2-4C)alkyl optionally substituted with one or more R ^c ;

(ii) (2-4C)fluoroalkyl;

(iii) (3-6C)cycloalkyl optionally substituted with one or more R ^c ;

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted with one or more R ^c ;

(v) a 3- to 6-membered heterocyclic ring optionally substituted with one or more R ^c ;

(vi) 3- to 6-membered heterocyclyl(1-2C)alkyl optionally substituted by one or more R ^c ;

(vii) phenyl optionally substituted with one or more R ^d ;

(viii) phenyl(1-2C)alkyl optionally substituted with one or more R ^d ;

(ix) 5- or 6-membered heteroaryl optionally substituted with one or more R ^d ;

(x) 5- or 6-membered heteroaryl(1-2C)alkyl optionally substituted with one or more R ^d ;

(52) _Ra is selected from:

(i) (2-4C)alkyl;

(ii) (2-4C)fluoroalkyl;

(iii) (3-6C)cycloalkyl optionally substituted by one or more fluorines; or

(iv) (3-6C)cycloalkyl(1-2C)alkyl optionally substituted by one or more fluorine groups;

(53) _Ra is selected from:

(i) (2-4C)alkyl;

(ii) (2-4C)fluoroalkyl;

(iii) (3-4C)cycloalkyl; or

(iv) (3-4C)cycloalkyl(1-2C)alkyl;

(54) _Ra is ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, or cyclopropylmethyl, each of which is optionally substituted with one or more fluorines;

(55) _Ra is ethyl, isopropyl, cyclopropyl, isobutyl or tert-butyl, each of which is optionally substituted with one or more fluorine groups;

(56) _Ra is ethyl, isopropyl, cyclopropyl, or isobutyl, each of which is optionally substituted with one or more fluorines;

(57) _Ra is ethyl, cyclopropyl or isopropyl, each of which is optionally substituted with one or more fluorine groups;

(58) _Ra is ethyl or cyclopropyl, each of which is optionally substituted with one or more fluorine groups;

(59) _Ra is ethyl optionally substituted with one or more fluorine groups;

(60) _Ra is ethyl;

(61) R _b is selected from:

(i)Hydrogen;

(ii) (1-4C)alkyl optionally substituted by one or more fluorine groups;

(iii) (3-4C)cycloalkyl optionally substituted by one or more fluorine groups;

(iv) (3-4C)cycloalkyl(1-2C)alkyl optionally substituted by one or more fluorine groups;

(62) R _b is selected from:

(i)Hydrogen;

(ii) (1-4C)alkyl optionally substituted by one or more fluorine groups;

(63) R _b is H or methyl;

(64) R _b is methyl;

(65) Each R ^c group present is independently selected from halogen or a group having the following chemical formula:

-X ⁵ -R ⁵⁰

in

X ⁵ is absent or selected from -O-, -N(R ⁵¹ )-, or -S-, wherein R ⁵¹ is selected from hydrogen, (1-4C)alkyl, or (1-4C)fluoroalkyl; and

R ⁵⁰ is hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl;

(66) Each R ^c group present is independently selected from fluorine or a group having the following chemical formula:

-X ⁵ -R ⁵⁰

in

X ⁵ is absent or selected from -O-, -N(R ⁵¹ )-, or -S-, wherein R ⁵¹ is selected from hydrogen, (1-2C)alkyl, or (1-2C)fluoroalkyl; and

R ⁵⁰ is hydrogen, (1-2C)alkyl, (1-2C)fluoroalkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl;

(67) Each R ^c group present is independently selected from fluoro, hydroxy or methoxy;

(68) each R ^c group present is fluoro;

(69) each R ^d group present is selected from halogen, cyano, hydroxy, mercapto, amino, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkylthio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl;

(70) Each ^Rd group present is selected from fluoro, hydroxy, amino, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkylthio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl.

Suitably, X is as defined in any of paragraphs (1) to (12) above. In one embodiment, X is as defined in any of paragraphs (2) to (4) above. In another embodiment, X is as defined in paragraphs (3) or (4) above. In another embodiment, X is as defined in any of paragraphs (5) or (8) above. In another embodiment, X is as defined in paragraphs (7) or (8) above. In another embodiment, X is as defined in any of paragraphs (9) to (12) above. In another embodiment, X is as defined in paragraphs (11) or (12) above.

Suitably, X ⁰ , m, n, R ¹ , R ^1a , R ^1b , R ^2a , R ^3a , R ^2b and R ^3b are as defined in any of paragraphs (1) to (4) above. In one embodiment, X ⁰ , m, n, R ¹ , R ^1a , R ^1b , R ^{2a , R 3a ,} R ^2b and R ^3b are as defined in any of paragraphs (2) to (4) above. In a specific embodiment, X ⁰ , m, n, R ¹ , R ^1a , R ^1b , R ^2a , R ^3a , R ^2b and R ^3b are as defined in paragraph (3) or (4) above.

In particular groups of compounds of the present invention, X ⁰ , n, R ¹ , R ^1a , R ^1b , R ^2b and R ^3b are as defined above in any of paragraphs (5) to (12). In one embodiment, X ⁰ , n, R ¹ , R ^1a , R ^1b , R ^2b and R ^3b are as defined above in any of paragraphs (7) or (8). In another embodiment, X ⁰ , n, R ¹ , R ^1a , R ^1b , R ^2b and R ^3b are as defined above in paragraphs (11) or (12).

Suitably, m is zero.

Suitably, n is 0 or 1, especially 0.

Suitably, Ar is as defined in any of paragraphs (13) to (19) above. In one embodiment, Ar is as defined in any of paragraphs (15) to (19) above. In a particular embodiment, Ar is as defined in paragraphs (17), (18) or (19) above.

Suitably, L ¹ , R ⁷ , R ⁸ , X ¹ , R ⁹ , R ¹⁰ , R ⁶ , L ² , X ² , R ¹⁴ , R ¹⁵ and R ¹¹ are each as defined above in any one of paragraphs (13) to (16). In one embodiment, L ¹ , R ⁷ , R ⁸ , X ^{1 , R 9 ,} R ¹⁰ , R ⁶ , L ² , X ² , R ¹⁴ , R ¹⁵ and R ¹¹ are each as defined above in any one of paragraphs (15) or (16).

Suitably, Q is as defined in any of paragraphs (20) to (36) above. In one embodiment, Q is as defined in any of paragraphs (23) to (36) above. In a specific embodiment, Q is as defined in any of paragraphs (28) to (36) above.

Suitably, ^R is as defined in any of paragraphs (20) to (25) above. In one embodiment, ^R is as defined in any of paragraphs (23) to (25) above. In a particular embodiment, ^R is as defined in paragraphs (24) or (25) above.

Suitably, L ³ , X ³ , R ³³ , R ³⁴ , R ³⁰ , L ⁴ , X ⁴ , R ³⁸ , R ³⁹ and R ³⁵ are each as defined above in any of paragraphs (20) to (25). In one embodiment, L ³ , X ³ , R ³³ , R ³⁴ , R ³⁰ , L ^{4 , X 4 ,} R ³⁸ , R ³⁹ and R ³⁵ are each as defined above in paragraphs (23) to (25). In a specific embodiment, L ³ , X ³ , R ³³ , R ³⁴ , R ³⁰ , L ⁴ , X ⁴ , R ³⁸ , R ³⁹ and R ³⁵ are each as defined above in paragraphs (24) or (25).

Suitably, R ^z1 is as defined in any of paragraphs (37) to (39) above. In one embodiment, R ^z1 is as defined in any of paragraphs (38) or (39) above. In a specific embodiment, R ^z1 is as defined in paragraph (39) above.

Suitably, R ^z2 is as defined in any of paragraphs (40) to (42) above. In one embodiment, R ^z2 is as defined in any of paragraphs (41) or (42) above. In a specific embodiment, R ^z2 is as defined in paragraph (42) above.

Suitably, _Ra is as defined in any one of paragraphs (43) to (60) above. In one embodiment, _Ra is as defined in any one of paragraphs (53) to (60) above. In a specific embodiment, _Ra is as defined in any one of paragraphs (57) to (60) above. In another embodiment, _Ra is ethyl.

Suitably, _Rb is as defined in any one of paragraphs (61) to (64) above. In one embodiment, _Rb is as defined in any one of paragraphs (62) to (64) above. In a particular embodiment, _Rb is as defined in paragraph (62) above.

Suitably, R ^c is as defined in any one of paragraphs (65) to (68) above. In one embodiment, R ^b is as defined in paragraph (66) or (68) above.

Suitably, ^Rd is as defined in paragraph (69) or (70) above.

In one particular group of compounds, these compounds have the structural formula I, wherein

_Ra is as defined in any of paragraphs (43) to (50) or (57) to (60) above;

R _b is as defined in any of paragraphs (61) to (64) above;

And Q, X and Ar each have any of the definitions set forth above.

In one particular group of compounds, these compounds have the structural formula I, wherein

R _a is as defined in any of paragraphs (52) to (60) above;

R _b is as defined in any of paragraphs (61) to (64) above;

And Q, X and Ar each have any of the definitions set forth above.

In one particular group of compounds, these compounds have the structural formula I, wherein

R _a is as defined in paragraph (53) above;

R _b is as defined in paragraph (62) above;

And Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have structural formula I, wherein

_Ra is as defined in any of paragraphs (44) to (50) or (57) to (60) above;

R _b is as defined in any of paragraphs (61) to (64) above;

And Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have the structural formula I

in

R _a is as defined in any of paragraphs (54) to (60) above;

R _b is as defined in any of paragraphs (61) to (64) above;

And Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have the structural formula I

in

R _a is as defined in paragraph (54) above;

R _b is as defined in paragraph (62) above;

And Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have structural formula I, wherein

_Ra is ethyl or isopropyl, each of which is optionally substituted with fluorine;

And R _b , Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have structural formula I, wherein

_Ra is ethyl optionally substituted with one or more fluorine atoms;

And R _b , Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have structural formula I, wherein

R _a is ethyl;

And R _b , Q, X and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have the structural formula I

in

R _a is as defined in any of paragraphs (52) to (60) above;

R _b is as defined in any of paragraphs (61) to (64) above;

Q is as defined in any of paragraphs (24) to (36) above;

X is as defined in any of paragraphs (5) to (12) above; and

Ar is as defined in any of paragraphs (13) to (19) above.

In another group of compounds, these compounds have the structural formula I

in

R _a is as defined in paragraph (53) above;

R _b is as defined in paragraph (62) above;

Q is as defined in paragraph (24) above;

X is as defined in paragraph (5) above; and

Ar is as defined in paragraph (13) above.

In another group of compounds, these compounds have the structural formula I

in

_Ra is ethyl or isopropyl, each of which is optionally substituted with fluorine;

R _b is as defined in paragraph (62) above;

Q is as defined in paragraph (26) above;

X is as defined in paragraph (6) above; and

Ar is as defined in paragraph (14) above.

In another group of compounds, these compounds have the structural formula I

in

_Ra is ethyl optionally substituted with one or more fluorine atoms;

R _b is as defined in paragraph (62) above;

Q is as defined in paragraph (27) above;

X is as defined in paragraph (7) above; and

Ar is as defined in any of paragraphs (15) above.

In another group of compounds, these compounds have the structural formula I

in

R _a is ethyl;

R _b is as defined in paragraph (62) above;

Q is as defined in paragraph (35) above;

X is as defined in paragraph (8) above; and

Ar is as defined in paragraph (15) above.

In another group of compounds, these compounds have the structural formula IA shown below

in

R _b , R ^z2 and Ar each have any of the definitions set forth above.

In another group of compounds, these compounds have the structural formula IA shown above, wherein

R _b is as defined in any of paragraphs (61) to (64) above;

R ^z2 is as defined in any of paragraphs (40) to (42) above; and

Ar is as defined in any of paragraphs (13) to (19) above.

In another group of compounds, these compounds have the structural formula IA shown above, wherein

R _b is as defined in paragraph (63) above;

R ^z2 is as defined in paragraph (41) above; and

Ar is as defined in paragraph (18) above.

In another group of compounds, these compounds have the structural formula IA shown above, wherein

R _b is as defined in paragraph (64) above;

R ^z2 is as defined in paragraph (42) above; and

Ar is as defined in paragraph (19) above.

In another group of compounds, these compounds have the structural formula IA shown above, wherein

R _b is (1-4C)alkyl optionally substituted by fluorine;

R ^z2 is selected from the group consisting of halogen, cyano, nitro, or a group having the following chemical formula:

-L ³ -X ³ -R ³⁰

in

L ³ does not exist;

X ³ is absent or selected from -O-, -N(R ³³ )-, -N(R ³³ )-C(O)-, -C(O)-N(R ³³ )-, -S-, -SO-, or -SO ₂ -, wherein R ³³ is selected from hydrogen or (1-2C)alkyl; and

R ³⁰ is hydrogen or (1-4C)alkyl;

and wherein R ³⁰ is optionally further substituted with one or more fluorine atoms;

Ar is as defined above.

In another group of compounds, these compounds have the structural formula IA shown above, wherein

R _b is methyl optionally substituted by fluorine;

R ^z2 is selected from the group consisting of halogen, methyl, methoxy, CF ₃ or -OCF ₃ ;

Ar is pyridyl, pyrimidinyl, pyrazinyl, which is optionally substituted by one or more substituent groups selected from the group consisting of halogen, cyano, hydroxy, thiol, amino, carbamoyl, sulfamoyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkylthio The compounds include, but are not limited to, a (1-2C)alkylsulfinyl group, a (1-2C)alkylsulfonyl group, a (1-2C)alkoxycarbonyl group, an N-(1-2C)alkylcarbamoyl group, an N,N-di-[(1-2C)alkyl]carbamoyl group, a (2C)alkanoyl group, a (2C)alkanoyloxy group, a (2C)alkanoylamino group, an N-(1-2C)alkylsulfamoyl group, and an N,N-di-[(1-2C)alkyl]sulfamoyl group.

Specific compounds of the present invention include any of the following:

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 1);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 2);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 3);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 4);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 5);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide (Example 6);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide (Example 7);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 8);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide (Example 9);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 10);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide (Example 11);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3,3-dimethylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 12);

(S)-N-(2-((5-chloropyridin-2-yl)amino)-1-cyclopropylethyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 13);

(S)-N-(1-((5-chloropyridin-2-yl)amino)propan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 14);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-cyclopropyl-[1,1′-biphenyl]-2-carboxamide (Example 15);

(S)-5-Chloro-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 16);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzamide (Example 17);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-fluoro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 18);

(S)-5-Bromo-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 19);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethoxy)benzamide (Example 20);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 21);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-morpholinobenzamide (Example 22);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-(dimethylamino)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 23);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)nicotinamide (Example 24);

(S)-5-chloro-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 25);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethyl-5-phenylthiazole-4-carboxamide (Example 26);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-phenyl-1H-indole-3-carboxamide (Example 27);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 28);

(S)-N-(1-((4-fluorobenzyl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 29);

(S)-N-(1-((4,6-dimethylpyrimidin-2-yl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 30);

(S)-N-methyl-N-(3-methyl-1-(quinazolin-2-yloxy)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 31);

(S)-N-Methyl-N-(3-methyl-1-((4-phenylpyrimidin-2-yl)oxy)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 32);

(S)-N-methyl-N-(3-methyl-1-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 33);

(S)-N-(1-((5-chloropyridin-2-yl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 34);

(S)-N-Methyl-N-(3-methyl-1-((4-phenylpyrimidin-2-yl)amino)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 35);

(S)-N-methyl-N-(3-methyl-1-(quinazolin-2-ylamino)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 36);

(S)-N-(1-((4,6-dimethylpyrimidin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 37);

(S)-N-Methyl-N-(3-methyl-1-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 38);

(S)-5-Chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)benzamide (Example 39);

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)benzamide (Example 40);

(S)-5-Chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridazin-3-yl)amino)butan-2-yl)benzamide (Example 41);

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)benzamide (Example 42);

(S)-N-(1-(Benzo[d]oxazol-2-ylamino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 43);

(S)-N-(1-(Benzo[d]thiazol-2-ylamino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 44);

(S)-5-Chloro-N-(1-((5-chloro-3-nitropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 45);

(S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 46);

(S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)picolinamide (Example 47);

(S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)picolinamide (Example 48);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 49);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,1-dimethyl-1H-indole-3-carboxamide (Example 50);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethylquinoline-4-carboxamide (Example 51);

(S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-(trifluoromethoxy)benzamide (Example 52);

(S)-5-Chloro-N-methyl-N-(1-((6-methylpyridin-2-yl)amino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 53);

(S)-5-Chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)butan-2-yl)benzamide (Example 54);

(S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)butan-2-yl)picolinamide (Example 55);

(S)-N-(1-(4-Fluorobenzamido)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 56);

(S)-N-(1-((4-Fluorobenzyl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 57);

(S)-N-Methyl-N-(3-methyl-1-(3-phenylureido)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide (Example 58);

(S)-N-(1-((4-chlorophenyl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 59);

(S)-N-(1-((3-amino-5-chloropyridin-2-yl)amino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 60);

(S)-N,6-Dimethyl-N-(1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 61);

(S)-N-(1-(Benzo[d]oxazol-2-ylamino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 62);

(S)-N-(1-(Benzo[d]thiazol-2-ylamino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 63);

(S)-N-(1-((5-chlorobenzo[d]oxazol-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 64);

(S)-N,6-Dimethyl-N-(1-(quinoxalin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 65);

(S)-N,6-Dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 66);

(S)-N,6-Dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 67);

(S)-N,6-Dimethyl-N-(3-methyl-1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 68);

(S)-N,6-Dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 69);

(S)-N-Ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)picolinamide (Example 70);

(S)-N-Ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)picolinamide (Example 71);

(S)-N-ethyl-6-methyl-N-(1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 72);

(S)-N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 73);

(S)-N-(1-cyclopropyl-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 74);

(S)-N,6-Dimethyl-N-(1-(quinolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 75);

(S)-N-(1-((1,5-naphthyridin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 76);

(S)-5-Chloro-N-methyl-N-(1-(quinolin-2-ylamino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 77);

(S)-N,3-Dimethyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide (Example 78);

(S)-N-Methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)quinoline-8-carboxamide (Example 79);

(S)-6-Chloro-N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)quinoline-8-carboxamide (Example 80);

(S)-3-(Dimethylamino)-N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide (Example 81);

(S)-N,6-Dimethyl-N-(1-(methyl(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 82);

(S)-N-(1-((2-methoxyethyl)(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 83);

(S)-N,6-Dimethyl-3-(pyrimidin-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formate (Example 84);

(S)-N-Methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide (Example 85);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,4,5-trimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 86);

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methoxy-N,4-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 87);

(S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(4,4,4-trifluoro-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 88);

(S)-N,6-Dimethyl-3-(1H-1,2,4-triazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formate (Example 89);

(S)-N,6-Dimethyl-3-(1H-pyrazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formate (Example 90);

(S)-2-Fluoro-N-methyl-6-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)benzamide (Example 91);

(S)-6-Methoxy-N-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 92); or a pharmaceutically acceptable salt or solvate thereof.

The various functional groups and substituents that make up the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, e.g., less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525, and for example, is 500 or less.

Suitable or preferred features of any compound of the invention may also be suitable features of any other aspect.

Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, with, for example, an acid addition salt of an inorganic or organic acid, the acid being, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts or salts formed with an organic base that provides a physiologically acceptable cation, for example, a salt formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

Compounds with the same molecular formula but different properties or order of their atomic bonding or the arrangement of their atoms in space are called "isomers". The term "stereoisomer" refers to isomers whose atoms are arranged differently in space. Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R and S sequencing rules of Cahn and Prelog, or by the method in which the molecule rotates the plane of polarized light, and are designated as right-handed or left-handed (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture comprising equal proportions of enantiomers is called a "racemic mixture".

The compounds of the present invention may have one or more asymmetric centers; therefore, these compounds can be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a specific compound in the specification and claims is intended to include two individual enantiomers and racemic mixtures or other mixtures thereof. Methods for stereochemical determination and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by splitting racemic forms. Some compounds of the present invention may have geometric isomerization centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having orexin-1 inhibitory activity.

The present invention also encompasses compounds of the present invention as defined herein that include one or more isotopic substitutions. For example, H can be in any isotopic form, including ¹ H, ² H (D), and ³ H (T); C can be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; and O can be in any isotopic form, including ¹⁶ O and ¹⁸ O; etc.

It will also be understood that certain compounds of the present invention can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. It will be understood that the present invention encompasses all such solvated forms that possess orexin-1 inhibitory activity.

It is also to be understood that certain compounds of the present invention may exhibit polymorphism and that the present invention encompasses all such forms that possess orexin-1 inhibitory activity.

Compound of the present invention can exist with many different tautomeric forms, and the compounds of this invention mentioned comprises all these forms.For the avoidance of doubt, when compound can exist with one of several tautomeric forms, and only have a kind of when being specifically described or showing, compound of the present invention still comprises every other form.The example of tautomeric form comprises ketone, enol and enolate form, as in for example following tautomerism pair: ketone/enol (as shown below), imines/enamine, amides/imino alcohol, amidine/amidine, nitroso-group/oxime, thioketone/enethiol and nitro/acid nitro.

The compounds of the present invention comprising an amine functional group can also form N-oxides. The compounds of formula I comprising an amine functional group mentioned herein also include N-oxides. When the compound comprises several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are tertiary amines of nitrogen-containing heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, edited by Jerry March, 4th edition, Wiley International Scientific Company, p. 166. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

The compounds of the present invention can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical properties and/or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include ester derivatives that can be formed in vivo at carboxyl groups or hydroxyl groups in the compounds of the present invention and amide derivatives that can be formed in vivo at carboxyl groups or amino groups in the compounds of the present invention.

The present invention therefore includes those compounds of formula I as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of their prodrugs. The present invention therefore includes those compounds of formula I produced by organic synthesis and also those compounds produced in the human or animal body by metabolism of precursor compounds, i.e. compounds of formula I which may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of the compounds of Formula I are those that are, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

For example, in the following documents various forms of prodrugs have been described:-

a) Methods in Enzymology, Vol. 42 , pp. 309-396, edited by K. Widder et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bondegar, Chapter 5, “Design and Application of Pro-drugs,” edited by H. Bondegar, pp. 113-191 (1991);

d) H. Bundgal, Advanced Drug Delivery Reviews , 8 , 1-38 (1992);

e) H. Bhandar et al., Journal of Pharmaceutical Sciences , 77 , 285 (1988);

f) N. Kakeya et al., Chem. Pharm. Bull ., 32 , 692 (1984);

g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14; and

h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which prodrugs have a carboxyl group) are, for example, in vivo cleavable esters thereof. An in vivo cleavable ester of a compound of formula I comprising a carboxyl group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters of carboxyl groups include C _1-6 alkyl esters such as methyl, ethyl and tert-butyl C _1-6 alkoxymethyl esters such as methoxymethyl ester, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthalyl ester, C _3-8 cycloalkylcarbonyloxy-C _1-6 alkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolanylmethyl ester such as 5-methyl-2-oxo-1,3-dioxolan-4-ylmethyl ester and C _1-6 alkoxycarbonyloxy-C _1-6 alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

Suitable pharmaceutically acceptable prodrugs (the prodrugs have hydroxyl groups) of compounds of formula I are, for example, esters or ethers thereof that can be cleaved in vivo. Esters or ethers that can be cleaved in vivo of compounds of formula I comprising hydroxyl groups are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include inorganic esters such as phosphates (including phosphoramidite cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include: C _1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C _1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C _1-6 ) 2carbamoyl, ₂ -dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C _1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

Suitable pharmaceutically acceptable prodrugs of the compounds of formula I (which prodrugs have a carboxyl group) are, for example, amides thereof which can be cleaved in vivo, for example amides formed from amines such as ammonia, C _1-4 alkylamines such as methylamine, (C _1-4 alkyl) ₂ amines such as dimethylamine, N-ethyl N-methylamine or diethylamine, C _1-4 alkoxy C _2-4 alkylamines such as 2-methoxyethylamine, phenyl C _1-4 alkylamines such as benzylamine and amino acids such as glycine, or esters thereof.

Suitable pharmaceutically acceptable prodrugs of compounds of Formula I (which have an amino group) are, for example, amide derivatives thereof that can be cleaved in vivo. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, amides formed with C _1-10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C _1-4 alkyl)piperazin-1-ylmethyl.

The in vivo effects of the compounds of formula I may be exerted in part through one or more metabolites formed in the human or animal body following administration of the compounds of formula I. As described above, the in vivo effects of the compounds of formula I may also be exerted by way of metabolic precursor compounds (prodrugs).

It will also be understood that the compounds of Formula I may also be covalently linked (at any suitable position) to other groups, such as, for example, solubilizing moieties (e.g., PEG polymers), moieties that enable them to bind to solid supports (such as, for example, biotin-containing moieties) and targeting ligands (such as antibodies or antibody fragments).

synthesis

In the descriptions of synthetic methods described below and in the referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, experimental durations, and work-up procedures, can be selected by one skilled in the art.

Those skilled in the art of organic synthesis will understand that the functionality present on the various portions of the molecule must be compatible with the reagents and reaction conditions employed.

The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variations and in the accompanying examples. Alternatively, the necessary starting materials can be obtained by procedures similar to those shown by the ordinary skill of an organic chemist.

It will be appreciated that during the synthesis of the compounds of the invention in the processes defined below, or during the synthesis of certain starting materials, it may be necessary to protect certain substituent groups to prevent their undesirable reactions. A skilled chemist will understand when such protection is necessary and how these protecting groups can be placed in the appropriate positions and subsequently removed.

For examples of protecting groups, see one of the many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist, suitable for the removal of the protecting group in question, the method being selected so as to effect removal of the protecting group with minimal perturbation of groups elsewhere in the molecule.

Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy groups, it may be necessary to protect this group in some of the reactions mentioned herein.

For example, the suitable protecting group of amino or alkylamino group is such as acyl group, for example alkanoyl group such as acetyl, alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, arylmethoxycarbonyl group, for example benzyloxycarbonyl, or aroyl group, for example benzoyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, can be by being hydrolyzed with suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide etc. and remove acyl group such as alkanoyl or alkoxycarbonyl group or aroyl group.Alternately, can be for example by using suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid treatment remove acyl group such as tert-butoxycarbonyl group, and can for example by through catalyst such as palladium carbon hydrogenation, or by using Lewis acid such as BF ₃ .OEt ₂ treatment remove arylmethoxycarbonyl group such as benzyloxycarbonyl group. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways in a known manner. Compounds of formula I can be prepared by the methods given below, by the methods given in the experiments, or by similar methods. The described pathways illustrate only some methods for synthesizing compounds of formula I, and those skilled in the art will understand that the order of reaction steps is not limited to those described. It will also be understood that the partitioning of nucleophiles and electrophiles is not limited to that described herein, and in some cases may be suitable for the partitioning to be reversed. Different approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

Compounds of formula I, or pharmaceutically acceptable salts thereof (wherein Q, X, Ar, _Ra and _R are as previously defined), can be prepared by reacting a compound of formula II (wherein Q is as previously defined in formula I) with an amine of formula III (wherein X, Ar, _Ra and _R are as previously defined in formula I) (Scheme A, step i).

A suitable reactive derivative of the carboxylic acid of formula II is formed, for example: an acyl halide formed by reaction of the acid with an inorganic acid chloride such as thionyl chloride; a mixed anhydride formed by reaction of the acid with a chloroformate such as isobutyl chloroformate; an ester formed by reaction with an alcohol in the presence of an acid or base; an activated ester formed by reaction of the acid with a phenol such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; or the product of reaction of the acid with an amide-coupling agent such as dicyclohexylcarbodiimide. When converting the carboxylic acid of formula II to an ester, for example, by reaction of the acid chloride with an organic alcohol such as methanol, this can be reacted with an amine of formula III in the presence of an organometallic activator, for example, a Grignard reagent such as isopropylmagnesium bromide. Typically, the carboxylic acid of formula II and the amine of formula III are treated with an amide-coupling agent such as HATU in a suitable solvent such as DMF in the presence of a non-nucleophilic base such as DIPEA.

Plan A

Compounds of formula II (wherein Q is as defined above in formula I) are commercially available or can be prepared by techniques known or apparent to those skilled in the art. Compounds of formula II are prepared by acid- or base-catalyzed hydrolysis of esters, amides, or nitriles, such as hydrolysis of methyl esters with sodium hydroxide; transition metal-catalyzed oxidation of aldehydes or alcohols; treatment with organolithium or Grignard reagents and carbon dioxide; or transition metal-catalyzed carbonylation of aryl halides in the presence of water. Transition metal-catalyzed carbonylation of aryl halides in the presence of amines of formula III can directly form compounds of formula I.

Those skilled in the art will appreciate that compounds of Formula I and Formula III, wherein X, Ar, Q, _Ra and _Rb are as previously defined in Formula I, can be prepared by incorporating appropriate protecting groups and routing strategies into the general synthetic chemistry described in Scheme B, wherein X, Ar, Q, _Ra and _Rb are as previously defined in Formula I and Y is: H; QC(O), wherein Q is as previously defined in Formula I; or an amine protecting group such as benzyl, 3,4-dimethoxybenzyl, p-methoxybenzyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, p-methoxyphenyl, toluenesulfonyl, p-nitrobenzenesulfonyl or trifluoroacetyl.

Compounds of formula IV, or pharmaceutically acceptable salts thereof, wherein Ar, R ₁ , _Ra and R _b are as previously defined in formula I, can be prepared by reacting an amine of formula V, wherein R ₁ , _Ra and R _b are as previously defined in formula I, with a compound of formula ZAr, wherein Ar is as previously defined in formula I, and Z is a substituent useful in transition metal-catalyzed amination chemistry (Scheme B, step ii). Compounds of formula ZAr (wherein Z is a halide such as bromide or chloride, a boronic acid or boronic _ester , or an activated alcohol such as a triflate) can be converted to compounds of formula _IV by reaction with an amine of formula V in the presence of a transition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or Pd 2 (dba) 3, in the presence of a base such as potassium carbonate or sodium tert-butoxide and a suitable ligand such as triphenylphosphine or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Typically, the reaction is carried out in toluene at reflux using Pd ₂ (dba) ₃ as a catalyst in the presence of BINAP and sodium tert-butoxide.

Alternatively, compounds of formula IV can be prepared by reacting an amine of formula V with a compound of formula ZAr, wherein Ar is as defined above in formula I, and Z is a leaving group such as a halide, for example, iodide or bromide, or an activated alcohol, for example, tosylate or mesylate, in the presence of a non-nucleophilic base such as DBU, sodium tert-butoxide, potassium carbonate, a tertiary amine such as DIPEA, or a heterocyclic base such as pyridine (Scheme B, step ii). Typically, the reaction is carried out in NMP at 130° C. using DIPEA as the base.

Compounds of formula IV, or pharmaceutically acceptable salts thereof (wherein Ar, R ₁ , Ra and R b are as defined above in formula I) can be prepared by reacting an amine of formula HNR ₁ Ar (wherein R _{1 and} Ar are as described above in formula I) with an aldehyde of formula VI (wherein _Ra and R _b are as defined above in formula I) (Scheme B, step iii). Compounds of formula IV can be prepared by reductive amination of compounds of formula VI with an amine of formula HNR 1 Ar in the presence of _a suitable reducing agent such as sodium cyanoborohydride, NaBH (OAc) ₃ or sodium borohydride in a polar solvent such as methanol, ethanol, _THF , DCE or DCM, alone or in combination with an acid such as AcOH. Typically, the reaction is carried out in DCE at ambient temperature using NaBH (OAc) ₃ .

Compounds of formula VII, or pharmaceutically acceptable salts thereof (wherein Ar, _Ra and _R are as defined above in formula I), can be prepared by reacting an alcohol of formula VIII (wherein _Ra and _R are as defined above in formula I) with a compound of formula ZAr (wherein Ar is as defined above in formula I and Z is a leaving group such as a halide or an activated alcohol) (Scheme B, step iv). Compounds of formula ZAr (wherein Z is a leaving group such as a halide, for example, iodide or bromide, or an activated alcohol such as a tosylate or mesylate) can be converted to compounds of formula VII by reaction with an alcohol of formula VIII in the presence of a non-nucleophilic base such as potassium carbonate, sodium hydride or lithium diisopropylamide. Alternatively, when Z is an alcohol, in situ activation can be used, for example, using diethyl azodicarboxylate and triphenylphosphine in a solvent such as THF. Typically, the reaction is carried out at ambient temperature using sodium hydride as base and THF as solvent, wherein ZAr is an aryl halide.

