EA042282B1 - KAPPA OPIOID RECEPTOR ANTAGONISTS AND RELATED PRODUCTS AND METHODS - Google Patents

Description

The field of technology to which the invention belongs

The invention relates to kappa opioid receptor (KOR) antagonists and products containing them, as well as to methods for their use and preparation.

Prerequisites for the creation of the invention

The kappa opioid receptor (KOR) is encoded by the OPRK1 gene and is a member of the opioid receptor family that binds to the opioid peptide dynorphin as a major endogenous ligand. KOR has a wide but unequal distribution in the brain, spinal cord, and peripheral tissues, especially in areas of the brain associated with reward, cognition, and stress response. Evidence suggests that dynorphin levels are elevated in painful and stressful conditions and that disruption of KOR produces anti-stress effects. These results have led to the development of KOR antagonists for the treatment of depressive, anxiety, addictive disorders, and other stress-related psychiatric conditions. The development of KOR antagonists is summarized in an article titled Kappa Opioid Receptor Antagonists, Urbano et al., Bioorganic & Medicinal Chemistry Letters, 24:2021-2032, 2014.

Pharmacological studies using prototypical KOR antagonists (ie ligands derived from morphinan nor-BNI and GNTI and non-morphinan JDTic) have confirmed the therapeutic potential of the KOR/dynorphin system. However, such prototype KOR antagonists exhibit a delayed onset of action ranging from hours to days, followed by antagonistic effects lasting several weeks at the lowest effective doses. In addition, such compounds have shown poor penetration across the blood-brain barrier. Thus, recent research has focused on the development of short-acting KOR antagonists with improved pharmacokinetics.

KOR antagonists have been extensively studied as they block marked stress-induced neuroadaptation; namely, increased expression of dynorphin in the nucleus accumbens (NAc). NAc is an element of the mesolimbic system that plays a role in the motivation and pathology of mental disorders. Stress, as well as repeated exposure to addictive drugs, triggers a complex sequence of intracellular events involving the transcription factor CREB, a protein that binds the cAMP response element, to NAc. As explained in Carlezon et al. Kappa Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials (Depression and Anxiety, 33:895-906, 2016), CREB-mediated upregulation of dynorphin induces depressive symptoms that are alleviated by KOR antagonists. According to the model presented by Carlezon et al., stress activates CREB in NAc, resulting in increased expression of dynorphin. An increase in dynorphin levels, in turn, promotes KOR activation. KORs are expressed on the cell bodies and terminals of mesocorticolimbic dopamine neurons (DA), and KOR activation inhibits DA release. Treatment with a KOR antagonist blocks the action of dynorphin, restoring DA function and thus providing antidepressant- and anxiolytic-like effects in various animal models.

These mechanisms of action, as well as the fairly extensive development and testing of KOR antagonists, including recent results from clinical studies (eg, CERC-501 and ALKS-5461), provide strong evidence that KOR antagonists may have therapeutic effects in people suffering from from a wide range of disorders, including mood disorders, anxiety disorders, and substance use disorders, as defined, for example, in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Another concept for classifying psychopathological disorders is the Research Domain Criteria (RDoC) project, which aims to classify such disorders based on observable behavioral and neurobiological features. In this context, KOR antagonists have a therapeutic effect on at least two types of RDoC specific regions; namely those associated with reward and those associated with the adverse effects of stress. In these areas, the use of KOR antagonists for the treatment of anhedonia (positive valence system) and for blocking the adverse effects of stress (negative valence system) has been recognized.

As a result of advances made in this field, KOR antagonists are recognized as useful in the treatment of major depression and addictive substance abuse or dependence disorders, especially in the context of fast-acting treatments that avoid the drawbacks associated with the prototypical KOR antagonists discussed above. . Other studies have shown that KOR antagonists may be particularly useful in the treatment of stress-related symptoms, as well as in the treatment of social anxiety disorder and phobias. Prophylactic therapy has also been proposed to prevent adverse conditions resulting from stress, and in this regard, KOR antagonism has been proposed as a preventive treatment for PTSD in individuals at risk of it. Other therapeutic applications of KOR antagonism include the treatment of reward-related dysfunction, as often occurs in patients with mood and anxiety spectrum disorders, and which can also occur in other types of conditions such as

- 1 042282 schizophrenia or schizoaffective disorder.

Thus, KOR antagonism holds promise for the treatment of a wide range of disorders and conditions. As such, a number of compounds are currently being developed that are highly selective and potent KOR antagonists for the treatment of various conditions such as addictive substance use disorders, major depression, anhedonia and stress-related symptoms. However, despite advances in this field, there is still a need for new and improved KOR antagonists, as well as pharmaceutical products containing them, and methods associated with their use and preparation.

The essence of the invention

The present invention is directed to compounds that antagonize the kappa opioid receptor (KOR), compositions containing them, and methods for their preparation and use in the treatment of a disease or condition where KOR antagonism is indicated or medically beneficial.

In one embodiment, compounds having the structure of formula (I), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof, are provided:

where X, Y, R ¹ , R ² , R ⁴ , R ⁵ R ⁶ , R ⁷ , R ⁸ and R ¹¹ have the meanings defined below.

In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

In one embodiment, the use of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, is provided for the preparation of a medicament.

In one embodiment, a method for antagonizing a KOR is provided, comprising contacting the receptor with an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound.

In one embodiment, a method is provided for treating a neuropsychiatric or behavioral condition, organic, stress-induced, or iatrogenic, that is characterized by elevated serum prolactin levels and responds to administration of a KOR antagonist with a decrease in serum prolactin levels. Such a method comprises administering to a subject an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such compound, at a frequency and for a duration sufficient to provide a beneficial effect. for the subject.

In one embodiment, a method is provided for treating a disorder in a subject wherein KOR antagonism is medically beneficial. Such a method comprises administering to a subject an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such compound, at a frequency and for a duration sufficient to provide a beneficial effect. for the subject.

In one embodiment, a method is provided for treating an addictive disorder, including disorders associated with substance abuse or dependence, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer thereof, a racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In one embodiment, a method of treating a central nervous system (CNS) disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In one embodiment, a method for treating an anxiety disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having

- 2 042282 the structure of formula (I), or its pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, with a frequency and duration sufficient to provide a beneficial effect for the subject. In one embodiment, the anxiety disorder is social anxiety. In one embodiment, the anxiety disorder is generalized anxiety disorder (GAD). In one embodiment, the anxiety disorder is a phobia. In one embodiment, the anxiety disorder is a stress-related disorder.

In one embodiment, a method is provided for treating a depressive disorder, depression, or depressive illness, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. In one embodiment, the depressive disorder is major depression.

In one embodiment, a method of treating a mood disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject. In one embodiment, the mood disorder is anhedonia. In one embodiment, the mood disorder is major depression.

In one embodiment, a method is provided for treating schizophrenia or schizoaffective disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition , including such a connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

In one embodiment, a method is provided for treating obesity or an eating disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical a composition comprising such a compound at a frequency and duration sufficient to provide a beneficial effect to the subject.

In one embodiment, a method for treating migraine is provided comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

In one embodiment, a method for treating postpartum depression is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

In one embodiment, a method is provided for treating mood and behavioral disorders associated with neurodegenerative diseases, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope thereof or a salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In one embodiment, a process is provided for synthesizing a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with at least one pharmaceutically acceptable carrier, diluent, or excipient.

Brief description of the drawings

Fig. 1 illustrates the activity of a representative compound, compound 142, as an antagonist in OPRK1 agonist-induced prolactin stimulation in 8-10 week old male C57BL/6J mice after i/p administration (Fig. 1A) and po administration (Fig. 1B) .

Fig. 2 illustrates the activity of a representative compound, compound 141, as an antagonist in OPRK1 agonist-induced prolactin stimulation in 8-10 week old males.

C57BL/6J mice after i/p administration (Fig. 2A) and p/o administration (Fig. 2B).

Fig. 3 illustrates the activity of a representative compound, compound 145, as an antagonist in OPRK1 agonist-induced prolactin stimulation in 8-10 week old males.

C57BL/6J mice after i/p administration (Fig. 3A) and p/o administration (Fig. 3B).

Fig. 4 illustrates the activity of a representative compound, Compound 146, as an antagonist in OPRK1 agonist-induced prolactin stimulation in 8-10 week old male C57BL/6J mice after ip (FIG. 4A) and po (FIG. 4B) administration. .

Fig. 5 illustrates the activity of a representative compound, Compound 147, as an antagonist in OPRK1 agonist-induced prolactin stimulation in 8-10 week old male C57BL/6J mice after ip (FIG. 5A) and po (FIG. 5B) administration. .

Fig. 6 illustrates Compound A tartrate salt activity as an antagonist in OPRK1 agonist-induced prolactin stimulation in 8-10 week old male C57BL/6J mice following ip administration.

Fig. 7 illustrates the activity of a representative compound, compound 142, as a potent functional antagonist of human OPRK1 in response to (a) (-)-U-50,488 and (b) Dynorphin A. Compound 142 is also selective for (c) OPRM1 and (d) OPRD.

Fig. 8 illustrates the activity of a representative compound, compound 142, as a potent and selective ligand for human OPRK1 over OPRM1 in a radioligand binding assay using ^[3u] diprenorphine.

Fig. 9 illustrates that Compound 142 (30mg/kg, po) given 1 hour but not 24 hours before (-)U-50.488 (20mg/kg, po) blocked the analgesic effect, induced by (-)-U-50,488, in a mouse tail flick assay. (A) Latency, (B) %MPR (maximum possible effect = [post-dose latency - baseline)/(15 - baseline)x100].

Fig. 10 illustrates that spiradoline (0.32 mg/kg, sc; OPRK1 agonist) significantly increased plasma prolactin concentrations in Sprague-Dawley rats (n=8-10/group), which was suppressed by compound 142 at time points 5 and 60 min, and compound LY-2456302/CERC-501 (OPRK1 antagonist) at time points 5, 30 and 60 min (*p<0.05 vs baseline).

Fig. 11 illustrates that the concentrations of compound 142 (40 nM) in the striatum were 3 times higher than those determined in the jugular vein (14 nM). Compound 142 plasma levels (total concentration) were also measured. Mean ± S.E.M. N=4/group.

Fig. 12 illustrates native tissue using horizontal sections of brain tissue (150 µm) containing the ventral tegmental region (VTA) from male Sprague-Dawley rats.

Fig. 13 illustrates a voltage clamp mode (Vm = -60 mV) that allows measurement of the pulse rate and/or membrane potential of the VTA from male Sprague-Dawley rats.

Fig. 14 illustrates a dose-response curve plotted as % inhibition of U69593 induced outward current delivered in each responder cell (FIG. 14A) by Compound 142, (FIG. 14B) by Compound A, (FIG. 14C) PF-04455242, and (FIG. 14D) LY2456302.

Fig. 15 illustrates a dose-response curve representing compound 142-induced blockade of the U69593 response specifically in VTA dopamine (DA) neurons that protrude into the prefrontal cortex (mPFC).

Fig. 16 illustrates the dose response of 0PRM1 and OPRD receptors to compound 142 and LY2456302 upon agonist induction.

Fig. 17 illustrates the return to the original response after washing out (a) Compound 142, (b) Compound A, (c) PF-04455242, and (d) LY2456302.

Detailed description of the invention

As indicated above, the invention relates to compounds that antagonize the kappa opioid receptor (KOR) (also referred to below as KOR antagonists), products comprising such compounds, and methods for their use and synthesis.

In one embodiment, compounds having the structure of formula (I) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

(I) where X is O when Y is N, or X is N when Y is O;

R ¹ is H or F;

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R ² is H or C1- _C8 alkyl;

R ⁴ and R ⁸ are each independently C1- _C8 alkyl, halo or cyano;

R ⁵ and R ⁷ are both H;

R ⁶ is C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halogen or cyano, where R ⁶ is not C1-C8 alkyl, when R ⁸ represents C1-C ₈ -alkyl;

R ¹¹ is -(CH ₂ ) ₀ . ₁ R ¹² where R ¹² is

or n is an integer having a value of 1-5.

In the context of the present invention, KOR and OPRK1 refer to the kappa opioid receptor (KOR), which is encoded by the OPRK1 gene. KOR and OPRK1 are used interchangeably in this application.

In the context of the present invention, DOR and OPRD refer to the delta opioid receptor (DOR), which is encoded by the OPRD gene. DOR and OPRD are used interchangeably in this application.

In the context of the present invention, MOR and 0PRM1 refer to the mu-opioid receptor (MOR), which is encoded by the OPRM1 gene. MOR and OPRM1 are used interchangeably in this application.

In the context of the present invention, lower alkyl means a linear or branched alkyl group containing from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of linear lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

Halo or halogen refers to fluorine, chlorine, bromine and iodine.

Cyano refers to -CN.

Lower haloalkyl refers to lower alkyl as defined above with one or more hydrogen atoms substituted with halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CH ₂ CF ₃ and the like.

Lower alkoxy refers to a lower alkyl as defined above attached via an oxygen atom (ie -O-(lower alkyl)). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, t-butoxy, and the like.

Lower haloalkoxy refers to a lower haloalkyl as defined above attached via an oxygen atom (ie, -O-(lower haloalkyl)). Examples of lower haloalkoxy groups include, but are not limited to, -OCF ₃ , -OCH ₂ CF _{3 ,} and the like.

An isolated optical isomer means a compound that is substantially purified from the corresponding optical isomer(s) of the same formula. For example, an isolated isomer may be at least about 80% pure, at least 80% pure, or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure, or at least 98% pure, or at least 99% pure by weight.

Substantially enantiomerically or diastereomerically pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer relative to another enantiomer or diastereomer of at least about 80%, and more particularly greater than 80, 85, 90, 95, 98, 99, 99.5, or 99.9 %.

Hydrate means a compound that exists in association with water molecules. The combination may include water in stoichiometric amounts, such as monohydrate or dihydrate, or may include water in arbitrary amounts. In the context of the present invention, the term hydrate refers to the solid form; that is, a compound in aqueous solution, although it may be hydrated, is not a hydrate as the term is used in this application.

A solvate is similar to a hydrate except that a solvent other than water is present. For example, methanol or ethanol can form an alcoholate, which can also be stoichiometric or non-stoichiometric. In the context of the present invention, the term solvate refers to the solid form; that is, a compound in a solvent solution, although it can be solvated, is not a solvate, as the term is used in this application.

Isotope refers to atoms with the same number of protons but different numbers of neutrons, and an isotope of a compound of formula (I) includes any such compound in which one or more atoms have been replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, while carbon 13 has six protons and seven neutrons.

- 5 042282 and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes: deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 19 is the longest-lived. Thus, an isotope of a compound having the structure of formula (I) includes, but is not limited to, compounds of formula (I) in which one or more carbon 12 atoms are replaced by carbon atoms 13 and/or 14, where one or more hydrogen atoms are replaced deuterium and/or tritium, and/or where one or more fluorine atoms have been replaced by fluorine 19.

Salt generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form in combination with a counterion. For example, salts formed between acids in their anionic form and cations are called acid addition salts. Conversely, salts formed between cationic bases and anions are called base addition salts.

The term pharmaceutically acceptable refers to a substance that has been approved for human consumption and is generally not toxic. For example, the term pharmaceutically acceptable salt refers to non-toxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int J. Pharm., 33, 201-217., 1986 ) (included in this application by reference).

Pharmaceutically acceptable base addition salts of the compounds of the invention include, for example, metal salts, including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts derived from alkali amines such as, for example, N,N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

Pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acids. Suitable organic acids may be selected from the classes of aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4hydroxybenzoic, phenylacetic, almond, hippuric, malonic, oxalic, embonic (pamic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic , sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acids.

Although non-pharmaceutically acceptable salts are generally not useful as drugs, such salts may be useful, for example, as intermediates in the synthesis of compounds having the structure of formula I, for example, for their purification by recrystallization.

In other embodiments, R ⁴ is H or C1-C8 alkyl; R ⁵ and R ⁷ are both H; R ⁸ is C1-C8 alkyl, halo or cyano; and n is 1 or 2.

In another embodiment, compounds having the structure of formula (II) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

In another embodiment, compounds having the structure of formula (III) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

(Sh).