Amines of formula V are prepared by reductive amination as previously described for Scheme B, step iii, between an aldehyde of formula _VI and an amine of formula _H2NR1 , an amine equivalent or a suitably protected amine (Scheme B, step v).

Those skilled in the art will recognize that aldehydes of formula VI can be prepared in a variety of ways. Typically, aldehydes of formula VI are prepared by oxidation of alcohols of formula VIII using Dess-Martin periodinane and NaHCO ₃ in DCM (Scheme B, step vi).

Compounds of formula V can also be prepared by reducing amides of formula IX with a hydrogenating agent such as LiAlH ₄ or by catalytic hydrogenation (Scheme B, step vii). Typically, the reaction is carried out at 0° C. using LiAlH ₄ in THF or diethyl ether. Those skilled in the art will recognize that the preparation of amines of formula V is not limited to the methods described herein and can be achieved in various ways in a known manner.

Those skilled in the art will recognize that alcohols of formula VIII (wherein _Ra and _Rb are as previously defined in formula I) can be prepared by various known methods. For example, alcohols _of formula VIII can be prepared by reducing a carbonyl-containing compound such as an aldehyde of formula VI (Scheme B, step viii), a carboxylic acid of formula _X , or a carboxylic acid equivalent such as a carboxylate (Scheme B, step ix) with a suitable reducing agent such as sodium borohydride, LiAlH4, diisobutylaluminum hydride, or LiBH4. Typically, alcohols of formula VIII are prepared by reducing a carboxylate equivalent of a carboxylic acid of formula X using _LiBH4 in THF at ambient temperature. Those skilled in the art will appreciate that carboxylate equivalents of a carboxylic acid of formula X can be prepared in various known ways.

Plan B

Compounds of formula X can be prepared from appropriately protected/activated derivatives of amino acids of formula XI (Scheme B, step xi). One skilled in the art will appreciate that the conversion of amino acids of formula XI to compounds of formula X via protection/activation synthetic strategies may require multiple reaction steps and can be achieved in a variety of known ways. For example, compounds of formula X can be prepared by the following steps: conversion of an amino acid of formula XI into an activated amide such as trifluoroacetamide by reaction with trifluoroacetic anhydride, followed by deprotonation with a base such as sodium hydride, alkylation with an alkyl halide of formula _RbZ (wherein _Rb is as described in formula I and Z is a leaving group such as a halide or an activated alcohol, for example methyl iodide), and hydrolysis with a suitable base such as sodium hydroxide; benzyl protection by reaction of an amino acid of formula XI with a suitable aldehyde or aldehyde equivalent such as benzaldehyde, followed by reductive amination with an aldehyde of formula _RbCHO , or an aldehyde equivalent, and then catalytic hydrogenation with a transition metal catalyst such as palladium under a hydrogen atmosphere; conversion of an amino acid of formula XI into a carbamate by reaction with an anhydride or an acid chloride, such as di-tert-butyl dicarbonate, followed by reduction with a metal hydride such as _LiAlH4 .

Natural and unnatural amino acids of formula XI and their derivatives are commercially available or can be prepared by methods known to those skilled in the art. For a review of amino acid synthesis, see (a) C. Najera and J. M. Sansano, Chem. Rev., 2007, 107, 4584; (b) R. M. Williams and J. A. Hendrix, Chem. Rev., 1992, 92, 889; (c) R. O. Duthaler, Tetrahedron, 1994, 50, 1539.

Pharmaceutical composition

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

The compositions of the present invention can be obtained by conventional procedures well known in the art using conventional pharmaceutical excipients. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

An effective amount of a compound of the invention for treating a proliferative disease is an amount sufficient to symptomatically alleviate the symptoms of infection in a warm-blooded animal, particularly a human, to slow the progression of the infection, or to reduce the risk of exacerbation in a patient already suffering from the symptoms of infection.

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

According to well-known medical principles, the size of the dose of the compound of formula I for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

When using the compounds of this invention for treatment or prevention purposes, it is usually given so that if divided doses are needed, a daily dose of, for example, 0.1mg/kg to 75mg/kg body weight is accepted. In general, when using parenteral route, a lower dose will be given. Therefore, for example, for intravenous or intraperitoneal administration, a dosage of, for example, 0.1mg/kg to 30mg/kg body weight will be usually used. Similarly, for administration by inhalation, a dosage of, for example, 0.05mg/kg to 25mg/kg body weight will be used. Oral administration can also be suitable, particularly in tablet form. Typically, a unit dosage form will comprise approximately 0.5mg to 0.5g of the compounds of this invention.

Therapeutic uses and applications

The compounds of the present invention are selective inhibitors of orexin-1 activity. Therefore, they are potentially useful therapeutic agents for treating diseases or conditions involving orexin-1 receptor activity.

Thus, in one aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition in which orexin- ₁ (OX1) activity is implicated.

In another aspect, the present invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which orexin-1 ( _OX1 ) activity is implicated.

In another aspect, the present invention relates to a method of treating a disease or condition in which orexin- ₁ (OX1) activity is implicated, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

Examples of specific diseases or conditions that can be treated using the compounds of formula (I) and their pharmaceutically acceptable salts include, but are not limited to, any of the following: schizophrenia and other psychiatric disorders (e.g., psychotic disorders, psychosis, or schizoaffective disorder); dementia and other cognitive disorders; anxiety disorders (e.g., generalized anxiety disorder, post-traumatic stress disorder, panic disorder, acute stress disorder, social anxiety disorder, phobias including agoraphobia, obsessive-compulsive disorder, trichotillomania, or body image disorder); mood disorders (e.g., depressive disorders, major depressive disorder, bipolar disorder including bipolar I and II, bipolar mania, bipolar depression); addiction, including These include substance dependence (e.g., cocaine, opioid, marijuana, or prescription drug dependence), alcohol dependence, nicotine dependence, or gambling disorder; eating disorders (e.g., binge eating, bulimia nervosa, anorexia nervosa, or obesity); sleep disorders (e.g., rapid eye movement sleep disorder); disorders typically first diagnosed in infancy, childhood, or adolescence (e.g., attention deficit disorder, autism spectrum disorder, Rett syndrome, fragile X syndrome, Asperger syndrome, and disruptive behavior disorders); restless legs syndrome; pain (e.g., neuropathic pain, including chemotherapy-induced pain or migraines); osteoporosis; and neurodegenerative disorders (e.g., Parkinson's disease or Alzheimer's disease).

Specifically, the compounds of the invention (including pharmaceutically acceptable salts) can be used to treat schizophrenia, schizophreniform disorder or schizoaffective disorder (e.g., voices or hallucinations), cognitive disorders (such as dementia and learning impairment), anxiety disorders (such as post-traumatic stress disorder or panic disorder), or positive symptoms of addiction.

The invention also provides a compound of formula I as defined herein for use in the treatment of at least one symptom or condition associated with the treatment of any of: schizophrenia and other psychiatric disorders (e.g., psychotic disorders, psychosis, or schizoaffective disorder); dementia and other cognitive disorders; anxiety disorders (e.g., generalized anxiety disorder, post-traumatic stress disorder, panic disorder, acute stress disorder, social anxiety disorder, phobias including agoraphobia, obsessive-compulsive disorder, trichotillomania, or body image disorder); mood disorders (e.g., depressive disorders, major depressive disorder, bipolar disorder including bipolar I and II, bipolar mania, bipolar depression); addiction, including substance dependence (e.g., cocaine, opioids, marijuana, or prescription drug dependence), alcohol dependence, nicotine dependence or gambling disorder; eating disorders (e.g., binge eating, bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g., rapid eye movement sleep disorder); disorders typically first diagnosed in infancy, childhood or adolescence (e.g., attention deficit disorder, autism spectrum disorder, Rett syndrome, fragile X syndrome, Asperger syndrome and disruptive behavior disorder); restless legs syndrome; pain (e.g., neuropathic pain, including chemotherapy-induced pain or migraine); osteoporosis and neurodegenerative disorders (e.g., Parkinson's disease or Alzheimer's disease), the treatment comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

These symptoms and conditions include, but are not limited to, anxiety, agitation, hostility, panic attacks, eating disorders, affective symptoms, mood symptoms, negative and positive psychotic symptoms commonly associated with psychotic and neurodegenerative disorders.

Further specific examples of disorders involving orexin- ₁ (OX1) activity include behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks), and/or anxiety.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of: schizophrenia and other psychiatric disorders (e.g., psychotic disorders, psychosis, or schizoaffective disorder); dementia and other cognitive disorders; anxiety disorders (e.g., generalized anxiety disorder, post-traumatic stress disorder, panic disorder, acute stress disorder, social anxiety disorder, phobias including agoraphobia, obsessive-compulsive disorder, trichotillomania, or body image disorder); mood disorders (e.g., depressive disorders, major depressive disorder, bipolar disorder including bipolar I and II, bipolar mania, bipolar depression). addictions, including substance dependence (e.g., cocaine, opioids, marijuana, or prescription drug dependence), alcohol dependence, nicotine dependence, or gambling disorder; eating disorders (e.g., binge eating, bulimia nervosa, anorexia nervosa, or obesity); sleep disorders (e.g., rapid eye movement sleep disorder); disorders typically first diagnosed in infancy, childhood, or adolescence (e.g., attention deficit disorder, autism spectrum disorder, Rett syndrome, fragile X syndrome, Asperger syndrome, and disruptive behavior disorders); restless legs syndrome; pain (e.g., neuropathic pain, including chemotherapy-induced pain or migraines); osteoporosis; and neurodegenerative disorders (e.g., Parkinson's disease or Alzheimer's disease).

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for use in the treatment of behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks) and/or anxiety).

In another aspect, the present invention provides the use of a compound or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of: schizophrenia and other psychiatric disorders (e.g., psychotic disorders, psychosis or schizoaffective disorder); dementia and other cognitive disorders; anxiety disorders (e.g., generalized anxiety disorder, post-traumatic stress disorder, panic disorder, acute stress disorder, social anxiety disorder, phobias including agoraphobia, obsessive-compulsive disorder, trichotillomania or body image disorder); mood disorders (e.g., depressive disorders, major depressive disorder, bipolar disorder including bipolar I and II, bipolar mania, bipolar depression); addiction , including substance dependence (for example, cocaine, opioid, marijuana, or prescription drug dependence), alcohol dependence, nicotine dependence, or gambling disorder; eating disorders (for example, binge eating, bulimia nervosa, anorexia nervosa, or obesity); sleep disorders (for example, rapid eye movement sleep disorder); disorders that are typically first diagnosed in infancy, childhood, or adolescence (for example, attention deficit disorder, autism spectrum disorder, Rett syndrome, fragile X syndrome, Asperger syndrome, and disruptive behavior disorders); restless legs syndrome; pain (for example, neuropathic pain, including chemotherapy-induced pain or migraines); osteoporosis; and neurodegenerative disorders (for example, Parkinson disease or Alzheimer disease).

In another aspect, the present invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks) and/or anxiety).

In another aspect, the present invention provides methods for treating: schizophrenia and other psychiatric disorders (e.g., psychotic disorders, psychosis, or schizoaffective disorder); dementia and other cognitive disorders; anxiety disorders (e.g., generalized anxiety disorder, post-traumatic stress disorder, panic disorder, acute stress disorder, social anxiety disorder, phobias including agoraphobia, obsessive-compulsive disorder, trichotillomania, or body image disorder); mood disorders (e.g., depressive disorders, major depressive disorder, bipolar disorder including bipolar I and II, bipolar mania, bipolar depression); addictions, including substance dependence (e.g., cocaine, opioids, marijuana, or prescription drug dependence), alcohol dependence, nicotine dependence, or gambling disorders; eating disorders. disorders (e.g., binge eating, bulimia nervosa, anorexia nervosa, or obesity); sleep disorders (e.g., rapid eye movement sleep disorder); disorders typically first diagnosed in infancy, childhood, or adolescence (e.g., attention deficit disorder, autism spectrum disorder, Rett syndrome, fragile X syndrome, Asperger syndrome, and disruptive behavior disorder); restless legs syndrome; pain (e.g., neuropathic pain, including chemotherapy-induced pain or migraine); osteoporosis and neurodegenerative disorders (e.g., Parkinson's disease or Alzheimer's disease), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition.

In another aspect, the present invention provides a method for treating behavioral arousal, eating disorders (e.g., binge eating, obesity), psychiatric disorders (e.g., schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g., nicotine) addiction, panic disorders (e.g., panic attacks) and/or anxiety), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition.

In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in producing an orexin-1 inhibitory effect.

In another aspect, the present invention provides use of a compound or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for producing an orexin-1 inhibitory effect.

In another aspect, the present invention provides a method for producing an orexin-1 inhibitory effect in vitro, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method for producing an orexin-1 inhibitory effect in vivo, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibiting orexin-1 (OX ₁ ) in vitro and/or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

Ways of Giving

The compounds of the invention or pharmaceutical compositions comprising the active compounds may be administered to the subject by any convenient route of administration, whether systemically/peripherally or locally (ie, at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or reservoir, e.g., subcutaneously or intramuscularly.

Combination therapy

The compounds of the present invention may be administered alone as a monotherapy or in combination with one or more additional therapeutic agents. The choice of one or more additional therapeutic agents will of course depend on the disease or condition to be treated and its severity.

Combination therapy is commonly used to treat certain medical conditions.

Thus, treatment as defined above may be administered as the sole therapy or may involve treatment with one or more additional therapeutic agents in addition to the compounds of the invention.

Such conjugate/combination therapy may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

According to a particular aspect of the invention there is provided a combination useful in the treatment of a disease or condition in which orexin-1 receptor activity is implicated, the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and another therapeutic agent.

According to this aspect of the invention there is provided a combination suitable for the treatment of behavioural arousal, eating disorders (e.g. binge eating, obesity), psychiatric disorders (e.g. schizophrenia, anxiety, mood disorders, reward seeking behaviour, alcohol or drug (e.g. nicotine) addiction and/or anxiety) comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and one or more additional therapeutic agents.

In another aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more additional therapeutic agents.

Herein, where the term "combination" is used, it is understood that this refers to simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, a delay in administering the second component should not result in a loss of the beneficial effects of the combination.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable diluent or carrier and in combination with one or more additional therapeutic agents.

According to particular aspects of the invention, there are provided combinations suitable for use in the treatment of: schizophrenia and other psychiatric disorders (e.g., psychotic disorders, psychosis, or schizoaffective disorder); dementia and other cognitive disorders; anxiety disorders (e.g., generalized anxiety disorder, post-traumatic stress disorder, panic disorder, acute stress disorder, social anxiety disorder, phobias including agoraphobia, obsessive-compulsive disorder, trichotillomania, or body image disorder); mood disorders (e.g., depressive disorders, major depressive disorder, bipolar disorder including bipolar I and II, bipolar mania, bipolar depression); addictions, including substance dependence (e.g., cocaine, opioids, marijuana, or prescription drug dependence), alcohol dependence, nicotine dependence, , edible oil or nicotine dependence or gambling disorder; eating disorders (e.g., binge eating, bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g., rapid eye movement sleep disorder); disorders typically first diagnosed in infancy, childhood or adolescence (e.g., attention deficit disorder, autism spectrum disorder, Rett syndrome, fragile X syndrome, Asperger syndrome and disruptive behavior disorder); restless legs syndrome; pain (e.g., neuropathic pain, including chemotherapy-induced pain or migraine); osteoporosis and neurodegenerative disorders (e.g., Parkinson's disease or Alzheimer's disease), the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and another therapeutic agent.

According to a particular aspect of the invention, there is provided a combination suitable for the treatment of behavioral arousal, eating disorders (e.g. binge eating, obesity), psychiatric disorders (e.g. schizophrenia, anxiety, mood disorders, reward-seeking behavior, alcohol or drug (e.g. nicotine) addiction, panic disorders (e.g. panic attacks) and/or anxiety), which combination comprises a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and another therapeutic agent.

Examples of additional therapeutic agents that may be used as part of combination therapy with the compounds of the invention include, but are not limited to, the following:

(i) antidepressants such as, for example, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, ezathonam, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ixabepilone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, vortioxetine, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites;

(ii) Antipsychotics include, for example, amisulpride, aripiprazole, asenapine, benzoxidil, bifenazol, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, triazine, loxapine, iurasidone, mesoridazine, olanzapine, paliperidone, perapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sulpiride, sulprotone, suliconol, thioridazine, trifluoperazine, trimetozine, sodium valproate, valproic acid, zolpiron, zotepine, zicronapine, ziprasidone, and equivalents thereof and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(iii) Anxiolytics include, for example, anesthesione, azaspirone, benzodiazepines, barbiturates, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites. Examples of anxiolytics include: adizalam, alprazolam, balezepam, benzazepam, bromazepam, brotizolam, buspirone, clonazepam, chlordiazepoxide, chlordiazepoxide, ciprozepam, diazepam, diphenhydramine, estazolam, fenobant, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclozepam, tracazolate, tripipam, temazepam, triazolam, uidazepam, and zolazepam; and equivalents thereof and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(iv) anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, levetiracetam and gabapentin, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites;

(v) Alzheimer's disease treatments including, for example, donepezil, galantamine, memantine, rivastigmine, tacrine, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites;

(vi) Parkinson's disease therapies including, for example, levodopa, ropinirole, pramipexole, monoamine oxidase type B (MAO-B) inhibitors such as deprenyi, selegiline and rasagiline, catechol-O-methyl S-transferase (COMT) inhibitors such as entacapone or tolcapone, adenosine A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine antagonists, and dopamine agonists and inhibitors of neuronal nitric oxide synthase, and equivalents and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(vii) treatments for migraine including, for example, almototan, amantadine, botulinum toxin A, bromocriptine, butalbital, cabergoline, dichloraiphenazone, hydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, topiramate, zolmitriptan, and zomitriptan, and equivalents thereof and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(viii) therapies for stroke including, for example, abciximab, activase, citicoline, desmoteplase, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites;

(ix) treatments for urinary incontinence including, for example, darafenacin, duloxetine, flavoxate, mirabegron, oxybutynin, propiverine, lobazotan, solifenacin, and tolterodine, and equivalents thereof and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(x) Therapies for neuropathic pain including, for example, capsaicin, gabapentin, iidoderm, and pregabalin, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites;

(xi) treatments for nociceptive pain including, for example, celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and acetaminophen, and equivalents thereof and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(xii) treatments for insomnia including, for example, allobarbital, aionimid, amobarbital, benzotamine, butabarbital, carpronil, chloral, cloperidone, chlorpheniramine, declamol, ethchlorvinox, eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine, iorediplon, mecloquinolone, melatonin, mephobarbital, methaqualone, midaflutol, nisolebamate, pentobarbital, phenobarbital, propofol, lamivudine, roremide, suvorexant, triclofos, secobarbital, zaleplon, and zolpidem, zopiclone, and equivalents thereof and one or more pharmaceutically active isomers and/or one or more metabolites thereof;

(xiii) mood stabilizers including, for example, carbamazepine, divalproex sodium, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and their equivalents and one or more pharmaceutically active isomers and/or one or more metabolites;

(xiv) 5HT1B ligands such as, for example, the compounds disclosed in WO 99/05134 and WO 02/08212;

(xv) mGluR2 agonists;

(xvi) α7 nicotinic agonists such as, for example, compounds disclosed in WO 96/006098, WO 97/030998, WO 99/003859, WO 00/042044, WO 01/029034, WO 01/60821, WO 01/36417, WO 02/096912, WO 03/087102, WO 03/087103, WO 03/087104, WO 2004/016617, WO 2004/016616, and WO 2004/019947;

(xvii) chemokine receptor CCR1 inhibitors;

(xviii) delta opioid agonists such as, for example, compounds disclosed in WO 97/23466 and WO 02/094794; and

(xviv) Osteoporosis treatments such as, for example, bisphosphonates, denosumab, raloxifene, calcitonin, strontium ranelate, HRT, calcium and vitamin D.

These combination therapies employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within an approved dosage range and/or dosage (as described in the publication reference).

Examples

Synthesis of compounds

General procedure:

Some methods for preparing the compounds of the present invention are shown in the following examples. Starting materials are prepared according to procedures known in the art or as described herein, or are commercially available. Commercial reagents can be used without further purification. When the reaction temperature is not included, the reaction is carried out at an ambient temperature of generally 18°C to 27°C.

When using ammonia solutions in normal phase chromatography, prepare stock solutions by serial dilution according to the following scheme:

A 7N solution of ammonia in methanol (30 mL) was diluted to a volume of 100 mL with methanol. This solution was further diluted to a volume of 1 L with DCM.

Where the compounds described herein were characterized by ^1H NMR spectroscopy, the spectra were recorded on 400 MHz Bruker, Varian, or JEOL instruments. When temperature was not included, the spectra were recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). Where NMR spectra were complex due to the presence of interconverting isomers, approximate partial integrals of the signals are reported. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, b = broad, t = triplet, q = quartet, m = multiplet, d = doublet.

Where compounds described in this invention are characterized by LCMS data, retention times and molecular weights are determined using the conditions outlined below. Where compounds of this invention exhibit slowly interconverting stereoisomers, multiple retention times are reported.

Method A: Agilent 1100 LC with MS detection (API electrospray) at 254 nM. Column: Waters X-Select C18 (2.5 μm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; 0.1% formic acid [eluent B]. Gradient: 5% to 95% B in 4 min.

Method B: Agilent 1100 LC with MS detection (API electrospray) at 254 nM. Column: Waters X-Select C18 (2.5 μm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; 0.1% ammonium bicarbonate [eluent B]. Gradient: 5% to 95% B in 4 min.

Method C: Agilent 1100 LC with MS detection (API electrospray) at 254 nM. Column: Waters X-Select C18 (2.5 μm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; 0.1% aqueous ammonia [eluent B]. Gradient: 5% to 95% B in 4 min.

Method D: Agilent 1100 LC with MS detection (API electrospray) at 254 nM. Column: Waters X-Select C18 (2.5 μm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; 0.1% formic acid [eluent B]. Gradient: 5% to 50% B in 4 min.

Method E: Shimadzu LCMS-2010EV, at 210-400 nM (ESI). Column: YMC ODS C18 (3 μm, 4.6 x 50 mm). Conditions: MeCN (containing 5% aqueous phase + 0.1% formic acid) [eluent A]; 5 mM ammonium formate + 0.1% formic acid [eluent B]. Gradient: 20% to 95% B in 4 min.

Method F: Shimadzu LCMS-2010EV, 210-400 nM (ESI). Column: YMC Triart C18 (3 μm, 4.6 x 50 mm). Conditions: MeCN (containing 5% aqueous phase + 0.1% formic acid) [eluent A]; 5 mM ammonium formate + 0.1% formic acid [eluent B]. Gradient: 30% to 95% B in 4 min.

Method G: Shimadzu LCMS-2010EV, at 210-420 nm (ESI). Column: Kinetex Core-Shell C18 (5 μm, 2.1 x 50 mm). Conditions: Water + 0.1% formic acid [eluent A]; MeCN + 0.1% formic acid [eluent B]. Gradient: 5% to 100% to 5% B over 1.31 min.

Method H: Shimadzu LCMS-2010EV, at 210-420 nm (ESI). Column: Waters Atlantis dC18 (3 μm, 2.1 x 100 mm). Conditions: Water + 0.1% formic acid [eluent A]; MeCN + 0.1% formic acid [eluent B]. Gradient: 5% to 100% to 5% B over 7 min.

Method I: Waters Acquity UPLC system at 200-400 nm (ESI). Column: Phenomenex Kinetix-XB C18 (1.7 μm, 2.1 x 100 mm). Conditions: Water + 0.1% formic acid [eluent A]; MeCN + 0.1% formic acid [eluent B]. Gradient: 5% to 100% to 5% B over 7 min.

Method J: Waters ZQ MS with Agilent 1100 HPLC at 210-420 nm (ESI). Column: Phenylephrine Gemini-NXC18 (3 μm, 2.0 x 50 mm). Conditions: 2 mM ammonium bicarbonate, buffered to pH 10 [eluent A]; MeCN [eluent B]. Gradient: 1% to 100% to 1% B over 3.5 min.

Method K: Waters Acquity UPLC with diode array (210-350 nm) and SQD mass detector. Column: XBridge BEH C18 2.5 μm 2.1 x 50 mm (flow rate 0.8 mL/min). Conditions: 10 mM ammonium bicarbonate, pH 10 [eluent A]; MeCN [eluent B]. Gradient: 2% to 98% B in 1.30 min.

Method L: Waters Acquity UPLC with diode array (210-350 nm) and SQD mass detector. Column: XBridge BEH C18 2.5 μm 2.1 x 50 mm (flow rate 0.8 mL/min). Conditions: 10 mM ammonium bicarbonate, pH 10 [eluent A]; MeCN [eluent B]. Gradient: 2% to 98% B in 4.70 min.

Method M: Agilent 1260 LC with MS detection (API electrospray). Column: Pheromones Kinetic XB C18 (2.6 μm, 4.6 x 50 mm). Conditions: Water + 0.1% formic acid [eluent A]; MeCN [eluent B]. Gradient: 5% to 98% to 5% B over 2.3 min.

Method N: Agilent 1260 LC with MS detection (API electrospray). Column: Agilent Poroshell 120EC-C18 (2.7 μm, 3.0 x 50 mm). Conditions: Water + 0.1% formic acid [eluent A]; MeCN [eluent B]. Gradient: 5% to 95% to 5% B over 3.5 min.

Method O: Waters ZQ MS with Agilent 1100 HPLC at 210-420 nm (ESI). Column: Phenylephrine Gemini-NXC18 (3 μm, 2.0 x 50 mm). Conditions: 2 mM ammonium bicarbonate, buffered to pH 10 [eluent A]; MeCN [eluent B]. Gradient: 5% to 100% to 5% B over 7 min.

abbreviation:

AcOH acetic acid

BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

Boc ₂ O tert-butyl dicarbonate

CDI Carbonyldiimidazole

Cs ₂ CO ₃ cesium carbonate

CsF cesium fluoride

CuI Cuprous iodide

DCE dichloroethane

DCM dichloromethane

DEAD Diethyl azodicarboxylate

Desmartin 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxyl-3(1H)-one

Periodane

DIAD Diisopropyl azodicarboxylate

DIPEA N,N-Diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EtOAc

HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl

Methylammonium hexafluorophosphate N-oxide

HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate

HCl Hydrogen chloride

HPLC high-performance liquid chromatography

hr(s) hours

IPA Isopropyl alcohol

LCMS liquid chromatography-mass spectrometry

_LiAlH4 Lithium Aluminum Hydride

_LiBH4 lithium borohydride

LiOH lithium hydroxide

MeCN Acetonitrile

MeMgCl methylmagnesium chloride

_MgSO4 magnesium sulfate

min(s) minutes

NaBH(OAc) ₃ -Triacetoxyborohydride

NaCl Sodium chloride

_NaHCO3 sodium bicarbonate

NaO ^t Bu sodium tert-butoxide

NaOMe sodium methoxide

Na ₂ SO ₄ sodium sulfate

Na ₂ SO ₄ .10H ₂ O Sodium sulfate decahydrate

NMP N-Methylpyrrolidone

NMR Nuclear Magnetic Resonance

Pd ₂ (dba) _3- tris(dibenzylideneacetone)dipalladium(0)

Pd(PPh ₃ ) ₄ -Tetrakis(triphenylphosphine)palladium(0)

SnCl ₂ .2H ₂ O Tin(II) chloride dihydrate

TBAF Tetrabutylammonium fluoride

tBME tert-butyl methyl ether

tBuXPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

THF Tetrahydrofuran

TFA trifluoroacetic acid

Synthesis of intermediates:

Preparation of (S)-N-(1-hydroxybutan-2-yl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 1a)

To a solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.60 g, 2.9 mmol) [prepared as described in WO 2012/148553], DIPEA (1.0 mL, 5.91 mmol) and (S)-2-aminobutan-1-ol (0.26 g, 2.9 mmol) in NMP (5 mL) was added HATU (1.23 g, 3.2 mmol) and the reaction mixture was stirred overnight. It was then poured into water (50 mL) and the crude product was extracted into EtOAc (2 x 30 mL). The combined organics were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane) to give the title compound (0.70 g) as an oil.

LCMS (Method A): 1.32 min, 275 [M+H] ⁺

Preparation of (S)-N-(1-((tert-butyldimethylsilyl)oxy)butan-2-yl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 1b)

To a solution of intermediate 1a (0.77 g, 2.8 mmol) and imidazole (0.21 g, 3.1 mmol) in anhydrous DMF (10 mL) was added tert-butyldimethylsilyl chloride (0.46 g, 3.1 mmol), and the reaction mixture was stirred for 48 hr. It was then poured into water (100 mL) and the crude product was extracted into diethyl ether (2 x 30 mL). The combined organics were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ (120 g column, 0% to 50% diethyl ether in isohexane) to obtain the title compound (0.72 g) as a solid. LCMS (method A): 2.83 min, 389 [M+H] ⁺

Preparation of (S)-N-(1-hydroxybutan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 1)

At 0-5 ℃, to the solution of intermediate 1b (0.81g, 2.1mmol) in anhydrous DMF (10mL), add 60% dispersion of sodium hydride in mineral oil (92mg, 2.3mmol), and the reaction mixture is stirred at this temperature for 30min. In the reaction, add iodomethane (0.52mL, 8.3mmol), and allow the mixture to heat to ambient temperature and stir overnight. To this solution, add 1M TBAF (4.2mL, 4.2mmol) in THF, and the reaction mixture is stirred for 1hr. Then pour it into water (50mL) and the crude product is extracted with EtOAc (2x50mL). The combined organic matter is washed with water and dried _over Na _SO , filtered and concentrated in a vacuum. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane) to give the title compound as an oil (0.55 g) which solidified on standing.

LCMS (Method A): two peaks at 1.48 min and 1.61 min, 289 [M+H] ⁺

Preparation of (S)-methyl 2-([1,1'-biphenyl]-2-ylcarboxamido)butyrate (Intermediate 2a)

To a stirred solution of (S)-methyl 2-aminobutyrate hydrochloride (0.53 g, 3.4 mmol), [1,1'-biphenyl]-2-carboxylic acid (0.68 g, 3.4 mmol) and HATU (1.70 g, 4.5 mmol) in DMF (20 mL) was added DIPEA (2.4 mL, 13.7 mmol) and the reaction mixture was stirred overnight. It was then poured into water ( ₃₀ mL) and the crude product was extracted with EtOAc. The combined organics were dried over _Na2SO4 , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% diethyl ether in isohexane) to give the title compound (0.73 g) as a gum.

LCMS (Method A): 2.05 min, 298 [M+H] ⁺

Preparation of (S)-methyl 2-(N-methyl-[1,1'-biphenyl]-2-ylcarboxamido)butyrate (Intermediate 2b)

At 0 ° C, to a solution of intermediate 2a (0.73g, 2.4mmol) in anhydrous THF (20mL), a 60% dispersion of sodium hydride in mineral oil (0.11g, 2.7mmol) was added, and the mixture was allowed to stir for 1 hour at 0 ° C. To the mixture, iodomethane (0.31mL, 4.9mmol) was added and stirring continued for 2 hours. The reaction mixture was quenched with water (30mL), and the product was extracted into EtOAc (50mL). The combined organic matter was washed with water (2x20mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the title compound (0.74g) as an oil.

LCMS (Method A): 2.33 min, 312 [M+H] ⁺

Preparation of (S)-N-(1-hydroxybutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 2)

A mixture of intermediate 2b (0.67 g, 2.1 mmol) and 2M LiBH ₄ in THF (5.4 mL, 10.8 mmol) was stirred for 4 hr. The reaction mixture was quenched by the addition of AcOH (1 mL). It was then poured into water and the crude product was extracted into diethyl ether. The combined organics were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane) to give the title compound (0.44 g) as a colloid.

LCMS (Method A): two peaks at 1.80 min and 1.88 min, 284 [M+H] ⁺

Preparation of (S)-methyl 2-([1,1'-biphenyl]-2-ylcarboxamido)-3-methylbutyrate (Intermediate 3a)

The title compound (7.2 g) was prepared as a gum from (S)-methyl 2-amino-3-methylbutanoate hydrochloride (5.0 g, 30 mmol) and [1,1′-biphenyl]-2-carboxylic acid (5.9 g, 30 mmol) using the method described for intermediate 2a. The crude product was purified by chromatography on a Biotage Companion ^™ (120 g column, 0% to 100% diethyl ether in isohexane).

LCMS (Method A): 2.12 min, 312 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-3-methylbutan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Intermediate 3)

The title compound (0.30 g) was prepared from intermediate 3a (0.35 g, 1.1 mmol) using the method described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 1.94 min, 284 [M+H] ⁺

Preparation of (S)-methyl 2-([1,1'-biphenyl]-2-ylcarboxamido)-4-methylpentanoate (Intermediate 4a)

The title compound (0.18 g) was prepared from (S)-methyl 2-amino-4-methylpentanoate hydrochloride (0.50 g, 2.7 mmol) and [1,1'-biphenyl]-2-carboxylic acid (0.55 g, 2.7 mmol) using the method described for intermediate 2a. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.37 min, 326 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-4-methylpentan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Intermediate 4)

The title compound (0.10 g) was prepared from intermediate 4a (0.18 g, 0.55 mmol) using the procedure described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.03 min, 298 [M+H] ⁺

Preparation of (S)-methyl 3-methyl-2-(2-methyl-4-phenylthiazole-5-carboxamido)butyrate (Intermediate 5a)

The title compound (0.22 g) was prepared from (S)-methyl 2-amino-3-methylbutanoate hydrochloride (0.15 g, 0.90 mmol) and 2-methyl-4-phenylthiazole-5-carboxylic acid (0.20 g, 0.90 mmol) using the method described for intermediate 2a. The crude product was used in the subsequent reaction without further purification. LCMS (Method A): 2.17 min, 333 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-3-methylbutan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide (Intermediate 5)

The title compound (0.20 g) was prepared from intermediate 5a (0.22 g, 0.66 mmol) using the method described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 1.97 min, 305 [M+H] ⁺

Preparation of (S)-methyl 4-methyl-2-(2-methyl-4-phenylthiazole-5-carboxamido) valerate (Intermediate 6a)

The title compound (0.28 g) was prepared from (S)-methyl 2-amino-4-methylpentanoate hydrochloride (0.17 g, 0.94 mmol) and 2-methyl-4-phenylthiazole-5-carboxylic acid (0.21 g, 0.94 mmol) using the method described for intermediate 2a. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.23 min, 347 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-4-methylpentan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide (Intermediate 6)

The title compound (0.26 g) was prepared from intermediate 6a (0.28 g, 0.81 mmol) using the method described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 1.83 min, 319 [M+H] ⁺

Preparation of (S)-methyl 4-methyl-2-(N-methyl-[1,1'-biphenyl]-2-ylcarboxamido) valerate (Intermediate 7a)

The title compound (0.57 g) was prepared as a gum from intermediate 4a (0.59 g, 1.8 mmol) using the procedure described for intermediate 2b. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.57 min, 340 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-4-methylpentan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 7)

The title compound (0.72 g, assumed quantitative yield) was prepared as a gum from intermediate 7a (0.55 g, 1.62 mmol) using the procedure described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.23 min, 312 [M+H] ⁺

Preparation of (S)-methyl 2-(N,2-dimethyl-4-phenylthiazole-5-carboxamido)-4-methylpentanoate (Intermediate 8a)

The title compound (0.44 g) was prepared as a gum from intermediate 6a (0.55 g, 1.59 mmol) using the procedure described for intermediate 2b. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.38 min, 361 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-4-methylpentan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide (Intermediate 8)

The title compound (0.26 g) was prepared from intermediate 8a (0.30 g, 0.83 mmol) using the method described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 1.83 min, 333 [M+H] ⁺

Preparation of (S)-methyl 3-methyl-2-(N-methyl-[1,1'-biphenyl]-2-ylcarboxamido)butyrate (Intermediate 9a)

The title compound (0.88 g) was prepared as a gum from (S)-methyl 3-methyl-2-(methylamino)butanoate hydrochloride (0.50 g, 2.7 mmol) and [1,1′-biphenyl]-2-carboxylic acid (0.55 g, 2.7 mmol) using the method described for intermediate 2a. The crude product was isolated by extraction into diethyl ether and used in subsequent reactions without further purification.

LCMS (Method A): 2.45 min, 326 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 9)

The title compound (0.72 g) was prepared as a gum from intermediate 9a (0.85 g, 2.6 mmol) using the procedure described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): two peaks at 1.96 min and 2.03 min, 298 [M+H] ⁺

Preparation of (S)-methyl 2-(N,2-dimethyl-4-phenylthiazole-5-carboxamido)-3-methylbutyrate (Intermediate 10a)

The title compound (0.83 g) was prepared as a solid from (S)-methyl 3-methyl-2-(methylamino)butanoate hydrochloride (0.45 g, 2.5 mmol) and 2-methyl-4-phenylthiazole-5-carboxylic acid (0.54 g, 2.5 mmol) using the method described for intermediate 2a. The crude product was isolated by extraction into diethyl ether and used in subsequent reactions without further purification.

LCMS (Method A): 2.23 min, 347 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-3-methylbutan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide (Intermediate 10)

The title compound (0.40 g) was prepared from intermediate 10a (0.44 g, 1.3 mmol) using the method described for intermediate 2. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 1.97 min, 319 [M+H] ⁺

Preparation of (S)-methyl 2-([1,1'-biphenyl]-2-ylcarboxamido)-3,3-dimethylbutyrate (Intermediate 11a)

The title compound (0.43 g) was prepared as a gum from (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride (0.25 g, 1.4 mmol) and [1,1′-biphenyl]-2-carboxylic acid (0.27 g, 1.4 mmol) using the method described for intermediate 2a. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% diethyl ether in isohexane).

LCMS (Method A): 2.23 min, 326 [M+H] ⁺

Preparation of (S)-methyl 3,3-dimethyl-2-(N-methyl-[1,1'-biphenyl]-2-ylcarboxamido)butyrate (Intermediate 11b)

The title compound (0.44 g) was prepared as an oil from intermediate 11a (0.47 g, 1.4 mmol) using the method described for intermediate 2b. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.56 min, 340 [M+H] ⁺

Preparation of (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 11)

The title compound (0.38 g) was prepared as an oil from intermediate 11b (0.47 g, 1.4 mmol) using the method described for intermediate 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% diethyl ether in isohexane).

LCMS (Method A): 2.17 min, 312 [M+H] ⁺

Preparation of (S)-methyl 2-([1,1'-biphenyl]-2-ylcarboxamido)-2-cyclopropyl acetate (Intermediate 12a)

The title compound (0.60 g) was prepared as a gum from (S)-methyl 2-amino-2-cyclopropyl acetate hydrochloride (0.42 g, 2.5 mmol) and [1,1'-biphenyl]-2-carboxylic acid (0.50 g, 2.5 mmol) using the method described for intermediate 2a. The crude product was separated from water by filtration and purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.08 min, 310 [M+H] ⁺

Preparation of (S)-methyl 2-cyclopropyl-2-(N-methyl-[1,1'-biphenyl]-2-ylcarboxamido) acetate (Intermediate 12b)

The title compound (0.60 g) was prepared as an oil from intermediate 12a (0.60 g, 1.9 mmol) using the procedure described for intermediate 2b. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.26 min, 324 [M+H] ⁺

Preparation of (S)-N-(1-cyclopropyl-2-hydroxyethyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 12)

The title compound (0.44 g) was prepared as a gum from intermediate 12b (0.47 g, 1.4 mmol) using the method described for intermediate 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 1.92 min, 296 [M+H] ⁺

Preparation of (S)-methyl 2-([1,1'-biphenyl]-2-ylcarboxamido)propionate (Intermediate 13a)

The title compound (0.56 g) was prepared as a gum from (S)-methyl 2-aminopropanoate hydrochloride (0.35 g, 2.5 mmol) and [1,1′-biphenyl]-2-carboxylic acid (0.50 g, 2.5 mmol) using the method described for intermediate 2a. The crude product was isolated by extraction into EtOAc and purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% diethyl ether in isohexane).

LCMS (Method A): 2.00 min, 284 [M+H] ⁺

Preparation of (S)-methyl 2-(N-methyl-[1,1'-biphenyl]-2-ylcarboxamido) propionate (Intermediate 13b)

The title compound (0.45 g) was prepared as an oil from intermediate 13a (0.45 g, 1.6 mmol) using the method described for intermediate 2b. The crude product was used in the subsequent reaction without further purification.

LCMS (Method A): 2.05 min, 298 [M+H] ⁺

Preparation of (S)-N-(1-hydroxypropan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 13)

The title compound (0.41 g) was prepared as a gum from intermediate 13b (0.45 g, 1.5 mmol) using the method described for intermediate 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 1.68 min, 270 [M+H] ⁺

Preparation of (S)-methyl 2-(benzylamino)-3-methylbutyrate (Intermediate 14a)

By triethylamine (3.7mL, 27mmol), benzaldehyde (2.7mL, 27mmol), (S)-methyl 2-amino-3-methylbutyrate hydrochloride (4.5g, 27mmol) and NaBH (OAc) ₃ (11.4g, 54mmol) mixture in DCE (20mL) stirs and spends the night.Reactant mixture is concentrated in a vacuum, and then residue is dissolved in diethyl ether (200mL).Solution is washed with water (3x100mL), and then organic matter is separated, and is extracted into 1M hydrochloric acid (100mL).Water layer is separated, alkalized with 2M sodium hydroxide solution, then crude product is extracted into diethyl ether (200mL) and washed with water (2x100mL).By the organic matter merged through Na ₂ SO ₄ drying, filter and concentrate in a vacuum, to obtain the title compound (5.4g) in oily matter.

LCMS (Method A): 0.81 min, 222 [M+H] ⁺

Preparation of (S)-2-(Benzylamino)-3-methylbutan-1-ol (Intermediate 14b)

To the ice-cold solution of intermediate 14a (1.8g, 8.1mmol) in anhydrous THF (20mL) is added dropwise 2MLiAlH ₄ (8.1mL, 16mmol) in THF, and the reaction mixture is stirred under ice bath for 2hr.The reaction mixture is quenched by adding water (2mL) followed by 2M sodium hydroxide solution (3mL).The mixture is passed through filtration, and concentrated in vacuo.The crude product is purified by chromatography on Biotage Companion ^™ (40g posts, 0% to 5% ammonia solution in DCM), to obtain the title compound (1.3g) in an oily state.

LCMS (Method A): 1.65 min, 194 [M+H] ⁺

Preparation of (S)-2-(Benzyl(cyclopropyl)amino)-3-methylbutan-1-ol (Intermediate 14c)

To a solution of intermediate 14b (1.8 g, 9.3 mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (4.9 g, 28 mmol) in methanol (100 mL) was added sodium cyanoborohydride (1.8 g, 28 mmol) and AcOH (0.7 mL), and the mixture was heated at reflux for 10 hr. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (40 mL). The solution was washed with water ( ₂ x 20 mL), dried over _NaSO , filtered, and concentrated in vacuo to give the title compound (2.3 g) as an oil.

LCMS (Method A): 0.89 min, 234 [M+H] ⁺ ; (Method B): 2.63 min, 234 [M+H] ⁺

Preparation of (S)-N-cyclopropyl-N-(1-hydroxy-3-methylbutan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Intermediate 14)

A mixture of intermediate 14c (2.2 g, 9.4 mmol), palladium hydroxide on carbon (0.40 g) and methanol (80 mL) in an autoclave was filled with hydrogen to a pressure of 1 bar, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in anhydrous DMF (10 mL) and treated with [1,1'-biphenyl]-2-carboxylic acid (2.3 g, 11 mmol), DIPEA (3.7 mL, 21 mmol) and HATU (4.4 g, 12 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours, then at 40 ° C for another 2 hours. The reaction mixture was allowed to cool and then diluted with diethyl ether (100 mL). The solution was washed with water (2x100 mL), brine (2x100 mL), and the organic matter was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ (120 g column, 50% EtOAc in isohexane) to give the title compound as an oil (0.40 g).

LCMS (Method A): 2.31 min, 324 [M+H] ⁺

Preparation of (S)-2-(Benzyl(methyl)amino)butan-1-ol (Intermediate 15a)

A mixture of (S) -2- aminobutan-1-ol (3.5 g, 39 mmol), benzaldehyde (4.2 g, 39 mmol), NaBH (OAc) ₃ (18.6 g, 98 mmol) and AcOH (2.3 mL, 39 mmol) in DCE (200 mL) was stirred at ambient temperature for 1 hour. A 37% aqueous solution (15 mL, 196 mmol) of formaldehyde was added, and the mixture was stirred for another 16 hours. The reaction mixture was quenched with saturated NaHCO ₃ aqueous solution, organic matter was separated, dried over MgSO ₄ , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (40% to 66% EtOAc in heptane) to obtain the title compound (4.6 g) as an oil.

¹ H NMR (400MHz; CDCl ₃ )7.51(m,5H),3.72(d,1H),3.59(m,1H),3.57(d,1H),3.42(m,1H),2.72(m,1H),2.23(s,3H),1.67(m,1H),1.20(m,1H) and 0.92(t,3H).

Preparation of (S)-tert-butyl (1-hydroxybutan-2-yl)(methyl)carbamate (Intermediate 15b)

The mixture of intermediate 15a (4.6g, 24mmol), di-tert-butyl dicarbonate (5.8g, 26mmol), palladium hydroxide carbon (6.5g) and methanol (135mL) in autoclave is filled with hydrogen, and stirred at ambient temperature for 18hr.The reaction mixture is passed through filtration, and concentrated in a vacuum.The crude product is purified by flash column chromatography (40% EtOAc in heptane), to obtain the title compound (4.4g) in an oily state.

¹ H NMR (400 MHz; CDCl ₃ ) 3.98 (m, 1H), 3.57 (m, 2H), 2.72 (s, 3H), 1.86 (m, 1H), 1.45 (s, 9H), 1.44 (m, 2H) and 0.88 (t, 3H).

Preparation of (S)-tert-butyl (1-((5-chloropyridin-2-yl)amino)butan-2-yl)(methyl)carbamate (Intermediate 15c)

At 0 DEG C, to the mixture of intermediate 15b (4.4g, 21mmol) and NaHCO ₃ (1.8g, 84mmol) in DCM (60mL), Dess-Martin periodinane (10g, 424mmol) is slowly added.The reaction mixture is allowed to heat to ambient temperature and stir for 18hr.The reaction mixture is quenched with saturated NaHCO ₃ aqueous solution, organic matter is separated, through MgSO ₄ drying, filter, and concentrate in a vacuum.Residue is dissolved in DCE (200mL) and 5-chloropyridine-2-amine (2.3g, 18mmol) is added.The reaction mixture is stirred for 5hr, then NaBH (AcO) ₃ (20g, 108mmol) is added, and it is continued to stir for 20hr.The reaction mixture is quenched with saturated NaHCO ₃ aqueous solution, organic matter is separated, through MgSO ₄ drying, filter, and concentrate in a vacuum. The crude product was purified by flash column chromatography (14% EtOAc in heptane) to give the title compound as an oil (1.9 g).

¹ H NMR (300MHz; CDCl ₃ )8.00(bd,1H),7.26(t,1H),7.31(s,1H),6.30(d,1H),4.84(bs,0.5H),4.53(bs,0.5H),4.20(bm,1.5H),3 .39(bm,1H),3.19(bm,1H),2.70(s,1.5H),2.65(s,1.5H),1.76(bs,0.5H),1.61-1.29(m,9H),0.91(t,3H).

Preparation of (S)-N ¹ -(5-chloropyridin-2-yl)-N ² -methylbutane-1,2-diamine trihydrochloride (Intermediate 15)

A mixture of intermediate 15c (1.9 g, 6.3 mmol) and 4M HCl in dioxane (50 mL) was stirred at ambient temperature for 18 hr. The reaction mixture was concentrated in vacuo to give the title compound (1.47 g) as a solid.

^1H NMR (400 MHz; MeOD) 8.06 (s, 1H), 7.89 (d, 1H), 7.08 (d, 1H), 3.75 (m, 2H), 3.62 (m, 1H), 3.40 (m, 1H), 2.76 (s, 3H), 1.81 (m, 2H) and 1.08 (t, 3H). Preparation of methyl 5-nitro-2-(2H-1,2,3-triazol-2-yl)benzoate (Intermediate 16a)

To a solution of methyl 2-bromo-5-nitrobenzoate (2.0 g, 7.7 mmol), copper (I) iodide (73 mg, 0.38 mmol), and potassium carbonate (2.7 g, 19 mmol) in a mixture of THF (56 mL) and DMF (12 mL) at 40° C., 2H-1,2,3-triazole (0.64 g, 9.2 mmol) was added, and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was poured into water (100 mL) and the precipitate was collected by filtration. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 5% to 50% diethyl ether in isohexane) to give the title compound (1.6 g) as a solid.

Preparation of methyl 5-amino-2-(2H-1,2,3-triazol-2-yl)benzoate (Intermediate 16b)

A mixture of intermediate 16a (0.62 g, 2.5 mmol), iron (0.42 g, 7.5 mmol) and ammonium chloride (1.34 g, 25 mmol) in ethanol (20 mL) and water (10 mL) was heated at reflux for 1 hr. The reaction mixture was allowed to cool, poured into water (100 mL), and the crude product was extracted into EtOAc. The combined organics were concentrated in vacuo, and the crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 50% diethyl ether in isohexane) to give the title compound (0.43 g) as a gum.

LCMS (Method A): 1.26 min, 219 [M+H] ⁺

Preparation of methyl 5-(dimethylamino)-2-(2H-1,2,3-triazol-2-yl)benzoate (Intermediate 16c)

A mixture of intermediate 16b (0.43 g, 2.0 mmol), 10% palladium on carbon (0.21 g, 2.0 mmol), a 37% aqueous solution of formaldehyde (1.5 mL, 20 mmol) and ethanol (20 mL) in an autoclave was filled to a pressure of 5 bar with hydrogen, and the reaction mixture was stirred at ambient temperature for 4 hr. The reaction mixture was filtered through HPLC and purified by ion exchange chromatography using an SCX resin column (5 g, washed with 10 column volumes of methanol, then eluted with 5% methanolic ammonia) to give the title compound (0.44 g) as a solid.

LCMS (Method A): 1.86 min, 247 [M+H] ⁺

Preparation of 5-(dimethylamino)-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 16)

A mixture of intermediate 16c (0.30 g, 1.2 mmol) and LiOH (0.12 g, 4.9 mmol) in water (10 mL) and THF (10 mL) was stirred at 40 ° C for 1 hour. The reaction mixture was allowed to cool, then acidified with AcOH and concentrated in vacuo. The crude product was purified by ion exchange chromatography using SCX resin column (5 g, washed with 10 column volumes of methanol, then eluted with 5% methanolic ammonia) to obtain the title compound (0.28 g) as a solid.

LCMS (Method A): 1.44 min, 233 [M+H] ⁺

Preparation of 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)nicotinic acid (Intermediate 17)

A mixture of (1R, 2R) ^-N1 , ^N2 -dimethylcyclohexane-1,2-diamine (63 mg, 0.44 mmol), 2H-1,2,3-triazole (0.61 g, 8.9 mmol), 2-chloro-5-(trifluoromethyl)nicotinic acid (1.0 g, 4.4 mmol), CuI (84 mg, 0.44 mmol) and _Cs2CO3 (2.9 g, 8.9 mmol) in _dioxane (10 mL) was heated under reflux for 4 hr. The reaction mixture was allowed to cool, poured into water (30 mL) and acidified to pH 1-2 with 1 M hydrochloric acid. The crude product was extracted into EtOAc (3x50 mL), and the combined organics were then dried over _Na2SO4 , _filtered and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 5% methanol in DCM containing 0.1% AcOH) to give the title compound as a solid (0.27 g).

LCMS (Method A): 1.37 min, 259 [M+H] ⁺

Preparation of (S)-tert-butyl (1-((5-chloropyridin-2-yl)amino)-1-oxobutan-2-yl)carbamate (Intermediate 18a)

To a solution of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (10 g, 50 mmol) in DMF (120 mL) was added HBTU (20 g, 52 mmol) and DIPEA (17 mL, 100 mmol) at 0°C. After 20 min, 2-amino-5-chloropyridine (6.4 g, 50 mmol) was added, and the reaction mixture was then allowed to warm to ambient temperature and stirred for 5 days. The reaction mixture was partitioned between EtOAc and water, and the organics were separated and washed with saturated aqueous _NaHCO3 and brine. The organics were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (20% to 30% EtOAc in heptane) to give the title compound (10 g) as a solid.

¹ H NMR (400MHz; DMSO-d ₆ )10.56(s,1H),8.34(s,1H),8.05(d,1H),7.87(d,1H),4.07(bq,1H),1.65(m,2H),1.39(s,9H),0.85(t,3H).

Preparation of (S)-tert-butyl (1-((5-chloropyridin-2-yl)amino)butan-2-yl)carbamate (Intermediate 18b)

To a solution of intermediate 18a (5.4 g, 17.4 mmol) in anhydrous THF (50 mL) was added LiAlH ₄ (3.9 g, 104 mmol) in portions at 0° C., maintaining the reaction temperature at <5° C. The reaction mixture was stirred for 6 hr at 0° C. and then quenched by the addition of Na ₂ SO ₄ 10H ₂ O. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (15% to 20% EtOAc in heptane) to give the title compound (2.3 g) as a solid.

¹ H NMR (400MHz; CDCl ₃ )7.98(s,1H),7.30(d,1H),6.36(d,1H),5.00(bs,1H),4.59(bs,1H),3.67 (m,1H),3.32(m,2H),1.60(m,1H),1.45(m,1H),1.40(s,9H),0.98(t,3H).

Preparation of (S)-N ¹ -(5-chloropyridin-2-yl)butane-1,2-diamine trihydrochloride (Intermediate 18)

A solution of intermediate 18b (1.4 g, 4.8 mmol) and 4M HCl in dioxane (25 mL) was stirred at ambient temperature for 18 hr. The reaction mixture was concentrated in vacuo to give the title compound (1.1 g) as a solid.

¹ H NMR (400 MHz; DMSO-d ₆ ) 8.15 (m, 3H), 7.98 (s, 1H), 7.66 (d, 1H), 6.85 (d, 1H), 3.47 (m, 2H), 3.21 (m, 1H), 1.60 (m, 2H) and 0.93 (t, 3H).

Preparation of (S)-methyl 2-(benzyl(methyl)amino)-3-methylbutyrate (Intermediate 19a)

To a solution of intermediate 14a (4.0 g, 18 mmol) in DCE (100 mL) were added molecular sieves (3 g), a 37% aqueous solution of formaldehyde (2.7 mL, 36 mmol) and NaBH(OAc) ₃ (7.7 g, 36 mmol), and the reaction mixture was stirred at ambient temperature for 1 hr. The solution was decanted and washed with saturated aqueous NaHCO ₃ (2 x 20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (4.2 g) as an oil.

LCMS (Method A): 1.33 min, 236 [M+H] ⁺

Preparation of (S)-2-(Benzyl(methyl)amino)-3-methylbutan-1-ol (Intermediate 19b)

To a solution of intermediate 19a (4.3 g, 18 mmol) in anhydrous THF (100 mL) cooled in an ice bath was slowly added a 2M solution of _LiAlH in THF (9.1 mL, 18 mmol). The mixture was allowed to heat to ambient temperature and stirred for 2 hours. The reaction mixture was quenched with water (100 mL) while cooling in an ice bath, and the product was then extracted into EtOAc (200 mL). The combined organics were washed with water, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the title compound (3.7 g) as an oil.

LCMS (Method A): 0.52 min, 208 [M+H] ⁺

Preparation of (S)-tert-butyl (1-hydroxy-3-methylbutan-2-yl)(methyl)carbamate (Intermediate 19c)

The title compound (3.7 g) was prepared as an oil from intermediate 19b (3.7 g, 18 mmol) using the method described for intermediate 15b.The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

Preparation of (S)-tert-butyl (1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)(methyl)carbamate (Intermediate 19d)

The title compound (0.71 g) was prepared as an oil from intermediate 19c (0.8 g, 3.7 mmol) and 5-chloropyridin-2-amine (0.47 g, 3.7 mmol) using the method described for intermediate 15c. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (10 g, washed with methanol then eluted with 10% methanolic ammonia) followed by chromatography on a Biotage Companion ^™ (40 g cartridge, 0% to 70% EtOAc in isohexane).

LCMS (Method A): 2.30 min, 328 [M+H] ⁺

Preparation of (S)-N ¹ -(5-chloropyridin-2-yl)-N ² ,3-dimethylbutane-1,2-diamine (Intermediate 19)

The title compound (0.42 g) was prepared as a gum from intermediate 19d (0.7 g, 2.1 mmol) using the method described for intermediate 15. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (10 g, washed with methanol then eluted with 5% methanolic ammonia).

LCMS (Method A): 0.90 min, 228 [M+H] ⁺

Preparation of (S)-2-(Benzylamino)-3-methylbutanamide (Intermediate 20a)

The title compound (12 g) was prepared as a solid from (S)-2-amino-3-methylbutanamide hydrochloride (10 g, 65 mmol) using the method described for intermediate 14a. The crude product was used in the subsequent reaction without further purification.

LCMS (Method C): 1.71 min, 207 [M+H] ⁺

Preparation of (S)-2-(Benzyl(methyl)amino)-3-methylbutanamide (Intermediate 20b)

The title compound (8.3 g) was prepared as a gum from intermediate 20a (10 g, 65 mmol) using the procedure described for intermediate 19a. The crude product was used in the subsequent reaction without further purification.

LCMS (Method C): 1.73 min, 221 [M+H] ⁺

Preparation of (S)-tert-butyl (2-(benzyl(methyl)amino)-3-methylbutyl)carbamate (Intermediate 20c)

To the solution (cooling in ice bath/salt bath) of intermediate 20b (4.0g, 18mmol) in anhydrous diethyl ether (100mL), LiAlH _1M solution (36mL, 36mmol) in THF is added. The reaction mixture is heated to ambient temperature, and then heated under reflux for 18hr. It is then cooled in an ice bath, and quenched with 4M sodium hydroxide solution (3mL) subsequently with water (1mL). The reaction mixture is passed through filtration, and concentrated in a vacuum. The residue is dissolved in DCM (100mL), and tert-Butyl dicarbonate (4.2mL, 18mmol) is added to the solution, and the mixture is stirred for 16hr. The reaction mixture is concentrated in a vacuum, and the crude product is purified by chromatography on Biotage Companion ^™ (120g posts, 0% to 100% ammonia solution in diethyl ether), to obtain the title compound (3.8g) in gum.

LCMS (Method A): 3.06 min, 307 [M+H] ⁺

Preparation of (S)-tert-butyl (3-methyl-2-(methylamino)butyl)carbamate (Intermediate 20d)

A mixture of intermediate 20c (5.6 g, 18 mmol), 20% palladium hydroxide on carbon (2.6 g) and methanol (200 mL) in an autoclave was filled with hydrogen to a pressure of 4 bar and stirred at ambient temperature for 18 hr. The reaction mixture was filtered through HPLC and concentrated in vacuo to give the title compound (3.5 g) as an oil.

LCMS (Method C): 1.56 min, 217 [M+H] ⁺

Preparation of (S)-N-(1-amino-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Intermediate 20)

To a solution of intermediate 20d (1.0 g, 4.6 mmol) and [1,1'-biphenyl]-2-carboxylic acid (1.0 g, 5.1 mmol) and DIPEA (2.4 mL, 14 mmol) in anhydrous DMF (10 mL) was added HATU (1.9 g, 5.1 mmol) and the mixture was stirred for 3 days. The reaction mixture was poured into water (40 mL) and the crude product was extracted with diethyl ether (1 x 30 mL). The combined organics were washed with brine (2 x 20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on a Biotage Companion ^™ (40 g column, gradient from 0% to 100% EtOAc in isohexane). The resulting intermediate was dissolved in 4M HCl (10 mL) in dioxane and allowed to stand at ambient temperature for 1 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by ion exchange chromatography using an SCX resin cartridge (10 g cartridge, washed with methanol then eluted with 2% methanolic ammonia) to give the title compound as an oil (0.58 g).

LCMS (Method A): 1.36 min, 297 [M+H] ⁺

Preparation of (S)-2-(Benzyl(methyl)amino)butanamide (Intermediate 21a)

By triethylamine (10mL, 72mmol), benzaldehyde (7.7g, 72mmol), (S)-2-aminobutanamide hydrochloride (10g, 72mmol) and NaBH (OAc) ₃ (30g, 140mmol) in DCE (200mL) solution is stirred for 16hr.Reactant mixture is concentrated in vacuo, and then residue is dissolved in diethyl ether (200mL).Solution is washed with water (3x100mL), and then organic matter is separated, and is extracted into 1M hydrochloric acid (100mL).Water layer is separated, alkalized with 2M sodium hydroxide solution, and then crude product is extracted into diethyl ether (200mL) and washed with water (2x100mL).By the organic matter that merges through Na ₂ SO ₄ drying, filter, and concentrate in vacuo. The residue is dissolved in DCE (200mL) and processed with 37% aqueous solution of formaldehyde (5.4mL, 72mmol) and AcOH (4.1mL, 72mmol), and the reaction mixture is stirred for 1hr. To the solution, NaBH (OAc) is added ( _31g , 145mmol), and the reaction mixture is stirred for 16hr. The saturated _NaHCO aqueous solution is then quenched, and the crude product is then extracted into DCM. The organic matter merged is separated and concentrated in a vacuum. Residue is distributed between diethyl ether (400mL) and _1M hydrochloric acid. The water layer is separated, alkalized with 2M sodium hydroxide solution, and the crude product is extracted into EtOAc (2x300mL). The organic matter merged is through Na _SO dry, filter and concentrate in a vacuum, to obtain title compound (13g). Alternative method: Under an atmosphere of hydrogen (2 bar), (S)-2-aminobutanamide hydrochloride (42 g, 0.30 mol), sodium hydroxide (12 g, 0.30 mol), 5% palladium on carbon (14 g, 50% water by mass) and benzaldehyde (33 mL, 0.32 mol) were combined in water (84 mL) and ethanol (0.34 L) and stirred at ambient temperature for 24 hours. Thereafter, 37% aqueous formaldehyde solution (56 mL, 0.76 mol) was added and the hydrogen pressure was restored for 24 hours. The mixture was filtered through Celite®. The liquid was concentrated to a low volume and partitioned between water (0.84 L) and tBME (0.84 L). The aqueous solution was extracted with tBME (0.42 L) and the combined organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was stirred in tBME (43 mL) and hexane (0.63 L) and heated to cause dissolution. The solution was then cooled to 5° C. and after stirring for 1 hr, the product was filtered, washed with cold hexane (0.42 L), and dried to obtain the title compound (42 g) as a solid.

LCMS (Method B): 1.45 min, 207 [M+H] ⁺

LCMS (Method N): 1.21 min, 207 [M+H] ⁺

Preparation of (S)-tert-butyl (2-(benzyl(methyl)amino)butyl)carbamate (Intermediate 21b)

_LiAlH is added to the ice-cold solution of intermediate 21a (13g, 63mmol) in anhydrous diethyl ether (100mL) 1M solution (126mL, 126mmol) in THF, and the reaction mixture is heated to environment temperature, and then heated under reflux for 18hr.Reactant mixture is cooled in an ice bath, and quenched with 4M sodium hydroxide solutions (12mL) subsequently with water (5mL).Then the reaction mixture is passed through filtration, and concentrated in a vacuum.Residue is dissolved in DCM (100mL) and tert-Butyl dicarbonate (14mL, 63mmol) is added.The reaction mixture is stirred for 16hr, then concentrated in a vacuum, and the crude product is purified by chromatography on Biotage Companion ^™ (120g posts, 0% to 5% ammonia solution in DCM), to obtain the title compound (15g) in an oily state.

LCMS (Method B): 2.77 min, 293 [M+H] ⁺

Preparation of (S)-tert-butyl (2-(methylamino)butyl)carbamate (Intermediate 21c)

The mixture of intermediate 21b (15g, 52mmol), 36L paste palladium carbon (1.1g, 10mmol) and methanol (100mL) in autoclave is filled with hydrogen to a pressure of 5 bar, and stirred at ambient temperature for 18hr.The reaction mixture is filtered through and concentrated in vacuo to obtain the title compound (10g) as an oil.

LCMS (Method A): 0.55 min, 203 [M+H] ⁺

Preparation of (S)-N-(1-aminobutan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 21)

To a solution of 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (2.3 g, 10 mmol) [prepared as described in WO 2011/050198], intermediate 21c (1.9 g, 9.3 mmol), and DIPEA (4.9 mL, 28 mmol) in anhydrous MeCN (60 mL) was added HATU (3.9 g, 10 mmol), and the reaction mixture was stirred for ₁₆ hr. It was concentrated in vacuo, and the residue was dissolved in EtOAc (300 mL). The solution was washed with saturated aqueous _NaHCO₃ (2 x 100 mL), brine (100 mL), and the organics were dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The crude intermediate was purified by chromatography on a Biotage Companion ^™ (220 g column, 0% to 40% EtOAc in isohexane). The resulting intermediate was dissolved in DCM (200 mL) and treated with TFA (40 mL), and the reaction mixture was allowed to stand at ambient temperature for 16 hr. It was concentrated in vacuo, and the crude product was purified by ion exchange chromatography using an SCX resin cartridge (50 g column, washed with methanol, then eluted with 10% methanolic ammonia) to give the title compound (2.4 g).