In another embodiment, compounds having the structure of formula (IV) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope thereof are provided.

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In another embodiment, compounds having the structure of formula (V), its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, salt isotope are provided:

or salt:

or or

or or

In another embodiment, provided are compounds having the structure of formula (VI), its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, salt isotope:

or or

In another embodiment, compounds having the structure of formula (VII), its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, salt isotope are provided:

In another embodiment

compounds having the structure of formula (VIII) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

or or

In another embodiment, compounds having the structure of formula (IX), its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, salt isotope are provided:

or or

In another embodiment, compounds having the structure of formula (X), its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, salt isotope are provided:

- 7 042282

In another embodiment, compounds are provided having the structure of formula (XI), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof:

In another embodiment, compounds having the structure of formula (XII) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

In another embodiment, compounds are provided having the structure of formula (XIII), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof:

In another embodiment, compounds are provided having the structure of formula (XIV), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof:

(xv).

In another embodiment, compounds having the structure of formula (XV) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

(XV).

In another embodiment, compounds having the structure of formula (XVI) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

- 8 042282

In another embodiment, compounds are provided having the structure of formula (XVII), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof:

(XVII).

In another embodiment, compounds are provided having the structure of formula (XVIII), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof:

(XVIII) .

In another embodiment, compounds are provided having the structure of formula (XIX), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof:

(XIX).

In another embodiment, compounds having the structure of formula (XX) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof are provided:

In more specific embodiments, compounds are provided having the structure of any of the previously mentioned formulas, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt of such a compound:

1 n । । Ο'Ν 2 GSF n

- 9 042282

- 10 042282

10 1 O'N 1 — ίΓϊί ^N L FL _D7 N abs^ H And A 1 ZT A -λ / ^z (A 12 1 O' ^N ί a _N b H 13 d | O' ^N ^__ VXw H 14 Λ 1 °'\ 4-Y J. 12. z 10ul ⁿ η^Ν n^ j^Q abs H 15 addDζΐΧΧ, l ^h '^> η 16 I crN tl1 Λ iOla ^N γ^Ν nX _r Q. _abs H

- 11 042282

17 i O'N X. Λϊ — ^N <^0 Ϊ <AA> H 18 _{T_H0} ? IZ ¹ b 19 chl 1 °ΤΎχ· I ssh Η thirty □0 IZ ¹ 0 31 VXxo Η 32 □□ 0% ‘b 33 1 ?V 'ΤΐΫνΛο,η Η

- 12 042282

34 O \ 35 1 Ο-Ν τCV? Η 36 F <A _N AJ Η 37 ι °'V ,., F <a _n aj Η 38 γ^Ν^Ν-^ Г° ^F Η 39 i?V '”ΌάΤ η V 40 \ ο ^Ζ >λ ΙΖ 'b

- 13 042282

41 ρ 1 ^ζτ \^ ^z °\ 42 \ r Ul \~o .........(_2 ^z v ^z / 1 ΞΕΖ ' ь 43 I O'H__ f <A _n A7 F ^H 44 Q \ 45 \ ^Ζ >Λ ^ζ γ^ ъ 46 ?Υνϋ 1 ⁿ

- 14 042282

47 WY .l F ^H 48 Y^n^n^ _r o. ^F F ^H 49 OxV* ^ i СЭ F ^H 50 γόό^ TA F J ^H 51 i θ'Ά Xet ⁴ χ αχ 1 ⁿ 52

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53 I O'N__ ^z °Tli ^N r-XyO F ^H 54 1 ^N J u _N b 1 ^H 55 56 1°\ Ύϊι r-\uo 57 1 θ'Λκ '°riY·· ι α.ο й ^н 58 ^F

- 16 042282

59 g 1 ζτ LL......... • \ 60 ^F ί Η V 61 1 °'N\ vic, ^F CHA ^ F Η V 67 1 N'Q__ '?Χχό Η 68 1 ^Ν '°\ o Ααχ ^Ν γ^Ν Ν^ ^F Η 69 1 ^N '°\ γΥ _Γ . F <Λ _Ν Λ> Η 70 1 ^Ν '°\ , _Ί F <a _n aj Η

- 17 042282

- 18 042282

83 T ^N CuO Η 84 1 ΥΥΎα ^{n F} H 85 1 ^N '°\ “Ύ _r . CN 2A _n A > H 86 zvYtk YOuY NN η Z > с <A _n AJ H 88 i °A\ 'Ίοό^ Г^О I, Y _N Y H 89 •q c2 ^s 91 1 O'N^__ ΥΥυϋ H

- 19 042282

94 ⁴¹m of 0 95 gr.0 Η 96 \ ^F 1 P^V-LeGl ^{Ν F} _Ν ^ζ Η 97 F 1 Ο'Ν Ζ— ί+ά, ο Η 98 F 1 °A\ r^O ^F Η 99 Q 100 ^^1XV cxx x , Y^ N N % > H

- 20 042282

101 ί O'N__ ϊ ο,η Η 103 ι?'V ί Η 104 g ^l sio Η 105 F <a _n aj Η 106 ^F H 107 ι O'N__ 'ΎΧΧ ^{4 F} <A _n aj H 109 । O'^__ ρ ₃ °' ^χχ >^γ^γ ^:ϊΝ Y^N^N^ <^Ο F <a _n aj H

- 21 042282

110 About γί O LL 111 1 °^ ^N γ_ CN Y H 112 “ΎΊιΜυ i>' 0.0 H FROM । O'N JL J^ - FsC'^Y^YY^N ψ^^Ν^ Z°> CN <A _n AJ H 114 4 LL 115 1 O'N^__ F ₃ C'^y^y\ ^/ ^N γ^Ν^Ν'^Υ eH4 CN <A _N Ay H 116 \ I °'^\ ΌΓ J H

- 22 042282

117 / Str oL ΙΖ ' s 118 i °A\ Χίχ Λ ^F <Α _ν Α> Η 119 1 Ο'Ν υΑ> ХсцО Η 120 °Q άό 121 Q 1 ^ζτ 122 Q v l V 123 ⁴

- 23 042282

124 1 O^N__ VXjw 125 ^F P ^H 126 V ^a 0, _n j0 J ^H 127 χά ⁴ ^ T QW 128 χά ¹ *^ V CW F ^H 129 1 ^N '°\ -ww V CW H

- 24 042282

130 1 x /x Λ Λ ΊΟΓχ ^Ν r α.η Η 131 1 N'Q χχΫϊ Г^О ^F <Λ _Ν Λ> Η 132 1 ^Ν '°\ χ ζχ Λ Λ Υϊι ^Ν ΐ <A _n aJ Η 133 τά ⁵ ^ ^F Η 134 Vyp 135 ι Ο'Ν ^Οόι ^Ν ΐ Ο- _Ν Λ> F ^Η 136 th

- 25 042282

137 Q 1 ^ZI 142 1 J Η 143 Ν Ν η ^F η V 144 St 0V IZ' t> 145 I O'N__ I o.n H 146 1 I ^Χ άχ> H 147 %sld NN η 1 ° F <a _n aj H

- 26 042282

148 Η 149 °Q id 150 1 ^Ν '°\ 1 Λ d ^F dA _N AA Η 151 1 ^Ν '°\ 1 1Α Ν 4d^ _N A _N /— ί Α _ν α7 Η 152 1 ^Ν '°\ 'ΎΙΫ+ I ' ΟΧ Η 166 \ 167 \ ο ^Ζ >Λ -оЪ 4 1 τζ ' S?

- 27 042282

168 Y^N^N^V ^F fh Vo 169 Jo mJ) Str .......Jz TZ I 170 'Oy IZ' b 171 vX ^CN Ο ^Λ Ν'-γ _Λ H Vo 172 i °'V_ χόΟ nV Vo ^F aa _n ao H 173 Q i JJz 174 ^W'V XXXI y^N nV <o ci AA--0O H

- 28 042282

175 1 Won Cl H 176 H 177 i °'V Clxz^x/LA/ C1KhL γΧ N ><o ^F H 178 1 °'l ^c 'Tlx ^N =O _F A\A2 H 179 । O'N ww Y^^N N'W. ^F /\A _n -A/ H 180 i °'V ¥ΥηόΓ ^F γ^Ν^Ν^ γθ f LDD/ H 181 , O-N tAW Y^N NW. CN H

- 29 042282

182 °Q 1 ZT / 183 Λ d IZ 1 b 184 1 ZI A 185 vb about H 186 Q1zi - 187 r<? f AAA H 188 C) ^F AA " _n -A / H

- 30 042282

- 31 042282

196 f ΑΑ _ν α? Η 197 γχΥ γχ ν% <ο ^f Η 198 ι °Ύ Ύχ ^ν Υ^ν^νΥ γ F ΑV Η 199 ^Χ οich ΙΖ'b 200 Yr Η 204 χά^ γ^Ν F ΑΑ> _ν Α7 Η 205 υΑ ⁴ '^ Υ-Ν^ΝΥ in-C) f AA _n aj Η

- 32 042282

206 2a 207 A pA IZ I b 208 i °'V _r . H 209 ii bQ ^N F _Z >, H 210 ii ^Ο Ύ o u nA FZ .v ' H 211 ^Λ οΥΫ~ ψΉ NA [ ° ^F H 212 A yb “o z

- 33 042282

213 । O'N χήν A^A Z-v,' H 214 XOoA ⁿ A^ A ^CN AA>» _N Az H 215 , O-N χάϊΧ CN AA/J H 218 219a A^n^A r°\ H 219b aa H 220a i °Λ ΧίχΑ A^n-^nA r°\ F aa _n aa H

- 34 042282

- 35 042282

- 36 042282

234 । O'N XiX ^F H 235 1 ΎΥΧ ⁴ J ДЪ Η 236a O JL ' XXjC ⁿ f AA _N A/ H 236b 1 °b\ 'ΎΎλ ⁿ f AA _N A2 H 237a \ ABOUT ' b 237b I O'N__ ^/Ο χχχ^ ^Ν T ^N o rb ^F AA _N ^y H 238 1 O'N__ ^D V ^N QjO H

- 37 042282

239 I O' ^N D Υ, Α -Α ν ν η n V 240 d 1°'V Υ^Ν Ν^ι <Ό Η 241 ^D χ °'^_ °^ΤΎλ ^Ν ίΑ f AAD/ Η 242 •YA _r , ^F ΑΑ» _Ν Α/ Η 243 1 ' AOlX ⁿ Υ^γΥνΎ ΥΎ ^f ΑΑ _ν Α> Η 244 v' 9/? 245 Yto CN AA _n JH

- 38 042282

246 th iz* 1 247 CN ΛΑ _ν ^Ο h Ly 248 Q AO 255 1 N'O ΥγΥγΥ ^F γ^Ν^Ν'^Ί 4^0 CN H 256 VXxo H 257 i °'V ΧίΥί ^ci H 258 0 /y <

- 39 042282

In another embodiment, compounds having the structure of formula (XI) or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof are provided:

(xi).

where R ¹ represents H, F or C1-C8-alkyl; R ² is H or C1-C8 alkyl; R ⁴ and R ⁸ are each independently H, C1-C8 alkyl, halo or cyano; R ⁵ and R ⁷ are both H; and R ⁶ is C1-C8 alkyl, C1- _C8 haloalkyl, C1- _C8 alkoxy, C1- _C8 haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halo, or cyano.

In more specific embodiments, compounds are provided having the structure of any of the previously mentioned formulas, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt of such a compound:

- 40 042282

1 TOCX ^Ν J q _n x> Η 12 ι ΟΝ VAX „ ψΉ Ν% <ο ^F 4A _n AJ Η 17 V-\. 1. ,χ. / dXaD ν ν η < ο ^F <a _n aj Η thirty ν^πο ^F <a _n aj Η 36 χάΐχ F _Ν Η 54 ι Ο'Ν Ο - τχχI Ν Ν η < ο F 4Λ _Ν Λ> F ^Η 55 -'όΑ' ^ I OW 56 1 ύιτ ^F 1 ⁿ 57 ι crN χήΑ A- CW F ^H 80 Wq _n o H 88 1 O' ^N Η

- 41 042282

94 RF ι ON Ύχ·· ί ογ./ ¹ H 97 e ι ?'V YNN η I ° ^F H 98 ΛγΟχ NN η < О ^F <a _n aj H 99 ι °A ^f ^XO ⁿ ι ⁿ α _Ν Ό° H 103 ι O' ^{N Е3С} TrL γ^Ν^Ν·^ ^F H 109 ι O' ^N ^__ F ₃ C^r^YY<^N r ^N ' a _N r? H 111 ^χγγγί^γ''^? v α _Ν Ό Η 116 q-N^__ Η

- 42 042282

118 1 °Λ _r . H 121 Q 122 Q ZIX? θ........ -^z 127 ^4? -O ^z v ^z 1 IZ ¹ 0 128 I O'N_ νΧχσ F ^H 134 Q7(% 135 1 γ^N N > Г^О F F ^H

- 43 042282

136 1 θΧ Ar τ ^ν ο ο ί ^Η 137 '· -ρ/τζ' P 142 %ίλΙ ψΉ Ν > 1 ° F Η 172 ι Ο'Ν - ADlX ^Ν ΐ ΛΑΧ > Η 173 ΑΙΖ' P 174 HELL- ΧΟΑ Ν Ν η < ο ci ΑΑ^ Η 177 τζ' P 181 χάΑ Α ^νΑ νΧ Α ^ο CN αλ _ν αχ Η

- 44 042282

186 1 °A Ύγ r Η 189 I O'N__ γ^ο ^F Η 190 __1ΧΎ γζχχ d uts ν η γο ^Cl Η 193 a^iIV XXaD γ^Ν Ν > Υθ F Η 197 γ^ Ν Ν η γ ο f ΑΑ^ Η 200 ΎΥ ρ, f ΑΑ _ν Α2 Η 208 ΥΌάΑ γ^ Ν Ν η < Ο F αα _ν αυ Η 211 Lgsl _ γ Ν Ν > γ Ο F αα _ν α> Η

- 45 042282

215 °—Oy Z \__/ 00 ъ 218 I Ο'Ν__ ΥΙΧ1 γ^Ν nV Up to F-' Η 221 % ΥΧ -^ζ Y / ^w o 226 ί Ο' ^Ν y.^1duI L 1 JL ^F Y^n^nV Vo i xDb Η 229 i O'N γ^ n n D To Η 232 % 235 \ο X Y 0 240 Υ^ν^νΎ D^o F λα _ν αο Η

- 46 042282

In another embodiment, compounds are provided having the structure of formula (XIII-A), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof:

where R ¹ represents H, F or C1-C8-alkyl; R ⁴ and R ⁸ are each independently H, C1-C8 alkyl, halo or cyano; R ⁵ and R ⁷ are each independently H, halogen, or cyano; where when R ⁴ and R ⁸ are H, R ⁷ is halogen or cyano; and R ⁶ is C1- _C8 alkyl, C1- _C8 haloalkyl, C1- _C8 alkoxy, C1- _C8 haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halo, or cyano.

In more specific embodiments, compounds are provided having the structure of any of the previously mentioned formulas, or a pharmaceutically acceptable isomer, racemate, hydrate, vat salt, isotope, or salt of such a compound:

- 47 042282

- 48 042282

In another embodiment, compounds are provided having the structure of formula

- 49 042282 (XIII-B), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt:

where R ² represents C1-C8-alkyl; R ⁴ and R ⁸ are each independently H, C1-C8 alkyl, halo or cyano; R ⁵ and R ⁷ are each independently H, halogen or cyano; R ⁶ is C1- _C8 alkyl, haloalkyl, C1- _C8 alkoxy, _C1 - _C8 haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halogen or cyano.

In more specific embodiments, compounds are provided having the structure of any of the previously mentioned formulas, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt of such a compound:

- 50 042282

- 51 042282

In some embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In some embodiments, the invention provides a method for antagonizing a kappa-opioid receptor (KOR) comprising contacting the KOR with an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof, or a composition comprising such compounds.