LCMS (Method A): 1.09 min, 308/310 [M+H] ⁺

Preparation of (S)-N-(1-aminobutan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Intermediate 22)

The title compound (510 mg) was prepared as an oil from 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinate hydrochloride (0.56 g, 2.3 mmol) [prepared as described in WO 2010/063662] and intermediate 21c (0.47 g, 2.3 mmol) using the method described for intermediate 21. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (20 g cartridge, washed with methanol, then eluted with 10% methanolic ammonia).

LCMS (Method A): two peaks at 0.53 min and 0.90 min, 289 [M+H] ⁺

Preparation of (S)-N-(1-amino-3-methylbutan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 23)

To a solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.38 g, 1.9 mmol) [prepared as described in WO 2012/148553], intermediate 20d (0.41 g, 1.9 mmol), and DIPEA (0.98 mL, 5.6 mmol) in anhydrous DMF (10 mL) was added HATU (0.78 g, 2.1 mmol), and the reaction mixture was stirred for 3 days. It was then poured into water (30 mL) and the crude product was extracted into EtOAc ( ₂ x 20 mL). The combined organics were dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The crude intermediate was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% ethyl acetate in isohexane). The intermediate produced is dissolved in 4M HCl (10mL) in dioxane and allowed to stand for 1hr at ambient temperature. The reaction mixture is concentrated in a vacuum, then 2M sodium hydroxide solution is added, and the product is extracted into EtOAc. The organic matter merged is dried over Na ₂ SO ₄ , filtered and concentrated in a vacuum to obtain the title compound (0.29g) as an oil.

LCMS (Method A): 1.14 min, 302 [M+H] ⁺

Preparation of (S)-N-(1-amino-3-methylbutan-2-yl)-N,1-dimethyl-1H-indole-3-carboxamide (Intermediate 24)

The title compound (0.38 g) was prepared as a gum from 1-methyl-1H-indole-3-carboxylic acid (0.30 g, 1.7 mmol) and intermediate 20d (0.37 g, 1.7 mmol) using the method described for intermediate 23. The reaction mixture was concentrated in vacuo and the residue was purified by ion exchange chromatography using an SCX resin cartridge (10 g cartridge, washed with methanol then eluted with 2% methanolic ammonia).

LCMS (Method A): 1.05 min, 274 [M+H] ⁺

Preparation of (S)-N-(1-amino-3-methylbutan-2-yl)-N,2-dimethylquinoline-4-carboxamide (Intermediate 25)

The title compound (0.37 g) was prepared from 2-methylquinoline-4-carboxylic acid (0.30 g, 1.6 mmol) and intermediate 20d (0.35 g, 1.6 mmol) using the method described for intermediate 23. The reaction mixture was concentrated in vacuo and the residue was purified by ion exchange chromatography using an SCX resin cartridge (10 g cartridge, washed with methanol, then eluted with 5% methanolic ammonia).

LCMS (Method A): 0.47 min, 286 [M+H] ⁺

Preparation of (S)-N-(1-amino-3-methylbutan-2-yl)-N-methyl-2-(trifluoromethoxy)benzamide (Intermediate 26)

The title compound (0.32 g) was prepared from 2-(trifluoromethoxy)benzoic acid (0.30 g, 1.5 mmol) and intermediate 20d (0.31 g, 1.5 mmol) using the method described for intermediate 23. The reaction mixture was concentrated in vacuo and the residue was purified by ion exchange chromatography using an SCX resin cartridge (10 g cartridge, washed with methanol, then eluted with 5% methanolic ammonia).

LCMS (Method A): 1.19 min, 305 [M+H] ⁺

Preparation of 5-methyl-2-morpholinobenzoic acid (Intermediate 27)

The mixture of ethyl 2-fluoro-5-methyl benzoate (0.5g, 2.7mmol) and morpholine (4.8g, 55mmol) is heated under reflux for 3hr.Then the mixture is poured in water (100mL), acidified with AcOH and extracted in ether (2x30mL).The organic matter water (20mL) merging is washed, through _{Na SO} dry, filter and concentrate in a vacuum.Residue is dissolved in THF (20mL) and water (20mL), processed with LiOH (0.2g, 8.2mmol), and heated under reflux for 3hr.The mixture is acidified with 1M hydrochloric acid, and concentrated in a vacuum, so that the product can be collected by filtration, and washed with cold water, to obtain the title compound (0.52g) in solid.

LCMS (Method A): 1.09 min, 220 [M+H] ⁺

Preparation of (S)-N-(1-amino-3-methylbutan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Intermediate 28)

To a solution of intermediate 20d (0.34 g, 1.6 mmol), 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [prepared as described in WO2011/023578] (0.35 g, 1.7 mmol) and DIPEA (0.82 mL, 4.72 mmol) in anhydrous DMF (7 mL) was added HATU (0.66 g, 1.7 mmol), and the mixture was stirred overnight. The reaction mixture was poured into water (30 mL) and extracted with EtOAc. The combined organics were dried over _MgSO , filtered, and concentrated in vacuo. The crude intermediate was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 0% to 100% EtOAc in heptane). The resulting intermediate was dissolved in 4M HCl in dioxane (10 mL) and stirred at ambient temperature for 1 hr. The reaction mixture is concentrated in a vacuum, and then 2M sodium hydroxide solution is added, and the product is extracted into EtOAc. The organic matter merged is dried over _MgSO4 , filtered and concentrated in a vacuum to obtain the title compound (0.27g) in a glassy state. The crude product is not further purified and used in subsequent reactions.

LCMS (Method J): 1.36 min, 303 [M+H] ⁺

Preparation of methyl (2S)-2-aminobutyrate hydrochloride (Intermediate 29a)

At -20 DEG C, to (S) -2- aminobutyric acid (5.0g, 48mmol) solution in methanol (50mL) thionyl chloride (3.9mL, 53mmol) was added dropwise, and the mixture was allowed to heat to ambient temperature, and stirred overnight. The reaction mixture was concentrated in a vacuum, and then the residue was washed with diethyl ether, filtered and dried in a vacuum, to obtain the title compound (6.2g) in a solid. The crude product was not further purified and used in subsequent reactions.

LCMS (Method G): 0.16 min, 119 [M+H] ⁺

Preparation of (S)-methyl 2-(benzylamino)butyrate (Intermediate 29b)

By triethylamine (0.91mL, 6.5mmol), benzaldehyde (0.66mL, 6.5mmol), intermediate 29a (1.0g, 6.5mmol) and NaBH (OAc) ₃ (2.1g, 9.8mmol) mixture in DCE (5mL) is stirred overnight at ambient temperature. The reaction mixture is concentrated in a vacuum and the residue is dissolved in diethyl ether (30mL). The organic phase is washed with water, and the product is extracted into 1M hydrochloric acid. The aqueous phase is separated, alkalized to pH 9 with 2M sodium hydroxide solution, and extracted with diethyl ether. The organic matter merged is washed with water, through Na ₂ SO ₄ is dried, filtered and concentrated in a vacuum. The crude product is purified by chromatography on Biotage Isolera Four ^™ (50g posts, 10% to 50% EtOAc in heptane), to obtain the title compound (0.63g) in an oily state.

LCMS (Method J): 1.46 min, 208 [M+H] ⁺

Preparation of (S)-methyl 2-(benzyl(ethyl)amino)butyrate (Intermediate 29c)

To a solution of intermediate 29b (0.63 g, 3.0 mmol) in DCE (20 mL) was added acetaldehyde (0.34 mL, 6.1 mmol) and NaBH(OAc) ₍ 1.29 g, 6.1 mmol), and the mixture was stirred for 3 hr. The reaction mixture was diluted with DCM and washed with a saturated _NaHCO aqueous solution. The organic phase was dried over _MgSO , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (50 g column, 1% to 20% EtOAc in heptane) to obtain the title compound (0.54 g) in an oily form.

LCMS (Method G): 0.78 min, 237 [M+H] ⁺

Preparation of (S)-2-(Benzyl(ethyl)amino)butan-1-ol (Intermediate 29d)

_LiAlH is added dropwise to the ice-cold solution of intermediate 29c (0.55g, 2.1mmol) in anhydrous THF (12mL) 1M solution (4.1mL, 4.1mmol) of THF, and the mixture is stirred for 2hr in an ice bath.The reaction mixture is diluted with diethyl ether, and quenched by sequentially adding water (0.15mL) followed by 2M sodium hydroxide solutions (0.15mL) and water (0.5mL).The organic phase is separated, and then through _MgSO4 drying, filtered and concentrated in a vacuum, to obtain the title compound (0.48g) in an oily matter.The crude product is not further purified and used in subsequent reactions.

LCMS (Method G): 1.78 min, 208 [M+H] ⁺

Preparation of (S)-tert-butyl (2-(benzyl(ethyl)amino)butyl)carbamate (Intermediate 29e)

A mixture of intermediate 29d (0.48 g, 2.1 mmol), ethyl 2-{[(tert-butoxy) carbonyl] amino}-2-oxyacetic acid ethyl ester (0.45 g, 2.1 mmol) and triphenylphosphine (0.60 g, 2.3 mmol) in anhydrous THF (10 mL) was stirred at -10 ° C, and DEAD (0.33 mL, 2.1 mmol) was slowly added subsequently. The mixture was allowed to heat to ambient temperature and stirred for 3 hours. The reaction mixture was poured into salt water (20 mL) and extracted with diethyl ether, and the organic matter merged was concentrated in a vacuum. The residue was dissolved in THF (10 mL), and then 1M LiOH solution (0.26 mL, 25 mmol) was added, and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water (50 mL) and extracted with diethyl ether. The organic phase merged was concentrated in a vacuum. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 1% to 40% EtOAc in heptane) to give the title compound (0.44 g) as an oil.

LCMS (Method G): 0.92 min, 308 [M+H] ⁺

Preparation of (S)-tert-butyl (2-(ethylamino)butyl)carbamate (Intermediate 29f)

To a solution of intermediate 29e (0.44 g, 1.4 mmol) in EtOH (10 mL) was added 10% palladium hydroxide on carbon (40 mg), and the mixture was stirred under a hydrogen atmosphere for 18 hr. The reaction mixture was filtered and then concentrated in vacuo to give the title compound (0.26 g). The crude product was used in subsequent reactions without further purification.

¹ H NMR (500MHz, CDCl ₃ )4.99(bs,1H),3.20(bm,1H),3.04(m,1H),2.63(m,2H),2.55(bm,1H),1.44(s,9H),1.41(m,2H),1.09(t,3H),0.92(t,3H).

Preparation of (S)-N-(1-aminobutan-2-yl)-N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Intermediate 29)

To a solution of intermediate 29f (0.26 g, 1.2 mmol), 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [prepared as described in WO2011/023578] (0.34 g, 1.1 mmol) and DIPEA (0.45 mL, 3.3 mmol) in anhydrous DMF (5 mL) was added HATU (0.50 g, 1.3 mmol), and the mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with water (2 _x 100 mL). The organics were dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The crude intermediate was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 1% to 100% EtOAc in heptane). The resulting intermediate was dissolved in 4M HCl in dioxane (5 mL) and stirred at ambient temperature for 2 hr. The reaction mixture is concentrated in vacuo, and then 2M sodium hydroxide solution (30mL) is added, and the product is extracted into EtOAc (2x30mL). The combined organic matter is dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the title compound (0.23g) as a solid. The crude product is not further purified and used in subsequent reactions.

LCMS (Method G): 0.7 min, 303 [M+H] ⁺

Preparation of (S)-2-cyclopropyl-2-(methylamino)ethanol (Intermediate 30a)

To an ice-cold solution of (S)-tert-butyl (1-cyclopropyl-2-hydroxyethyl) carbamate [prepared as described in WO 2013/046136] (0.61 g, 2.3 mmol) in anhydrous THF (10 mL) was added dropwise _a 1 M solution of LiAlH in THF (4.6 mL, 4.6 mmol). The reaction mixture was heated to ambient temperature and then heated at 55 ° C for 2 hours. It was then allowed to cool to ambient temperature, the mixture was diluted with diethyl ether (10 mL) and quenched by sequentially adding water (0.2 mL), 2 M sodium hydroxide solution (0.2 mL), water (0.6 mL), and the mixture was stirred for 15 min. The organic phase was separated and dried over _MgSO , filtered and concentrated in vacuo to obtain the title compound (0.32 g) as an oil. The crude product was used in subsequent reactions without further purification.

¹ H NMR (500MHz, CDCl ₃ )3.71(dd,1H),3.48(dd,1H),2.48(s,3H),1.76(m,1H),0.77(m,1H),0.59(m,1H),0.48(m,1H),0.27(m,1H),0.14(m,1H).

Preparation of (S)-N-(1-cyclopropyl-2-hydroxyethyl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Intermediate 30b)

To an ice-cold solution of intermediate 30a (0.27 g, 1.9 mmol), HATU (0.81 g, 2.1 mmol) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [prepared as described in WO 2011/023578] (0.68 g, 2.1 mmol) in anhydrous DMF (10 mL) was added DIPEA (1.7 mL, 9.7 mmol), and the mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo, and the residue was then dissolved in EtOAc and washed with water. The aqueous phase was extracted with EtOAc, and the combined organics were washed with water and brine. The organics were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 0% to 100% EtOAc in heptane). The crude product obtained is dissolved in methanol (5mL), and added in 0.5M LiOH solution (0.88mL, 0.44mmol), and the mixture is stirred for 2hr. The reaction mixture is neutralized with AcOH, and then concentrated in a vacuum. The residue is then redissolved in DCM (5mL), and washed with saturated NaHCO the aqueous solution. Organic phase is through _{Na 2 SO 4} is dried, filtered, and concentrated in a vacuum. The crude product is purified by chromatography on Biotage Isolera Four ^™ (25g posts, 0% to 10% methanol in DCM), to obtain the title compound (0.29g) in an oily state.

LCMS (Method G): 0.9 min, 302 [M+H] ⁺

Preparation of (S)-tert-butyl (2-cyclopropyl-2-(N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridinylamino)ethyl)carbamate (Intermediate 30c)

To a solution of intermediate 30b (0.29 g, 0.98 mmol), ethyl 2-{[(tert-butoxy)carbonyl]amino}-2-oxoacetate (0.20 mL, 0.98 mmol), and triphenylphosphine (0.28 g, 1.1 mmol) in anhydrous THF (12 mL) at -10°C was slowly added DIAD (0.19 mL, 0.98 mmol). The mixture was stirred at ambient temperature for 3 hours, and then DIAD (0.39 mL, 2.0 mmol) and triphenylphosphine (0.56 g, 2.1 mmol) were added, and stirring continued for 16 hours. Additional portions of DIAD (0.39 mL, 2.0 mmol) and triphenylphosphine (0.56 g, 2.1 mmol) were added, and stirring continued for an additional 3 hours. The mixture was then poured into brine (12 mL) and extracted with diethyl ether. The combined organics were concentrated in vacuo. The residue is redissolved in THF (6mL), and 1M LiOH (12mL, 0.28mmol) is added, and the mixture is stirred to 16hr at ambient temperature.The reaction mixture is poured in water (30mL) and extracted with diethyl ether.The organic matter that this merges is concentrated in a vacuum.The crude product is purified by chromatography on Biotage Isolera Four ^TM (10g posts, 0% to 100% ethyl acetate in heptane), to obtain the title compound (0.15g) that is an oily matter.

¹ H NMR (500MHz, CDCl ₃ )8.25(d,0.43H),8.21(d,0.57H),7.90(s,0.86H),7.84(s,1.14H),7.30(m,1H),7.04( bs,0.57H),5.53(bs,0.43H),4.03(m,0.43H),3.66(m,0.43H),3.44(m,1H),3.32(m,0. 57H),3.19(m,0.57H),3.11(s,1.71H),2.87(s,1.29H),2.63(m,3H),1.48(s,3.87H),1 .38(s,5.13H),1(m,1.00H),0.68(m,1H),0.60(m,1.43H),0.49(m,1H),0.18(m,0.57H).

Preparation of (S)-N-(2-amino-1-cyclopropylethyl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Intermediate 30)

The solution of intermediate 30c (0.15g, 0.29mmol) in 4M HCl (in dioxane) (3mL) is stirred at ambient temperature for 2hr. The reaction mixture is concentrated in a vacuum, and then the residue is dissolved in 1M hydrochloric acid (10mL) and extracted with EtOAc. The aqueous phase is adjusted to pH 12 with 2M sodium hydroxide solution. The aqueous phase is extracted with EtOAc, followed by IPA/ chloroform (1:9, 10mL then 1:2, 10mL). The organic matter merged is dried over Na ₂ SO ₄ , filtered, and concentrated in a vacuum. The crude product is purified on Biotage Isolera Four ^™ (11g KP-NH columns, 0% to 100% EtOAc in heptane, followed by 0% to 10% alcohol in DCM) to obtain the title compound (33mg) in an oily form.

LCMS (Method G): 0.77 min, 302 [M+H] ⁺

Preparation of (S)-N ² -benzyl-N ² -methylbutane-1,2-diamine D-(-)-tartrate (1:1) (Intermediate 31a)

Intermediate 21a (50g, 0.24mol) is stirred in THF (0.42L) and is cooled to an internal temperature of 5°C. Add LiAlH _41M solution (0.36L, 0.36mol) in THF. Then allow the mixture to be heated to ambient temperature, and heat overnight at 30°C. After this, cool down the reaction. Add water (14mL), then add 15% sodium hydroxide solution (14mL) and water (42mL). Add tBME (52mL) and the mixture is stirred for 1hr at ambient temperature. Then the mixture is filtered, and the liquid is concentrated to provide an oily substance. The oily substance is stirred in THF (820mL), and the D-(-)-tartaric acid (31g, 0.21mol) added in methanol (180mL). Then the mixture is heated to 60°C, and keeps 1hr before allowing to cool back to ambient temperature, and stirs for 1hr. The product was filtered and washed with THF (2 x 333 mL) and dried to give the title compound as a solid (50 g).

LCMS (Method N): 1.09 min, 193 [M+H] ⁺

Preparation of (S)-N ² -benzyl- ^{N 2} -methyl-N ¹ -(5-(trifluoromethyl)pyrimidin-2-yl)butane-1,2-diamine (Intermediate 31b)

Intermediate 31a (89 g, 260 mmol) was stirred in water (710 mL). Potassium carbonate (108 g, 780 mmol) was added at approximately 22-25 ° C. A solution of 2-chloro-5-trifluoromethylpyrimidine (45 g, 250 mmol) in tBME (710 mL) was added and the mixture was left overnight at ambient temperature. The organic layer was separated, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the title compound (78 g) as an oil.

LCMS (Method N): 1.91 min, 339 [M+H] ⁺

Preparation of (S)-N ² -methyl-N ¹ -(5-(trifluoromethyl)pyrimidin-2-yl)butane-1,2-diamine (Intermediate 31)

Under a hydrogen atmosphere, intermediate 31b (26 g, 77 mmol) and 10% palladium on carbon (2.6 g, 50% water by mass) were combined in ethanol (200 mL) and stirred at ambient temperature for 48 hours. The mixture was then filtered through Celite® and concentrated in vacuo. The residue was dissolved in isopropyl acetate (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (18.5 g) as an oil.

LCMS (Method N): 1.65 min, 249 [M+H] ⁺

Preparation of 1-bromo-N,N-dimethylisoquinolin-3-amine (Intermediate 32a)

To a solution of 3-amino-1-bromoisoquinoline (685 mg, 3.1 mmol) in THF (12 mL) was added NaH (60% dispersion in oil) (294 mg, 7.4 mmol). After 30 min, iodomethane (0.46 mL, 7.4 mmol) was added. The reaction was stirred at ambient temperature for 18 hr. EtOAc (15 mL) and water (15 mL) were added, and the aqueous phase was extracted with EtOAc (10 mL). The combined organics were washed with water (25 mL), dried over _MgSO₄ , filtered, and concentrated in vacuo to give the title compound (700 mg) as an oil.

LCMS (Method K): 1.01 min, 251 [M+H] ⁺

Preparation of 3-(dimethylamino)isoquinoline-1-carboxylic acid (Intermediate 32)

A mixture of intermediate 32a (50 mg, 0.20 mmol), N-hydroxysuccinimide (46 mg, 0.40 mmol), triethylamine (40 mg, 0.40 mmol), xantphos (12 mg, 0.02 mmol) and Pd(OAc) ₂ (4 mg, 0.02 mmol) in DMSO (10 mL) was heated at 85°C in an autoclave under CO(g) (200 psi) for 18 hr. The mixture was filtered through 4% HCl (50 mL) washing with THF (50 mL). The filtrate was concentrated in vacuo to give a crude residue which was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (10 mL). The combined organics were washed with water (20 mL), dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 50% EtOAc in heptane) to give the title compound as a solid (17 mg).

LCMS (Method L): 0.46 min, 217 [M+H] ⁺

Preparation of (S)-tert-butylmethyl (1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)carbamate (Intermediate 33a)

To a solution of intermediate 31 (300 mg, 1.2 mmol) and K ₂ CO ₃ (167 mg, 1.2 mmol) in dioxane (3 mL) and water (3 mL) was added di-tert-butyl dicarbonate (290 mg, 1.3 mmol), and the mixture was stirred overnight at ambient temperature. The mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the title compound (380 mg) as a solid. The crude product was used in subsequent reactions without further purification.

LCMS (Method G): 1.28 min, 349 [M+H] ⁺

Preparation of (S)-tert-butylmethyl(1-(methyl(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)carbamate (Intermediate 33b)

To the solution of intermediate 33a (100mg, 0.29mmol) in anhydrous DMF (3mL), add 60% dispersion (23mg, 0.57mmol) of sodium hydride in mineral oil, and the mixture is stirred to 1hr at ambient temperature.Add iodomethane (18 μ L, 0.29mmol), and continue stirring overnight.The reaction mixture is diluted with EtOAc, and the organic phase is washed with water.Aqueous phase is extracted with EtOAc, and the organic matter water, salt solution merged are washed, and concentrated in a vacuum.The crude product is purified by chromatography on Biotage Isolera Four ^™ (25g posts, 0% to 100% EtOAc in heptane), to obtain the title compound (101mg) in oily matter.

LCMS (Method G): 1.40 min, 363 [M+H] ⁺

Preparation of (S)-N ¹ ,N ² -dimethyl-N ¹ -(5-(trifluoromethyl)pyrimidin-2-yl)butane-1,2-diamine (Intermediate 33)

A solution of intermediate 33b (101 mg, 0.29 mmol) in 4M HCl (in dioxane) (3 mL, 12 mmol) was stirred at ambient temperature for 2 hours. The mixture was diluted with EtOAc and washed with 1M sodium hydroxide solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (72 mg) as an oil. The crude product was used in subsequent reactions without further purification.

LCMS (Method G): 0.80 min, 264 [M+H] ⁺

Preparation of (S)-tert-butyl(1-((2-methoxyethyl)(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)(methyl)carbamate (Intermediate 34a)

To the solution of intermediate 33a (100mg, 0.29mmol) in anhydrous DMF (3mL), add 60% dispersion (23mg, 0.57mmol) of sodium hydride in mineral oil, and the mixture is stirred to 1hr at ambient temperature.Add 1-bromo-2-methoxyethane (27 μ L, 0.29mmol), and continue stirring overnight.The reaction mixture is diluted with EtOAc, and the organic phase is washed with water.Aqueous phase is extracted with EtOAc, and the organic matter water, salt solution merged are washed, and concentrated in a vacuum.The crude product is purified by chromatography on Biotage Isolera Four ^™ (25g posts, 0% to 100% EtOAc in heptane), to obtain the title compound (126mg) in oily matter.

LCMS (Method G): 1.42 min, 408 [M+H] ⁺

Preparation of (S)-N ¹ -(2-methoxyethyl)-N ² -methyl-N ¹ -(5-(trifluoromethyl)pyrimidin-2-yl)butane-1,2-diamine (Intermediate 34)

A solution of intermediate 34b (126 mg, 0.28 mmol) in 4M HCl (in dioxane) (3 mL, 12 mmol) was stirred at ambient temperature for 2 hours. The mixture was diluted with EtOAc and washed with 1M sodium hydroxide solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (49 mg) as an oil. The crude product was used in subsequent reactions without further purification.

LCMS (Method G): 0.87 min, 308 [M+H] ⁺

Preparation of (S)-2-(Benzylamino)-4,4,4-trifluorobutyramide (Intermediate 35a)

By (S) -2- amino -4,4,4- trifluorobutyramide hydrochloride (508mg, 2.6mmol), benzaldehyde (280mg, 2.6mmol) and triethylamine (280mg, 2.6mmol) in 2,2,2- trifluoroethanol (10mL) is heated at 60 DEG C. After 1hr, _NaBH4 (300mg, 7.9mmol) is added, and before being allowed to cool to ambient temperature, the reaction mixture is heated for another 2hr. DCM (20mL) and water (20mL) are added, and these phases are separated. Organic matter is dried over _MgSO4 , filtered and concentrated in vacuo. Residue is purified by dry flash chromatography (0% to 75% EtOAc in heptane) to obtain the title compound (467mg) as a solid.

LCMS (Method K): 0.65 min, 247 [M+H] ⁺

Preparation of (S)-2-(Benzyl(methyl)amino)-4,4,4-trifluorobutyramide (Intermediate 35b)

To a mixture of intermediate 35a (430 mg, 1.8 mmol), a 37% aqueous solution of formaldehyde (106 mg, 3.5 mmol) and AcOH (0.11 mL, 1.8 mmol) in DCM (10 mL) was added NaBH(OAc) ₍ 0.89 g, 4.2 mmol). The reaction mixture was stirred at ambient temperature for 2.5 hr. A saturated _aqueous solution of NaHCO (10 mL) was added and the phases were separated. The organics were dried over _MgSO , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 60% EtOAc in heptane) to give the title compound (431 mg) as an oil.

LCMS (Method K): 0.75 min, 261 [M+H] ⁺

Preparation of (S)-N ² -benzyl-4,4,4-trifluoro-N ² -methylbutane-1,2-diamine (Intermediate 35c)

_LiAlH4 (203mg, 5.3mmol) is suspended in THF (8mL), and heated at 50 DEG C for 18hr.Then it is allowed to cool to environment temperature, and add a solution of intermediate 35b (431mg, 1.7mmol) in THF (2mL).The reaction mixture is heated to 50 DEG C for 2.5 hours, and then cooled in an ice bath.Water (0.25mL) is added dropwise, followed by addition of 2M sodium hydroxide solution (0.25mL) and water (0.75mL).The mixture is stirred for 30min, filtered, and concentrated in a vacuum.Residue is passed through into dry flash chromatography (0% to 10% ammonia solution in DCM) and purified to obtain the title compound (120mg) as an oil.

LCMS (Method L): 2.09 min, 247 [M+H] ⁺

Preparation of (S)-N ² -benzyl-4,4,4-trifluoro- ^N 2 -methyl-N ¹ -(5-(trifluoromethyl)pyrimidin-2-yl)butane-1,2-diamine (Intermediate 35d)

A mixture of intermediate 35c (120 mg, 0.49 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (93 mg, 0.51 mmol) and DIPEA (0.17 mL, 0.97 mmol) in MeCN (10 mL) was heated at 60 ° C for 2 hr. EtOAc (10 mL) and water (10 mL) were added and the phases were separated. The organics were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 30% EtOAc in heptane) to give the title compound (153 mg) as an oil.

LCMS (Method K): 0.99 min, 393 [M+H] ⁺

Preparation of (S)-4,4,4-trifluoro- ^N 2 -methyl-N ¹ -(5-(trifluoromethyl)pyrimidin-2-yl)butane-1,2-diamine (Intermediate 35)

To the solution of intermediate 35d (153mg, 0.39mmol) in methanol (8mL) add 10% palladium carbon (25mg) and the mixture is stirred under a hydrogen atmosphere for 18hr.Add another 10% palladium carbon (50mg), and under a hydrogen atmosphere, the mixture is stirred for another 18hr.The reaction mixture is passed through filtration and concentrated in a vacuum.Residue is purified by dry flash chromatography (0% to 2.5% methanol in EtOAc) to obtain the title compound (70mg) in an oily form.

LCMS (Method K): 0.75 min, 303 [M+H] ⁺

Preparation of lithium 3-iodo-6-methylpicolinate (Intermediate 36a)

1M LiOH (3.4mL, 3.4mmol) is added to a solution of methyl 3-iodo-6-methylpicolinic acid (0.5g, 1.7mmol) in methanol (10mL) and THF (5mL), and the reaction mixture is stirred for 2hr at ambient temperature. The reaction mixture is concentrated in a vacuum, and the residue is subjected to azeotropy from methanol (2x10mL), to obtain the title compound (0.5g) as a solid. The crude product is not further purified and used in subsequent reactions.

LCMS (Method G): 0.38 min, 264 [M+H] ⁺

Preparation of (S)-3-iodo-N,6-dimethyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Intermediate 36)

To a solution of intermediate 36a (0.5 g, 1.7 mmol) and intermediate 31 (0.42 g, 1.7 mmol) in DMF (10 mL) was added HATU (0.72 g, 1.88 mmol), followed by DIPEA (0.81 mL, 4.7 mmol), and the reaction mixture was stirred at ambient temperature for 3 days. The mixture was then diluted with EtOAc (80 mL) and washed with water. The organic phase was dried _{over Na₂SO₄} , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (100 g column, 10% to 100% EtOAc in heptane) to give the title compound (0.73 g) as a gum.

LCMS (Method G): 1.21 min, 495 [M+H] ⁺

Preparation of 2-methyl-5-(2H-1,2,3-triazol-2-yl)pyridine (Intermediate 37a)

5-Bromo-2-methylpyridine (124g, 720mmol), 1H-1,2,3-triazole (210mL, 3600mmol), racemic trans-N, N'-dimethylcyclohexane-1,2-diamine (26.0g, 183mmol), copper powder (46g, 720mmol) and potassium carbonate (200g, 720mmol) are merged into NMP (250mL).The mixture is heated to 120°C and stirred for 4hr.The mixture is allowed to cool to 50°C-90°C and diluted with water (600mL).Then the mixture is added to the stirred mixture of water (1900mL) and concentrated ammonia solution (124mL).T-BME (600mL) is added, and the mixture is stirred for 0.5hr, and then filtered and washed with tBME (300mL).The two-phase filtrate is separated. The aqueous solution was extracted with tBME (2 x 500 mL) and the combined organic phases were used directly in the next step.

LCMS (Method N): 1.67 min, 161 [M+H] ⁺

Preparation of 2-methyl-5-(2H-1,2,3-triazol-2-yl)pyridine 1-oxide (Intermediate 37b)

3-chloroperbenzoic acid (≤77%, 156g, 670mmol) is added to the intermediate 37a tBME solution, and the mixture is stirred overnight at ambient temperature.Then the mixture is heated to 45°C-50°C. Triethylamine (4mL) is added and the mixture is stirred for 15min.Then the mixture is subjected to azeotropic drying when tBME is added.Then the mixture is cooled to 10°C-20°C, and the crude solid product is filtered, washed and dried with tBME (300mL). The crude product is stirred in IPA (680mL), and heated to reflux to cause dissolution. The mixture is then allowed to cool to ambient temperature and stirred overnight. The mixture is then cooled to approximately 5°C and stirred for 0.5hr. The mixture is filtered, washed with cold IPA (95mL) and tBME (160mL), and dried to obtain the title compound (62.5g) as a solid.

LCMS (Method N): 1.56 min, 177 [M+H] ⁺

Preparation of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile (Intermediate 37c)

At ambient temperature, trimethylsilyl cyanide (56.3g, 568mmol) is added to the intermediate 37b (50.0g, 284mmol) in DCM (250mL). The mixture is stirred for 1hr and then cooled to 10°C. Benzoyl chloride (59.8g, 425mmol) is added, and the mixture is heated to 40°C and stirred overnight. The mixture is then poured into a saturated NaHCO ₃ aqueous solution (750mL). Triethylamine (7.5mL) is added and the mixture is stirred overnight at 40°C. The aqueous phase is separated and extracted with DCM (100mL). The combined organic matter is washed with water (200mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product. This material is stirred overnight in hexane (504mL) and ethyl acetate (56mL). The product was filtered, washed with hexanes (100 mL), and dried to give the title compound as a solid (48.7 g).

LCMS (Method N): 1.99 min, 186 [M+H] ⁺

Preparation of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid lithium salt (1:1) (Intermediate 37)

Lithium hydroxide monohydrate (16.5g, 393mmol) in water (130mL) is added to intermediate 37c (66.1g, 357mmol) in warm IPA (460mL), and the mixture is heated to 80°C, and stirred overnight.Then the mixture is subjected to azeotropic drying under the addition of IPA. The resulting suspension is stirred overnight at ambient temperature. The product is filtered, washed with IPA, and dried to obtain the title compound (67.8g) as a solid.

LCMS (Method N): 1.42 min, 205 [M+H] ⁺

Preparation of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38)

A suspension of 2-fluoro-6-iodobenzoic acid (300 mg, 1.1 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2 _- diamine (32 mg, 0.23 mmol), _Cs2CO3 (735 mg, 2.3 mmol), 1H-1,2,3-triazole (0.13 mL, 2.3 mmol), and water (0.01 mL) in 1,4-dioxane (5 mL) was degassed under nitrogen for 10 min. CuI (10.7 mg, 0.06 mmol) was added and the mixture was further degassed under nitrogen for 10 min. The pressure tube was sealed and the mixture was heated to 100°C for 18 hr. After cooling, the reaction mixture was quenched with 13% wt NaCl in 2.5 M hydrochloric acid (50 mL) and extracted with EtOAc. The combined organics were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 0% to 75% (10% AcOH in EtOAc) in heptane) to give the title compound as an oil (140 mg).

¹ H NMR (250MHz, MeOD) 7.94 (s, 2H), 7.80 (m, 1H), 7.62 (m, 1H), 7.29 (m, 1H).

Preparation of methyl 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinic acid (Intermediate 39a)

To a stirred suspension of 3-bromo-6-chloropyridine-2-carboxylic acid (3.6 g, 15 mmol) in 1,4-dioxane (35 mL) was added (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (220 mg, 1.5 mol), _Cs2CO3 (10 g, 31 mmol), 1H-1,2,3-triazole (2.1 g, 31 mmol), and water (0.3 mL), and the mixture was degassed under nitrogen for 10 _min . CuI (295 mg, 1.6 mmol) was added, and the mixture was heated at 100°C for 6 hr. The reaction mixture was then allowed to cool to ambient temperature and concentrated in vacuo. MeOH (20 mL) was added to the residue, and the mixture was acidified to pH 2 with 6N hydrochloric acid (approximately 6 mL) and concentrated in vacuo. MeOH (20 mL) was added to the residue, and the mixture was concentrated in vacuo (x2). The residue is dissolved in MeOH (15mL) and DCM (35mL), and is cooled to 0 DEG C.TMS diazomethane (39mL, 77mmol) (in 15min) is added dropwise, and the reaction mixture is stirred for 18hr at ambient temperature.The reaction mixture is concentrated in a vacuum.The crude product is purified by chromatography on Biotage Isolera Four ^TM (100g posts, 10% to 80% EtOAc in heptane), to obtain the title compound (1.8g) in an oily state.

LCMS (Method G): 1.03 min, 239 [M+H] ⁺

Preparation of sodium 6-methoxy-3-(2H-1,2,3-triazol-2-yl)picolinate (Intermediate 39)

A suspension of intermediate 39a (100 mg, 0.38 mmol) in a solution of NaOMe (5.4 M in MeOH; 2 mL, 10.8 mmol) was heated in a microwave reactor at 100 ° C for 10 min. The reaction mixture was concentrated in vacuo to give the title compound (110 mg) as a solid. The crude product was used in subsequent reactions without further purification.

¹ H NMR (250MHz, DMSO-d ₆ ) 8.12 (s, 2H), 8.05 (d, 1H), 6.99 (d, 1H), 4.08 (s, 3H).

Example synthesis:

Route 1: Typical procedure for preparing examples by reductive amination as exemplified by the preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 1)

By NaHCO ₃ (0.26g, 3.1mmol), intermediate 1 (0.60g, 2.1mmol) and Dess-Martin periodinane (0.97g, 2.3mmol) in anhydrous DCM (10mL) stir 2hr.The reaction mixture is diluted with diethyl ether, saturated aqueous NaHCO ₃ and saturated aqueous sodium thiosulfate. After vigorous stirring for 1hr, the two layers are separated, and the water layer is extracted with diethyl ether. The organic matter is combined with saturated aqueous NaHCO ₃ and salt solution is washed, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is dissolved in DCE (10mL), 5-chloropyridine-2-amine (0.27g, 2.1mmol) and NaBH (OAc) ₃ (0.88g, 4.2mmol) are added, and the reaction mixture is stirred at ambient temperature for 18hr. The reaction mixture was purified by ion exchange chromatography using an SCX resin cartridge (10 g column, washed with methanol, then eluted with 2% methanolic ammonia). The crude product was further purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Bridge Prep-C18, 5 μm, 19x50 mm columns, 40% to 80% MeCN in water) to give the title compound (145 mg) as a solid.

LCMS (Method A): 2.11 min, 399 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,375K)8.03-7.89(m,3H),7.79(bd,0.15H),7.77-7.66(m,1H),7.43(dd,0.85H), 7.40-7.24(m,1.3H),6.98(bs,0.85H),6.58(d,0.85H),6.44(bs,0.15H),6.31(bs ,0.85H),4.56(m,1H),3.47(m,2H),3.16(m,0.15H),2.84(s,0.45H),2.64(m,2.5 5H),2.38(s,2.7H),2.19(m,0.3H),1.63(m,1.7H),0.97(t,3H),0.67(bs,0.15H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 2)

The title compound (98 mg) was prepared as a solid from intermediate 1 (0.65 g, 2.4 mmol) and 5-chloropyridin-2-amine (0.30 g, 2.4 mmol) using the method described for Route 1. The crude product was purified by recrystallization from MeCN.

LCMS (Method A): 1.73 min, 385/387 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,289K)8.16(d,1H),7.98(s,2H),7.96(d,1H),7.64(d,1H),7.47-7.38(m,2H),7.25(d,1H),6.65( t,1H),6.54(d,1H),3.88(m,1H),3.31(m,2H),2.39(s,3H),1.54(m,1H),1.42(m,1H),0.90(t,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 3)

The title compound (63 mg) was prepared as a gum from intermediate 2 (0.50 g, 1.8 mmol) and 5-chloropyridin-2-amine (0.23 g, 1.8 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, gradient 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.33 min, 394/396 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.94(bs,0.62H),7.76(bs,0.29H),7.55-7.27(m,9.4H),7.21-7.02(m,1 .21H),6.51(d,0.48H),6.40(bd,0.32H),6.17(bs,0.68H),4.50(bm,0.82H),3.3 0(bm,1.82H),2.93(bs,0.85H),2.71(s,1.15H),2.56(bm,0.18H),2.47-2.40(m ,2.05H),1.48(bm,0.59H),1.34(bm,0.54H),0.62(bt,1.95H),0.46(bs,1.05H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 4)

The title compound (0.10 g) was prepared as a glass from intermediate 3 (0.27 g, 0.96 mmol) and 5-chloropyridin-2-amine (0.13 g, 0.98 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, diethyl ether).

LCMS (Method A): 2.31 min, 394/396 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )7.98(d,1H),7.94(dd,1H),7.52-7.46(td,1H),7.46-7.27(m,9H),6.56(t,1H),6. 53(dd,1H),3.86(m,1H),3.36-3.28(m,1H),3.19(m,1H),1.75(m,1H),0.77(t,6H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 5)

The title compound (0.91 g) was prepared as a glass from intermediate 4 (0.10 g, 0.31 mmol) and 5-chloropyridin-2-amine (65 mg, 0.51 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 10% to 40% EtOAc in isohexane).

LCMS (Method A): 2.41 min, 408/410 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )7.93(dd,1H),7.58(dd,1H),7.47(td,1H),7.43-7.29(m,8H),6.34(d,1H),5.34(d,1H),5.04(bt ,1H),4.14(m,1H),3.17(m,2H),1.25(m,1H),1.15(m,1H),1.00(m,1H),0.80(d,3H),0.79(d,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide (Example 6)

The title compound (53 mg) was prepared as a glass from intermediate 5 (0.20 g, 0.66 mmol) and 5-chloropyridin-2-amine (68 mg, 0.53 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 10% to 40% EtOAc in isohexane) and then further purified by chromatography on a Biotage Companion ^™ (40 g column, diethyl ether).

LCMS (Method A): 2.17 min, 415/417 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.04(d,1H),7.92(dd,1H),7.67-7.72(m,2H),7.43(dd,1H),7.39-7.34(bm,3H),6.67(t,1H),6.54 (dd,1H),3.97(m,1H),3.37(m,1H),3.24(m,1H),2.69(s,3H),1.81(m,1H),0.87(d,3H),0.80(d,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide (Example 7)

The title compound (71 mg) was prepared as a gum from intermediate 6 (0.26 g, 0.82 mmol) and 5-chloropyridin-2-amine (0.11 g, 0.88 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, diethyl ether).

LCMS (Method A): 2.32 min, 429 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )7.85(d,1H),7.59(dd,1H),7.39-7.32(m,2H),7.10(dd,1H),7.06-6.99(m,3H),6.45(t,1H),6.20( dd,1H),3.82(bm,1H),2.94(m,2H),2.37(s,3H),1.23(m,1H),1.02(m,1H),0.92(m,1H),0.53(d,6H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 8)

The title compound (94 mg) was prepared from intermediate 7 (0.46 g, 1.47 mmol) and 5-chloropyridin-2-amine (0.17 g, 1.32 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, diethyl ether).

LCMS (Method A): 2.72 min, 422/424 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.15-8.04(m,0.61H),7.96(d,0.05H),7.79(d,0.12H),7.73-7.43(m,9.76 H),7.40(bm,0.12H),7.14-7.04(m,0.6H),7.00(bt,0.54H),6.94(td,0.13H ),6.86(dd,0.15H),6.79(bm,0.05H),6.72(d,0.65H),6.62(bd,0.12H),6.5 3(d,0.05H),6.35(bm,0.05H),4.97(bm,0.6H),4.80(bs,0.05H),3.63-3.45( m,1H),3.38(m,0.84H),3.13(m,0.15H),3.00(m,0.18H),2.89(s,0.6H),2.8 4(s,0.15H),2.61(s,0.45H),2.46(s,1.8H),1.84(bm,0.12H),1.65(bm,0.2 1H),1.42(bm,0.3H),1.32(bm,0.87H),1.15(bm,0.6H),1.04(bm,0.87H),0. 94-0.79(m,4.08H),0.79-0.70(dd,1.8H),0.67(d,0.15H),-0.00(m,0.18H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide (Example 9)

The title compound (69 mg) was prepared as a gum from intermediate 8 (0.26 g, 0.8 mmol) and 5-chloropyridin-2-amine (94 mg, 0.73 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, diethyl ether) and then further purified by chromatography on a Biotage Companion ^™ (12 g column, tBME).

LCMS (Method A): 2.60 min, 443/445 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )7.94(dd,0.5H),7.75(dd,0.5H),7.69-7.63(m,2H),7.47-7.40(m,2H),7.40-7.32(m,2H),6.96(t,0.5H) ,6.86(t,0.5H),6.53(dd,0.5H),6.48(dd,0.5H),4.90(bm,0.5H),3.81(m,0.5H),3.50-3.42(m,0.5H),3.4 2-3.35(m,0.5H),3.27(m,0.5H),2.93(m,0.5H),2.89(s,1H),2.69(s,1H),2.53(s,1.5H),2.52(s,1.5H), 1.48(m,0.5H),1.41-1.15(m,2H),0.94(d,1.5H),0.88(d,1.5H),0.56(m,0.5H),0.51(d,2H),0.45(d,2H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 10)

The title compound (52 mg) was prepared from intermediate 9 (0.38 g, 1.3 mmol) and 5-chloropyridin-2-amine (94 mg, 0.73 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, tBME).

LCMS (Method A): 2.58 min, 408/410 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )7.68(d,0.82H),7.60(bd,0.18H),7.54(d,0.18H),7.38(dd,0.18H),7.30(bdd,0.18H),7.28-6.98(m,8.82H),6.77-6.66(m,0.82H),6.58- 6.47(bm,0.82H),6.34-6.19(bm,0.82H),6.10(bd,0.18H),4.09(bm,0 .36H),3.92(bs,0.18H),3.39-3.20(bm,0.82H),3.10-3.01(bm,0.82H ),2.83-2.82(m,0.18H),2.66-2.59(td,0.18H),2.51(s,0.36H),2.12 (s,2.02H),1.72(bs,0.18H),1.32(bs,0.82H),1.11-1.04(bm,0.18H) ,1.00(bm,0.18H),0.74(bs,0.36H),0.66(d,2.46H),0.55(bs,0.18H) ,0.49(bm,0.18H),0.42(d,0.54H),-0.01(d,2.46H),-0.42(d,0.54H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide (Example 11)

The title compound (45 mg) was prepared as a gum from intermediate 10 (0.40 g, 1.26 mmol) and 5-chloropyridin-2-amine (98 mg, 0.77 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, tBME).

LCMS (Method A): 2.40 min, 429/431 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.93(bs,1H),7.79-7.67(m,2H),7.46-7.28(m,4H),6.64-6.36(bs,1H),6.33-6.13(bm,1H), 4.42(bs,0.5H),3.61-3.41(m,2H),2.67(bs,6H),1.91(bs,0.5H),1.15-0.68(bm,6H),0.46(bm,1H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3,3-dimethylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 12)

The title compound (59 mg) was prepared as a solid from intermediate 11 (0.30 g, 0.95 mmol) and 5-chloropyridin-2-amine (0.12 g, 0.92 mmol) using the method described for Route 1. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Bridge Prep-C18, 5 μm, 19x50 mm column, 5% to 95% MeCN in water).

LCMS (Method A): 2.71 min, 422 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)8.40(s,0.1H),7.98(bm,0.1H),7.94(d,0.9H),7.89(bm,0.1H),7.83(bm,0 .1H),7.58(bm,0.2H),7.50-7.24(m,9.4H),7.07(bs,0.9H),6.52(d,0.9H),5.99( bm,0.3H),4.68(bs,0.9H),3.65-3.39(m,1.8H),2.96(bs,0.1H),2.84(bs,0.1H), 2.60(bs,0.1H),2.55(bs,2.7H),2.46(bs,0.3H),0.85(bs,8.1H),0.62(bs,0.9H).

Preparation of (S)-N-(2-((5-chloropyridin-2-yl)amino)-1-cyclopropylethyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 13)

The title compound (0.16 g) was prepared from intermediate 12 (0.67 g, 2.3 mmol) and 5-chloropyridin-2-amine (0.29 g, 2.3 mmol) using the method described for Route 1. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Bridge Prep-C18, 5 μm, 19x50 mm column, 5% to 95% MeCN in water).

LCMS (Method A): 2.38 min, 406 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)8.05(s,0.2H),7.72(s,0.8H),7.55(s,0.2H),7.35-7.06(m,9H) ,6.92(m,1H),6.29(d,0.8H),6.12(bd,0.2H),5.95(bs,0.8H),3.63(m, 0.8H),3.25(m,2H),3.08(bm,0.2H),2.68(bm,1H),2.65(bs,0.6H),2.3 5(s,2.4H),0.66(bm,0.8H),0.28(m,1H),0.04(m,1.2H),-0.30(bm,1H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)propan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 14)

The title compound (0.17 g) was prepared as a gum from intermediate 13 (0.48 g, 1.8 mmol) and 5-chloropyridin-2-amine (0.23 g, 1.8 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.09 min, 380/382 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.93(bs,0.4H),7.71(bs,0.49H),7.54-7.28(m,8.58H),7.22(bm,0.76H),7.04 (bm,0.78H),6.52(bd,0.49H),6.40(bd,0.68H),6.22(bs,0.82H),4.65(bm,0.45H),3.6 0(bm,0.64H),3.27(bm,0.74H),3.12(bm,0.46H),3.04-2.85(bm,0.82H),2.70(bs,1.2H ),2.55(m,0.18H),2.46(bs,0.3H),2.42(bs,1.02H),0.91(bm,1.9H),0.32(bs,1.29H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-cyclopropyl-[1,1'-biphenyl]-2-carboxamide (Example 15)

The title compound (0.12 g) was prepared as a gum from intermediate 14 (0.36 g, 1.1 mmol) and 5-chloropyridin-2-amine (0.14 g, 1.1 mmol) using the method described for Route 1. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 70% EtOAc in isohexane).

LCMS (Method A): 2.79 min, 434/436 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.94(d,1H),7.54-7.28(m,10H),6.45(d,1H),5.91(bs,1H),3.74-3. 48(bm,3H),2.30-2.11(m,2H),0.95(d,3H),0.57(d,3H),0.37-0.15(m,4H).

Route 2: Typical procedure for preparing examples via amide coupling as exemplified by the preparation of (S)-5-chloro-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 16)

To a solution of 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (91 mg, 0.41 mmol) [prepared as described in WO2011/050198], Intermediate 15 (0.12 g, 0.37 mmol), and DIPEA (0.32 mL, 1.8 mmol) in anhydrous DMF (2 mL) was added HATU (0.15 g, 0.41 mmol), and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in methanol (10 ml). This was purified by ion exchange chromatography using an SCX resin cartridge (2 g cartridge, washed with 10 volumes of methanol, then eluted with 2% methanolic ammonia). The crude product was further purified by chromatography on a Biotage Companion ^™ (12 g cartridge, 0% to 5% ammonia in DCM) to give the title compound (43 mg).

LCMS (Method A): 2.26 min, 419/421 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.11(m,1.21H),8.06(s,0.76H),8.00(bm,0.18H),7.96(bd,0.42H),7.89(bd ,0.42H),7.77(d,0.29H),7.72(d,0.33H),7.71-7.61(m,0.65H),7.51-7.37(m, 1.4H),7.27(dd,0.1H),7.04(d,0.9H),6.98(m,0.65H),6.88(s,0.1H),6.65(s ,0.1H),6.64-6.53(bm,0.84H),6.49(d,0.35H),6.45(dd,0.1H),6.23(d,0.1H) ,6.13(bs,0.1H),4.62(bm,0.48H),4.45(bs,0.12H),3.63(bs,0.1H),3.56-3.3 5(m,1.65H),3.32-3.31(m,0.9H),3.12-2.95(m,0.4H),2.87(s,0.24H),2.80(s ,0.75H),2.66(s,1.59H),1.64(bm,0.27H),1.55(m,0.87H),1.36(s,0.42H),1. 27(m,0.3H),0.95(t,1.65H),0.83(t,0.21H),0.75(m,0.27H),0.47(t,0.78H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzamide (Example 17)

The title compound (39 mg) was prepared as a gum from 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (50 mg, 0.19 mmol) [prepared as described in WO 2012/085857] and intermediate 15 (63 mg, 0.19 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 10% methanol in DCM).

LCMS (Method A): 2.41 min, 453/455 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.34(dd,0.12H),8.16-8.11(m,0.88H),8.07-7.92(s,0.25H),8.14(m,1. 44H),8.00(m,1.64H),7.82(ddd,0.25H),7.71(bs,0.12H),7.69(d,0.27H) ,7.65(bd,0.12H),7.60(dd,0.10H),7.51-7.38(m,1.44H),7.35(dd,0.25H ),7.26(dd,0.10H),7.03(t,0.51H),6.91(t,0.24H),6.70-6.95(m,0.23H), 6.57(dd,0.65H),6.44(dd,0.25H),6.21(dd,0.14H),4.67(bm,0.59H),4.4 8(bm,0.16H),3.64-3.35(m,1.71H),3.26-3.11(m,0.45H),3.06(m,0.26H) ,2.91(s,0.30H),2.84(s,0.75H),2.64(m,1.95H),1.67(m,0.33H),1.56(m ,1.25H),1.30(m,0.25H),0.99(m,1.95H),0.81(m,0.30H),0.46(t,0.75H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-fluoro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 18)

The title compound (115 mg) was prepared as a gum from 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (75 mg, 0.33 mmol) [prepared as described in WO 2012/145581] and intermediate 15 (70 mg, 0.36 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 60% EtOAc in isohexane).

LCMS (Method A): 2.09 min, 403/405 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.09(bm,1.12H),8.03(bs,0.8H),7.96(bs,0.5H),7.88(bm,0.52H),7.76(dd,0.42H),7.70(d,0.4H),7.53-7.34(bm,1.62H),7.3 4-7.19(bm,0.83H),6.96(bm,1.27H),6.80(dd,0.85H),6.58(d,0.28H),6.48(d,0.28H),6.25(d,0.11H),4.61(t,0.45H),4.46(bs, 0.10H),3.64(bs,0.15H),3.41(m,1.32H),3.29(m,0.63H),3.10-2.84(m,0.45H),2.85(s,0.10H),2.79(s,0.81H),2.70(s,0.36H) ,2.67(bs,1.73H),1.72-1.46(m,1.30H),1.35-1.20(m,0.45H),0.93(t,1.73H),0.84(bt,0.32H),0.74(m,0.25H),0.48(t,0.85H).

Preparation of (S)-5-bromo-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 19)

The title compound (59 mg) was prepared as a gum from 5-bromo-2-(2H-1,2,3-triazol-2-yl)benzoic acid (97 mg, 0.36 mmol) [prepared as described in WO 2008/147518] and intermediate 15 (70 mg, 0.33 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 70% EtOAc in isohexane).

LCMS (Method A): 2.36 min, 463/465 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.16-8.11(m,0.82H),8.10(s,0.15H),8.09-7.99(m,1H),7.96(m,0.52H),7.92( bd,0.07H),7.86-7.73(m,1.44H),7.71(d,0.28H),7.65(d,0.07H),7.61(dd,0.28H ),7.58(bs,0.12H),7.50(d,0.09H),7.49-7.39(m,1H),7.27(dd,0.06H),7.23-7.1 8(m,0.85H),7.02-6.92(m,0.92H),6.63-6.53(d,1H),6.49(d,0.24H),6.23(d,0.0 9H),4.62(bm,0.51H),4.45(bm,0.2H),3.63(bm,0.06H),3.56-3.33(m,1.35H),3. 28(m,0.28H),3.23-3.07(bm,0.21H),3.02(m,0.27H),2.87(s,0.18H),2.80(s,0.8 1H),2.70(s,0.21H),2.66(bs,1.86H),1.65(bm,0.3H),1.55(m,0.99H),1.34-1.21 (m,0.5H),0.99-0.91(t,1.92H),0.84(m,0.27H),0.76(m,0.29H),0.47(t,0.79H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethoxy)benzamide (Example 20)

The title compound (110 mg) was prepared as a solid from 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethoxy)benzoic acid (98 mg, 0.36 mmol) [prepared as described in WO 2012/085857] and Intermediate 15 (70 mg, 0.33 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 60% EtOAc in isohexane).

LCMS (Method A): 2.47 min, 469/471 [M+H] ⁺

¹ H NMR 400MHz, DMSO-d ₆ )8.18(d,0.11H),8.13(m,0.82H),8.12-8.05(m,1.25H),8.00(d,0.51H),7.95(bd,0.45H),7.90(d,0.09H),7.72(dd,0.27H),7.63( m,0.92H),7.41(m,1.48H),7.34(bd,0.09H),7.27(dd,0.09H),6.98(m,1.53H),6.55(m,1.3H),6.22(d,0.09H),4.63(bm,0.46H),4.4 6(bm,0.1H),3.64(bm,0.09H),3.57-3.33(m,1.51H),3.28(m,0.35H),3.20(m,0.09H),3.16-2.95(m,0.27H),2.87(s,0.24H),2.81(s ,0.81H),2.66(m,1.95H),1.65(bs,0.24H),1.55(m,1.11H),1.29(m,0.39H),0.96(t,1.83H),0.91-0.77(m,0.63H),0.47(t,0.93H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 21)

The title compound (42 mg) was prepared as a gum from 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (87 mg, 0.36 mmol) [prepared as described in WO 2010/063662] and intermediate 15 (70 mg, 0.33 mmol) using the method described for Route 2. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Bridge Prep-C18, 5 μm, 19 x 50 mm column, 35% to 65% MeCN in water).

LCMS (Method A): two peaks at 1.79 min and 1.98 min, 400/402 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ )8.24(d,0.5H),8.22(d,0.5H),8.12(m,2H),7.99(dd,0.5H),7.73(d,0.5H),7.51(dd,0.5H ),7.48(dd,0.5H),7.46(dd,0.5H),7.34(dd,0.5H),6.79(bt,0.5H),6.60(t,0.5H),6.55(dd ,0.5H),6.34(d,0.5H),4.54(m,0.5H),3.65(m,0.5H),3.34-3.21(m,2H),2.85(s,1.5H),2.7 1(s,1.5H),2.56(s,1.5H),2.48(s,1.5H),1.71-1.38(m,2H),0.95(t,1.5H),0.77(t,1.5H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-morpholinobenzamide (Example 22)

The title compound (54 mg) was prepared as a glass from intermediate 27 (90 mg, 0.41 mmol) and intermediate 15 (120 mg, 0.41 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 5% ammonia in DCM).

LCMS (Method A): 2.21 min, 417/419 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.95(bd,0.6H),7.83(bs,0.35H),7.77(bs,0.35H),7.42(dd,0.6H),7.35(dd,0.42H),7.14(dd,0.58H),7.06-6. 99(m,0.99H),6.93(bd,0.35H),6.88(bd,0.35H),6.64(bs,0.35H),6.58(d,0.66H),6.45(d,0.54H),6.38(bt,0.51H),6. 24(bs,0.35H),4.67(bs,0.7H),3.77-3.32(bm,6.72H),3.29-2.98(bm,2.09H),2.87-2.66(s,1.1H),2.74(bm,1.05H),2. 59(bm,2.28H),2.25(bs,2.04H),2.00(s,0.65H),1.64(bm,2.01H),1.00(bt,1.95H),0.86(bt,1.05H),0.74(bm,0.36H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-(dimethylamino)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 23)

The title compound (45 mg) was prepared as a gum from intermediate 16 (84 mg, 0.62 mmol) and intermediate 15 (117 mg, 0.36 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 10% methanol in DCM).

LCMS (Method A): 2.18 min, 428/430 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.03-7.96(bm,0.60H),7.96-7.93(bm,0.83H),7.92(s,0.15H),7.91(bs,0.72H),7.80(d ,0.12H),7.74(d,0.12H),7.72-7.64(m,0.43H),7.56(bd,0.43H),7.51-7.47(dd,0.45H), 7.47-7.38(dd,0.52H),7.33(dd,0.13H),7.30(dd,0.22H),6.98-6.78(m,1.50H),6.73(d, 0.03H),6.67(dd,0.33H),6.60-6.40(m,1.20H),6.43(d,0.35H),6.38(d,0.35H),6.26(m,0 .52H),4.63(bm,0.50H),4.48(bs,0.15H),3.76(bm,0.13H),3.52(bm,0.56H),3.40(bm,0. 80H),3.31(bm,0.50H),3.08(m,0.12H),3.03-2.94(m,1.86H),2.91(bs,2.32H),2.84(s,1. 24H),2.82(s,0.30H),2.75(s,0.80H),2.63(m,1.86H),2.19(s,0.15H),1.62(m,0.48H),1 .50(m,0.84H),1.36(s,0.84H),1.30-1.17(bm,0.55H),0.90(bm,2.13H),0.51(bm,0.87H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)nicotinamide (Example 24)

The title compound (49 mg) was prepared as a solid from intermediate 17 (93 mg, 0.36 mmol) and intermediate 15 (70 mg, 0.33 mmol) using the method described for Route 2. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Bridge Prep-C18, 5 μm, 19x50 mm column, 20% to 50% MeCN in water).

LCMS (Method A): 2.14 min, 454/456 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )9.12-9.04(bm,0.75H),8.95(m,0.27H),8.39(bs,0.12H),8.29(bd,0.12H),8.2 7-8.22(m,0.81H),8.22-8.16(m,1.2H),8.01(bdd,0.9H),7.95(bd,0.44H),7.70 (dd,0.27H),7.62(dd,0.09H),7.50-7.40(bdd,0.63H),7.37(dd,0.23H),7.26(d d,0.12H),7.04(bt,0.47H),6.88(t,0.3H),6.71-6.62(m,0.21H),6.59-6.53(d,0 .68H),6.45(dd,0.27H),6.25(dd,0.12H),4.64(bm,0.43H),4.41(bs,0.15H),3. 59(bm,0.09H),3.52-3.35(m,1.39H),3.19(m,0.4H),3.10(m,0.28H),2.92(s,0. 27H),2.85(s,0.81H),2.72(m,1.92H),1.67(bm,0.21H),1.59(m,1.23H),1.41-1 .28(m,0.29H),0.99(m,2.06H),0.88(m,0.23H),0.81(t,0.39H),0.49(t,0.85H).

Preparation of (S)-5-chloro-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 25)

The title compound (53 mg) was prepared as a solid from 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (56 mg, 0.25 mmol) [prepared as described in WO 2011/050198] and intermediate 18 (70 mg, 0.23 mmol) using the method described for Route 2. The crude product was purified by trituration with MeCN.

LCMS (Method A): 1.92 min, 405/407 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.34(d,1H),8.04(s,2H),7.96(dd,1H),7.81(d,1H),7.69(dd,1H),7.54(dd,1H),7.43(d,1H),6.73 (t,1H),6.55(dd,1H),3.88(m,1H),3.38(m,1H),3.28(m,1H),1.56(m,1H),1.42(m,1H),0.92(m,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethyl-5-phenylthiazole-4-carboxamide (Example 26)

The title compound (89 mg) was prepared as a gum from 2-methyl-4-phenylthiazole-5-carboxylic acid (120 mg, 0.53 mmol) and Intermediate 19 (120 mg, 0.53 mmol) using the method described for Route 2. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 5% to 95% MeCN in water).

LCMS (Method A): 2.30 min, 429 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ,374K)8.13(s,0.5H),7.95(bs,1H),7.86(bs,0.5H),7.56-7.43(m,1.5H) ,7.43-7.24(m,4H),6.49(d,0.5H),6.31(m,0.5H),6.07(bs,0.5H),4.39(m ,0.5H),3.67-3.28(m,2.5H),2.85(s,1.5H),2.69(m,3H),2.62(s,1.5H), 1.97(m,0.5H),1.80(m,0.5H),1.05(d,1.5H),0.88(m,3H),0.64(d,1.5H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-phenyl-1H-indole-3-carboxamide (Example 27)

The title compound (89 mg) was prepared as a solid from 2-phenyl-1H-indole-3-carboxylic acid (300 mg, 0.88 mmol) and Intermediate 19 (200 mg, 0.88 mmol) using the method described for Route 2. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 50% EtOAc in isohexane).

LCMS (Method A): 2.83 min, 447 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,375K)7.95(bs,1H),7.74(m,2H),7.48-7.29(m,7H),7.14(td,1H),6.98(t,1H),6.57(bs,1H),6. 24(bs,1H),4.61(bm,1H),3.57(bs,2H),2.67(bs,3H),1.97(bs,1H),1.09(bs,3H),0.96(bs,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 28)

The title compound (91 mg) was prepared as a solid from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (100 mg, 0.53 mmol) and Intermediate 19 (120 mg, 0.53 mmol) using the method described for Route 2. The reaction mixture was poured into water and the solid was collected by filtration. It was purified by chromatography on a Biotage Companion ^™ (12 g column, 10% to 70% EtOAc in isohexane).

LCMS (Method A): two peaks at 2.12 min and 2.21 min, 399 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,375K)8.00(m,2.8H),7.94-7.80(m,1H),7.58(td,1H),7.48(t,1H),7.44(dd,1H),7. 35(bd,0.1H),7.25(bd,1H),6.58(d,1H),6.39(bm,0.1H),6.16(bs,1H),4.35(td,0.9H ),3.64(dt,0.9H),3.50(m,1H),3.23(m,0.1H),2.95(bs,0.3H),2.70(s,2.7H),2.02(m ,0.9H),1.80(bm,0.1H),1.08(d,2.7H),1.01(d,3H),0.90(bm,0.3H),0.68(bm,0.1H).