In some embodiments, the invention provides a method for reducing serum prolactin levels, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

- 52 042282

In some embodiments, the invention provides a method of treating a neuropsychiatric or behavioral condition, organic, stress-induced, or iatrogenic, characterized by elevated serum prolactin levels, wherein administering a kappa-opioid receptor (KOR) antagonist reduces serum prolactin, comprising administering to a subject in need thereof, an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising such compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating substance abuse or dependence disorders, wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating a CNS-related disorder wherein kappa-opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer thereof, a diastereomer , racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating an anxiety disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable enantiomer, diastereomer, racemate thereof , hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating a depressive disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable enantiomer, diastereomer, racemate thereof , hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating a mood disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof a compound of the invention or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate thereof , solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating schizophrenia or schizoaffective disorder, wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer thereof, a diastereomer , racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method for treating obesity or an eating disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer thereof, a diastereomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating migraine wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer, diastereomer, racemate thereof, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In some embodiments, the invention provides a method of treating postpartum depression wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer thereof. , diastereomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

Representative compounds include the compounds listed in table. 1, as well as their pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes and salts.

Table 1

Representative Compounds

- 54 042282

- 55 042282

- 56 042282

41 1 Άχ Αφ,,ο 47 χόΧ ο ΧθΧ ____________________F ^Η 42 Αοχ ___________________ ^Η 48 Αρχ 43 Χοχ ___________________ί ^Η 49 ^: χ< ____________________β ^Η 44 ι Ο-Ν 50 οχΧ τ ςν? ____________________j ^Η 45 Auch 51 1 O'-N χά% I ΟΧ ___________________1 ^Η 46 g ^l aa ___________________? ⁿ 52 xX* ^ ΧφΧ

- 57 042282

- 58 042282

- 59 042282

- 60 042282

- 61 042282

- 62 042282

- 63 042282

- 64 042282

- 65 042282

- 66 042282

- 67 042282

- 68 042282

- 69 042282

- 70 042282

- 71 042282

In some embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound is usually mixed with a carrier, or diluted with a carrier, or enclosed in a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it may be a solid, semi-solid, or liquid substance which acts as a carrier, excipient, or vehicle for the active compound. The active compound may be adsorbed onto a granular solid carrier, such as contained in a sachet. Some examples of suitable carriers include water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, calcium sulfate, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin. , agar, pectin, gum arabic, stearic acid or

- 72 042282 cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any release retardant known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in admixture with a wax.

The compositions may be mixed with adjuvants that do not interact adversely with the active compounds. Such additives may include wetting agents, emulsifying and suspending agents, salt to influence the osmotic pressure, buffers and/or colorants, preservatives, sweeteners or flavoring agents. The compositions can also be sterilized if desired.

The route of administration may be any route that effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral. , intramuscular, intranasal, ophthalmic solution or ointment, with the oral route being preferred.

For parenteral administration, the carrier will typically include sterile water, although other ingredients that aid solubility or serve as preservatives may also be included. In addition, injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, and the like can be used.

The compounds of the present invention may be formulated for topical administration using mild moisturizing bases such as ointments or creams.

If a solid carrier is used for oral administration, the preparation may be in tablet form, in a hard gelatin capsule in the form of a powder or granules, or it may be in the form of a lozenge or lozenge. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Injectable dosage forms typically include aqueous suspensions or oily suspensions, which can be prepared using a suitable dispersing or wetting agent and a suspending agent. Injectable forms may be in the solution phase or in the form of a suspension, which is prepared using a solvent or diluent. Acceptable diluents or carriers include sterilized water, Ringer's solution, or isotonic aqueous saline. Alternatively, sterile oils may be used as solvents or suspending agents. Preferably the oil or fatty acid is non-volatile and includes natural or synthetic oils, fatty acids, mono-, di- or triglycerides.

For injection, the composition may also be a powder, suitable for reconstitution with a suitable solution as described above. Examples include, but are not limited to, lyophilized, rotary-evaporated, or spray-dried powders, amorphous powders, granules, precipitated particles, or suspended particles. Compositions for injection may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of such substances. The compounds may be formulated for parenteral administration by injection, such as a bolus injection or continuous infusion. The unit dosage form for injection may be in ampoules or in multi-dose containers.

Compositions of the invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures well known in the art. Thus, compositions may also be formulated for controlled release or sustained release.

Compositions contemplated by the present invention may include, for example, micelles or liposomes or some other encapsulated form, or may be administered in sustained release form to provide a sustained accumulation and/or delivery effect. Therefore, the compositions can be compressed into granules or cylindrical particles and implanted intramuscularly or subcutaneously as depot injections. Known inert materials such as silicones and biodegradable polymers such as polylactide polyglycolide can be used in such implants. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation may contain a compound of the invention dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol administration. The carrier may contain additives such as solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

For parenteral use, injectable solutions or suspensions, preferably aqueous solutions, with the active compound dissolved in polyhydroxylated castor oil are particularly suitable.

Dosage forms can be administered once a day or more than once a day, for example two or three times a day. Alternatively, dosage forms may be administered less frequently than daily, such as every other day or weekly, as directed by the prescribing physician. Dosing regimens include, for example, titrating the dose to the extent necessary or beneficial for the indication being treated, thus allowing the patient's body to adapt to treatment and/or minimize or avoid unwanted side effects associated with treatment. Other dosage forms include delayed or controlled release forms. Suitable dosage regimens and/or forms include those described, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.

When used to prevent the onset of a disease or condition, the compounds provided herein should be administered to a subject at risk of developing the condition, usually on the advice and supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular disease or condition typically include those who have a family history of such disease or condition, or who have been identified by genetic testing or screening as being particularly susceptible to developing such a disease or condition.

Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over an extended period of time, such as more than 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or an administration that can continue indefinitely , for example, for the rest of the subject's life. In some embodiments, the continuous administration is designed to provide a constant blood level of the compound, such as within a therapeutic window, over an extended period of time.

In another embodiment, methods are provided for preparing a composition of a compound described herein, comprising formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, a pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods may further include the step of formulating the composition into tablet or capsule form. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further comprise the step of lyophilizing the composition to obtain a lyophilized preparation.

In another embodiment, a method of antagonizing KOR is provided, comprising contacting the receptor with an effective amount of a compound having the structure of formulas (I)(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, isotope solvate, or salt thereof, or a pharmaceutical composition comprising such a compound.

The term antagonism is used herein to encompass molecules that interact in some way with a receptor and yet function as an antagonist, either by binding to the receptor at its natural ligand binding site or at locations other than the binding site. The kappa opioid receptor or KOR is a member of the opioid receptor family that binds the opioid peptide dynorphin as a major endogenous ligand. The phrase KOR antagonism is used herein to encompass molecules that interact with KOR in some way and yet function as an antagonist, either by binding to KOR at the dynorphin site or at a location other than the binding site (i.e., allosteric binding ).

In one embodiment, a method is provided for treating a neuropsychiatric or behavioral condition, organic, stress-induced, or iatrogenic, which is characterized by an increase in serum prolactin levels and responds to administration of a KOR antagonist with a decrease in serum prolactin levels. Such a method includes administering to a subject an effective amount of a compound having the structure of formulas (I) to (XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

In yet another embodiment, a method is provided for treating a condition in a subject in which KOR antagonism is medically beneficial. Such a method includes administering to a subject an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

In the context of the present invention, the subject means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, such as higher apes and apes; cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds.

The implementation of treatment or treatment in the context of the present invention refers to the alleviation of symptoms associated with a disorder or disease, or to inhibit the further progression or worsening of these symptoms, or to prevent or prevent a disease or disorder under certain conditions.

The expression effective amount, when used to describe the use of a compound of the invention for the treatment of a subject with a KOR-mediated disorder or condition, refers to the amount of a compound of the invention that is effective to bind to KOR as its antagonist in tissues of an individual where KOR is involved in a disorder wherein such binding occurs to a degree sufficient to provide a beneficial effect to the subject.

The term pathological condition is used to describe any disease, disorder or condition and is used interchangeably, and in the context of the present invention refers to a disease, disorder or condition where KOR plays a role in the biochemical mechanisms involved in the pathological condition or its symptoms, thus therapeutically useful the effect can be achieved by acting on such a KOR.

In some embodiments, the present invention provides a method for antagonizing KOR with a compound of the invention. The method includes contacting the receptor with a suitable concentration of the compound to provide an antagonistic effect on the receptor. Contacting may occur in vitro, for example, when performing an assay to determine the KOR inhibitory activity of a compound of the invention that is being experimentally evaluated in connection with a submission for regulatory approval.

In some embodiments, the KOR antagonizing method can also be performed in vivo, ie, in a living mammalian body, such as a human patient or test animal (referred to herein as a subject). The compound of the invention may be administered to a living organism by one of the routes described above, for example orally, or may be administered at a specific site in body tissues. In the presence of a compound of the invention, receptor inhibition occurs and its effect can be investigated.

The methods of treatment provided by the invention include administering a compound of the invention, alone or in combination with another pharmacologically active agent or a second drug, to a subject or patient having a pathological condition shown to have a KOR antagonizing effect, such as: addictive disorder, including disorders associated with substance abuse or dependence; disorders associated with the central nervous system; anxiety disorders; depressive disorders; mood disorders; schizophrenia or schizoaffective disorders; stress-related disorders; obesity and eating disorder; migraine; postpartum depression; neurodegenerative diseases and disorders, including mood and behavioral disorders associated with neurodegenerative diseases; postpartum depression; anesthesia and/or sedation; epilepsy; epileptic status; and convulsions.

In one embodiment, a method is provided for treating an addictive disorder, including substance abuse or dependence disorders, and compulsive behavior, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I) to (XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

Substance abuse or dependence disorders as described herein may include gambling, substance abuse, substance dependence, alcohol dependence, alcohol abuse, substance-induced depression, and mood disorders, caused by substances such as alcohol, nicotine, amphetamine, methamphetamine, cocaine, opiates, heroin, benzodiazepines, etc.

In one embodiment, a method of treating a CNS disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

CNS disorders include substance abuse disorders and/or withdrawal syndromes, mood disorders, anxiety disorders, schizophrenia spectrum disorders, pain, personality disorders, autism spectrum disorders, eating disorder; sleep disorder; memory and / or cognitive impairment, head trauma and traumatic brain injury; vascular diseases and cognitive disorders.

Examples of CNS conditions include substance abuse disorders and/or withdrawal syndromes (including dependence on opiates, cocaine and/or alcohol); mood disorders (including depression, dysthymic disorder, bipolar disorder); anxiety disorders, including compulsive disorders such as obsessive-compulsive disorder (OCD), social phobias, generalized anxiety disorder (GAD), social anxiety disorder; stress, post-traumatic stress disorder (PTSD); schizophrenia spectrum disorders (including schizophrenia, schizoaffective disorder); pain (including migraine, neuropathic pain, trauma-related pain syndromes, acute pain, chronic pain); personality disorders (including antisocial personality disorder, obsessive-compulsive personality disorder); autism spectrum disorders (ASD) (including autism, monogenic causes of autism such as synaptopathy, eg Rett syndrome, fragile X syndrome, Angelman syndrome); eating disorders; sleep disorders (including insomnia); memory and/or cognitive disorders (including attention disorders (eg, attention deficit hyperactivity disorder (ADHD)), dementia (including Alzheimer's disease dementia, Lewy body dementia, vascular dementia), head injury and traumatic brain injury (TBI ); vascular disease (including stroke, ischemia, vascular malformations) and cognitive impairment (including Alzheimer's disease and other forms of dementia).

In one embodiment, a method of treating an anxiety disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

Anxiety disorder is a general term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders, including generalized anxiety disorder, panic disorder, stress-related disorders, obsessive-compulsive disorder, phobia, social anxiety disorder, separation anxiety disorder, and post-traumatic stress disorder (PTSD). In one embodiment, the anxiety disorder is a social anxiety disorder. In one embodiment, the anxiety disorder is a phobia. In one embodiment, the anxiety disorder is a stress-related disorder. In one embodiment, the anxiety disorder is PTSD.

Generalized anxiety disorder is a common chronic disorder characterized by long-term anxiety that is not focused on any one object or situation. A person suffering from generalized anxiety disorder experiences non-specific persistent fear and anxiety and becomes overly preoccupied with daily activities. Generalized anxiety disorder is the most common anxiety disorder in the elderly.

In panic disorder, a person suffers from brief bouts of intense fear and anxiety, often accompanied by tremors, tremors, confusion, dizziness, nausea, and difficulty breathing. These panic attacks, defined by the ARA as sudden fear or discomfort that come on suddenly and peak in less than 10 minutes, can last several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always obvious. In addition to recurring unexpected panic attacks, the diagnosis of panic disorder also requires that these attacks have chronic consequences: either anxiety about the possible consequences of the attack, a constant fear of future attacks, or significant changes in behavior associated with attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by panic disorder sufferers, leading them to think that something is wrong with their heart, or that they are about to have another panic attack. In some cases, heightened awareness (hyper-alertness) of body functioning occurs during panic attacks, where any perceived physiological change is interpreted as a possible life-threatening illness (i.e., extreme hypochondria).

Obsessive-compulsive disorder is a type of anxiety disorder predominantly characterized by repetitive obsessions (anxious, persistent, and intrusive thoughts or images) and impulsive desires (an urge to perform certain actions or rituals). The mindset in OCD can be compared to superstition in that it suggests belief in causation when in fact there is none. Often the process is completely illogical; for example, the urge to walk in a particular pattern can be used to alleviate obsessive thoughts about approaching danger. And in many cases the urge is completely inexplicable, just a desire to complete the ritual, driven by nervousness. In a minority of cases, OCD sufferers may only experience compulsions without overt urges; far fewer patients experience only urges.

The largest category of anxiety disorders is the phobia, which includes all instances where

- 76 042282 fear and anxiety are caused by a certain stimulus or situation. Phobics tend to expect dire consequences from confronting the object of their fear, which can be anything from social phobia, specific phobia, agoraphobia, location-related animal phobia, to bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder resulting from trauma. PTSD can result from an extreme situation such as a fight, rape, a hostage situation, or even a serious accident. It can also be the result of long-term (chronic) exposure to a strong stressor, such as soldiers who endure occasional battles but cannot handle continuous combat. Common symptoms include past flashes, avoidance behavior and depression.

In one embodiment, a method is provided for treating a depressive disorder, depression, or depressive illness, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. Examples of such disorders include major depression, drug-resistant depression, dysthymia, and bipolar disorder. In one embodiment, a method of treating a mood or affective disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof , or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

Examples of a mood or affective disorder include major depressive disorder (MDD); bipolar disorder; anhedonia; dysthymia; major depression, psychotic major depression (PMD) or psychotic depression; postpartum depression; seasonal affective disorder (SAD); and catatonic depression is a rare and severe form of severe depression involving movement disorders and other symptoms.

The terms anhedonia and anhedonic symptom are used interchangeably and are defined as the inability to experience pleasure from activities that are normally considered pleasurable, such as exercise, hobbies, music, sexual activity, or social interactions. Anhedonia and the anhedonic symptom are closely related to the criterion depressive disorder with melancholic features, which is defined in the DSM-5 as melancholic depression characterized by loss of pleasure in most or all activities, inability to respond to pleasurable stimuli, a quality of depressed mood more pronounced than in grief or loss, worsening of symptoms in the morning hours, early morning awakening, psychomotor delay, excessive weight loss, or excessive guilt. The term treatment of a depressive disorder with melancholic features includes the treatment of both the depressive disorder and the melancholic features associated with it. In one embodiment, the mood disorder is anhedonia. In one embodiment, the mood disorder is major depression. In one embodiment, the mood disorder is seasonal affective disorder (SAD).

In other embodiments, a method for treating schizophrenia or schizoaffective disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. , or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In other embodiments, a method for treating obesity or an eating disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. The obesity and eating disorders described herein may include bulimia, anorexia nervosa, and the like.

In other embodiments, a method for treating migraine is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical a composition comprising such a compound at a frequency and duration sufficient to provide a beneficial effect to the subject. In another embodiment, prophylactic treatment is provided to prevent migraine. In this regard, KOR antagonist action has been suggested as a prophylactic treatment for migraine in

- 77 042282 subjects at risk of such disease.

In one embodiment, a method of treating postpartum depression is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

Immediately after childbirth, progesterone levels plummet, resulting in postpartum depression (PND). Symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with extreme anxiety and irritability. PND-associated depression is not responsive to classical antidepressants, and women with PND have an increased incidence of premenstrual syndrome (PMS).

In other embodiments, a method is provided for treating a neurodegenerative disease or disorder, including mood and behavioral disorders associated with neurodegenerative diseases; anesthesia and/or sedation; epilepsy; convulsions; diabetes, diabetic complications, diabetic retinopathy; sexual/reproductive disorders; hypertension; hemorrhage in the brain; chronic heart failure; atherosclerosis; rheumatoid arthritis; hyperlipidemia, hypertriglycemia, hyperglycemia, hyperlipoproteinemia; compulsive behavioral disorders (such as dog paw licking) and spinal injury, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formulas (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate thereof, an isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

In one embodiment, a method is provided for treating mood and behavioral disorders associated with a neurodegenerative disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer thereof, a racemate , hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

The term neurodegenerative disease includes diseases and disorders that are associated with progressive loss of neuronal structure or function, or neuronal death. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic damage; ataxia and convulsions (including for the treatment, prevention and prevention of convulsions caused by schizoaffective disorder or drugs used to treat schizophrenia); benign forgetfulness; swelling of the brain; cerebellar ataxia, including Macleod's neuroacanthocytosis syndrome (MLS); closed head injury; to whom; contusion injuries (for example, spinal cord injury and head trauma); dementias, including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or treatment-induced parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head injury; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesia and akinetic (rigid) syndromes (including calcification of the basal ganglia, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS complex dementia, Parkinson's disease, postencephalitic parkinsonism and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasticity or weakness, including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics, such as complex tics, simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal cycloclonus), tremor (eg, rest tremor, postural tremor, and intention tremor), and dystonia (including axial dystonia, dystonic graphospasm, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia and spastic dysphonia, and torticollis); neuronal damage, including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic damage after cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; convulsions; epileptic status; stroke; noise in ears; tubular sclerosis; and viral infection-induced neurodegeneration (eg, caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury following cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral spasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest. Methods for treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of a neurodegenerative disorder.

In one embodiment, a method of anesthesia and/or sedation is provided comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof , or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.

Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of response, loss of skeletal muscle reflexes, decreased response to stress, or both. These effects can be achieved using a single drug that, when used alone, provides the right combination of effects, or sometimes using a combination of drugs (eg, hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the stress and pain they would otherwise experience. Sedation is the reduction of irritability or agitation by the administration of a pharmacological agent, typically to facilitate a medical procedure or diagnostic procedure. Sedation and analgesia include a range of states of consciousness from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced condition in which the patient normally responds to verbal commands. Cognitive function and coordination may be impaired. Respiratory and cardiovascular functions are usually not affected.

Moderate sedation/analgesia (conscious sedation) is a drug-induced suppression of consciousness during which the patient purposefully responds to verbal commands either as such or accompanied by mild tactile stimulation. As a rule, no intervention is required to maintain a free airway. Spontaneous breathing is usually sufficient. Cardiovascular function is usually preserved.

Deep sedation/analgesia is a drug-induced suppression of consciousness during which the patient cannot easily wake up but responds purposefully (not reflex withdrawal from a painful stimulus) after repeated or painful stimulation. Independent respiratory function may be impaired and the patient may require assistance to maintain a clear airway. Spontaneous breathing may be insufficient. Cardiovascular function is usually preserved.

General anesthesia is a drug-induced loss of consciousness in which the patient does not awaken even in response to painful stimuli. The ability to maintain independent respiratory function is often impaired, and assistance is often required to maintain a clear airway. Positive pressure ventilation may be required due to suppressed spontaneous ventilation or drug-induced suppression of neuromuscular function. Cardiovascular function may be impaired. Sedation in the Intensive Care Unit (ICU) allows patients to suppress their perception of the environment and reduce their response to external stimulation. It can play a role in the care of the critically ill patient and covers a wide range of symptom control, which will vary between patients and individuals over the course of their illness. Severe critically ill sedation is used to facilitate endotracheal tube tolerance and respiratory synchronization, often with neuromuscular blocking agents.

Duration of sedation (eg, continuous sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (eg, 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months ). Long-acting sedatives can have a long-lasting effect. Sedatives in ICU may have a short half-life. Procedural sedation and analgesia, also referred to as conscious sedation, is a method of administering sedatives or dissociative agents, with or without analgesics, to induce a condition that allows the subject to endure unpleasant procedures while maintaining cardiorespiratory function.

In one embodiment, a method for treating epilepsy is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

- 79 042282

Epilepsy is a brain disorder characterized by recurring seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with severe seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy lobe, benign focal epilepsy of childhood.

In one embodiment, a method is provided for treating status epilepticus, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising such connection, with a frequency and duration sufficient to provide a beneficial effect for the subject.

Status epilepticus (SE) may include, for example, status epilepticus, eg, early status epilepticus, established status epilepticus, refractory status epilepticus, superrefractory status epilepticus; non-convulsive status epilepticus, eg generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Status epilepticus is characterized by the presence of convulsive epileptic seizures and may include early status epilepticus, established status epilepticus, refractory status epilepticus, superrefractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by epileptic seizures that persist despite treatment with first-line therapy and second-line therapy is initiated. Refractory status epilepticus is characterized by epileptic seizures that persist despite treatment with first-line and second-line therapy, and a general anesthetic is usually used. Superrefractory status epilepticus is characterized by epileptic seizures that persist despite treatment with first-line therapy, second-line therapy, and general anesthetic for 24 hours or more.

Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, eg complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, implicit non-convulsive status epilepticus; generalized epileptic status epilepticus, for example, late-onset absentee status epilepticus, atypical absence status epilepticus, or typical absence status epilepticus.

In one embodiment, a method of treating seizures is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of formula (I)-(XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical a composition comprising such a compound at a frequency and duration sufficient to provide a beneficial effect to the subject.

Seizures are physical abnormalities or behavioral changes that occur after an episode of abnormal electrical activity in the brain. The term convulsions is often used interchangeably with convulsions. Convulsions are when a person's body trembles rapidly and uncontrollably. During convulsions, a person's muscles repeatedly contract and relax. Depending on the type of behavior and brain activity, seizures fall into two broad categories: generalized and partial (also called local or focal). Seizure type classification helps doctors determine if a patient has epilepsy.

Generalized seizures are caused by electrical impulses throughout the brain, while partial seizures are caused (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that causes seizures is sometimes called the focus.

There are six types of generalized seizures. The most common and dramatic, and therefore best known, is the generalized seizure, also called a grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls. The loss of consciousness is followed by a general immobility of the body (called tonic convulsions) for 30-60 seconds, then a sharp twitching (clonic phase) for 30-60 seconds, after which the patient goes into deep sleep (post-seizure or post-convulsive phase). During grand mal seizures, injuries and accidents can occur, such as tongue biting and urinary incontinence.

Absence seizures cause a brief loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, usually interrupts the activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually unaware that they are having seizures, except that they may be aware of the loss of time. Myoclonic seizures consist of sporadic convulsive twitches, usually on both sides of the body. Patients sometimes describe the twitches as brief electrical shocks. If severe, these convulsions may result in a fall or the subject involuntarily dropping objects. Clonic seizures are repetitive, rhythmic jerks that affect both sides of the body at the same time. Tonic convulsions are characterized by muscle immobility. Atonic seizures consist of a sudden and general loss of muscle tone, especially in the arms and legs, often resulting in a fall.

Seizures described in this application may include epileptic convulsions; acute repetitive convulsions; cluster seizures; continuous convulsions; incessant convulsions; prolonged convulsions; periodic convulsions; convulsive status epilepticus, eg refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory convulsions; myoclonic convulsions; tonic convulsions; tonic-clonic convulsions; simple partial convulsions; complex partial convulsions; secondarily generalized convulsions; atypical absence seizures; absence seizures; atonic convulsions; benign rolandic convulsions; febrile convulsions; emotional cramps; focal seizures; gelastic spasms;

generalized initial convulsions; infantile spasms; Jacksonian convulsions; massive bilateral myoclonic convulsions; multifocal seizures; convulsions in newborns; night cramps; convulsions of the occipital lobe; post-traumatic convulsions; weak convulsions; sylvan convulsions; visual reflex convulsions; or withdrawal cramps.

Compounds having the structure of formula (I), as well as substructures for formulas (II)-(XVII), can be synthesized using standard synthetic methods known to those skilled in the art. For example, the compounds of the present invention can be synthesized using the general synthetic methods shown in Schemes 1 and 2.

Therefore, the reactions, processes and methods of synthesis described in this application are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide for a person skilled in the art. For example, the reactions can be carried out in any suitable solvent or other reagents to effect the desired transformation(s). Typically, suitable solvents are protic or aprotic solvents that are substantially unreactive with the reactants, intermediates, or products at the temperatures at which the reactions are carried out (ie, temperatures that can range from freezing to boiling). This or that reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction, suitable solvents may be used for the particular post-reaction treatment.

Scheme 1

Reagents and conditions: i) A (1.0 eq.), B (1.2 eq.), POCl ₃ , 110° C., 1 h; ii) 1,4-dioxa-8-azaspiro[4,5]decane (1.2 eq.), DIPEA (1.2 eq.), EtOH, 120°C, 18 h, 33% (over two steps) ; iii) 10% aq. H2SO4, THF, 45°С, 2 h, quantitative yield; iv) amine (2.0 eq.), NaBH(OAc) ₃ (3.0 eq.), AcOH (3.0 eq.), DIPEA (2.0 eq.), 1,2 dichloroethane (DCE), room temperature (room temp.), 18 h, 93% yield.

- 81 042282

Scheme 2 o o

Reagents and conditions: i) DMF (2.5 eq.), POCI3 (7.0 eq.), 0-75°C, 48 h, 36-39%; ii) NaH2PO4 (5.0 eq.), NaClO ₂ (3.0 eq.), Na ₂ SO ₃ (4.0 eq.), CH3CN, 94-98%; iii) a) 15 (1.0 eq.), SOCl ₂ (3.0 eq.), CH ₂ Cl ₂ , DMF (catalytic), 50° C., 2 h, b) Acetamidoxime (1.2 eq. ), DIPEA (1.2 eq.), dioxane, 100°C, 4 h, 48-54%; iv) 1,4-dioxa-8-azaspiro[4,5]decane (1.2 eq.), DIPEA (2.0 eq.), EtOH, 125°C, overnight, 70-73%; v) 10% aq. H ₂ SO ₄ , THF, 45°C, 2 h, 73-78%; vi) Amine (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.), AcOH (2.0 eq.), DIPEA (2.0 eq.), 1,2-dichloroethane, rt. temp., during the night.

Examples

The invention is further illustrated by the following examples. The following examples are not limiting and merely represent various aspects of the invention. The solid and dotted wedges in the structures disclosed herein illustrate relative stereochemistry, with absolute stereochemistry shown only when specifically stated or indicated.

General methods.

Analytical high performance liquid chromatography-mass spectrometry (HPLCMS) was performed using a Shimadzu LC-2030C HPLC system, in combination with a Shimadzu LC-2020 mass detector (electrospray ionization, ESI). The RP-HPLC column was Shimadzu C18 (3 µm, 50x4.6 mm). HPLC method 1:50~100% acetonitrile in water (0.1% formic acid) as mobile phase, flow rate 1.0 ml/min, and chromatography time 5 min. HPLC method 2: 10~100% acetonitrile in water (0.1% formic acid) as mobile phase, flow rate 1.0 ml/min, and chromatography time 10 min.

Purification by preparative HPLC was performed using an Interchim PF4250 system and collection of fractions was initiated by UV absorption at 254 nm. The reverse phase HPLC column was Phenomenex 00D-4454-U0-AX (Gemini 5 µm NX-C18, 100x30 mm). Preparative HPLC method 1:5-85% acetonitrile in water as mobile phase, flow rate 35 ml/min and chromatography time 20 min. Preparative HPLC method 2: 5-85% acetonitrile in water (0.05% trifluoroacetic acid) as mobile phase, flow rate 35 ml/min and chromatography time 20 min.

Normal phase column chromatography was performed using a Biotage Isolera One system or an Interchim PF4250 system. Silica gel columns were purchased from either Teledyne (RediSep Rf) or Biotage (SNAP Ultra). The mobile phase was either ethyl acetate in hexane or methanol in dichloromethane in various ratios, and collection of fractions was triggered by UV absorption at 254 nm.

The microwave reaction was carried out on a Biotage Initiator (max. 400 W with internal temperature control).

All starting materials and reagents are commercially available and have been used as such.

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Example 1

Stage 1: Synthesis of compound Int-1-1c

A mixture of aniline Int-1-1a (1.52 g, 6.5 mmol), oxadiazole acid derivative Int-1-1b (1.12 g, 7.9 mmol) and POCl ₃ (10 ml) was stirred at 110°C within 1 h After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. H ₂ O was added to the residue at 0°C and the mixture was stirred at 0°C for 10 minutes. The precipitated crude chloroquinoline Int-1-1c was filtered, washed with H ₂ O and dried under reduced pressure. The crude product Int-1-1c was used for the next reaction without further purification.

Stage 2: Synthesis of compound Int-1-1d

To a suspension of crude chloroquinoline Int-1-1c (2.33 g, 6.5 mmol) and DIPEA (1.4 ml, 7.9 mmol) in EtOH (33 ml) 4.5]decane (1.0 ml, 7.9 mmol) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give quinoline Int-1-1d as a dark brown solid (1.0 g, 33% yield over two steps). LCMS: (M+1) m/z=463, 465.

Step 3: Synthesis of compound Int-1-1e

To a suspension of compound Int-1-1d (0.85 g, 1.83 mmol), Pd(OAc) ₂ (41 mg, 0.09 mmol) and P(tBu) ₃ HBF4 (32 mg, 0.11 mmol) in THF (10 ml) was added 1M ZnBr ₂ in THF (0.55 ml) at room temperature. To the mixture was added 2M PrMgCl in THF (3.3 ml, 6.6 mmol) over 30 minutes at room temperature and the resulting mixture was stirred at ambient temperature overnight. The mixture was poured onto ice and partitioned between EtOAc (50 ml) and 1% aq. HCl (50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (1-10% EtOAc in CH ₂ Cl ₂ ) then preparative TLC to give 6isopropylquinoline Int-1-1e as a yellow oil (0.37 g, 47% yield). LCMS: (M+1) m/z=427.

Step 4: Synthesis of compound Int-1-1f

To a solution of Int-1-1e (0.23 g, 0.55 mmol) in THF (2.5 ml) was added 10% aq. H ₂ SO ₄ (5 ml) at room temperature. The mixture was then stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x20 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. Ketone Int-1-1f (yellow oil) was used for the next reaction without further purification. (210 mg, quantitative yield). LCMS: (M+1) m/z=383.

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Step 5: Synthesis of Compound 1.

Mixture of Int-1-1f (10.5 mg, 0.027 mmol), tetrahydro-2H-pyran-4-amine (0.054 mmol) and DIPEA (10 µl, 0.054 mmol) in 1,2-dichloroethane (1.5 ml) stirred at room temperature for 10 min. NaBH(OAc) ₃ (17.4 mg, 0.081 mmol) and AcOH (5 μl, 0.081 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=96:4) to give compound 1 (93% yield). LCMS: (M+1) m/z=468.

Examples 2-7.

The procedure of Example 1 was used to prepare compounds 2-7 except that the tetrahydro-2H-pyran-4-amine in step 5 was replaced by (R)-tetrahydro-2H-pyran-3-amine to give compound 2, LCMS: (M +1) m/z=468; (S)-tetrahydro-2H-pyran-3-amine to give compound 3, LCMS: (M+1) m/z=468); (R)-tetrahydrofuran-3-amine to give compound 4, LCMS: (M+1) m/z=454); (S)-tetrahydrofuran-3-amine to give compound 5, LCMS: (M+1) m/z=454); cyclopropylmethanamine to give compound 6, LCMS: (M+1) m/z=438); and cyclobutylmethanamine to give compound 7, LCMS: (M+1) m/z=452), respectively.

Examples 8-10.

Synthesis of compound 8.