Route 3: Typical procedure for preparing examples by nucleophilic substitution with alcohols as exemplified by the preparation of (S)-N-(1-((4-fluorobenzyl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide (Example 29)

To the solution of intermediate 9 (150mg, 0.50mmol) in anhydrous THF (3mL) was added 60% dispersion of sodium hydride in oil (50mg, 1.3mmol), and the reaction mixture was stirred at ambient temperature for 30min. 1-(bromomethyl)-4-fluorobenzene (240mg, 1.3mmol) was added to the reaction, and the reaction mixture was stirred at ambient temperature for 1hr. The reaction mixture was then quenched with water (2mL) and the crude product was extracted into diethyl ether (20mL). The combined organic matter was washed with water (2x10mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography on Biotage Companion ^™ (12g posts, 0% to 100% isohexane in EtOAc), to obtain the title compound (185mg) as a colloid.

LCMS (Method A): 2.86 min, 406 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.69-7.25(m,11H),7.25-7.11(m,2H),4.49-4.34(m,1.45H),4.30(m,1H),3.59(dd,1H),3 .47(bm,0.55H),2.97(m,1H),2.79(s,1H),2.51(s,2H),1.89(bm,1H),0.92(d,3H),0.67(bm,3H).

Preparation of (S)-N-(1-((4,6-dimethylpyrimidin-2-yl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 30)

The title compound (45 mg) was prepared as a foam from intermediate 9 (150 mg, 0.50 mmol) and 2-chloro-4,6-dimethylpyrimidine (120 mg, 0.84 mmol) using the method described for Route 3. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.51 min, 280 [M-(4,6-dimethylpyrimidin-2-one) + H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )7.60-6.95(m,10H),4.57-4.47(d,0.27H),4.47-4.33(dd,0.44H),4.33-4.12(bm,1H),4 .05-3.94(d,0.25H),3.63-3.36(bm,0.9H),3.11(bd,0.2H),2.84(bm,0.1H),2.76-2.63( m,3H),2.45(s,3H),2.38(s,3H),1.95(m,0.4H),1.64(bs,0.3H),1.50(bs,0.14H),0.98- 0.71(m,3H),0.67(d,0.5H),0.62(d,0.5H),0.54(d,0.5H),0.27(d,1H),-0.19(d,0.5H).

Preparation of (S)-N-methyl-N-(3-methyl-1-(quinazolin-2-yloxy)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 31)

The title compound (105 mg) was prepared as a foam from intermediate 9 (150 mg, 0.50 mmol) and 2-chloroquinazoline (180 mg, 1.1 mmol) using the method described for Route 3. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.62 min, 280 [M-(quinazolin-2-one)+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)9.47-9.38(bs,1H),8.07(dd,1H),7.93(td,1H),7.79(d,0.8H),7.74(bd,0.2H),7.62-7.12(m,10H),4.72-4.42(m ,3.2H),3.28(bs,0.2H),2.84(s,0.6H),2.58(s,2.4H),2.02(bs,1.2H),1.03(bd,2.4H),0.78(bd,0.6H),0.67(bs,2.4H).

Preparation of (S)-N-methyl-N-(3-methyl-1-((4-phenylpyrimidin-2-yl)oxy)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 32)

The title compound (98 mg) was prepared as a foam from intermediate 9 (130 mg, 0.4 mmol) and 2-chloro-4-phenylpyrimidine (210 mg, 1.1 mmol) using the method described for Route 3. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.81 min, 280 [M-(4-phenylpyrimidin-2-one) + H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)8.65(d,0.8H),8.61(bs,0.2H),8.18(td,1.8H),8.12(bs,0.6H),7.70-7.10(m,12.6H),4.70-4.41(m,3.2H ),3.27(bs,0.4H),2.85(s,0.6H),2.57(s,2.4H),2.00(bs,1.2H),1.02(d,2.4H),0.77(bd,0.6H),0.66(bs,2.2H).

Preparation of (S)-N-methyl-N-(3-methyl-1-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 33)

The title compound (132 mg) was prepared as a foam from intermediate 9 (150 mg, 0.50 mmol) and 2-chloro-1-methyl-1H-benzo[d]imidazole (84 mg, 0.50 mmol) using the method described for Route 3. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.17 min, 280 [M-(1-methyl-1H-benzo[d]imidazol-2-one)+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.60-7.26(m,9.8H),7.26-6.96(m,3.2H),4.69(dd,1H),4.58(d,1H),4.42(bt,1H),3.49( s,3H),2.87(s,0.6H),2.58(s,2.4H),2.02(bs,1H),1.00(d,2.4H),0.75(bd,0.6H),0.63(bs,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 34)

The title compound (105 mg) was prepared as a gum from intermediate 9 (150 mg, 0.50 mmol) and 2,5-dichloropyridine (187 mg, 1.3 mmol) using the method described for Route 3. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.90 min, 280 [M-(5-dichloropyridin-2-one) + H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,375K)8.16(d,1H),8.09(bs,0.1H),7.75(dd,1H),7.55-7.38(m,5.1H),7.38-7.24(m,3H),7.19(d,0.9H),6.77(d,0 .9H),4.37(bm,2.7H),3.17(bs,0.3H),2.92(s,2.7H),2.79(s,0.3H),1.95(bs,1H),0.96(d,3H),0.75-0.54(bm,3H).

Route 4: Typical procedure for preparing examples by nucleophilic substitution with amines as exemplified by the preparation of (S)-N-methyl-N-(3-methyl-1-((4-phenylpyrimidin-2-yl)amino)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 35)

A mixture of 2-chloro-4-phenylpyrimidine (71 mg, 0.37 mmol), intermediate 20 (100 mg, 0.34 mmol) and DIPEA (120 μL, 0.68 mmol) in NMP (1 mL) was heated at 130° C. for 3 hr. The reaction mixture was allowed to cool to ambient temperature and diluted with water (10 mL). The crude product was extracted into diethyl ether (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% diethyl ether in isohexane) to give the title compound (65 mg) as a gum.

LCMS (Method A): two peaks at 2.45 min and 2.66 min, 451 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)8.36(d,0.8H),8.30(bd,0.2H),8.15-8.07(m,1.6H),7.97(bm,0.3H),7.56-7. 46(m,3.92H),7.46-7.24(m,7.38H),7.16-7.05(m,1.8H),6.33(bs,1H),4.41(td,1H) ,3.71(m,1H),3.50(m,1.1H),3.26(bm,0.2H),2.84(s,0.3H),2.82(s,0.3H),2.63(s, 0.3H),2.48(s,2.1H),1.82(bm,0.7H),1.00(d,2.5H),0.78(bd,0.5H),0.56(bs,3H).

Preparation of (S)-N-methyl-N-(3-methyl-1-(quinazolin-2-ylamino)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 36)

The title compound (67 mg) was prepared as a solid from intermediate 20 (100 mg, 0.34 mmol) and 2-chloroquinazoline (61 mg, 0.37 mmol) using the method described for Route 4. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% diethyl ether in isohexane).

LCMS (Method A): 2.31 min, 425 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ,374K)9.10(s,0.8H),9.06(bs,0.1H),7.80(dd,1H),7.69(m,1H),7.53(bd,0.3 H),7.47(d,1H),7.44-7.33(m,6H),7.33-7.20(m,3H),7.14-6.98(bd,1H),6.52 (bs,0.8H),4.40(td,1H),3.71(m,1H),3.55(m,1H),3.28(bm,0.2H),2.82(s,0. 4H),2.54(m,2.4H),1.83(bm,1H),1.01(d,2.4H),0.80(d,0.6H),0.55(bs,3H).

Preparation of (S)-N-(1-((4,6-dimethylpyrimidin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 37)

The title compound (33 mg) was prepared as a gum from intermediate 20 (150 mg, 0.51 mmol) and 2-chloro-4,6-dimethylpyrimidine (72 mg, 0.51 mmol) using the method described for Route 4. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): two peaks at 1.83 min and 1.98 min, 403 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ,374K)8.14(s,0.45H),7.54(bd,0.3H),7.48-7.27(m,7.71H),7.08(bd,1H), 6.37(s,0.9H),6.33(bs,0.22H),5.93(bm,0.42H),4.29(td,0.7H),3.57(m,1 H),3.44(m,1H),3.19(bm,0.2H),2.77(s,0.4H),2.47(s,2.4H),2.22(s,5.4H ),2.16(s,0.9H),1.77(bs,1H),0.96(d,2.7H),0.74(d,0.3H),0.55(bs,3H).

Preparation of (S)-N-methyl-N-(3-methyl-1-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 38)

The title compound (26 mg) was prepared as a solid from intermediate 20 (150 mg, 0.51 mmol) and 2-chloro-1-methyl-1H-benzo[d]imidazole (93 mg, 0.56 mmol) using the method described for Route 4. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 1.69 min, 427 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.55(bd,0.2H),7.46-7.37(m,3H),7.37-7.16(m,5.4H),7.16-7 .11(m,1.2H),7.05-6.90(m,3.1H),6.08(bs,1.1H),4.33(td,1H),3.70 -3.55(m,2.7H),3.51(bs,0.3H),3.47(s,2.7H),2.83(s,0.3H),2.54(s ,2.7H),1.84(bm,0.3H),0.99(d,2.7H),0.78(bd,0.3H),0.53(bd,3H).

Preparation of (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)benzamide (Example 39)

The title compound (201 mg) was prepared as a solid from intermediate 21 (150 mg, 0.49 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (89 mg, 0.49 mmol) using the method described for Route 4. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 5% methanol in DCM) and then further purified by trituration in diethyl ether.

LCMS (Method D): two peaks at 2.25 min and 2.54 min, 454/456 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ ⁾ )8.73-8.62(m,1.62H),8.48(bs,0.07H),8.39(bd,0.34H),8.37-8.28( m,0.85H),8.18(bs,0.34H),8.13(s,0.63H),8.09-8.07(m,0.15H),8.0 6(bs,0.81H),8.01(bd,0.09H),7.90(d,0.47H),7.77(d,0.4H),7.73-7 .60(m,0.86H),7.46(bs,0.13H),7.44-7.40(m,0.44H),7.20(d,0.43H) ,6.95(d,0.37H),4.73(m,0.43H),4.61(bm,0.12H),3.76-3.61(m,0.18 H),3.58-3.37(m,1.38H),3.31(m,0.61H),3.07(m,0.33H),2.87(s,0.1 8H),2.81(s,0.99H),2.68(s,1.83H),1.71-1.48(m,1.35H),1.29(m,0. 33H),0.96(t,1.83H),0.85(t,0.15H),0.70(m,0.3H),0.48(t,0.99H).

Preparation of (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)benzamide (Example 40)

The title compound (104 mg) was prepared as a solid from intermediate 21 (150 mg, 0.49 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (89 mg, 0.49 mmol) using the method described for Route 4. The crude product was collected by filtration after addition of water to the reaction mixture and purified by trituration with diethyl ether.

LCMS (Method A): two peaks at 2.25 min and 2.49 min, 454/456 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ )8.44-8.39(bm,0.67H),8.23-8.14(m,0.76H),8.13(s,0.54H),8.11-8.00(m,3.09H),7.97(bd,0.1H),7.90(d,0.45H),7.78(d ,0.27H),7.76-7.63(m,0.93H),7.47(bs,0.12H),7.43(dd,0.32H),7.40(d,0.09H),7.24(bd,0.39H),7.07(d,0.27H),4.70(bm ,0.65H),4.49(bs,0.2H),3.69(bt,0.12H),3.62-3.45(m,1.53H),3.29(m,0.62H),3.16(m,0.43H),2.89(s,0.22H),2.84(s,0. 94H),2.68(s,1.87H),1.73-1.50(m,0.21H),1.33(m,0.34H),0.96(t,1.98H),0.86(t,0.37H),0.81(m,0.35H),0.49(t,1.17H).

Preparation of (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridazin-3-yl)amino)butan-2-yl)benzamide (Example 41)

The title compound (62 mg) was prepared as a gum from intermediate 21 (150 mg, 0.49 mmol) and 3-chloro-6-(trifluoromethyl)pyridazine (89 mg, 0.49 mmol) using the method described for Route 4. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 60% EtOAc in isohexane).

LCMS (Method A): two peaks at 2.12 min and 2.38 min, 454/456 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ )8.17-8.14(m,0.75H),8.14-8.09(bm,0.34H),8.09-8.04(m,1.1H),7.98(m, 0.12H),7.93-7.79(m,0.86H),7.78-7.62(m,2.28H),7.61-7.54(bm,0.25H),7 .52-7.45(bm,0.23H),7.44(bd,0.06H),7.36(dd,0.38H),7.20(bs,0.39H),7. 03(d,0.57H),6.98(d,0.46H),6.97(bs,0.15H),6.83(d,0.03H),6.63(d,0.03 H),4.73(bm,0.39H),4.51(bs,0.09H),3.81-3.56(m,1.49H),3.36(bm,0.4H), 3.19-3.08(m,0.35H),2.90(s,0.12H),2.87(s,0.06H),2.84(s,0.99H),2.70( s,1.83H),1.69(bm,0.24H),1.60(m,0.99H),1.43(m,0.06H),1.38-1.22(m,0. 52H),0.98(t,1.83H),0.92-0.87(m,0.32H),0.69(bm,0.3H),0.53(t,1.02H).

Preparation of (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)benzamide (Example 42)

The title compound (55 mg) was prepared as a gum from intermediate 21 (150 mg, 0.49 mmol) and 2-bromo-5-(trifluoromethyl)pyridine (110 mg, 0.49 mmol) using the method described for Route 4. The crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 60% EtOAc in isohexane).

LCMS (Method A): 2.58 min, 453/455 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.40(bs,0.05H),8.34(bs,0.18H),8.30(bs,0.52H),8.13(s,0.83H),8.10- 8.03(m,1.61H),7.98(bs,0.18H),7.92-7.85(d,0.52H),7.76(d,0.24H),7.7 3-7.61(m,1.65H),7.56(bt,0.42H),7.52-7.49(bm,0.54H),7.43-7.38(m,0. 35H),7.20(bs,0.15H),7.14(bt,0.09H),7.07(bs,0.42H),7.04(d,0.3H),6.6 6(d,0.69H),6.57(bd,0.21H),6.32(d,0.05H),4.65(bm,0.53H),4.47(bs,0. 1H),3.65-3.41(bm,1.46H),3.29(m,0.4H),3.12-3.03(m,0.35H),2.88(s,0. 15H),2.82(s,0.75H),2.68(m,2.1H),1.66(bm,0.35H),1.57(m,1.22H),1.29 (m,0.34H),0.96(m,2.05H),0.85(t,0.21H),0.77(m,0.15H),0.49(t,0.84H).

Preparation of (S)-N-(1-(Benzo[d]oxazol-2-ylamino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 43)

The title compound (300 mg) was prepared as a solid from intermediate 21 (700 mg, 2.3 mmol) and 2-chlorobenzo[d]oxazole (420 mg, 2.3 mmol) using ethanol (10 mL) as the solvent at reflux and the method described for Route 4. The crude product was purified by preparative HPLC (Waters, acidic (10 mM ammonium formate + 0.1% formic acid), YMC ODSPrep C-18, 10 μm, 500×30 mm column, 20% to 60% MeCN in water).

LCMS (Method E): two peaks at 2.31 min and 2.55 min, 425 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.93-8.72(m,1H),8.72-8.62(m,0.9H),8.34-8.00(m,5H),8.00-7.88(m,0 .9H),7.88-7.76(m,0.9H),6.98(bm,0.3H),6.60(bm,0.1H),5.88(bm,0.9H), 5.16(bm,0.2H),4.86-4.67(bm,0.9H),4.61(bm,0.9H),4.50(bm,0.1H),4.3 4(m,1.1H),3.79(s,0.3H),2.71-2.41(m,1.8H),2.34(s,2.7H),0.78(m,3H).

Preparation of (S)-N-(1-(Benzo[d]thiazol-2-ylamino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 44)

The title compound (15 mg) was prepared as a solid from intermediate 21 (200 mg, 0.65 mmol) and 2-bromobenzo[d]thiazole (153 mg, 0.72 mmol) using ethanol (5 mL) as the solvent at reflux and the method described for Route 4. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid), YMC ODS Prep C-18, 10 μm, 500×30 mm column, 10% to 50% MeCN in water).

LCMS (Method F): two peaks at 3.11 min and 3.37 min, 441 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.29-8.20(m,0.72H),8.20-8.14(m,1H),8.14-8.07(m,1H),8.05-7.88(m,1H),7.81(d,0.39H),7.77-7.67(m,1.3H),7.67-7.5 8(m,0.43H),7.54(bs,0.2H),7.48-7.40(m,0.75H),7.38(dd,0.2H),7.34-7.16(m,2.05H),7.12-6.98(m,0.86H),6.83-6.76(m, 0.1H),4.76(bs,0.25H),4.49(bm,0.05H),3.80(bm,0.1H),3.72-3.44(m,2H),2.92(s,0.05H),2.86(s,0.45H),2.75(m,1.5H),2 .04(m,0.05H),1.79-1.70(bm,0.05H),1.70-1.56(m,1H),1.44-1.17(m,2.1H),1.01(t,2.1H),0.95-0.81(m,1H),0.56(t,0.3H).

Preparation of (S)-5-chloro-N-(1-((5-chloro-3-nitropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 45)

The title compound (520 mg) was prepared as a solid from intermediate 21 (500 mg, 1.6 mmol) and 5-chloro-2-fluoro-3-nitropyridine (290 mg, 1.6 mmol) using MeCN (10 mL) as solvent at reflux and the method described for Route 4. The crude product was purified by column chromatography (50% to 100% EtOAc in hexanes).

LCMS (Method E): two peaks at 2.87 min and 3.09 min, 464 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )9.06-8.90(m,0.95H),8.74(bt,0.31H),8.67(bt,0.35H),8.63-8.47(m,1.35H),8.46-8.33(m,0.2H),8.31-8.25(m,0.2H),8.22(d,0.2 4H),8.09-7.99(m,1H),8.03(s,0.35H),7.98-7.85(m,0.7H),7.80-7.73(m,0.35H),7.73-7.60(m,0.7H),7.48-7.38(m,0.35H),7.35(d, 0.15H),7.25(d,0.15H),7.02(bs,0.35H),6.79(d,0.3H),4.78(bm,0.2H),3.70(m,0.55H),3.44(m,0.8H),2.89(s,0.1H),2.83(s,0.6H) ,2.67(m,1.35H),1.71-1.48(m,0.9H),1.37-1.21(m,0.9H),1.17(m,3H),0.95(t,1.2H),0.85(m,0.6H),0.68(bm,0.2H),0.50(t,0.6H).

Preparation of (S)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 46)

The title compound (81 mg) was prepared as a solid from intermediate 22 (120 mg, 0.42 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (84 mg, 0.46 mmol) using the method described for Route 4. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (5 g cartridge, washed with methanol then eluted with 5% methanolic ammonia) and further purified by chromatography on a Biotage Companion ^™ (12 g cartridge, 0% to 5% methanol in DCM).

Alternative method: intermediate 37 (2.5g, 12mmol) is stirred in thionyl chloride (12.5mL), and heated for 1hr when reflux.Then the mixture is concentrated in a vacuum, toluene (10mL) is added, and the mixture is concentrated to residue.The residue is absorbed in isopropyl acetate (40mL) and processed with a solution of triethylamine (3.3mL, 24mmol) in isopropyl acetate (20mL), and the mixture is cooled.A solution of intermediate 31 (2.7g, 11mmol) in isopropyl acetate (20mL) is added, and the mixture is stirred for 30min at ambient temperature.Water (40mL) is then added and stirred.The organic layer is separated, washed with saturated NaHCO ₃ aqueous solution (40mL), dried over Na ₂ SO ₄ , filtered and concentrated in a vacuum.The crude product is heated in ethyl acetate (19mL) and hexane (56mL) to cause dissolution. The mixture was then allowed to cool, and the product was collected by filtration and dried to give the title compound (3.6 g, 77%) as a solid.

LCMS (Method A): 2.32 min, 435 [M+H] ⁺

LCMS (Method N): 2.46 min, 435 [M+H] ⁺ ; 2.51 min, 435 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.71(m,1H),8.59(bd,0.5H),8.45(bd,0.5H),8.27(s,0.5H),8.24(s,0.5H),8.19(bs,0. 5H),8.18(bs,1H),8.14(s,1H),7.77(bt,0.5H),7.53(d,0.5H),7.50(d,0.5H),4.69(m,0.5 H),3.75(m,0.5H),3.62(t,1H),3.48(m,0.5H),3.39(m,0.5H),2.89(s,1.5H),2.76(s,1.5 H),2.55(s,1.5H),2.49(s,1.5H),1.65(m,1H),1.53(m,1H),1.00(t,1.5H),0.80(t,1.5H).

Preparation of (S)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)picolinamide (Example 47)

The title compound (81 mg) was prepared as a gum from intermediate 22 (120 mg, 0.42 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (84 mg, 0.46 mmol) using the method described for Route 4. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (5 g cartridge, washing with methanol then eluting with 5% methanolic ammonia) and further purified by chromatography on a Biotage Companion ^™ (12 g cartridge, 0% to 5% methanol in DCM).

LCMS (Method A): 2.17 min, 435 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.42(s,0.5H),8.22(d,0.5H),8.17(d,0.5H),8.15-8.10(m,2.5H),8.07(s,0.5H),8 .08-7.90(bm,1H),7.88(s,0.5H),7.51(d,0.5H),7.43(d,0.5H),4.65(m,0.5H),3.70( m,1H),3.52(m,0.5H),3.43(m,1H),2.90(s,1.5H),2.74(s,1.5H),2.51(s,1.5H),2.4 0(s,1.5H),2.21(t,0.5H),1.67(m,1H),1.52(m,0.5H),1.00(t,1.5H),0.78(t,1.5H).

Preparation of (S)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)picolinamide (Example 48)

The title compound (61 mg) was prepared as a gum from intermediate 22 (120 mg, 0.42 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (103 mg, 0.46 mmol) using the method described for Route 4. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (5 g cartridge, washed with methanol then eluted with 5% methanolic ammonia) and further purified by chromatography on a Biotage Companion ^™ (12 g cartridge, 0% to 5% methanol in DCM).

LCMS (Method A): 2.27 min, 434 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.35(m,0.5H),8.25(d,0.5H),8.23(d,0.5H),8.16-8.13(m,2H),8.08(bs,0.5H),7.70(dd,0.5H),7 .57(dd,0.5H),7.54(dd,0.5H),7.47(d,0.5H),7.37(bs,0.5H),7.24(bs,0.5H),6.67(d,0.5H),6.46( d,0.5H),4.60(m,0.5H),3.71(m,0.5H),3.58(t,0.5H),3.42(m,1H),2.89(s,1.5H),2.75(s,1.5H),2 .56(s,1.5H),2.47(s,1.5H),2.21(t,0.5H),1.67(m,1H),1.51(m,1H),0.99(t,1.5H),0.80(t,1.5H).

Route 5: Typical procedure for preparing examples by palladium-catalyzed coupling of amines and aryl halides as exemplified by the preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 49)

A mixture of 2,5-dichloropyridine (0.26 g, 1.7 mmol), intermediate 23 (0.44 g, 1.4 mmol), _Pd2 (dba) ₃ (66 mg, 0.07 mmol), BINAP (45 mg, 0.07 mmol) and ^NaOtBu (0.17 g, 1.7 mmol) in toluene (20 mL) was heated at reflux for 20 hr. The reaction mixture was allowed to cool to ambient temperature and then purified by ion exchange chromatography using an SCX resin cartridge (10 g column, washed with methanol then eluted with 2% methanolamine) and then further purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5% to 95% MeCN in water) to give the title compound (145 mg) as a glass.

LCMS (Method A): two peaks at 2.28 min and 2.40 min, 413/415 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ ,374K)8.00(d,0.85H),7.95(s,2H),7.86(bs,0.15H),7.78-7.69(m,1H),7.44(dd,1H),7. 37(bd,1H),7.29(bs,0.15H),7.04(bs,0.15H),6.95(bs,0.85H),6.58(d,1H),6.18(bs,0. 85H),4.33(m,1H),3.59(m,2H),2.93(s,0.45H),2.89(s,0.45H),2.70(s,2.55H),2.37(s, 2.55H),2.20(bm,0.15H),2.01(m,0.85H),1.07(d,3H),0.99(d,2.55H),0.90(bm,0.45H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,1-dimethyl-1H-indole-3-carboxamide (Example 50)

The title compound (131 mg) was prepared as a glass from intermediate 24 (0.20 g, 0.73 mmol) and 2,5-dichloropyridine (130 mg, 0.88 mmol) using the method described for Route 5. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): 2.26 min, 385/387 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.97(dd,1H),7.87(dt,1H),7.57(s,1H),7.41(dt,1H),7.39(dd,1H),7.18(m,1H),7.07(m,1H),7.05(bs,1H),6 .64(bdd,1H),4.48(m,1H),3.76(s,3H),3.69(m,1H),3.51(m,1H),2.89(s,3H),2.02(m,1H),1.10(d,3H),0.83(d,3H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethylquinoline-4-carboxamide (Example 51)

The title compound (98 mg) was prepared as a solid from intermediate 25 (0.32 g, 1.12 mmol) and 2,5-dichloropyridine (0.20 g, 1.3 mmol) using the method described for Route 5. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane).

LCMS (Method A): two peaks at 1.58 min and 1.66 min, 397/399 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ ,375K)8.01-7.92(m,1.3H),7.88(bd,0.3H),7.78-7.60(m,2.4H),7.50-7.38(m,2.1H),7.28( s,0.3H),7.05(s,0.6H),6.97(bs,0.3H),6.67(d,0.7H),6.53(bs,1H),4.62(m,0.6H),3.80-3. 57(m,1.6H),3.32(bm,0.6H),3.07(s,0.7H),2.92(bs,0.7H),2.67(s,2.1H),2.63(s,2.1H),2. 43(bs,0.7H),2.03(bm,0.6H),1.87(bm,0.3H),1.16(d,2.1H),1.07(d,2.1H),0.84(bd,1.8H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-(trifluoromethoxy)benzamide (Example 52)

The title compound (95 mg) was prepared as a gum from intermediate 26 (0.22 g, 0.72 mmol) and 2,5-dichloropyridine (0.13 g, 0.87 mmol) using the method described for Route 5. The crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 60% EtOAc in isohexane).

LCMS (Method A): 2.48 min, 416 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,375K)7.96(d,0.6H),7.79(bs,0.3H),7.52(btd,0.7H),7.46-7.34(m,2.8H),7.29 -7.17(m,1H),7.11(bs,0.3H),7.03(bs,0.3H),6.63-6.43(m,1.4H),6.26(bs,0.6H ),4.42(m,1H),3.66(m,1H),3.54(m,1H),3.25(bm,0.6H),2.65(s,2.1H),1.99(m,1 H),1.87(bm,0.3H),1.10(d,2.1H),0.96(d,2.1H),0.93(bd,0.9H),0.89(bd,0.9H).

Preparation of (S)-5-chloro-N-methyl-N-(1-((6-methylpyridin-2-yl)amino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 53)

The title compound (25 mg) was prepared as a gum from intermediate 21 (0.15 g, 0.49 mmol) and 2-bromo-6-methylpyridine (0.10 g, 0.59 mmol) using the method described for Route 5. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (10 g cartridge, washed with methanol then eluted with 5% methanolamine) and then further purified by preparative HPLC (Waters, acidic (0.1% formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 0% to 35% MeCN in water).

LCMS (Method A): 1.42 min, 399/401 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.24(s,0.3H),8.20(s,0.24H),8.17(s,0.12H),8.15(s,0.48H),8.09(s,0.9H),8.06-7.98( m,0.18H),7.91(d,0.45H),7.77(d,0.31H),7.75-7.68(m,0.21H),7.65(dd,0.45H),7.52-7.4 7(bs,0.15H),7.47-7.41(m,0.31H),7.39-7.28(m,0.62H),7.25(td,0.26H),7.15-7.01(m,0. 06H),7.09(d,0.24H),6.91(d,0.48H),6.56(m,0.78H),6.43(d,0.24H),6.39(d,0.45H),6.34 (d,0.72H),6.31-6.26(m,0.54H),6.20(d,0.3H),6.08(bm,0.15H),5.96(d,0.06H),4.69-4.5 2(m,0.56H),3.64(m,0.3H),3.52-3.23(m,3.5H),3.01(m,0.1H),2.90(s,0.12H),2.81(s,0.5 H),2.73-2.68(m,1.6H),2.33(s,0.6H),2.27(s,1.2H),2.10(m,0.93H),1.69(bm,0.4H),1.58 (m,0.8H),1.28(bm,0.1H),0.99(t,2.19H),0.91(t,0.15H),0.69(bm,0.2H),0.57(t,0.75H).

Route 6: Alternative procedure for preparing examples by palladium-catalyzed coupling of amines and aryl halides as exemplified by the preparation of (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)butan-2-yl)benzamide (Example 54)

A mixture of 5-iodo-2-(trifluoromethyl)pyridine (0.11 g, 0.39 mmol), intermediate 21 (100 mg, 0.33 mmol), _Pd2 (dba) ₃ (15 mg, 0.02 mmol), xantphos (9.4 mg, 0.02 mmol) and _Cs2CO3 (0.21 g, 0.65 mmol) in anhydrous _dioxane (10 mL) was heated at 100°C for 19 hr. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 60% EtOAc in isohexane) and further purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 5% methanol in DCM) to give the title compound (45 mg) as a solid.

LCMS (Method A): two peaks at 2.25 min and 2.49 min, 453/455 [M+H]+

¹ H NMR (400MHz, DMSO-d ₆ )8.17-8.10(m,1.59H),8.06(s,0.91H),8.03-7.95(m,0.32H),7.95-7.86(m,0.62H),7.83(d,0.08H),7.79(d,0.32H),7.74-7.64(m,0.81 H),7.54(d,0.67H),7.50-7.40(m,1.07H),7.36(d,0.12H),7.16-7.07(m,1.03H),6.92-6.81(m,0.84H),6.81-6.72(m,0.46H),6.70(bdd, 0.08H),6.40(bm,0.08H),4.62(bm,0.32H),4.43(bm,0.15H),3.58(b m,0.09H),3.35(bm,0.52H),3.19(bm,0.42H),3.01(bm,0.08H),2.88 (s,2.39H),2.83(s,0.62H),2.68(bm,2.12H),1.78-1.52(bm,1.21H),1.35(bm,0.15H),0.97(m,1.98H),0.89(t,0.39H),0.51(t,0.56H).

Preparation of (S)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)butan-2-yl)picolinamide (Example 55)

The title compound (58 mg) was prepared as a solid from intermediate 22 (90 mg, 0.31 mmol) and 5-iodo-2-(trifluoromethyl)pyridine (0.10 g, 0.38 mmol) using the method described for Route 6. The crude product was purified by ion exchange chromatography using an SCX resin cartridge (10 g cartridge, washed with methanol then eluted with 5% methanolic ammonia) and then further purified by chromatography on a Biotage Companion ^™ (12 g cartridge, 0% to 70%, EtOAc in isohexane).

LCMS (Method A): 2.14 min, 434 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.27(d,0.5H),8.25(d,0.5H),8.18(s,1H),8.15(d,0.5H),8.14(s,1H),7.96(d,0.5H) ,7.56(dd,1H),7.51(dd,0.5H),7.45(d,0.5H),7.15(dd,0.5H),6.83(dd,0.5H),6.73(m, 1H),4.55(m,0.5H),3.66(m,0.5H),3.37(m,1.5H),3.28(m,0.5H),2.89(s,1.5H),2.77(s ,1.5H),2.60(s,1.5H),2.50(s,1.5H),1.82-1.53(m,2H),0.99(t,1.5H),0.84(t,1.5H).

Preparation of (S)-N-(1-(4-fluorobenzamido)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 56)

To a solution of intermediate 20 (0.11 g, 0.39 mmol), 4-fluorobenzoic acid (59 mg, 0.42 mmol) and DIPEA (0.13 mL, 0.77 mmol) in anhydrous DMF (10 mL) was added HATU (0.16 g, 0.42 mmol) and the reaction mixture was stirred for 2 hr. It was poured into water and the product was collected by filtration, washed with water (20 mL) and dried in vacuo to give the title compound (102 mg) as a solid.

LCMS (Method A): 2.44 min, 419 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.99(bs,0.95H),7.94-7.84(td,1.8H),7.55(bd,0.05H),7.51-7.21(m,10.25H),7.07(d,0.95H),4.29(td,1H ),3.57-3.35(m,1.8H),2.81(s,0.25H),2.53(m,3H),1.78(bm,0.95H),0.95(d,3H),0.74(bd,0.15H),0.48(d,2.85H).