Int-8-5 was prepared from Int-11-42 and 1,4-dioxa-8-azaspiro[4,5]decane in two steps using conditions similar to those of the general methods used to synthesize Int-1-1d and Int -1-1f.

A mixture of Int-8-5 (11 mg, 0.029 mmol) and cyclopropylmethanamine (4.1 mg, 0.058 mmol) in 1,2 dichloroethane (0.2 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (12 mg, 0.058 mmol) and AcOH (3.3 μl, 0.058 mmol) were added to the mixture.

The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 8 as a yellow solid (8.8 mg, 0.020 mmol). LCMS: (M+1) m/z=436, 437.

Synthesis of compound 9.

A mixture of Int-8-5 (11 mg, 0.029 mmol), cyclobutylmethanamine hydrochloride (7.0 mg, 0.058 mmol) and DIPEA (10 μl, 0.058 mmol) in 1,2-dichloroethane (0.2 ml) was stirred at room temperature within 10 min. NaBH(OAc) ₃ (12 mg, 0.058 mmol) and AcOH (3.3 μl, 0.058 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ C1 ₂ :McOH=95:5) to give compound 9 as a yellow solid (9.0 mg, 0.020 mmol). LCMS: (M+1) m/z=450, 451.

Synthesis of compound 10.

Mixture of Int-8-5 (11 mg, 0.029 mmol), (S)-tetrahydro-2H-pyran-3-amine hydrochloride (7.9 mg, 0.058 mmol) and DIPEA (10 µl, 0.058 mmol) in 1.2 -dichloroethane (0.2 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (12 mg, 0.058 mmol) and AcOH (3.3 μl, 0.058 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 10 as a yellow solid (9.7 mg, 0.021 mmol). LCMS: (M+1) m/z=466, 467.

- 84 042282

Examples 11-12.

Synthesis 40.

A mixture of Int-11-1 bromide (1.0 eq.), potassium cyclopropyl trifluoroborate (3.0 eq.), K ₃ PO ₄ (3.3 eq.) and

Pd(PPh ₃ ) ₄ (0.02 eq.) in toluene:H ₂ O (3:1) was heated at 100°C overnight. The mixture was concentrated under reduced pressure and the product was purified by column chromatography using hexane/CH ₂ Cl ₂ (9:1). The product was obtained as a pale yellow solid in 39-41% yield. LCMS: (M+1) m/z=194.

Synthesis 42.

A mixture of Int-11-40 (1.0 eq.) and Int-11-41 (1.0 eq.) in POCl ₃ was heated at 80° C. for 1 hour. Excess POCl ₃ was removed under reduced pressure. The residue was quenched with ice and the mixture was stirred for 15 minutes. The pale brown product was collected by filtration and used in the next step without further purification (53-55% yield). LCMS: (M+1) m/z=318.

Synthesis of compound 11.

A mixture of Int-11-42 (1.0 eq.), Int-11-44 (2.0 eq.) and DIPEA (4.0 eq.) in ethanol was heated at 130° C. overnight. The mixture was concentrated under reduced pressure and the product was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 11 in 62-64% yield as a pale yellow oil. LCMS: (M+1) m/z=466.

Synthesis of compound 12.

A mixture of Int-11-42 (1.0 eq.), Int-11-43 (2.0 eq.) and DIPEA (2.0 eq.) in ethanol was heated at 130° C. overnight. The mixture was concentrated under reduced pressure and the product was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 12 in 67-69% yield as a pale yellow solid. LCMS: (M+1) m/z=466.

Examples 13-14.

Compound 13 and compound 14 were prepared according to the procedure for preparing compound 11 and compound 12 using the appropriate intermediates. Compound 13 was obtained as a pale yellow solid in 69% yield (last step). LCMS: (M+1) m/z=452. Compound 14 was obtained as a pale yellow solid in 73% yield (last step). LCMS: (M+1) m/z=452.

Examples 15-16.

Synthesis of Int-15-2.

To a mixture of Int-1-1d (227 mg, 0.49 mmol), potassium cyclobutyl trifluoroborate (159 mg, 0.98 mmol), Cs ₂ CO ₃ (479 mg, 1.47 mmol), CataCXium (18 mg, 0.049 mmol ) and Pd(OAc) ₂ (11 mg, 0.049 mmol) were added toluene

- 85 042282 (1.8 ml) and H ₂ O (0.16 ml). The reaction mixture was degassed in vacuo and purged with nitrogen, then heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered (Whatman syringe filters, pore size 0.2 μM), loaded dry onto silica gel, and purified by column chromatography (hexane/EtOAc gradient) to give Int-15-2 as a yellow solid ( 86 mg, 39% yield. LCMS: (M+1) m/z=439.

Synthesis 3.

To a solution of Int-15-2 (68 mg, 0.15 mmol) in THF (0.5 ml) was added 10% aq. H ₂ SO ₄ (1.1 ml) at room temperature. The mixture was then stirred at 45°C for 4 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x10 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. Ketone Int-15-3 was used in the next step without further purification (56 mg, quantitative yield). LCMS: (M+1) m/z=395.

Synthesis of compound 15.

Mixture of Int-15-3 (10 mg, 0.025 mmol), (S)-tetrahydro-2H-pyran-3-amine hydrochloride (7 mg, 0.051 mmol) and DIPEA (9 µl, 0.051 mmol) in 1,2-dichloroethane (0.2 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (11 mg, 0.051 mmol) and AcOH (3 μl, 0.051 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 15 as a yellow solid (10.2 mg, 84% yield). LCMS: (M+1) m/z=480, 481.

Synthesis of compound 16.

A mixture of Int-15-3 (10 mg, 0.025 mmol) and (S)-tetrahydrofuran-3-amine (4.4 mg, 0.051 mmol) in 1,2dichloroethane (0.2 ml) was stirred at room temperature for 10 min. . NaBH(OAc) ₃ (11 mg, 0.051 mmol) and AcOH (3 μl, 0.051 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 16 as a yellow solid (10 mg, 84% yield). LCMS: (M+1) m/z=466, 467.

Example 17.

To a solution of 1-(6-cyclobutyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2yl)piperidin-4-one (Int-15- 3.12 mg, 0.03 mmol) and tetrahydro-2H-pyran-4-α-min (6.2 mg, 0.061 mmol) in 1,2-dichloroethane (0.2 ml) were added acetic acid (3.7 mg, 0.061 mmol) followed by the addition of sodium triacetoxyborohydride (13 mg, 0.061 mmol) and the reaction mixture was stirred at 25°C for 6 h. The reaction was quenched with methanol and aqueous sodium carbonate to pH ~10. The mixture was then extracted with ethyl acetate twice. The organic layers were combined, washed with brine, dried over magnesium sulfate and finally evaporated to dryness. The residue was purified by preparative HPLC to give compound 17 (8.0 mg, 55% yield) as a white solid. LCMS: (M+1) m/z=480; retention time: 2.79 min (method 1).

Example 18.

Compound 18 was obtained in the same way as 1-(6-cyclobutyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol5-yl)quinolin-2-yl)-N-(tetrahydro -2H-pyran-4-yl)piperidin-4-amine (compound 17), replacing tetrahydro-2H-pyran-4-amine with (R)-tetrahydro-2H-pyran-3-amine hydrochloride (2.0 eq. ) and N,Ndiisopropylethylamine (2.0 eq.). LCMS: (M+1) m/z=480; retention time: 3.10 min (method 1).

Example 19.

Compound 19 was obtained in the same way as 1-(6-cyclobutyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazole-86 042282

5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 17), replacing tetrahydro-2H-pyran-4-amine with (R)-tetrahydrofuran -3-amine hydrochloride (2.0 eq.); and Ν,N-diisopropylethylamine (2.0 eq.). LCMS: (M+1) m/z=466; retention time: 2.67 min (method 1).

Examples 20-29.

Et: Compound 20 Compound 21 Compound 22 Compound 23 Compound 24

AWG Compound 25 Compound 26 Compound 27 Compound 28 Compound 2 9

Reagents and conditions i) DMF (2.5 eq.), POCl ₃ (7.0 eq.), 0-75°C, 48 h, 36-39%, ii) NaH ₂ PO ₄ (5.0 eq. ), NaClO2 (3.0 eq.), Na2SO3 (4.0 eq.), CH3CN, 94-98%, iii) a) 15 (1.0 eq.), SOCl2 (3.0 eq.), CH ₂ Cl2, 50°C, 2 h, b) Acetamidoxime (1.2 eq.), DIPEA (1.2 eq.), dioxane, 100° C., 4 h, 48-54%, iv) 1.4- dioxa-8azaspiro[4,5]decane (1.2 eq), DIPEA (2.0 eq), EtOH, 125°C, overnight, 70-73%, v) 16 (1.0 eq) , Et ₃ B (2.0 eq.), CS2CO3 (2.0 eq.), Pd(dppf)Cl2 CACh (1.20 eq.), THF, 70°C, 1.5 h, 27-29%, vi ) 10% aq H2SO4, THF, 45°C, 2 h, 73-78%, vii) Amine (2.0 eq.), NaBH(OAc)3 (2.0 eq.), AcOH (2.0 eq. .), DIPEA (2.0 equiv.), 1,2 dichloroethane, rt. temp., overnight, viii) cPrMgBr (3.2 eq.), Pd(OAc) ₂ (0.2 eq.), P(tBu) ₃ -BF ₄ (0.1 eq.), 1M ZnBr ₂ in THF (0.3 equiv.), THF, room. temp., 25-28%.

Synthesis of Int-20-14.

DMF (2.5 eq.) was slowly added to POCl ₃ (7.0 eq.) at 0°C, the mixture was stirred at room temperature for another 30 min, followed by the addition of amide Int-20-13 in one portion. The mixture was stirred at room temperature for 30 minutes and then for 48 hours at 75°C. The mixture was quenched with ice water and stirred for 30 minutes. The Int-20-14 solid was collected and used without further purification by LCMS (M+1) m/z=287.289.

Synthesis of Int-20-15.

To a suspended mixture of aldehyde Int-20-14 (1.0 eq) in CH3CN was slowly added an aqueous solution of NaH ₂ PO ₄ (5.0 eq) followed by NaClO ₂ (3.0 eq). The mixture was stirred overnight at room temperature. The mixture was quenched with Na ₂ SO ₃ and stirred for 30 min at room temperature followed by acidification (pH 1-2) with 2M HCl. The product was extracted with EtOAc four times, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound Int-20-15 was used without further purification by LCMS: (M-1) m/z=301, 303.

Synthesis of Int-20-16.

To a mixture of Int-20-15 acid (1.0 equiv.) and SOCl ₂ (3.0 equiv.) in CH ₂ Cl ₂ was added a drop of DMF and the reaction mixture was heated at 50°C for 2 h. The mixture was concentrated under reduced pressure. The crude material was dissolved in anhydrous dioxane and slowly added to a solution of acetamidoxime (1.2 eq.) and DIPEA (1.2 eq.) in dioxane at 0°C. The mixture was stirred at room temperature for 30 minutes and for 4 hours at 100°C. The mixture was diluted with water and the solid was collected and used without further purification. LCMS: (M+1) m/z=441, 443.

A solution of the product from the previous step (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1.2 eq.) and DIPEA (2.0 eq.) in EtOH was heated at 125° C during the night. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-20-16 ketal as a pale yellow solid. LCMS: (M+1) m/z=449, 451.

Synthesis of Int-20-17.

_{A 1M solution of _} Et ₃ B (2.0 eq.) in THF and the reaction mixture was heated at 70°C for 1.5 hours. After cooling to room temperature, the crude material was filtered through celite and purified by column chromatography (hexane:EtOAc) to give Int-20-17 as a pale yellow solid.

LCMS: (M+1) m/z=399.

Synthesis of Int-20-18.

A solution of ketal Int-20-17 (1.0 eq.) in THF and 10% aq. H ₂ SO ₄ was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous NaOH and was extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the ketone Int-20-18 as a pale yellowish solid (90-95% yield) which was used in the next step without further purification by LCMS: (M+1 ) m/z=355.

Synthesis of compounds 20-24.

A mixture of ketone Int-20-18 (1.0 eq.), amine (2.0 eq.), DIPEA (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) 0 eq.) in 1,2-dichloroethane was stirred at room temperature overnight. The mixture was filtered through Celite, concentrated under reduced pressure and purified by HPLC to give the desired products. Compound 20 was obtained as a pale yellow solid in 92-94% yield. LCMS: (M+1) m/z=440. Compound 21 was obtained as a pale yellow solid in 78-80% yield. LCMS: (M+1) m/z=440. Compound 22 was obtained as a pale yellow solid in 79-80% yield. LCMS: (M+1) m/z=440. Compound 23 was obtained as a pale brown solid in 82-83% yield. LCMS: (M+1) m/z=426. Compound 24 was obtained as a pale yellow solid in 86-87% yield. LCMS: (M+1) m/z=426.

Synthesis of Int-20-19.

1M _{ZnBr 2 in} THF (0.3 eq.) at room temperature. To the mixture was added 1M cPrMgBr in THF (3.2 eq.) over 30 minutes at room temperature and the resulting mixture was stirred overnight. The mixture was quenched with ice/NH ₄ Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude material was used without further purification as no difference in Rf was observed between the remaining Int-20-16 bromide (~30%) and the Int-20-19 product. LCMS: (M+1) m/z=411.

Synthesis of Int-20-20.

A solution of the above mixture in THF/10% aq. H ₂ SO ₄ was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous NaOH and extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc to give Int-20-20 ketone as a pale yellow solid (20-25% yield). LCMS: (M+1) m/z=367.

Synthesis of compounds 25-29.

A mixture of the ketone Int-20-20 (1.0 eq.), the appropriate amine (2.0 eq.), DIPEA (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) 0 eq.) in 1,2-dichloroethane was stirred at room temperature overnight. The mixture was filtered through Celite, concentrated under reduced pressure and purified by HPLC to give the title compounds. Compound 25 was obtained as a pale yellow solid in 87-88% yield. LCMS: (M+1) m/z=452. Compound 26 was obtained as a pale yellow solid in 68-69% yield. LCMS: (M+1) m/z=452. Compound 27 was obtained as a pale yellow solid in 72-73% yield. LCMS: (M+1) m/z=452. Compound 28 was obtained as a pale yellow solid in 69-70% yield. LCMS: (M+1) m/z=438. Compound 29 was obtained as a pale yellow solid in 75-76% yield. LCMS: (M+1) m/z=438.

Example 30.

Stage 1

To a solution of 8-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-1,4-dioxa-8azaspiro [4,5]decane (Int-1-1d, 258 mg, 0.56 mmol) in tetrahydrofuran (3 ml) was added a solution of sulfuric acid (10% aq., 3 ml) and the reaction mixture was stirred at 45°C for 3 h. The mixture was neutralized with sodium carbonate solution to pH 10 and extracted with ethyl acetate twice. organic layers

- 88 042282 were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4 -oxadiazol-5yl)quinolin-2-yl)piperidin-4-one (Int-30-11f) as a brown solid (248 mg) which was used in the next step without further purification. LCMS (ESI): m/z 419 (M+H); retention time: 2.93 min (method 1).

Stage 2

Compound 30 was obtained in the same way as 1-(6-cyclobutyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol5-yl)quinolin-2-yl)-N-(tetrahydro -2H-pyran-4-yl)piperidin-4-amine (compound 17), replacing 1-(6cyclobutyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5- yl)quinolin-2-yl)piperidin-4-one bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)piperidin- 4-one LCMS (ESI): m/z 504 (M+H); retention time: 2.34 min (method 1).

Example 31.

on

1-(6(Int-30-11f).

Compound 31 was obtained using the procedure as in step 2 in example 30, where tetrahydro-2H-pyran-4-amine was replaced by (R)-tetrahydro-2H-pyran-3-amine hydrochloride (2.0 eq.) and N ,Ndiisopropylethylamine (2.0 eq.). LCMS (ESI): m/z 504 (M+H); retention time: 2.48 min (method 1).

Example 32.

The procedure for obtaining compound 32 was the same as in step 2 in example 30, where tetrahydro-2H-pyran-4-amine was replaced by (S)-tetrahydro-2H-pyran-3-amine hydrochloride (2.0 eq.) and N,Ndiisopropylethylamine (2.0 eq.). LCMS (ESI): m/z 504 (M+H); retention time: 2.45 min (method 1).

Examples 33-35.

Synthesis of 2-amino-5-bromo-3-fluorobenzoic acid Int-33-14b

To a suspension of 2-amino-3-fluorobenzoic acid Int-33-14a (15.36 g, 99 mmol) in CH ₂ Cl ₂ (247.5 ml) was added N-bromosuccinimide (17.62 g, 99 mmol). The mixture was stirred at room temperature overnight. The product was collected by vacuum filtration to give 2-amino-5-bromo-3-fluorobenzoic acid Int-33-14b as an off-white solid (20.81 g, 90% yield) which was used in the next step without further purification. LCMS: (M-1) m/z=232, 234.

- 89 042282

Synthesis of 1-(2-amino-5-methoxy-3-fluorophenyl)ethanone 14f

lnt-33-14b lnt-33-14c lnt-33-14d

lnt-33-14e lnt-33-14f

A mixture of Int-33-14b (13.38 g, 57.17 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (10 g, 102.9 mmol), DIPEA (19.9 ml), EDCI (13.15 g, 68 .8 mmol) and HOBt (9.27 g, 68.6 mmol) in DMF (142 mL) were stirred at room temperature for 4 h. solution to give Int33-14c as a brown oil (8.6 g, 85% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=277, 279.

To a solution of Int-33-14c (6.0 g, 22 mmol) in CH ₂ Cl ₂ (75 ml) at 0°C was added TEA (3.6 ml, 26 mmol) followed by dropwise addition of trifluoroacetic anhydride (3, 9 ml, 28 mmol). The reaction mixture was stirred at room temperature overnight. Then a saturated aqueous solution of NaHCO ₃ was added and the organic phase was separated and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to give Int-33-14d as a yellow solid (9.4 g, 80% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=371, 373.

To a solution of Int-33-14d (0.180 g, 0.554 mmol) in THF (1 ml) at -78°C was added a 3M solution of MeMgCl in THF (0.66 ml, 2.22 mmol) and the reaction mixture was stirred at room temperature in for 2 hours the Reaction mixture was poured into ice, acidified to pH 2 with a solution of 2M HCl and was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness to give Int-33-14e as a yellow oil which was used in the next step without further purification. LCMS: (M+1) m/z=328.

To a solution of Int-33-14e (0.138 g, 0.370 mmol) in MeOH (0.75 ml) was added 2 M aq. NaOH solution (0.75 ml), the reaction mixture was heated at 90°C for 1.5 h. Water was added and the product was extracted with EtOAc and concentrated to dryness. Int-33-14f was obtained as a yellow solid (0.110 g, 92% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=232.

Synthesis of 2-chloroquinoline Int-33-14h

lnt-33-14f lnt-33-14g lnt-33-14h

A solution of 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid Int-33-14g (72 mg, 0.50 mmol) in POCl ₃ (1.5 ml) was stirred at 50°C for 5 min, then the ketone Int-33-14f (92 mg, 0.50 mmol) was added. The mixture was heated to 110°C for 1 h Excess POCl ₃ was removed in vacuum. Saturated aqueous NaHCO ₃ was added to the residue and the product was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was purified by column chromatography (hexane/EtOAc) to give 2-chloroquinoline Int-33-14h as a yellow solid (69 mg, 45% yield). LCMS: (M+1) m/z=357.

Synthesis of ketal Int-33-14i

lnt-33-14h lnt-33-14i

To a suspension of Int-33-14h (56 mg, 0.182 mmol) in EtOH (0.4 mL) was added 1,4-dioxa-8azaspiro[4.5]decane (29 mg, 0.200 mmol) and DIPEA (38 μL, 0.218 mmol). The mixture was subjected to microwave irradiation at 110° C. for 45 minutes. The mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-33-14i ketal as a yellow solid (60 mg, 80% yield). LCMS: (M+1) m/z=464.

Synthesis of 8-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-1,4-dioxa-8- 90 042282 azaspiro[4,5]decane Int-33-14j

lnt-33-14i lnt-33-14j

Int-33-14i (1.08 g, 2.89 mmol), Pd ₂ (dba) ₃ (0.119 g, 0.130 mmol), tBuXPhos (0.116 g, 0.275 mmol) and KB(OMe) ₄ (1.51 g, 8.68 mmol) and the atmosphere was replaced with nitrogen three times, then DMF (3 ml) was added. The mixture was heated to 100° C. for 2 hours. After cooling to room temperature, the crude product was filtered through celite and purified by column chromatography (hexane/EtOAc) to give Int-33-14j as a yellow solid (0.348 g, 37% yield) . LCMS: (M+1) m/z=415.

Synthesis of ketone Int-33-14k

lnt-33-14j lnt-33-14k

To a solution of ketal Int-33-14j (60 mg, 0.145 mmol) in THF (0.5 ml) was added 10% aq. H2SO4 (0.71 ml). The mixture was stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated to dryness to give the ketone Int-33-14k as yellow oil (224 mg, 90% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=371.

Synthesis of compound 33.

Mixture of ketone Int-33-14k (10 mg, 0.027 mmol), 3-(R)-amunotetrahydropyran HCl (5.6 mg, 0.040 mmol), DIPEA (4 µl, 0.030 mmol) and AcOH (2 µl, 0.054 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (11.5 mg, 0.0540 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 33 as a yellow solid (4.3 mg, 35% yield) . LCMS: (M+1) m/z=456.

Synthesis of compound 34.

A mixture of ketone Int-33-14k (20 mg, 0.054 mmol), 3-(R)-aminotetrahydrofuran (7.1 mg, 0.081 mmol) and AcOH (5 µl, 0.11 mmol) in 1,2-dichloroethane (0 .1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (22.9 mg, 0.108 mmol) was added. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 34 as a yellow solid (10 mg, 42% yield). LCMS: (M+1) m/z=442.

Synthesis of compound 35.

Mixture of ketone Int-33-14k (10 mg, 0.027 mmol), 3-oxetanamine (3.0 mg, 0.040 mmol) and AcOH (2.0 μl, 0.054 mmol) in 1,2-dichloroethane (0.1 ml) stirred at room temperature for 15 min, then NaBH(OAc) ₃ (11.5 mg, 0.0540 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 35 as a yellow solid (2.5 mg, yield

22%). LCMS: (M+1) m/z=428. Examples 36-39. ⁰ 1 'nV — γ^ΝΗ ^F O^CF ₃ lnt-33-14d TT * Y^NH ₂ F lnt-36-7 θθγΆ/ ^Μβ °γΑ ^F O^CF3 ^F O^CF3 lnt-36-5 lnt-36-6

- 91 042282

Synthesis of Int-36-7.

Int-33-14d (1.08 g, 2.89 mmol), Pd ₂ (dba) ₃ (0.119 g, 0.130 mmol), tBuXPhos (0.116 g, 0.275 mmol) and KB(OMe ) ₄ (1.51 g, 8.68 mmol) and the atmosphere was replaced with nitrogen three times, then DMF (3 ml) was added. The mixture was heated to 100°C for 2 hours. After cooling to room temperature, the crude product was filtered through celite and purified by column chromatography (hexane:EtOAc) to give Int-36-5 as a yellow solid (0.348 g, yield 27.9 %). LCMS: (M+1) m/z=325.

To a solution of Int-36-5 (0.180 g, 0.554 mmol) in THF (1 ml) at -78°C was added a solution of 3M MeMgCl in THF (0.66 ml, 2.22 mmol) and the reaction mixture was stirred at room temperature in for 2 hours the Reaction mixture was poured onto ice, acidified (pH 2) with a solution of 2M HCl and was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness to give Int-36-6 as a yellow oil which was used in the next step without further purification. LCMS: (M+1) m/z=280.

To a solution of Int-36-6 (0.138 g, 0.370 mmol) in MeOH (0.75 ml) was added 2 M aq. NaOH solution (0.75 ml), the reaction mixture was heated at 90°C for 1.5 h. Water was added and the product was extracted into EtOAc and concentrated in vacuo to give Int-36-7 as a yellow solid (0.110 g, yield 92%), which was used in the next step without further purification. LCMS: (M+1) m/z=182.

Oh I ^O'N

F F lnt-36-7 lnt-33-14g lnt-36-14h

Connection 36 Connection 37 Connection 38 Connection 39

Synthesis of Int-36-14h.

A solution of 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid Int-33-14g (72 mg, 0.50 mmol) in POCl ₃ (1.5 ml) was stirred at 50°C for 5 min, then Int-36-7 ketone (92 mg, 0.50 mmol) was added. The mixture was heated to 110°C for 1 h Excess POCl ₃ was removed in vacuum. Saturated aqueous NaHCO ₃ was added to the residue and the product was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was purified by column chromatography (hexane/EtOAc) to give 2-chloroquinoline Int-36-14h as a yellow solid (69 mg, 45% yield). LCMS: (M+1) m/z=307, 309.

Synthesis of Int-33-14j.

To a suspension of Int-36-14h (56 mg, 0.18 mmol) in EtOH (0.4 mL) was added 1,4-dioxa-8azaspiro[4.5]decane (29 mg, 0.20 mmol) and DIPEA ( 38 µl, 0.22 mmol). The mixture was subjected to microwave irradiation at 110° C. for 45 minutes. The mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-33-14j ketal as a yellow oil (60 mg, 80% yield). LCMS: (M+1) m/z=415.

Synthesis of Int-33-14k.

To a solution of ketal Int-33-14j (60 mg, 0.15 mmol) in THF (0.5 ml) was added 10% aq.

H2SO4 (0.71 ml). The mixture was stirred at 45°C for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na2CO3 and extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated to dryness to give the ketone Int-33-14k as a yellowish oil ( 224 mg, 90% yield) which was used in the next step without further purification by LCMS: (M+1) m/z=371.

Synthesis of compound 36.

A mixture of Int-33-14k ketone (10 mg, 0.027 mmol), 4-aminotetrahydropyran (4.1 mg, 0.040 mmol) and

- 92 042282

AcOH (2.0 μl, 0.054 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (11.5 mg, 0.0540 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 36 as a yellow solid (2.5 mg, 20% yield) . LCMS: (M+1) m/z=456.

Synthesis of compound 37.

Mixture of ketone Int-33-14k (10 mg, 0.027 mmol), 3-(S)-aminotetrahydropyran HCl (4.1 mg, 0.030 mmol), DIPEA (4 µl, 0.030 mmol) and AcOH (2 µl, 0.054 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (11.5 mg, 0.0540 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 37 as a yellow solid (2.3 mg, yield 18.7 %). LCMS: (M+1) m/z=456.

Synthesis of compound 38.

A mixture of Int-33-14k ketone (10 mg, 0.027 mmol), 3-(S)-aminotetrahydrofuran (3.5 mg, 0.040 mmol) and AcOH (2 µl, 0.054 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (11.5 mg, 0.0540 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 38 as a yellow solid (2.5 mg, 20% yield) . LCMS: (M+1) m/z=442.

Synthesis of compound 39.

A mixture of Int-33-14k ketone (10 mg, 0.027 mmol), cyclopropylmethanamine (2.9 mg, 0.040 mmol) and AcOH (2 μl, 0.054 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (11.5 mg, 0.0540 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 39 as a yellow solid (2.5 mg, 20% yield) . LCMS: (M+1) m/z=426.

Examples 40-82.

Synthesis of compound 40.

Stage 1: a mixture of tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (300 mg, 1.38 mmol), (S)-tetrahydrofuran-3-yl methanesulfonate (344 mg, 2, 07 mmol) and K ₂ CO ₃ (286 mg, 2.07 mmol) in DMF (1.5 ml) was stirred at 72-85°C for 18 h. After evaporation of the solvent, the residue was purified by chromatography (silica gel, 0-10% MeOH/DCM) to give tert-butyl (3S,4R)-3-fluoro-4-(((R)tetrahydrofuran-3-yl)amino)piperidine-1-carboxylate (129 mg, 32% yield) as white solid. LCMS (ESI): m/z 289 (M+H); retention time: 1.47 min (method 1).

Step 2: a solution of the indicated product (65 mg, 0.22 mmol) in TFA (0.35 ml, 4.5 mmol) in CH ₂ Cl ₂ (1 ml) was stirred at 25°C for 1 h. The solution was diluted with CH ₂ Cl ₂ and MeOH, washed with NaHCO ₃ (sat. aq.), dried over MgSO ₄ and finally concentrated under reduced pressure. The residue was used without further purification. LCMS (ESI): m/z 189 (M+H).

Stage 3: This stage is similar to the last stage in the synthesis of compound 134, the solvents were chosen from dioxane, ethanol, acetonitrile and/or DMF, and the temperature ranged from 120°C to 155°C. Compound 40 (20 mg, 23% yield) was obtained as a yellow solid after purification by RP-HPLC. LCMS (ESI): m/z 460 (M+H); retention time: 2.00 min (method 1).

Compounds 41-43 were prepared as described above for compound 40 using the appropriate fluoro-substituted piperidine(s) with the desired stereochemistry and the appropriate amines. Compound 41 (10.9 mg, 24% yield) was obtained as a white solid after purification by preparative TLC. LCMS (ESI): m/z 460 (M+H); retention time: 4.18 min (method 2). Compound 42 (2.9 mg, 6.4% yield) was obtained as a white solid after purification by preparative TLC. LCMS (ESI): m/z 460 (M+H); retention time: 1.74 min (method 1). Compound 43 (25 mg, 34% yield) was obtained as a yellow solid after purification by RP-HPLC. LCMS (ESI): m/z 460 (M+H); retention time: 1.88 min (method 1).

- 93 042282

Compounds 44-59 were prepared as described below for compounds 134-137 using the appropriate amines with the desired stereochemistry and intermediate Int-36-14h described above for compounds 36-39.

Examples 55 and 58.

Synthesis of compound 55.

Compound 55 (1.3 mg, 7% yield) was obtained as a yellow solid after purification by RP-HPLC. LCMS (ESI): m/z 474 (M+H); retention time: 2.00 min (method 1). Compound 58 (41 mg, 50% yield) was obtained as an off-white solid after purification by RP-HPLC. LCMS (ESI): m/z 444 (M+H); retention time: 2.03 min (method 1).

Synthesis of compounds 60-61.

Compounds 60-61 were prepared according to the procedure described for compounds 40-59 using the amine Int-60-3 with the appropriate stereochemistry and intermediate Int-118-7, the preparation of which is described in Example 118.

Synthesis of compounds 62-66.

Compounds 62-66 were prepared as described below for compound 141, starting from intermediate Int-62-1 and according to the synthetic method used for compound 35.

Synthesis of compounds 67-71.

Compounds 67-71 were obtained by the method disclosed above for compounds 36-39.

Synthesis of compounds 72-76.

Compounds 72-76 were prepared by the method disclosed above for compounds 36-39 starting from Intermediate Int-156-28 described for compounds 156-158 below.

Synthesis of compounds 77-82.

Compounds 77-82 were prepared as described above for compound 35.

- 94 042282

Compound 78 was obtained as an off-white solid after purification by RP-HPLC. LCMS (ESI): m/z 456 (M+H); retention time: 4.00 min (method 2).

Compound 80 was obtained as an off-white solid after purification by RP-HPLC. LCMS (ESI): m/z 470 (M+H); retention time: 3.88 min (method 2).

Examples 83-84.

lnt-33-14h Int-83-2 lnt-83-3

Int-83-4

Compound 83 Compound 84

Synthesis of Int-83-2.

To a suspension of Int-33-14h (1009 mg, 2.830 mmol) in EtOH (0.4 mL) was added 1,4-dioxa-8azaspiro[4,5]decane (449.8 mg, 3.141 mmol) and DIPEA (0. 59 ml, 3.4 mmol). The mixture was subjected to microwave irradiation at 120° C. for 45 minutes. The mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-83-2 ketal as a yellow oil (1198 mg, 91.4% yield). LCMS: (M+1) m/z=463, 465.

Synthesis of Int-83-3.