Preparation of (S)-N-(1-((4-fluorobenzyl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 57)

To a solution of intermediate 20 (0.12 g, 0.42 mmol) and 4-fluorobenzaldehyde (52 mg, 0.42 mmol) in anhydrous DCE ( ₁₀ mL) was added NaBH(OAc) (0.13 g, 0.63 mmol) and the reaction mixture was stirred for ₄ hr. It was then washed with saturated aqueous NaHCO ( ₂ x 5 mL), dried over _NaSO , filtered and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Companion ^™ to give the title compound (56 mg) as a gum. LCMS (Method A): 1.68 min, ⁴⁰⁵ [M+H]

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.56(bd,0.1H),7.52-7.17(m,11.9H),7.14-7.04(m,2H),4.23(td,0.9H),3.72-3.53(dd,2H),3.4 2(bm,0.2H),2.74(s,0.3H),2.69-2.52(m,2H),2.42(s,2.7H),1.70(m,0.9H),0.85(d,3H),0.63(bs,3H).

Preparation of (S)-N-methyl-N-(3-methyl-1-(3-phenylureido)butan-2-yl)-[1,1'-biphenyl]-2-carboxamide (Example 58)

A mixture of intermediate 20 (0.12 g, 0.42 mmol) and benzene isocyanate (50 mg, 0.42 mmol) in toluene (10 mL) was heated at 60° C. for 30 min. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on a Biotage Companion ^™ (12 g column, 0% to 100% EtOAc in isohexane) to give the title compound (0.14 g) as a solid. LCMS (Method A): two peaks at 2.29 min and 2.44 min, 416 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ,374K)7.57(bd,0.2H),7.48-7.34(m,8.9H),7.34-7.28(m,2.7H),7.28-7.21(m,2.3H),6.93(tt,1H),5.81(bm,0.9H),4.1 6(bm,0.9H),3.41-3.24(m,1.8H),2.78(s,0.3H),2.47(s,2.7H),1.72(bm,1H),0.92(d,3H),0.70(bd,0.3H),0.47(bd,3H).

Preparation of (S)-N-(1-((4-chlorophenyl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Example 59)

A mixture of intermediate 20 (0.16 g, 0.54 mmol), DIPEA (0.47 mL, 2.7 mmol), copper (II) acetate (98 mg, 0.54 mmol) and (4-chlorophenyl) boronic acid (0.17 g, 1.1 mmol) in anhydrous DCM (10 mL) was stirred at ambient temperature for 16 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on a Biotage Companion ^™ (40 g column, 0% to 100% EtOAc in isohexane) to give the title compound (76 mg) as a solid.

LCMS (Method A): 2.94 min, 407 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ,374K)7.55(bd,0.1H),7.51-7.29(m,8.6H),7.25-7.15(bdd,1H),7.08(m ,2H),7.02(bd,0.2H),6.79(d,0.1H),6.56(d,1.8H),6.34(bs,0.2H),4.95 (bs,0.3H),4.23(m,1H),3.22(m,0.9H),3.12(m,0.9H),2.77(s,0.3H),2.4 6(s,2.7H),1.85(bm,0.9H),0.96(d,2.7H),0.73(bd,0.3H),0.61(bs,3H).

Preparation of (S)-N-(1-((3-amino-5-chloropyridin-2-yl)amino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 60)

To a solution of Example 45 (0.36 g, 0.79 mmol) in ethanol (10 mL) was added _{SnCl₂2H₂O} ( _0.44 g, 2.0 mmol), and the reaction mixture was heated at reflux for 2 hr. It was then cooled to ambient temperature and concentrated in vacuo to afford a residue, which was neutralized with saturated aqueous _NaHCO₃ (20 mL) and extracted into EtOAc ( ₂ x 10 mL). The combined organics were dried over _Na₂SO₄ , filtered, and concentrated in vacuo to afford the title compound (0.26 g) as a solid.

LCMS (Method E): two peaks at 2.40 min and 2.57 min, 434 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.14(d,0.3H),8.09(s,0.6H),8.07-7.91(m,1.3H),7.91-7.81(m,0.5 H),7.75-7.56(m,0.8H),7.51-7.26(m,1H),7.13(m,0.2H),7.10(bs,0. 4H),7.02(d,0.3H),6.97(d,0.4H),6.92(m,0.1H),6.72(m,0.7H),6.67 (d,0.2H),6.54(m,0.2H),5.92(bm,0.6H),5.86-5.53(m,0.4H),5.18-5. 0(m,0.83H),4.87(s,0.05H),4.66(bm,0.19H),4.42(bm,0.05H),4.19- 3.96(m,0.13H),3.75(m,0.05H),2.79(s,0.4H),2.69-2.59(m,1.5H),2 .33(s,0.45H),1.65(bm,0.27H),1.59-1.42(m,0.87H),1.32-1.04(m,3 .4H),0.94(t,1.14H),0.83(m,0.93H),0.70(bm,0.34H),0.47(t,0.4H).

Preparation of (S)-N,6-dimethyl-N-(1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 61)

The mixture of intermediate 22 (30mg, 0.09mmol), 2-chloroquinazoline (28mg, 0.17mmol) and DIPEA (36mg, 0.27mmol) in DMSO (2mL) is heated at 120 DEG C for 18hr. Allow the reaction mixture to cool to environment temperature, and then add EtOAc (10mL) and water (10mL), and separate each layer. The aqueous phase is extracted with EtOAc (10mL). The combined organic matter is washed with water (20mL), dried over _MgSO4 , filtered and concentrated in a vacuum. The residue is passed through dry flash chromatography (0% to 2.5% methanol in EtOAc) and then purified by reverse phase column chromatography (C18 30g cartridges, 5% to 95% pH _10NH4HCO3 in MeCN) to obtain the title compound (8mg) as _a solid.

LCMS (Method L): two peaks at 2.04 and 2.22 min, 417 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )9.37(bs,0.5H),9.25(bs,0.5H),8.50-8.20(bm,3H),8.00(bdd,1H),7.88(bm,2H ),7.69(bm,1H),7.60-7.30(bm,1.5H),7.18(bs,0.5H),4.90(bs,0.5H),4.15-4.00 (bs,0.5H),3.97-3.82(bs,1H),3.82-3.67(bm,1H),3.06(bm,1.5H),2.96(bm,1.5H ),2.66(bs,1.5H),2.61(bs,1.5H),1.77(bm,2H),1.18(bt,1.5H),1.00(bt,1.5H).

Preparation of (S)-N-(1-(Benzo[d]oxazol-2-ylamino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 62)

The mixture of intermediate 22 (20 mg, 0.062 mmol), 2-chlorobenzoxazole (9 mg, 0.055 mmol) and DIPEA (24 mg, 0.19 mmol) in MeCN (1.5 mL) was heated at 70 ° C for 18 hours. The reaction mixture was allowed to cool to ambient temperature, and then DCM (10 mL) and water (10 mL) were added, and each layer was separated. The organic phase was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 100% EtOAc in heptane) to obtain the title compound (17 mg) as a solid.

LCMS (Method L): two peaks at 1.95 and 2.03 min, 406 [M+H] ⁺

¹ H NMR (300MHz, DMSO-d ₆ )8.39(m,1H),8.30(m,2H),8.16(bm,0.5H),8.03(bm,0.5H),7.67(d, 0.5H),7.57(m,1H),7.46(bm,1H),7.29(m,1.5H),7.16(m,1H),4.85(b m,0.5H),4.01-3.85(bm,0.5H),3.85-3.63(bm,2H),3.07(s,1.5H),2. 95(s,1.5H),2.55(m,3H),1.75(m,2H),1.17(t,1.5H),0.97(t,1.5H).

Preparation of (S)-N-(1-(Benzo[d]thiazol-2-ylamino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 63)

The mixture of intermediate 22 (100mg, 0.31mmol), 2-chlorobenzothiazole (78mg, 0.46mmol) and DIPEA (0.16mL, 0.92mmol) in DMSO (3mL) is heated at 70 DEG C for 18hr.The reaction mixture is allowed to cool to ambient temperature, and then DCM (10mL) and water (10mL) are added, and each layer is separated.The organic phase is dried over _MgSO4 , filtered and concentrated in vacuo.The residue is purified by dry flash chromatography (50% to 100% EtOAc in heptane) to obtain the title compound (44mg) as a solid.

LCMS (Method L): two peaks at 1.95 and 1.98 min, 422 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.42(m,1H),8.33(m,2H),8.19(m,1H),7.88(d,0.39H),7.82(d,0.61H),7.6 9(d,0.39H),7.61(m,1H),7.40(m,1.61H),7.20(m,1H),4.80(m,0.39H),3.96( m,0.61H),3.79(m,1.39H),3.64(m,0.61H),3.07(s,1.83H),2.94(s,1.17H),2 .67(s,1.17H),2.61(s,1.83H),1.76(m,2H),1.16(t,1.17H),0.99(t,1.83H).

Preparation of (S)-N-(1-((5-chlorobenzo[d]oxazol-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 64)

The mixture of intermediate 22 (30 mg, 0.09 mmol), 2,5-dichlorobenzoxazole (13 mg, 0.08 mmol) and DIPEA (36 mg, 0.27 mmol) in MeCN (2 mL) was heated at 70 ° C for 18 hours. The reaction mixture was allowed to cool to ambient temperature, and then DCM (10 mL) and water (10 mL) were added, and each layer was separated. The organic phase was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (50% to 100% EtOAc in heptane) to obtain the title compound (11 mg) as a solid.

LCMS (Method L): two peaks at 2.31 and 2.37 min, 440 [M+H] ⁺

¹ H NMR (300MHz, DMSO-d ₆ )8.32(m,4H),7.67(d,0.53H),7.59(d,1H),7.49(bm,1H),7.36(bm,0.47H),7.19(m,1H),4.85(m,0.47H),4.00 -3.59(m,2.53H),3.07(s,1.41H),2.94(s,1.59H),2.53(m,3H),1.74(m,2H),1.17(t,1.59H),0.96(t,1.41H).

Route 7: Alternative procedure for preparing examples by nucleophilic substitution with amines as exemplified by the preparation of (S)-N,6-dimethyl-N-(1-(quinoxalin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 65)

A mixture of intermediate 22 (100 mg, 0.31 mmol), 2-chloroquinoxaline (76 mg, 0.46 mmol) and DIPEA (0.27 mL, 1.54 mmol) in NMP (3 mL) was heated to 100 ° C for 8 hours. 2-Chloroquinoxaline (51 mg, 0.31 mmol) was added and heating was continued for another 8 hours. The reaction mixture was allowed to cool to ambient temperature, and then the mixture was diluted with EtOAc and water, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with saturated aqueous NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 0% to 10% methanol in DCM). The crude product was further purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 0% to 100% EtOAc in heptane, then 0% to 10% methanol in DCM) followed by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30×100 mm column, 10% to 95% MeCN in water) to give the title compound as a solid (29 mg).

LCMS (Method H): 3.79 min, 417 [M+H] ⁺

¹ H NMR (500MHz, CDCl ₃ )8.16(bm,1.6H),7.84-7.80(bm,1.6H),7.79-7.75(bd,0.6H),7.70-7.65(s,0.8H),7.63-7. 55(bm,1H),7.48(bm,1.6H),7.34-7.26(bm,1.4H),7.25-7.21(bm,1H),5.92(bm,0.4H),4.82( bs,0.6H),3.94(m,0.4H),3.81-3.44(m,2H),2.94(s,1.8H),2.73(bs,1.2H),2.57(bs,1.8H), 2.51(bs,1.2H),1.88-1.71(bm,1.2H),1.70-1.58(bm,0.8H),1.08(t,1.2H),0.89(bt,1.8H).

Preparation of (S)-N,6-dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 66)

The title compound (30 mg) was prepared as a solid from intermediate 28 (50 mg, 0.17 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (45 mg, 0.25 mmol) using the method described for route 7. The crude product was purified by chromatography on a Biotage IsoleraFour ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane). The crude product was further purified by washing with diethyl ether.

LCMS (Method I): two peaks at 3.68 and 3.85 min, 449 [M+H] ⁺

¹ H NMR (500MHz, CDCl ₃ )8.46(bd,1.76H),8.39(bd,0.24H),8.21(d,0.88H),8.15(bd,0.12H),8.11(s,1.76H),7.83(s,0.24H ),7.27(d,0.12H),7.23(d,1.00H),6.69(bd,0.88H),4.55(bm,0.88H),4.04(m,0.88H),3.68-3.46(bm, 0.24H),3.45-3.33(bm,1H),2.92(s,0.36H),2.77(s,2.64H),2.62(s,0.36H),2.54(s,2.64H),1.96(b m,0.88H),1.30-1.17(bm,0.12H),1.11(d,2.64H),1.07(d,2.64H),0.98(bd,0.36H),0.93(bd,0.36H).

Preparation of (S)-N,6-dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 67)

The title compound (13 mg) was prepared as a solid from intermediate 28 (50 mg, 0.17 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (30 μL, 0.25 mmol) using the method described for route 7. The crude product was purified by chromatography on a Biotage IsoleraFour ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane). The crude product was further purified by washing with diethyl ether.

LCMS (Method I): two peaks at 4.38 and 4.45 min, 449 [M+H] ⁺

¹ H NMR (500MHz, CDCl ₃ )8.27(s,0.85H),8.21(s,0.15H),8.18(d,1H),7.87(d,0.85H),7.85-7.78(m,0.45H),7.78-7.75( m,1.85H),7.28(d,0.15H),7.25(d,0.85H),6.09(bm,0.85H),4.43(bm,0.85H),3.84(m,0.85H),3.6 3(bm,0.15H),3.58-3.44(m,1H),2.90(s,0.45H),2.73(s,2.55H),2.57(s,0.45H),2.53(s,2.55H), 2.01(m,0.85H),1.92(m,0.15H),1.21(dd,0.15H),1.10(d,2.55H),1.07(d,2.55H),0.95(m,0.9H).

Preparation of (S)-N,6-dimethyl-N-(3-methyl-1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 68)

The title compound (4 mg) was prepared as a solid from intermediate 28 (30 mg, 0.1 mmol) and 2-chloroquinazoline (25 mg, 0.15 mmol) using the method described for route 7. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane). The crude product was further purified by preparative HPLC (Gilson, basic (0.2% ammonium hydroxide), Waters Xbridge Prep-C18, 10 μm, 30x100 mm column, 10% to 95% MeCN in water).

LCMS (Method O): two peaks at 4.83 and 5.08 min, 431 [M+H] ⁺

¹ H NMR (500MHz, CDCl ₃ )9.31(s,0.03H),9.01(s,0.69H),8.95(s,0.03H),8.92(s,0.25H),8.26(m,2H),8.17(d,0.26H),7.99(m,0.12H) ,7.95(s,0.45H),7.82(bm,0.31H),7.72-7.68(m,0.24H),7.68(s,0.65H),7.67-7.65(m,0.72H),7.65-7.63(m,0. 81H),7.63-7.60(bm,0.39H),7.57(bd,0.27H),7.51(m,0.03H),7.40(d,0.03H),7.29(d,0.72H),7.26(d,0.24H), 7.24-7.22(m,0.5H),7.22-7.20(m,0.27H),7.20-7.19(t,0.12H),7.18(d,0.06H),7.05(s,0.03H),6.77(m,0.03H ),6.46(s,0.75H),4.70(bs,0.7H),4.31(m,0.05H),4.19(m,0.72H),3.81-3.72(m,0.25H),3.72-3.63(bm,0.56H ),3.56(t,0.72H),3.11(s,0.03H),3.02(s,0.75H),2.87(s,2.22H),2.73(s,0.03H),2.68(s,0.72H),2.65(s,0.0 6H),2.61(s,2.19H),2.32(m,0.02H),2.07(m,0.87H),1.56(d,0.09H),1.53(d,0.02H),1.30(d,0.2H),1.26(bm,0 .15H),1.19(m,3.95H),1.14-1.10(bm,0.09H),1.05(m,1.45H),0.99(d,0.08H),0.89(m,0.05H),0.79(m,0.03H).

Preparation of (S)-N,6-dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 69)

The title compound (44 mg) was prepared as a solid from intermediate 28 (45 mg, 0.15 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (27 μL, 0.22 mmol) using the method described for Route 7. The crude product was purified by chromatography on a Biotage IsoleraFour ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane). The crude product was further purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30×100 mm column, 10% to 95% MeCN in water).

LCMS (Method O): two peaks at 5.25 and 5.32 min, 448 [M+H] ⁺

¹ H NMR (500MHz, CDCl ₃ )8.30(bs,0.67H),8.24(bs,0.33H),8.18(m,1H),7.87(m,1.33H),7.80(s,0.67H),7.50(dd,0.67H),7.40( dd,0.33H),7.27(d,0.33H),7.24(d,0.67H),6.46-6.29(m,1H),5.92(bm,1H),4.47(bm,0.67H),3.76(bm,0 .66H),3.63-3.48(bm,1H),3.48-3.37(bm,0.67H),2.90(s,0.99H),2.74(s,2.01H),2.57(s,0.99H),2.54( s,2.01H),2.06-1.95(bm,0.67H),1.95-1.85(m,0.33H),1.10(d,2.01H),1.07(d,2.01H),0.92(bm,1.98H).

Preparation of (S)-N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)picolinamide (Example 70)

The title compound (56 mg) was prepared as an oil from intermediate 29 (50 mg, 0.17 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (44 mg, 0.24 mmol) using the method described for Route 7. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (10 g column, 20% to 100% EtOAc in heptane).

LCMS (Method I): two peaks at 4.18 and 4.35 min, 450 [M+H] ⁺

¹ H NMR (250MHz, DMSO-d ₆ ,353K)8.37(bs,0.45H),8.20(d,0.45H),8.17-8.11(bm,1.1H),8.06(d,0.45H),8.03(bs,2 H),7.88(m,0.55H),7.59(bm,1H),7.50(d,0.45H),7.43(d,0.55H),3.95(m,0.45H),3.76(m ,1.45H),3.54-3.33(m,2H),3.24(m,1H),2.56(s,1.35H),2.48(s,1.65H),2.08-1.85(m,0. 55H),1.85-1.65(m,0.45H),1.57(m,1.1H),1.22(t,1.65H),1.03(t,2.7H),0.84(t,1.65H).

Preparation of (S)-N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)picolinamide (Example 71)

The title compound (49 mg) was prepared as a solid from intermediate 29 (50 mg, 0.16 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (30 μL, 0.24 mmol) using the method described for Route 7. The crude product was purified by chromatography on a Biotage IsoleraFour ^™ (10 g column, 20% to 100% EtOAc in heptane).

LCMS (Method H): two peaks at 4.35 and 4.39 min, 448 [M+H] ⁺

¹ H NMR (250MHz, DMSO-d ₆ ,353K)8.32(bm,0.4H),8.23-8.16(m,1H),8.12(bm,0.6H),8.05(m,2H),7.64(dd,0.4H),7.57 -7.42(m,1.6H),7.08(bm,0.6H),6.94(bm,0.4H),6.66(d,0.4H),6.46(d,0.6H),3.94(m,0.4H) ,3.74(m,1.4H),3.55-3.29(m,2H),3.24(m,1H),2.58(s,1.2H),2.52(s,1.8H),2.05-1.85(m,0 .6H),1.85-1.68(m,0.4H),1.68-1.52(m,1.2H),1.21(t,1.8H),1.04(m,2.4H),0.85(t,1.8H).

Preparation of (S)-N-ethyl-6-methyl-N-(1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 72)

The title compound (90 mg) was prepared as a glass from intermediate 29 (80 mg, 0.26 mmol) and 2-chloroquinazoline (66 mg, 0.40 mmol) using the method described for Route 7. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (10 g column, 20% to 100% EtOAc in heptane).

LCMS (Method H): 3.53 min, 431 [M+H] ⁺

¹ H NMR (250MHz, DMSO-d ₆ ,353K)9.14(s,0.45H),9.03(s,0.55H),8.28-8.20(d,0.45H),8.20-8.15(d,0.55H),8.14-8.12(s,0.9H),8.08(s,1 .1H),7.87-7.61(m,2H),7.57-7.44(m,1H),7.44-7.32(m,1.45H),7.31-7.18(m,1H),6.85(bs,0.55H),4.14-3.99(m, 0.55H),3.99-3.72(m,1.45H),3.70-3.48(m,1H),3.49-3.36(m,1H),3.35-3.24(m,1H),2.58(s,1.35H),2.53(s,1.6 5H),2.12-1.88(m,0.55H),1.88-1.76(m,0.45H),1.76-1.58(m,1H),1.22(t,1.65H),1.07(m,2.7H),0.89(t,1.65H).

Preparation of (S)-N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 73)

The title compound (28 mg) was prepared as a glass from intermediate 29 (50 mg, 0.16 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (45 mg, 0.25 mmol) using the method described for Route 7. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (11 g KP-NH column, 0% to 10% methanol in DCM).

LCMS (Method H): two peaks at 4.36 and 4.50 min, 449 [M+H] ⁺

¹ H NMR (250MHz, DMSO-d ₆ )8.88(s,0.35H),8.85(s,0.35H),8.76(s,0.65H),8.64(s,0.65H),8.48-8.36(m,1.65H),8.34(s,0 .7H),8.30(s,1.3H),8.03(bm,0.35H),7.72(d,0.35H),7.67(d,0.65H),4.09(bm,0.65H),3.94(m,1. 35H),3.83-3.63(bm,1H),3.62-3.54(m,1H),3.42(d,1H),2.75(s,1.05H),2.70(s,1.95H),2.25-2. 02(bm,0.65H),1.96-1.81(bm,0.35H),1.73(m,1H),1.36(t,1.95H),1.21(m,2.1H),0.99(t,1.95H).

Preparation of (S)-N-(1-cyclopropyl-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 74)

The title compound (10 mg) was prepared as an oil from intermediate 30 (33 mg, 0.1 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (18 mg, 0.1 mmol) using the method described for Route 7. The crude product was purified by chromatography on a Biotage IsoleraFour ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane).

LCMS (Method I): 3.39 min, 447 [M+H] ⁺

¹ H NMR (250MHz, DMSO-d ₆ ,353K)8.62(s,1.1H),8.43(s,0.9H),8.18(m,1H),8.08(s,1.1H),8.04(s,0.9H ),7.85(bm,0.45H),7.55-7.42(m,1H),7.42-7.32(bm,0.55H),4.02(m,0.55H),3 .75(m,1.55H),3.55(m,0.45H),3.35(m,0.45H),3.02(s,1.35H),2.86(s,1.65H) ,2.55(s,1.65H),2.53(s,1.35H),1.10(m,1H),0.49(m,3.55H),0.15(m,0.45H).

Preparation of (S)-N,6-dimethyl-N-(1-(quinolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 75)

To a mixture of intermediate 22 (65 mg, 0.20 mmol), 2-chloroquinoline (29 mg, 0.18 mmol), NaO ^t Bu (48 mg, 0.50 mmol), and BINAP (12 mg, 0.02 mmol) in degassed dioxane (12 mL) was added Pd ₂ (dba) ₃ (9 mg, 0.01 mmol). The reaction mixture was heated at 100° C. for 18 hr. EtOAc (10 mL) and water (10 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL). The combined organics were washed with water (20 mL), dried over MgSO ₄ , filtered, and concentrated in vacuo. The residue was purified by dry flash chromatography (50% to 100% EtOAc in heptane) and then reverse phase column chromatography (C18 30 g cartridge, 5% to 95% pH _{10 NH4HCO3} in MeCN) to give the title compound as a solid (23 mg).

LCMS (Method B): two peaks at 2.27 and 2.31 min, 416 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.41(d,0.55H),8.34(s,1H),8.33-8.28(m,1.45H),8.07(d,0.45H),7.97(d,0.55H),7.85-7.74(dd,1H ),7.74-7.57(m,2H),7.46(m,1H),7.33(m,1H),7.22(bm,0.55H),7.11(bm,0.45H),7.00(d,0.45H),6.81( bd,0.55H),4.80(m,0.45H),4.12-3.96(m,0.55H),3.92-3.76(m,0.9H),3.76-3.61(m,1.1H),3.07(s,1. 65H),2.96(s,1.35H),2.69(s,1.35H),2.56(bs,1.65H),1.76(m,2H),1.18(bt,1.35H),1.02(bt,1.65H).

Preparation of (S)-N-(1-((1,5-naphthyridin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 76)

A mixture of intermediate 22 (100 mg, 0.31 mmol), 2-bromo-1,5-naphthyridine (64 mg, 0.31 mmol), NaO ^t Bu (71 mg, 0.74 mmol) and BINAP (4 mg, 0.01 mmol) in toluene (3 mL) was degassed under nitrogen for 5 min. Pd ₂ dba ₃ (11 mg, 0.01 mmol) was added and the mixture was degassed under nitrogen for 5 min. The mixture was heated to 120° C. for 4 hr. The reaction mixture was allowed to cool to ambient temperature, and then BINAP (4 mg, 0.01 mmol), Pd ₂ dba ₃ (11 mg, 0.01 mmol) and NaO ^t Bu (27 mg, 0.31 mmol) were added and the mixture was degassed for 5 min. Heating was continued at 120° C. for 3 hr. The reaction mixture was then allowed to cool to ambient temperature, and the mixture was diluted with EtOAc/water and the phases were separated. The aqueous phase is extracted with EtOAc. The combined organic matter is washed with saturated aqueous _NaHCO and brine, dried over _MgSO , filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30x100mm posts, 10% to 95% MeCN in water) to obtain the title compound (23 mg) in a glassy state.

LCMS (Method I): two peaks at 1.64 and 1.69 min, 417 [M+H] ⁺

¹ H NMR (500MHz, CDCl ₃ )8.53(dd,0.4H),8.50(dd,0.6H),8.30-8.20(bm,0.6H),8.19-8.12(m,1.4H),7.97(m,1H),7.90(d,1H),7. 81(s,1.2H),7.71(s,0.8H),7.41-7.38(dd,0.4H),7.38-7.33(dd,0.6H),7.25-7.21(bm,1H),6.94(bm,0.4H ),6.81(bm,0.6H),4.76(m,0.4H),3.88(bm,0.6H),3.86-3.67(bm,1H),3.67-3.45(bm,1H),2.93(s,1.8H), 2.72(s,1.2H),2.57(s,1.8H),2.51(s,1.2H),1.75(m,1.2H),1.61(m,0.8H),1.06(t,1.2H),0.86(t,1.8H).

Preparation of (S)-5-chloro-N-methyl-N-(1-(quinolin-2-ylamino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 77)

To a solution of intermediate 21 (400 mg, 1.3 mmol) in dioxane (8 mL) was added 2-bromoquinoline (300 mg, 1.4 mmol) and NaO ^t Bu (310 mg, 3.2 mmol), and the mixture was degassed under argon for 20 min. tBuXPhos (110 mg, 0.26 mmol) and Pd ₂ (dba) ₃ (120 mg, 0.13 mmol) were added, and the mixture was degassed under argon for another 10 min. The reaction mixture was heated at 120 ° C in a microwave reactor for 3 hr, and then allowed to cool to ambient temperature. EtOAc was added, and the organic matter was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (5% methanol in DCM) to obtain the title compound (90 mg) as a solid.

LCMS (Method E): two peaks at 2.32 and 2.72 min, 435 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.12(s,1H),8.05(s,1H),8.02-7.92(bm,0.35H),7.92-7.74(bm,1.47H),7.74-7.33(bm,3.9H),7.28-6.95(bm,2.8 3H),6.92-6.79(bm,1.1H),6.73(d,0.35H),4.68(bm,0.34H),4.51(bm,0.07H),3.78(bm,0.6H),3.63-3.41(m,0.63H ),3.25-3.04(bm,1.32H),2.91(s,0.08H),2.83(s,0.8H),2.74(m,1.2H),2.72-2.63(m,0.6H),2.33(m,0.17H),1.72 (bm,0.19H),1.62(t,0.78H),1.39-1.16(m,1.25H),0.99(m,1.42H),0.89(m,0.6H),0.74(bm,0.25H),0.62(t,0.7H).

Preparation of (S)-N,3-dimethyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide (Example 78)

To a mixture of 3-methylisoquinoline-1-carboxylic acid [prepared as described in J. Med. Chem. 2014, 57, 1976-1994] (40 mg, 0.21 mmol) and triethylamine (43 mg, 0.43 mmol) in DMF (1 mL) was added HATU (97 mg, 0.26 mmol). After 15 min, intermediate 31 (53 mg, 0.21 mmol) was added, and the reaction mixture was stirred at ambient temperature for 30 min. EtOAc (10 mL) and water (10 mL) were added. The layers were separated, and the aqueous phase was then extracted with EtOAc (10 mL). The combined organics were washed with water (20 mL), dried over MgSO ₄ , filtered, and concentrated in vacuo. The residue was purified by dry flash chromatography (50% to 100% EtOAc in heptane) to give the title compound (20.4 mg) as a solid.

LCMS (Method L): 2.47 min, 418 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )8.70(bs,0.5H),8.54-8.41(m,2.1H),8.07(d,0.9H),7.84(bd,0.1H),7.77(d,1.15H),7.67(t,1.05H ),7.58-7.48(m,2.2H),5.09(bm,0.1H),3.85-3.65(m,2.4H),3.61(m,0.2H),3.48(m,0.15H),3.22(m,0 .8H),3.06(s,2.55H),2.79(s,2.55H),2.74-2.69(m,0.33H),2.68(s,0.33H),1.82-1.69(m,0.21H),1 .41(m,1.2H),1.33-1.21(bm,0.18H),1.16(t,0.3H),1.06(t,0.09H),0.92(t,0.09H),0.77(t,2.52H).

Preparation of (S)-N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)quinoline-8-carboxamide (Example 79)

To a mixture of 8-quinolinecarboxylic acid (35 mg, 0.20 mmol) and triethylamine (22 mg, 0.22 mmol) in MeCN (0.5 mL) was added HATU (92 mg, 0.20 mmol). After 15 min, intermediate 31 (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hr. EtOAc (10 mL) and water (10 mL) were added. The organic phase was washed with water (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 10% MeOH in EtOAc) to obtain the title compound (35.2 mg) as a solid.

LCMS (Method L): Peaks at 1.79, 1.83 and 2.03 min, 404 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )9.37(bd,0.5H),9.31(bd,0.5H),8.69(bs,0.5H),8.53(m,1.5H),8.46-8.37(m,1H),8.23(d,1H) ,7.90(d,1H),7.77(d,0.5H),7.74(d,0.5H),7.62(t,1H),7.51(m,1H),5.26(bm,0.5H),4.09(bm,0 .5H),3.72(bm,0.5H),3.55(m,0.5H),3.23(bt,0.5H),3.16-3.10(bm,0.5H),3.09(s,1.5H),2.60 (s,1.5H),1.77-1.62(m,1H),1.55-1.40(m,0.5H),1.11(t,1.5H),0.92(t,1.5H),0.83(bm,0.5H).

Preparation of (S)-6-chloro-N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)quinoline-8-carboxamide (Example 80)

To the mixture of 6-chloroquinoline-8-formic acid (42 mg, 0.20 mmol) and triethylamine (22 mg, 0.22 mmol) in MeCN (0.5 mL) was added HATU (92 mg, 0.20 mmol). After 15 min, intermediate 31 (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. EtOAc (10 mL) and water (10 mL) were added and each layer was separated. The aqueous phase was extracted with EtOAc (10 mL). The combined organic matter was washed with water (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (50% to 100% EtOAc in heptane) to obtain the title compound (23.6 mg) as a solid.

LCMS (Method A): Peaks at 0.80, 0.86 and 0.94 min, 438 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )9.36(dd,0.39H),9.29(dd,0.39H),9.25(bd,0.1H),8.53(bm,1.41H) ,8.48(bm,0.45H),8.44(m,0.36H),8.23(bs,0.18H),8.21(bs,0.18H), 8.16(t,0.84H),8.14(t,0.45H),8.12(d,0.06H),7.88(d,0.89H),7.8 5(d,0.15H),7.72(d,0.39H),7.67(d,0.5H),7.59(d,0.11H),7.53(m,1 .15H),5.22(m,0.4H),4.09(m,0.4H),3.68(m,0.45H),3.55(m,0.62H) ,3.24(t,0.4H),3.19-3.12(m,0.52H),3.08(s,1.41H),2.70(s,0.28H) ,2.62(s,1.29H),1.77-1.60(m,1.47H),1.25(bs,0.39H),1.17(t,0.1 8H),1.10(t,1.29H),0.95(t,1.32H),0.83(bm,0.48H),0.73(t,0.1H).

Preparation of (S)-3-(dimethylamino)-N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide (Example 81)

To a mixture of intermediate 32 (17 mg, 0.08 mmol) and triethylamine (16 mg, 0.16 mmol) in MeCN (1 mL) was added HATU (36 mg, 0.09 mmol). After 15 min, intermediate 31 (20 mg, 0.08 mmol) was added and the reaction mixture was stirred at ambient temperature for 30 min. EtOAc (10 mL) and water (10 mL) were added and the aqueous phase was extracted with EtOAc (10 mL). The combined organics were washed with water (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 100% EtOAc in heptane) to obtain the title compound (22.2 mg) as a solid.