Allylpalladium chloride dimer (2.0 mg, 0.0054 mmol), Cs ₂ CO ₃ (527.4 mg, 1.619 mmol), RockPhos (7.6 mg, 0.015 mmol) and Int-83- 2 (500 mg, 1.07 mmol). The atmosphere was replaced with nitrogen 3 times, then isopropyl alcohol (163 μl, 2.15 mmol) and toluene (2 ml) were added. The mixture was heated to 90° C. overnight. After cooling to room temperature, the crude product was filtered through celite and diluted with EtOAc.

Water was added and the layers were separated. The aqueous layer was extracted three times with EtOAc. The organic layers were combined and washed with brine, then dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the crude product was purified by reverse phase chromatography (20-100% ACN:H2O) to give Int-83-3 as a yellow solid (52 mg, 15% yield). LCMS(M+1) m/z=443.

Synthesis of Int-83-4.

To a solution of Int-83-3 ketal (60 mg, 0.14 mmol) in THF (0.5 ml) was added 10% aq. H ₂ SO ₄ (0.71 ml). The mixture was stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated to dryness to give the ketone Int-83-4 as a yellowish oil (224 mg, 90% yield) which was used in the next step without further purification by LCMS: (M+1) m/z=399.

Synthesis of compound 83.

A mixture of ketone Int-83-4 (10 mg, 0.025 mmol), 3-(R)-aminotetrahydropyran HCl (5.2 mg, 0.038 mmol), DIPEA (4.0 µl, 0.03 mmol) and AcOH (2 µl , 0.050 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (10.6 mg, 0.0502 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 83 as a yellow solid (1.83 mg, yield 15.1 %). LCMS: (M+1) m/z=484.

Synthesis of compound 84.

A mixture of ketone Int-83-4 (10 mg, 0.025 mmol), 3-(R)-aminotetrahydrofuran (3.3 mg, 0.037 mmol) and AcOH (2 μl, 0.050 mmol) in 1,2-dichloroethane (0.1 ml) was stirred at room temperature for 15 min, then NaBH(OAc)3 (10.6 mg, 0.050 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 84 as a yellow solid (2.8 mg, 20% yield) . LCMS: (M+1) m/z=470.

- 95 042282

Example 85.

Synthesis of Int-85-40.

To a solution of Int-85-38 (1.0 eq) in CH2C12 was added NBS (1.05 eq) and the mixture was stirred at room temperature for 18 h. The mixture was concentrated and purified by column chromatography using CH ₂ Cl ₂ LCMS (M +1) m/z=283, 285 A mixture of aldehyde intermediate (1.0 eq), Int-85-39 (2.0 eq) and NH ₄ OAc (5.0 eq) in dioxane was heated at 90°C within 18 hours the Mixture was concentrated and the crude material was diluted with water (3x) and was extracted with a mixture of hexane/EtOAc (9/1) (2x). The organic solution was concentrated under reduced pressure and the product was used without further purification by LCMS (M+1) m/z=332.334.

Synthesis of Int-85-41.

A mixture of Int-85-40 (1.0 eq.) and POCl ₃ was heated at 120° C. for 18 hours. The mixture was concentrated under reduced pressure, quenched with ice/water and basified with NaHCO ₃ . The product was extracted with CH ₂ Cl ₂ (3x), the organic phase was dried over Na ₂ SO ₄ and concentrated. The product (Int-85-41) was used without further purification by LCMS (M+1) m/z=350.352.

Synthesis of Int-85-42.

A mixture of Int-85-41 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.) and DIPEA (2.0 eq.) in iPrOH was heated at 110 °C for 18 hours After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (EtOAc/hexane) to give the corresponding ketal. LCMS: (M+1) m/z=458, 460.

A mixture of ketal (1.0 eq.), NH ₂ OH.HCl (5.0 eq.) and Na ₂ CO ₃ (5.0 eq.) in iPrOH was heated at 120°C for 18 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The solid was used without further purification. LCMS: (M+1) m/z=491, 493.

A mixture of amidoxime (1.0 eq.), Ac ₂ O (1.1 eq.) and DIPEA (1.1 eq.) in dioxane was heated at 100° C. for 18 hours. The mixture was concentrated under reduced pressure and the product was purified by column chromatography using hexane:EtOAc to give Int-85-42. LCMS: (M+1) m/z=515, 517.

Synthesis of Int-85-43.

A mixture of Int-85-42 (1.0 eq.), KI (1.0 eq.), zinc cyanide (3.0 eq.), Pd(OAc) ₂ (0.2 eq.), dppe (0, 3 eq.), Na ₂ CO ₃ (3.0 eq.) and TMEDA (1.0 eq.) in DMF were heated at 130°C overnight. The mixture was diluted with EtOAc and washed with brine (3x). The organic phase was concentrated and the product was purified by preparative TLC. LCMS: (M+1) m/z=462.

A mixture of the above product in THF/10% aq. H2SO4 was stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous NaHCO ₃ and the product was extracted with EtOAc (3x). The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the ketone Int-85-43, which was used in the next step without further purification by LCMS: (M+1) m/z=418.

Synthesis of compound 85.

A mixture of ketone Int-85-43 (1.0 eq.), 4-aminotetrahydropyran (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) in 1, 2-dichloroethane was stirred at room temperature overnight. The mixture was filtered through celite, concentrated under reduced pressure and purified by HPLC with

- 96 042282 obtaining compound 85 in the form of a yellow solid with a yield of 84-86%. LCMS: (M+1) m/z=503.

Example 86.

Compound 86 was obtained according to the procedure disclosed below for compound 88, starting from the ketone Int-88-24 and the appropriate amine, as a pale yellow solid in 49-51% yield. LCMS: (M+1) m/z=470.

Example 87.

Synthesis of Int-87-2.

To a suspension of 2-amino-3-chlorobenzoic acid Int-87-1 (4.57 g, 26.6 mmol) in CH ₂ Cl ₂ (100 ml) was added N-bromosuccinimide (4.74 g, 26.6 mmol) . The mixture was stirred at room temperature for 2.5 hours. The product was filtered, washed with CH ₂ Cl ₂ and dried under reduced pressure to give Int-87-2 as an off-white solid (5.67 g, 85% yield ). LCMS (M-1) m/z=248, 250.

Synthesis of Int-87-3.

To a solution of Int-87-2 (5.41 g, 21.6 mmol) in THF (50 ml) was added dropwise a 1M solution of the BH3-THF complex in THF (108 ml, 108 mmol) at 0°C. The mixture was then stirred at room temperature for 18 hours. The reaction was quenched by slow addition of MeOH at 0°C. After removal of volatiles under reduced pressure, the residue was partitioned between EtOAc and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The product Int-87-3 as a pink solid was used for the next reaction without further purification (quantitative yield).

Synthesis of Int-87-4.

A mixture of Int-87-3 (5.10 g, 21.6 mmol) and activated MnO ₂ (11.2 g, 129.4 mmol) in CH ₂ Cl ₂ (100 ml) was stirred at room temperature overnight. After filtration through celite, the filtrate was concentrated. The residue was purified on a short silica gel column to give Int-87-4 as a yellow solid (5.06 g, quant.).

Synthesis of Int-87-6.

Mixture of aldehyde Int-87-4 (1.52 g, 6.48 mmol), oxadiazole ester Int-87-5 (1.10 g, 6.48 mmol) and p-TSA (0.15 g, 10% wt.) was heated at 150°C for 1 h. After cooling to room temperature was added CH ₂ Cl ₂ :MeOH (9:1, v/v, 20 ml) and hexane:EtOAc (8:2, v/v, 20 ml) and the resulting mixture was vigorously stirred. The desired product precipitated out of solution during the evaporation of the solvents under reduced pressure. The solid was filtered, washed with

H2O and dried under reduced pressure. Product 6 as a brown solid was used for the next reaction without further purification (338 mg, 15% yield). LCMS: (M+1) m/z=340,

342.

Synthesis of Int-87-7.

A mixture of Int-87-6 (0.50 g, 1.47 mmol) and POCl ₃ (5 ml) was stirred at 110° C. for 1 hour. After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. H ₂ O was added to the residue at 0°C. The mixture was stirred at 0° C. for 10 minutes. The precipitated solid was filtered, washed with H2O and dried under reduced pressure to give Int-87-7 as a pale brown solid which was used for the next reaction without further purification (447 mg, 85% yield).

Synthesis of Int-87-8.

A mixture of Int-87-7 (272 mg, 0.76 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (0.20 ml, 1.52 mmol) and DIPEA (0.26 ml, 1.52 mmol) in EtOH (7.6 ml) was heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give Int-87-8 as a yellow oil (287 mg, 82% yield). LCMS: (M+1) m/z=465, 467.

Synthesis of Int-87-9.

_A solution of _1M Et ₃ B in THF (1.3 ml, 1.24 mmol) at room temperature. The mixture was then heated at 70° C. overnight. After cooling to room temperature, the mixture was filtered through celite. Filter, concentrate and purify by column chromatography (hexane/EtOAc gradient) to give Int-87-9 as a yellow oil (70 mg, 27% yield). LCMS: (M+1) m/z=415.

Synthesis of Int-87-10.

To a solution of Int-87-9 (70 mg, 0.17 mmol) in THF (1 ml) was added 10% aq. H2SO4 (2 ml, v/v). The mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (-2). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated to dryness. Product Int-87-10, a yellow solid, was used for the next reaction without further purification. (62 mg, quantitative yield). LCMS: (M+1) m/z=371.

Synthesis of compound 87.

Mixture of Int-87-10 ketone (10.9 mg, 0.029 mmol), tetrahydro-2H-pyran-4-amine (6.0 mg, 0.058 mmol) and DIPEA (10 µl, 0.058 mmol) in 1,2-dichloroethane (1.0 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (18.4 mg, 0.087 mmol) and AcOH (5 μl, 0.087 mmol) were added to the mixture. The resulting mixture was stirred at room temperature for 18 hours. After filtration through celite, the filtrate was concentrated. The residue was purified by preparative TLC (EtOAc:/PrOH=9:1) to give compound 87 as a yellow oil (12.0 mg, 91% yield). LCMS: (M+1) m/z=456.

Example 88.

Oh oh

_N ,OMe

CF ₃ [nt-88-17 ee ₂ s^LH

Compound 88

Reagents and conditions: i) DMF (2.5 eq.), POCl ₃ (7.0 eq.), 0-75°C, 48 h, 36-39%; ii) NaH ₂ PO ₄ (5.0 eq.), NaClO ₂ (3.0 eq.), Na ₂ SO ₃ (4.0 eq.), CH3CN, 94-98%; iii) a) Int-20-15 (1.0 eq.), SOCl ₂ (3.0 eq.), CH ₂ Cl ₂ , 50°C, 2 h, b) Acetamidoxime (1.2 eq.), DIPEA (1.2 eq.), dioxane, 100°C, 4 h, 48-54%; iv) 1,4-dioxa-8-98 042282 azaspiro[4,5]decane (1.2 eq.), DIPEA (2.0 eq.), EtOH, 125°C, overnight, 70-73% ; v) Int-20-16 (1.0 eq.), Et ₃ B (2.0 eq.), CS2CO3 (2.0 eq.), Pd(dppf)Cl2.CH2Cl2 (I/20 eq.), THF, 70°C, 1.5 h, 27-29%; vi) 10% aq. H ₂ SO ₄ , THF, 45°C, 2 h, 73-78%; vii) Amine (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.), AcOH (2.0 eq.), DIPEA (2.0 eq.), 1,2-dichloroethane, rt. temp., during the night; viii) cPrMgBr (3.2 eq.), Pd(OAc) ₂ (0.2 eq.),

P(tBu) ₃ -HBF ₄ (0.1 equiv.), 1M ZnBr ₂ in THF (0.3 equiv.), THF, room. temp., 25-28%.

Synthesis of Int-88-15.

A suspension of Int-88-14 acid (1.0 eq.) and NBS (1.0 eq.) in CH ₂ Cl ₂ was stirred at room temperature overnight. The product was collected by filtration to give Int-88-15 acid as an off-white solid (84-86% yield) which was used in the next step without further purification. LCMS: (M-1) m/z=247, 249.

Synthesis of Int-88-16.

A mixture of Int-88-15 (1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (1.8 eq.), DIPEA (2.0 eq.), EDCl (1.2 eq.) and HOBt (1.2 eq.) 2 eq) in DMF was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine and concentrated in vacuo to give Int-88-16 as a brown oil (yield 84-86 %). The product was used in the next step without further purification. LCMS: (M+1) m/z=292, 294.

Synthesis of Int-88-17.

Trifluoroacetic anhydride (1.3 eq.) was added dropwise to a solution of Int-88-16 (1.0 eq.) and TEA (1.2 eq.) in CH ₂ Cl ₂ at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO ₃ and brine (2·). The organic layer was dried over Na ₂ SO ₄ and concentrated to give Int-88-17 as a pale yellow solid (90-92% yield) which was used in the next step without further purification. LCMS: (M-1) m/z=386, 388.

Synthesis of Int-88-18.

To a suspension of Int-88-17 (1.0 equiv.), Cs ₂ CO ₃ (3.0 equiv.) and Pd(dppf)Cl ₂ (0.02 equiv.) in THF was added a 1M solution of Et ₃ B in THF (3.0 eq.) and the reaction mixture was heated at 70°C for 1.5 h. After cooling to room temperature, the crude material was filtered through celite and purified by column chromatography (hexane:EtOAc) to obtain Int-88-18 as yellow solid (yield 4547%). LCMS: (M+1) m/z=339.

Synthesis of Int-88-19.

To a solution of Int-88-18 (1.0 equiv.) in THF at 0°C was added a 1.4 M solution of MeMgBr in THF:toluene (5.0 equiv.) and the reaction mixture was stirred at room temperature for 2.5 hours The reaction was quenched with ice, acidified to pH 2 with a solution of 2M HCl and was extracted with EtOAc (2x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give Int-88-19 as a yellow solid (85-87% yield) which was used in the next step without further purification. LCMS: (M-1) m/z=294.

Synthesis of Int-88-20.

To a solution of Int-88-19 (1.0 eq.) in MeOH was added 2 M aq. NaOH solution (1.7 eq.) and the reaction mixture was heated at 90°C for 3 hours. The mixture was diluted with water and the solid was collected by filtration to give Int-88-20 as a yellow solid (yield 80-82%), which was used in the next step without further purification. LCMS: (M+1) m/z=198.

Synthesis of Int-88-21.

A mixture of ketone Int-88-20 (1.0 equiv.), Int-88-8 (2.0 equiv.) and p-TsOH (cat.) was stirred at 150°C for 2 hours. After cooling to room temperature the reaction mixture was washed successively with EtOAc:hexane (8:2, v/v) (2x) and water to give quinolone Int-88-21 as a yellow solid (yield 19-21%). LCMS: (M+1) m/z=304.

Synthesis of Int-88-22.

A suspension of Int-88-21 in POC13 was stirred at 110° C. for 2 hours. Excess POC13 was removed under reduced pressure. The crude material was quenched with saturated aqueous NaHCO3 and the product was extracted with EtOAc (3x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The product was purified by column chromatography (hexane/EtOAc) to give 2chloroquinoline Int-88-22 as a pale yellow solid (97-98% yield). LCMS: (M+1) m/z=322, 324.

Synthesis of Int-88-23.

A suspension of Int-88-22 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.) and DIPEA (2.0 eq.) in EtOH was heated at 110 °C during the night. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-88-23 ketal as a pale yellow solid (73-75% yield). LCMS: (M+1) m/z=429.

Synthesis of Int-88-24.

To a solution of ketal Int-88-23 in THF was added 10% aq. H ₂ SO ₄ and the mixture was stirred at 45°C in

- 99 042282 for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO 3 and extracted with EtOAc (3x), dried over Na ₂ SO ₄ and concentrated to obtain the ketone Int-88-24 as a yellow solid (yield 83-85%), which was used in the next step without further purification. LCMS: (M+1) m/z=385.

Synthesis of compound 88.

A mixture of ketone Int-88-24 (1.0 eq.), 4-aminotetrahydropyran (1.5 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) in 1, 2-dichloroethane was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 88 as a yellow solid (89-90% yield). LCMS: (M+1) m/z=470.

Example 89.

Compound 89 was obtained according to the procedure described below for compound 91 as a pale yellow solid in 96% yield (last step). LCMS (M+1) m/z=447.