LCMS (Method B): two peaks at 2.64 and 2.89 min, 447 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.90(d,0.25H),8.81(d,0.25H),8.44(m,1H),8.22(t,0.75H),8.17(bs,0.75H),7.83(d,0.25H),7.69-7.5 7(m,1.75H),7.50(t,1H),7.21(t,0.25H),7.10(t,0.75H),6.96(s,0.25H),6.84(s,0.75H),5.16(bm,0.25H) ,4.02(bm,0.5H),3.89(bm,0.25H),3.52(s,2.25H),3.43(bm,0.75H),3.24(s,3.75H),3.23(s,0.75H),3.19( s,2.25H),2.76(s,0.75H),1.80(m,1.5H),1.70(m,0.75H),1.43(m,0.25H),1.18(t,0.75H),1.09(t,2.25H).

Preparation of (S)-N,6-dimethyl-N-(1-(methyl(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 82)

To a solution of intermediate 33 (72 mg, 0.28 mmol), HATU (115 mg, 0.3 mmol) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [prepared as described in WO 2011023578] (97 mg, 0.3 mmol) in anhydrous DMF (2 mL) was added DIPEA (0.24 mL, 1.38 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and the residue was purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30 x 100 mm column, 10% to 95% MeCN in water). The crude product was further purified by chromatography on a Biotage Isolera Four ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane) to give the title compound (20 mg) as a solid.

LCMS (Method H): two peaks at 4.23 and 4.62 min, 449 [M+H] ⁺

¹ H NMR (500MHz, DMSO-d ₆ )8.92(s,0.85H),8.85(s,0.85H),8.77(s,0.15H),8.48(s,0.15H),8.36-8.31(m,1H),8.26(s,0.3H),8.23(s,1.7H),7 .64(d,0.85H),7.56(d,0.15H),5.04(m,0.85H),4.40(dd,0.85H),3.97-3.89(bm,0.15H),3.97-3.89(d,0.15H),3.83-3 .77(dd,0.15H),3.77-3.71(dd,0.85H),3.42(s,2.55H),3.23(s,0.45H),3.11(s,0.45H),2.91(s,2.55H),2.61(s,2.55 H),2.58(s,0.45H),1.90-1.80(m,0.85H),1.80-1.70(m,0.85H),1.63-1.47(m,0.3H),1.19(t,2.55H),0.91(t,0.45H).

Preparation of (S)-N-(1-((2-methoxyethyl)(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide (Example 83)

To a solution of intermediate 34 (49 mg, 0.16 mmol), HATU (65 mg, 0.17 mmol), and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [prepared as described in WO 2011023578] (55 mg, 0.17 mmol) in anhydrous DMF (2 mL) was added DIPEA (0.14 mL, 0.78 mmol), and the reaction mixture was stirred at ambient temperature for 5 hr. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (25 mL) and washed with water. The aqueous phase was extracted with EtOAc, and the combined organics were washed with water, brine, _dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (11 g KP-NH column, 0% to 100% EtOAc in heptane). The crude product was further purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30 x 100 mm column, 10% to 95% MeCN in water) to give the title compound (31 mg) as a solid.

LCMS (Method I): two peaks at 3.54 and 3.99 min, 493 [M+H] ⁺

¹ H NMR (500MHz, DMSO-d ₆ )8.92(s,0.6H),8.87(s,0.6H),8.77(s,0.4H),8.49(s,0.4H),8.38-8.32(d,0.6H),8.32-8.30(d,0.4H), 8.27(s,0.8H),8.23(s,1.2H),7.65(d,0.6H),7.55(d,0.4H),5.01(bm,1H),4.30(dd,0.6H),4.17-3.95(m ,1.4H),3.95-3.81(m,1.4H),3.77(m,1.6H),3.63(m,1H),3.46(s,1.8H),3.36(s,1.2H),3.10(s,1.2H),2 .91(s,1.8H),2.63(s,1.8H),2.60(s,1.2H),1.79(m,1.4H),1.55(m,0.6H),1.18(t,1.8H),0.89(t,1.2H).

Preparation of (S)-N,6-dimethyl-3-(pyrimidin-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formate (Example 84)

To a solution of lithium 6-methyl-3-(pyrimidin-2-yl)picolinate [prepared as described in WO 2012/089607] (29 mg, 0.13 mmol), intermediate 31 (32 mg, 0.13 mmol), and HATU (54 mg, 0.14 mmol) in DMF (5 mL) at 0°C was added DIPEA (62 μL, 0.36 mmol), and the reaction mixture was allowed to warm to ambient temperature and stirred for 88 hr. The mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous _NaHCO₃ . The organic phase was dried _{over Na₂SO₄} , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (10 g column, 1% to 10% methanol in DCM). The crude product was further purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30×100 mm column, 10% to 95% MeCN in water) and lyophilized from 10% MeCN in water (3 mL) to give the title compound as a solid (39 mg).

LCMS (Method I): 3.30 min, 446 [M+H] ⁺

¹ H NMR (500MHz, DMSO-d ₆ )9.11(d,1.2H),9.09(d,0.8H),8.87(s,0.4H),8.82(s,0.4H),8.71(s,0.6H),8.67(s,0.6H ),8.64-8.62(d,0.4H),8.62-8.59(d,0.6H),8.49(bm,0.6H),8.02(t,0.4H),7.66(m,1H),7. 62(m,1H),4.84(m,0.4H),3.98(m,0.6H),3.87-3.75(m,1H),3.75-3.66(m,1H),3.06(s,1.8H ),2.92(s,1.2H),2.72(s,1.8H),2.70(s,1.2H),1.80(m,2H),1.20(t,1.2H),1.03(t,1.8H).

Preparation of (S)-N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide (Example 85)

To a mixture of isoquinoline-1-carboxylic acid (150 mg, 0.87 mmol) in DMF (1 mL) was added CDI (140 mg, 0.87 mmol). After 10 min, Intermediate 31 (195 mg, 0.79 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hr and then partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (10 mL) and the combined organics were washed with water (20 mL), dried over _MgSO₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (50% to 100% EtOAc in heptane) to give the title compound (76.4 mg) as a solid.

LCMS (Method B): two peaks at 2.23 and 2.28 min, 404 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )8.56(d,0.85H),8.53-8.45(m,1.3H),8.43(bs,0.85H),8.35(bs,0.85H),8.13(d,0.85H),7.90 -7.82(m,1H),7.77-7.68(m,2H),7.68-7.65(d,0.15H),7.65-7.60(td,0.85H),7.50(tt,0.15H) ,6.24(m,0.15H),5.11(m,0.15H),3.91-3.61(m,1.85H),3.24(m,0.85H),3.07(s,2.55H),2.67( s,0.45H),1.75(m,0.3H),1.70-1.62(m,0.85H),1.42(m,0.85H),1.15(t,0.45H),0.78(m,2.7H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,4,5-trimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 86)

To a solution of 4,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid [prepared as described in WO 2014/141065] (30 mg, 0.14 mmol) in DCM (2 mL) was added oxalyl chloride (35 mg, 0.28 mmol). The reaction mixture was stirred at ambient temperature for 1 hr. Toluene (2 mL) was added, and the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (1 mL) and added to an ice-cold solution of Intermediate 15 (30 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in DCM (1 mL). The reaction was allowed to warm to ambient temperature and stirred for 1 hr. EtOAc (10 mL) and saturated aqueous _NaHCO₃ (10 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL) and the combined organics were washed with water (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 100% EtOAc in heptane) to give the title compound (11.1 mg) as a solid.

LCMS (Method B): two peaks at 2.52 and 2.79 min, 413 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.26(bm,0.24H),8.23(s,0.64H),8.18(bm,0.80H),8.14(bm,0.31H),7.96 (bm,0.06H),7.95-7.85(m,0.63H),7.79(bm,0.47H),7.70-7.63(m,1.03H), 7.62(d,0.16H),7.59(d,0.22H),7.35-7.25(bm,0.34H),7.20-7.10(bm,0.8 8H),6.89(s,0.41H),6.80-6.70(bm,1.50H),6.65(d,0.31H),4.85-4.70(bm, 0.52H),3.85-3.70(bm,0.23H),3.52(m,3.50H),3.25-3.05(bm,0.18H),3.0 1(s,0.16H),2.95(s,0.79H),2.79(s,1.38H),2.55-2.45(m,2.42H),2.40(m ,1.68H),2.27(s,0.45H),2.11(s,0.84H),1.71(bm,0.77H),1.43(bm,1.09H ),1.11(t,1.51H),1.08-0.98(bt,0.55H),0.86(bt,0.10H),0.67(t,0.84H).

Preparation of (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methoxy-N,4-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 87)

To a solution of 5-methoxy-4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid [prepared as described in WO 2014/141065] (30 mg, 0.13 mmol) in DCM (2 mL) was added oxalyl chloride (33 mg, 0.26 mmol). The reaction mixture was stirred at ambient temperature for 1 hr. Toluene (2 mL) was added, and the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (1 mL) and added to an ice-cold solution of Intermediate 15 (27 mg, 0.13 mmol) and triethylamine (26 mg, 0.26 mmol) in DCM (1 mL). The reaction was allowed to warm to ambient temperature and stirred for 1 hr. EtOAc (10 mL) and saturated aqueous _NaHCO₃ (10 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL) and the combined organics were washed with water (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by dry flash chromatography (0% to 100% EtOAc in heptane) to give the title compound (6.2 mg) as a solid.

LCMS (Method B): two peaks at 2.50 and 2.75 min, 429 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )8.19(m,2H),7.98-7.92(m,0.2H),7.92-7.83(m,0.49H),7.79(bs,0.46H),7.67 (s,0.33H),7.65-7.55(bm,0.49H),7.55-7.45(m,0.46H),7.20-7.10(bm,0.52H), 7.10-6.95(bm,0.62H),6.85(s,0.33H),6.83-6.70(bm,1.63H),6.61(d,0.36H), 6.44(d,0.13H),4.87-4.77(bs,0.41H),4.75-4.60(bs,0.12H),4.09-4.03(bm,0. 53H),4.02(s,0.26H),3.96(bs,1.17H),3.87(s,0.99H),3.75-3.60(bm,1H),3.2 5-3.15(bm,0.43H),3.02(s,0.26H),2.94(s,1.08H),2.85-2.75(bm,2.08H),2.47 -2.37(bm,2.36H),2.34(s,0.90H),2.27(s,0.15H),1.90-1.75(bm,0.23H),1.75- 1.65(bm,0.81H),1.50-1.35(bm,0.38H),1.15-0.95(bm,2.90H),0.68(t,0.93H).

Preparation of (S)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(4,4,4-trifluoro-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 88)

To a solution of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [prepared as described in WO 2010/063662] (20 mg, 0.10 mmol) in DCM (1.5 mL) was added oxalyl chloride (37 mg, 0.29 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. Toluene (2 mL) was added, and the mixture was concentrated in vacuo. The residue was dissolved in DCM (1 mL) and added to an ice-cold solution of intermediate 35 (35 mg, 0.12 mmol) and triethylamine (30 mg, 0.29 mmol) in DCM (1 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. DCM (10 mL) and saturated aqueous _NaHCO₃ (10 mL) were added, and the layers were separated. The organics were dried over _MgSO₄ , filtered, and concentrated in vacuo. The residue was purified by dry flash chromatography (50% to 100% EtOAc in heptane) to give the title compound as a solid (37 mg).

LCMS (Method L): two peaks at 2.37 and 2.48 min, 489 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )8.90(m,1H),8.78(bs,0.58H),8.55(bs,0.42H),8.44(m,1H),8.41-8.36(bm ,0.42H),8.35-8.32(m,1.16H),8.26(m,0.84H),8.20(bm,0.58H),7.71(m,0.5 8H),7.65(m,0.42H),5.13(bs,0.58H),4.41(bs,0.42H),4.00-3.60(m,2H),3. 15(s,1.26H),2.99(s,1.74H),2.87(bm,2H),2.69(s,1.74H),2.51(s,1.26H).

Route 8: Procedure for preparing examples via copper-catalyzed coupling of aryl halides with heterocycles as exemplified by the preparation of (S)-N,6-dimethyl-3-(1H-1,2,4-triazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formate (Example 89)

A suspension of intermediate 36 (250 mg, 0.42 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (6 mg, 0.04 mmol), CuI (8 mg, 0.04 mmol), Cs2CO3 (274 mg, 0.84 mmol) and 1,2,4 _{- triazole} (58 mg, 0.84 mmol) in DMF (3 mL) was degassed under nitrogen at ambient temperature for 10 min in a sealed tube. The mixture was then heated at 100°C for 18 hr. The mixture was allowed to cool to ambient temperature, and CuI (8 mg, 0.04 mmol) and 1,2,4-triazole (58 mg, 0.84 mmol) were then added and degassed under nitrogen for 10 min before heating at 100°C for a further 6 hours. The reaction mixture was concentrated in vacuo. EtOAc (50 mL) was added and the organic phase was washed with saturated aqueous NaHCO ₃ . The organic phase was dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (10 g column, 1% to 10% methanol in DCM). The product was further purified by preparative TLC (3% x 3% methanol in DCM) and subsequently by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30x100 mm column, 10% to 95% MeCN in water) to obtain the title compound (28 mg) as a gum.

LCMS (Method O): two peaks at 4.28 and 4.34 min, 435 [M+H] ⁺

¹ H NMR (500MHz, DMSO-d ₆ )9.08(s,0.45H),8.99(s,0.55H),8.84(s,0.45H),8.85(s,0.45H),8.71(s,0.55H),8.62(s,0.55H),8.44 -8.42(s,0.45H),8.42-8.41(s,0.55H),8.41-8.36(m,0.55H),8.25(d,0.45H),8.18(d,0.55H),8.01(m,0. 45H),7.70(d,0.45H),7.64(d,0.55H),4.79(m,0.45H),3.97(bm,0.55H),3.71(m,1H),3.54(m,1H),3.03( s,1.65H),2.89(s,1.35H),2.70(s,1.35H),2.65(s,1.65H),1.70(m,2H),1.01(t,1.35H),0.91(t,1.65H).

Preparation of (S)-N,6-dimethyl-3-(1H-pyrazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formate (Example 90)

The title compound (70 mg) was prepared as a solid from intermediate 36 (250 mg, 0.42 mmol) and 1H-pyrazole (57 mg, 0.84 mmol) using the method described for Route 8. The crude product was purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 10% to 100% EtOAc in heptane). The product was further purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30×100 mm column, 10% to 95% MeCN in water).

LCMS (Method H): 4.16 min, 435 [M+H] ⁺

¹ H NMR (500MHz, DMSO-d ₆ )8.66(m,1H),8.58(m,0.4H),8.47(m,0.6H),8.23(t,0.6H),8.12(d,0.4H),8.10(d,0.6H),8.00(d,0.4H),7 .98(d,0.6H),7.83-7.75(m,1.4H),7.44(d,0.4H),7.39(d,0.6H),6.51(t,0.6H),6.48(t,0.4H),4.64(m,0. 6H),3.62(bm,0.6H),3.58-3.50(m,1H),2.82(s,1.8H),2.66(s,1.2H),2.65(m,0.4H),2.49(s,1.2H),2.41( s,1.8H),2.37(m,0.4H),1.63-1.51(m,1H),1.45(bm,0.6H),1.34(bm,0.4H),0.89(t,1.2H),0.64(bm,1.8H).

Preparation of (S)-2-fluoro-N-methyl-6-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)benzamide (Example 91)

Using the method described in Route 2, the title compound (158 mg) was prepared as a solid from intermediate 31 (168 mg, 0.68 mmol), intermediate 38 (140 mg, 0.68 mmol), HATU (0.26 g, 0.68 mmol) and DIPEA (0.29 mL, 1.69 mmol). The crude product was isolated by extraction into EtOAc and then purified by chromatography on a Biotage Isolera Four ^™ (25 g column, 0% to 10% MeOH in DCM). The product was further purified by preparative HPLC (Gilson, acidic (0.1% formic acid), Waters Sunfire Prep-C18, 10 μm, 30×100 mm column, 10% to 95% MeCN in water).

LCMS (Method I): four peaks at 3.11, 3.37, 3.52 and 3.82 min, 438 [M+H] ⁺

¹ H NMR (250MHz, DMSO-d ₆ ,353K)8.65(s,0.82H),8.59(s,0.65H),8.41(bs,0.12H),8.35(bs,0.13H),8.16(s,0.9H),8.06(s,0.35H),8.05-8.02(m,0.75 H),7.92-7.83(m,0.57H),7.81-7.69(m,0.72H),7.68(t,0.31H),7.66-7.55(m,0.75H),7.54-7.19(m,1.81H),6.95(td,0.12H), 4.77(m,0.42H),4.59(m,0.58H),3.82-3.67(m,0.54H),3.67-3.41(m,1.18H),3.40-3.19(m,0.48H),2.92(s,0.29H),2.87(s,0. 39H),2.79(s,1.46H),2.78(s,0.98H),1.79-1.55(m,1.56H),1.33(m,0.12H),0.98(m,2.25H),0.85(t,0.39H),0.48(t,0.36H).

Preparation of (S)-6-methoxy-N-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide (Example 92)

The title compound (30 mg) was prepared as a solid from intermediate 39 (110 mg, 0.34 mmol), intermediate 31 (84 mg, 0.34 mmol), HATU (141 mg, 0.37 mmol) and DIPEA (160 μL, 0.92 mmol) using the method described in Route 2. The crude product was isolated by extraction into EtOAc and then purified by preparative HPLC (Gilson, basic (0.2% ammonium hydroxide), Waters Xbridge Prep-C18, 10 μm, 30×100 mm column, 10% to 95% MeCN in water) followed by lyophilization.

LCMS (Method H): two peaks at 3.92 and 4.11 min, 451 [M+H] ⁺

¹ H NMR (250 MHz, DMSO-d ₆ ,353K)8.62(s,1.6H),8.43(s,0.6H),8.26-8.13(m,1H),8.03(d,1.8H),7.6 6(bs,0.4H),7.35(bs,0.6H),7.04(d,0.6H),6.98(d,0.4H),4.65(m,0.6H), 3.91(s,1.2H),3.89(s,1.8H),3.81(m,0.6H),3.64(m,1.2H),3.50(m,0.6H) ,2.87(s,1.2H),2.79(s,1.8H),1.60(m,2H),0.99(t,1.8H),0.82(t,1.2H).

Biological assays

The antagonism of each example compound at the orexin receptor has been measured using at least one of the following procedures. Antagonism is reported as _pIC50 , where _pIC50 = _-log10 ( _IC50 ), and where _IC50 is the concentration of the example compound required to inhibit the agonist response by 50%. These values may fluctuate depending on daily cell assay performance. Such fluctuations are known to those skilled in the art. Data reported as less than (<) represent the highest measurable _pIC50 , or the highest concentration tested that failed to achieve 50% inhibition of the agonist response. Data highlighted with an asterisk (*) are derived from a single experiment; otherwise, all data reported are the average of at least two independent replicates.

Intracellular calcium measurements using division-arrested cells (Table 1):

Test compounds were prepared as 10 mM stock solutions in DMSO and then serially diluted in DMSO at half-log concentrations before being diluted in assay buffer (HBSS (Sigma-Aldrich, H8264) containing 20 mM HEPES (Sigma-Aldrich, H4034), 0.1% (w/v) bovine serum albumin and adjusted to pH 7.4) to a final assay concentration of 10 μM.

Mitation-arrested cells expressing human _OX1 (CT-A474) and human _OX2 (CT-A475) receptors were plated into 384-well black, clear-bottom, cell-bound plates at a seeding density of 10,000 cells/50 μL growth medium. The inoculated plates were incubated at 37°C in an atmosphere supplemented with 5% _CO2 for 16 hours. The medium was removed and replaced with 30 μL/well of cell loading buffer (one vial of calcium 5 dissolved in 22 mL of assay buffer, to which was added a freshly prepared 250 mM solution of probenecid in a 1:1 1M NaOH to assay buffer solution (200 μL)), and the cells were incubated at 37°C for 1 hour. Serially diluted test compounds (10 μL/well) were added to the plates, which were then incubated for 10 minutes and placed in the FlexStation III reader. Finally, 10 μL of the agonists, orexin A for OX ₁ and orexin B for OX ₂ , were added at a concentration of 2xEC ₅₀ , which was determined for each assay run. Fluorescence was measured at excitation and emission wavelengths of 485 nm and 525 nm, respectively, and this data was analyzed using GraphPad Prism to determine the IC ₅₀ value for each compound.

Table 1:

Intracellular calcium measurements using stably replicating cells:

Method A (Table 2): Test compounds were prepared as 10 mM stock solutions in DMSO, heated briefly at 37°C for 20 seconds, and serially diluted in DMSO at half-log concentrations, followed by dilution in assay buffer (HBSS (Sigma-Aldrich, H8264) containing 10 mM HEPES (Invitrogen, 15630080) and adjusted to pH 7.4) to achieve a final assay concentration of 10 μM.

Stable replicating cells expressing human OX ₁ (CT-A674) and human OX ₂ (CT-A675) receptors were grown at a concentration of 400 μg/mL in Ham F12 (Invitrogen, 31765-035) containing 10% fetal bovine serum (Invitrogen, 16000044), 1% non-essential amino acids (Invitrogen, 11140-050), 100 U/mL penicillin/streptomycin (Invitrogen, 15140-122), and G418 (Invitrogen, 11811023). Cells were seeded at a density of 7,000 cells/well in black, clear bottom, 384-well plates (Corning, 3683) and incubated at 37°C in an atmosphere supplemented with 5% CO ₂ for 16 hours.

The loading dye (Loading dye) (25 μ L/ wells) and the test compound (10 μ L/ wells) of serial dilution prepared according to the specification sheets of FLIPR calcium 6 assay kit (Molecular Devices, R8190-Explorer) are added to the plate.Then the plate is incubated at 37 ℃ for 30 min in 5% CO ₂ , then at ambient temperature for 30 min, and is placed in the FlexStation III reader. Finally, orexin-A is added to each hole with a concentration of 4x EC ₅₀ , which is determined for each mensuration operation. Fluorescence is measured at the excitation wavelength and emission wavelength of 485 nm and 525 nm, respectively, and GraphPad Prism is used to analyze this data to determine the IC ₅₀ value of every kind of compound.

Table 2:

Method B (Table 3): Test compounds were prepared as 20 mM stock solutions in DMSO, then serially diluted in DMSO at half-log concentrations, followed by dilution in assay buffer (HBSS (Gibco, 14065-049) containing 20 mM HEPES (Gibco, 15630-56), 2.5 mM probenecid, 0.1% (w/v) pluronic F127 (Sigma, P2443) and adjusted to pH 7.4) to a final assay concentration of 1 μM or 10 μM, depending on the potency of a given human OX receptor.

CHO cells expressing human _OX1 or human _OX2 receptor were plated at a seeding density of 10,000 cells/75 μL growth medium into 384-well black, clear-bottom CellBIND plates. The seeded plates were incubated overnight at 37°C in an atmosphere supplemented with 5% _CO2 .

In the second day, remove medium and replace (one bottle of calcium 5 is dissolved in 20mL mensuration buffer) with the cell loading buffer of 30 μ L/ holes, and cell is hatched 1hr at 37 ℃.By FLIPR Tetra, the test compound of serial dilution (10 μ L/ holes) is added in the cell plate, and by instrument, this interpolation is monitored 5min.Remove cell plate then, and before putting back into FLIPR Tetra, in humid incubator, hatch 25min again at 37 ℃.Finally, 10 μ L orexins A in mensuration buffer+0.1% (w/v) bovine serum albumin are distributed by FLIPR Tetra with the _EC75 concentration determined for each mensuration operation.Fluorescence is measured at the excitation wavelength and the emission wavelength place of 485nm and 525nm respectively, and uses GraphPad Prism to analyze this data to determine the _IC50 value of often test compound for the _EC75 value of orexin A and A plus (Aplus).

Table 3:

As shown herein, compounds of the present invention provide increased selectivity for the orexin-1 receptor over the orexin-2 receptor by whole cell FLIPR functional assay data and by comparison to reference compounds not claimed in the present invention.

Example 10

hOX1R pIC ₅₀ =7.1 hOX1R pIC ₅₀ =6.0 hOX1R pIC ₅₀ =7.2

hOX2R pIC ₅₀ =5.2 hOX2R pIC ₅₀ =5.7 hOX2R pIC ₅₀ =7.1

Selectivity 80x Selectivity 1.9x Selectivity 1.1x

Increased selectivity for the orexin-1 receptor over the orexin-2 receptor in the whole-cell FLIPR functional assay provides enhanced predictive value for determining in vivo efficacy. Increasing the functional selectivity for the orexin-1 receptor reduces the potential for dual receptor antagonism in vivo. This greater functional selectivity may provide benefits over other orexin receptor antagonists known in the art.

Typically, compounds of the invention have _IC50 values of 10 μM ( _pIC50 5) or less for orexin-1 in the above-identified assays and exhibit selectivity for orexin-1 over orexin-2 of greater than or equal to 0.4 log units in the above-identified assays. Preferred compounds of the invention have IC50 values of 3 μM (pIC50 _5.5 ) or less for orexin-1 in the above-identified assays and exhibit selectivity for orexin-1 over orexin-2 of greater than or equal to 1.0 log units in the above-identified assays. Most preferred compounds have _IC50 values of ₅₀₀ nM ( _pIC50 6.3) or less for orexin-1 in the above-identified assays and exhibit selectivity for orexin-1 over orexin-2 of greater than or equal to 1.5 log units in the above-identified assays.

The following compounds did not show any activity against orexin-1 in the above assay (ie they had an _IC50 greater than 10 μM):

(S)-5-methyl-N-(1-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)-N,5-Dimethyl-N-(1-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

N-(2-((5-chloropyridin-2-yl)amino)-1-(oxetan-3-yl)ethyl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methyl-2-(4-methylpiperazin-1-yl)benzamide;

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methyl-2-morpholinobenzamide;

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-(4-methylpiperazin-1-yl)benzamide;

(S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,2-dimethyl-5-(2H-1,2,3-triazol-2-yl)pyrimidine-4-carboxamide;

(S)-N-(2-(5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamido)butyl)picolinamide;

(S)-5-chloro-N-(1-(imidazo[1,2-a]pyridin-6-ylamino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)-ethyl 6-((2-(5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide)butyl)amino)nicotinate;

(S)-6-(2-Hydroxypropan-2-yl)-N-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide.

In one embodiment, the invention provides a compound of formula I as defined herein, which is not selected from one of the compounds listed in the above paragraph.

The following compound has an _IC50 of 4.9 μM in the above assay: (S)-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzamide. In one embodiment, the present invention provides compounds of Formula I excluding this specific compound.

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Claims (8)

1. A compound with the chemical formula IA: in R _b is selected from: (i) (1-4C) alkyl groups optionally substituted with one or more fluorine molecules; (ii) (3-6C) cycloalkyl groups optionally substituted with one or more fluorine atoms; or (iii) (3-6C)cycloalkyl(1-2C)alkyl groups optionally substituted with one or more fluorine molecules; Ar is a phenyl group or a 5-12 heteroaryl group comprising 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur, each optionally selected from halogen, cyano, hydroxyl, mercapto, amino, carbamoyl, aminosulfonyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkylthio, (1-2C)... C) alkylsulfinyl, (1-2C)alkylsulfonyl, (1-2C)alkoxycarbonyl, N-(1-2C)alkylcarbamoyl, N,N-di-[(1-2C)alkyl]carbamoyl, (2C)alkanoyl, (2C)alkanoyloxy, (2C)alkanoylamino, N-(1-2C)alkylaminosulfonyl and N,N-di-[(1-2C)alkyl]aminosulfonyl are substituted with one or more substituents; and R ^z2 is selected from halogens, cyano groups, nitro groups, or groups with the following chemical formulas: -L ³ -X ³ -R ³⁰ in ^L3 does not exist; ^X3 is absent or selected from -O-, -N( ^R33 )-, -N( ^R33 )-C(O)-, -C(O)-N( ^R33 )-, -S-, -SO-, or -SO2-, wherein ^R33 is selected from hydrogen or ( _1-2C )alkyl; and R ³⁰ is hydrogen or (1-4C) alkyl; Furthermore, R ³⁰ may optionally be further substituted with one or more fluorine atoms; Or its pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein _Rb is an (1-4C) alkyl group optionally substituted with fluorine. 3. The compound according to claim 1, wherein... _Rb is a methyl group that is optionally substituted with fluorine; R ^z2 is selected from the group consisting of the following: halogen, methyl, methoxy, _CF3 or _-OCF3 ; Ar is pyridyl, pyrimidinyl, or pyrazinyl, optionally substituted with one or more substituents selected from: halogen, cyano, hydroxyl, mercapto, amino, carbamoyl, aminosulfonyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkyl Thio, (1-2C)alkylsulfinyl, (1-2C)alkylsulfonyl, (1-2C)alkoxycarbonyl, N-(1-2C)alkylcarbamoyl, N,N-di-[(1-2C)alkyl]carbamoyl, (2C)alkanoyl, (2C)alkanoyloxy, (2C)alkanoylamino, N-(1-2C)alkylaminosulfonyl and N,N-di-[(1-2C)alkyl]aminosulfonyl. 4. A compound selected from any one of the following: (S)-N-(1-((5-chloropyridin-2-yl)amino)but-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbut-2-yl)-N,2-dimethyl-4-phenylthiazolyl-5-carboxamide; (S)-5-chloro-N-(1-((5-chloropyridin-2-yl)amino)but-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N-(1-((5-chloropyridin-2-yl)amino)but-2-yl)-5-fluoro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-5-bromo-N-(1-((5-chloropyridin-2-yl)amino)but-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N-(1-((5-chloropyridin-2-yl)amino)but-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N-(1-((5-chloropyridin-2-yl)amino)but-2-yl)-5-(dimethylamino)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)benzamide; (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)but-2-yl)benzamide; (S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridazin-3-yl)amino)but-2-yl)benzamide; (S)-N-(1-(benzo[d]oxazol-2-ylamino)but-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N-(1-(benzo[d]thiazo-2-ylamino)but-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)pyridineamide; (S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)but-2-yl)pyridineamide; (S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)but-2-yl)pyridineamide; (S)-N-(1-((5-chloropyridin-2-yl)amino)-3-methylbut-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)but-2-yl)pyridineamide; (S)-N-(1-((3-amino-5-chloropyridin-2-yl)amino)but-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N,6-Dimethyl-N-(1-(quinazolin-2-ylamino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N-(1-(benzo[d]oxazol-2-ylamino)but-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N-(1-(benzo[d]thiazo-2-ylamino)but-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N-(1-((5-chlorobenzo[d]oxazol-2-yl)amino)but-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N,6-Dimethyl-N-(1-(quinoxalo-2-ylamino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N,6-Dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrazin-2-yl)amino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N,6-Dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)amino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)but-2-yl)pyridineamide; (S)-N-Ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)but-2-yl)pyridineamide; (S)-N-ethyl-6-methyl-N-(1-(quinazolin-2-ylamino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N-Ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)pyridineamide; (S)-N,6-Dimethyl-N-(1-(quinolin-2-ylamino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-5-chloro-N-methyl-N-(1-(quinolin-2-ylamino)but-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide; (S)-N,6-Dimethyl-N-(1-(methyl(5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)-3-(2H-1,2,3-triazol-2-yl)pyridineamide; (S)-N,6-Dimethyl-3-(pyrimidin-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)pyridinecarboxylate; (S)-N,6-Dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(4,4,4-trifluoro-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)pyridineamide; (S)-N,6-Dimethyl-3-(1H-pyrazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)pyridinecarboxylate; (S)-2-fluoro-N-methyl-6-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)benzamide; and (S)-6-methoxy-N-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)but-2-yl)pyridineamide; Or its pharmaceutically acceptable salt. 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 6. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for treating a disease or condition selected from: schizophrenia and other mental disorders; dementia and other cognitive impairments; anxiety disorders; mood disorders; addiction; eating disorders; sleep disorders; disorders usually first diagnosed in infancy, childhood or adolescence; restless legs syndrome; pain; osteoporosis and neurodegenerative disorders. 7. The use according to claim 6, wherein the addiction is selected from substance dependence, alcohol dependence, nicotine dependence and gambling disorder. 8. The use according to claim 7, wherein the substance dependence is selected from cocaine dependence, opioid dependence, cannabis dependence, and prescription drug dependence.