Example 90.

Synthesis of Int-90-11.

To a suspension of 2-amino-5-bromobenzoic acid Int-90-8 (10.80 g, 50.0 mmol) in CH ₂ Cl ₂ (200 ml) was added N-iodosuccinimide (11.25 g, 50.0 mmol) . The mixture was stirred at room temperature for 4 hours. The product was filtered, washed with CH ₂ Cl ₂ and dried under reduced pressure to give iodobenzoic acid Int-90-9 as a light brown solid. To a solution of Int-90-9 (13.51 g, 39.5 mmol) in THF (100 ml) was added dropwise a solution of the BH3-THF complex (1M in THF, 200 ml, 200 mmol) at 0°C. The mixture was then stirred at room temperature overnight. The reaction was quenched by slow addition of MeOH at 0°C. After the solvent was removed by evaporation to dryness, the crude alcohol Int-90-10 was dissolved in CH ₂ Cl ₂ (200 ml) and activated MnO ₂ (20.60 g, 237 mmol) was added. The mixture was stirred at room temperature overnight. The crude product was purified on a short silica gel column to give aldehyde Int-90-11 as a yellow solid (10.3 g, 63% yield over three steps). LCMS (M-1) m/z=324, 326.

Synthesis of Int-90-14.

A mixture of aldehyde Int-90-11 (4.50 g, 13.8 mmol), acid derivative of oxadiazole Int-90-12 (2.36 g, 16.6 mmol) and POCl ₃ (14 ml) was stirred at 110°C within 1 h After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. H ₂ O was added to this residue at 0°C. The mixture was stirred at 0° C. for 10 minutes. The crude Int-90-13 chloride was filtered, washed with H2O and dried under reduced pressure. To a suspension of Int-90-13 in EtOH (70 ml) was added 1,4dioxa-8-azaspiro[4,5]decane (3.5 ml, 27.6 mmol) and DIPEA (4.8 ml, 27.6 mmol ) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give quinoline Int-90-14 as a yellow oil (2.61 g, 34% yield over two steps). LCMS: (M+1) m/z=557, 559.

Synthesis of Int-90-15.

Mixture of Int-90-14 (2.35 g, 4.22 mmol), Zn(CN) ₂ (0.50 g, 4.22 mmol), Zn powder (30 mg, 0.42 mmol) and Pd(PPh ₃ ) ₄ (0.50 g, 0.42 mmol) in THF/DMF (60 ml, 1:1 (v/v)) was heated at 80° C. overnight. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give cyanoquinoline Int-90-15 as a yellow oil (0.86 g, 45% yield). LCMS: (M+1) m/z=456, 458.

Synthesis of Int-90-16.

To a mixture of Int-90-15 (0.86 g, 1.88 mmol), K2CO3 (0.52 g, 3.76 mmol) and Pd(PPh ₃ ) ₄ (0.22 g, 0.19 mmol) in DMF (20 ml) was added 1M solution of Et ₃ B in THF (3.8 ml, 3.80 mmol) at room temperature. The mixture was then heated at 70° C. overnight. After cooling to room temperature, the mixture was partitioned between brine (30 ml) and EtOAc (30 ml). The aqueous layer was extracted at

- 100 042282 EtOAc (30 ml) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give ethylquinoline 16 as a yellow oil (0.23 g, 30% yield). LCMS: (M+1) m/z=406.

Synthesis of Int-90-17.

To a solution of Int-90-16 (0.14 g, 0.35 mmol) in THF (1 ml) was added 10% aq. H ₂ SO ₄ (5 ml, v/v). The mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x20 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. Ketone Int-90-17 as a yellow solid was used for the next reaction without further purification. (116 mg, 92% yield). LCMS: (M+1) m/z=362.

Synthesis of compound 90.

Mixture of Int-90-17 ketone (14.4 mg, 0.04 mmol), (S)-3-aminotetrahydropyran hydrochloride (11.0 mg, 0.08 mmol) and DIPEA (14 µl, 0.08 mmol) in 1,2-dichloroethane (1.5 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (25.4 mg, 0.12 mmol) and AcOH (7 μl, 0.12 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 90 as a yellow oil (15.6 mg, 88% yield). LCMS: (M+1) m/z=447.

Example 91.

Reagents and conditions: i) Int-91-18 (1.0 eq.), PyICl (1.0 eq.), MeOH, reflux, 18 h, 69%; ii) Int-91-19 (1.0 eq.), Int-91-12 (1.2 eq.), POCl ₃ , 110° C., 1 h; iii) 1,4-dioxa-8azaspiro[4,5]decane (2.0 eq.), DIPEA (2.0 eq.), EtOH, 120° C., 18 h, 30% (two steps); iv) Zn(CN) ₂ (1.0 equiv.), Zn (0.1 equiv.), Pd(PPh ₃ ) ₄ (0.1 equiv.), THF/DMF, 80°C, 18 h, 86 %; v) Et ₃ B (2.0 eq.), K ₂ CO ₃ (2.0 eq.), Pd(PPh ₃ ) ₄ (0.1 eq.), DMF, 70°C, 57%; vi) 10% aq. H2SO4, THF, 45°С, 2 h, 89%; vii) amine (2.0 eq.), NaBH(OAc)3 (3.0 eq.), AcOH (3.0 eq.), DIPEA (2.0 eq.), 1,2-dichloroethane, rt. temp., 18 h, 93%.

Synthesis of Int-91-19.

A mixture of 2-amino-5-bromoacetophenone Int-91-18 (4.6 g, 21.5 mmol) and pyridinium iodochloride (5.2 g, 21.5 mmol) in MeOH (54 ml) was refluxed for night. After cooling to room temperature, the mixture was concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give iodoacetophenone Int-91-19 as a yellow solid (5.04 g, 69% yield). LCMS: (M+1) m/z=340, 342.

Synthesis of Int-91-21.

A mixture of ketone Int-91-19 (5.02 g, 14.8 mmol), acid derivative of oxadiazole Int-91-12 (2.52 g, 17.7 mmol) and POCl ₃ (15 ml) was stirred at 110°C within 1 h. After cooling to room temperature, excess POCl3 was removed under reduced pressure. H2O was added to this residue at 0°C. The mixture was stirred at 0° C. for 10 minutes. The crude Int-91-20 chloride was filtered, washed with H ₂ O and dried under reduced pressure. To a suspension of Int-91-20 in EtOH (74 ml) was added 1,4-dioxa-8-azaspiro[4,5]decane (3.8 ml, 29.6 mmol) and DIPEA (5.2 ml, 29. 6 mmol) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give quinoline Int-91-21 as a yellow oil (2.54 g, 30% yield over two steps). HCMS: (M+1)

- 101 042282 m/z=571, 573.

Synthesis of Int-91-22.

Mixture of Int-91-21 (1.28 g, 2.24 mmol), Zn(CN)2 (0.26 g, 2.24 mmol), Zn powder (15 mg, 0.22 mmol) and Pd(PPh ₃ ) ₄ (0.26 g, 0.22 mmol) in THF/DMF (22 ml, 1:1 (v/v)) was heated at 80° C. overnight. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give cyanoquinoline Int-91-22 as a light green solid (0.90 g, 86% yield). LCMS: (M+1) m/z=470, 472.

Synthesis of Int-91-23.

To a mixture of Int-91-22 (0.90 g, 1.91 mmol), K2CO3 (0.53 g, 3.82 mmol) and Pd(PPh3) ₄ (0.22 g, 0.19 mmol) in DMF (20 ml) was added a 1M solution of Et ₃ B in THF (3.8 ml, 3.8 mmol) at room temperature. The mixture was then heated at 70° C. overnight. After cooling to room temperature, the mixture was partitioned between brine (30 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (30 ml) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-91 23 ethylquinoline as a yellow oil (0.45 g, 57% yield). LCMS: (M+1) m/z=420.

Synthesis of Int-91-24.

To a solution of Int-91-23 (0.45 g, 1.08 mmol) in THF (4 mL) was added 10% aq. H2SO4 (12 ml, v/v). The mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The ketone Int-91-24 as an orange solid was used for the next reaction without further purification. (0.36 g, 89% yield). LCMS: (M+1) m/z=376.

Synthesis of compound 91.

Mixture of Int-91-24 ketone (15.1 mg, 0.04 mmol), (R)-3-αminotetraαhydropyran hydrochloride (11.0 mg, 0.08 mmol) and DIPEA (14 µL, 0.08 mmol) in 1,2-dichloroethane (1.5 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (25.4 mg, 0.12 mmol) and AcOH (7 μl, 0.12 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:/PrOH=9:1) to give compound 91 as a yellow solid (17.2 mg, 93% yield). LCMS: (M+1) m/z=461.

Examples 92-93.

Reagents and conditions: i) Int-92-1 (1.0 eq.), Int-142-9 (1.5 eq.), NaH (1.0 eq.), DMF, 120° C., 4 h; ii) POCl ₃ , 110° C., 1.5 h, 19% over two steps; iii) Int-92-4 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.), Pd(PPh ₃ ) ₄ (0.1 eq. ), 1,4-dioxane, 80°C, 3 h, 11% for Int-92-5 (and 48% for Int-92-6); iv) 5 (1.0 eq.), Et ₃ B (1.2 eq.), K ₂ CO ₃ (2.0 eq.), Pd(PPh ₃ ) ₄ (0.1 eq.), THF/ DMF, 70°C, overnight, 67%; v) 10% aq. H2SO4,

- 102 042282

THF, 45°C, 2 h, 80%; vi) Int-92-8 (1.0 eq.), Amine (2.0 eq.), NaBH(OAc) ₃ (3.0 eq.), AcOH (3.0 eq.), DIPEA (2, 0 equiv.), 1,2-dichloroethane, room. temp., during the night, 62%; vii) 7 (1.0 eq.), KCN (2.0 eq.), DMSO,

110°C, overnight, 30%; viii) 10% aq. H ₂ SO ₄ , THF, 45°C, 1.5 h, quantitative yield; ix) Int-92-11 (1.0 eq.), amine (2.0 eq.), NaBH(OAc) ₃ (3.0 eq.), AcOH (3.0 eq.), DIPEA (2, 0 equiv.), 1,2-dichloroethane, room.

temp., 18 h, 61%.

Synthesis of Int-92-3.

To a suspension of NaH (60% in oil, 0.83 g, 20.7 mmol) in DMF (60 ml) was added oxadiazole ester Int-92-2 (5.30 g, 31.0 mmol) dropwise at 0° WITH. The mixture was stirred at 0° C. for 10 min then 5-bromo-N-carboxyanthranilic acid anhydride Int-92-1 (5.00 g, 20.7 mmol) was added. The mixture was then heated at 120° C. for 4 hours. After cooling to room temperature, the reaction was quenched by adding H ₂ O and acidified with concentrated HCl (pH 4~5, litmus paper). The mixture was extracted with CH ₂ Cl ₂ (x3) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated to dryness. Product Int-92-3, a dark brown oil, was used for the next reaction without further purification.

Synthesis of Int-92-4.

A mixture of Int-92-3 (6.67 g, 20.7 mmol) and POCl ₃ (5 ml) was stirred at 110° C. for 1.5 h. After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. H ₂ O was added to the residue at 0°C. The mixture was partitioned between CH ₂ Cl ₂ and saturated aqueous NaHCO ₃ . The aqueous layer was separated and extracted with CH ₂ Cl ₂ (x2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-92-4 as a yellow solid (1.41 g, 19% yield over two steps).

Synthesis of Int-92-5.

A mixture of Int-92-4 (4.29 g, 11.95 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (3.0 ml, 23.90 mmol) and Pd(PPh ₃ ) ₄ (1.38 g, 1.12 mmol) in 1,4-dioxane (80 ml) was heated at 80° C. for 3 hours. After cooling to room temperature, the mixture was filtered through celite. Filter, concentrate and purify by column chromatography (hexane/EtOAc gradient) to give Int-92-5 as a pale yellow solid (0.59 g, 11% yield) and 4-aminated Int-92-6 as a pale yellow crystal (2.67 g, 48% yield). The structure of Int-92-6 was confirmed by X-ray crystallography. LCMS: (M+1) m/z=465, 467.

Synthesis of Int-92-7.

To a mixture of Int-92-5 (590 mg, 1.27 mmol), K ₂ CO ₃ (350 mg, 2.54 mmol) and Pd(PPh ₃ ) ₄ (146 mg, 0.127 mmol) in THF/DMF (1 :1, v/v, 12 ml) was added a 1M solution of Et ₃ B in THF (1.52 ml, 1.52 mmol) at room temperature. The mixture was then heated at 70° C. overnight. After cooling to room temperature, the mixture was filtered through celite. Filter, concentrate and purify by column chromatography (hexane/EtOAc gradient) to give Int-92-7 as a yellow oil (352 mg, 67% yield). LCMS: (M+1) m/z=415.

Synthesis of Int-92-8.

To a solution of Int-92-7 (125 mg, 0.30 mmol) in THF (3 ml) was added 10% aq. H ₂ SO ₄ (5 ml, v/v). The mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (x2). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-92-8 as a yellow oil (88.7 mg, 80% yield). LCMS: (M+1) m/z=371.

Synthesis of compound 92.

Mixture of Int-92-8 ketone (10.0 mg, 0.027 mmol), 4-aminotetrahydropyran (5.5 mg, 0.054 mmol) and DIPEA (10 µl, 0.054 mmol) in 1,2-dichloroethane (1.5 ml) stirred at room temperature for 10 min. NaBH(OAc) ₃ (17.0 mg, 0.081 mmol) and AcOH (5 μl, 0.081 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through celite, the filtrate was concentrated. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=93:7) to give compound 92 as a yellow oil (7.6 mg, 62% yield). LCMS: (M+1) m/z=456.

Synthesis of Int-92-10.

A mixture of Int-92-7 (334 mg, 0.805 mmol) and KCN (105 mg, 1.61 mmol) in DMSO (10 mL) was heated at 110° C. overnight. After cooling to room temperature, the mixture was partitioned between EtOAc and brine. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc) followed by preparative TLC (hexane:EtOAc=6:1) to give Int-92-10 as a yellow solid (97 mg, 30% yield). LCMS: (M+1) m/z=406.

Synthesis of Int-92-11.

To a solution of Int-92-10 (23 mg, 0.057 mmol) in THF (1 ml) was added 10% aq. H ₂ SO ₄ (1 ml, v/v). The mixture was stirred at 45°C for 1.5 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (x2). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-92-11 as a yellow oil was used for the next reaction without further purification (20.5 mg, quant.). LCMS: (M+1) m/z=362.

Synthesis of compound 93.

Mixture of Int-92-11 ketone (10.2 mg, 0.028 mmol), (R)-3-aminotetrahydropyran (7.7 mg, 0.056 mmol) and DIPEA (10 µl, 0.056 mmol) in 1,2-dichloroethane (1 .5 ml) was stirred at room temperature for 10 min. NaBH(OAc) ₃ (17.8 mg, 0.084 mmol) and AcOH (5 μl, 0.084 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through celite, the filtrate was concentrated. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 93 as an orange oil (7.7 mg, 61% yield). LCMS: (M+1) m/z=447.

Examples 94-96.

lnt-33-14h Int-94-2 lnt-94-3

lnt-94-4 lnt-94-5 lnt-94-6

Compound 94 Compound 95 Compound 96

Synthesis of Int-94-2.

A solution of Int-33-14h (1.753 g, 4.92 mmol) and tributyl-(1-ethoxyvinyl)tin (2.33 ml, 6.89 mmol) in toluene (15 ml) was degassed with nitrogen. Bis(triphenylphosphine)palladium(I)dichloride (172.7mg, 0.245mmol, 5mol%) was added and the reaction mixture was heated at 80°C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated and the residue was purified by silica gel chromatography (hexane:EtOAc=90:1) to give Int-94-2 as a white solid (537 mg, 31% yield). LCMS: (M+1) m/z=348, 350.

Synthesis of Int-94-3.

To a mixture of Int-94-2 (537 mg, 1.54 mmol) in 1,4-dioxane (3 ml) was added a solution of 2 M hydrochloric acid (3 ml). The reaction mixture was stirred at room temperature for 30 minutes. 1,4-dioxane was removed under reduced pressure. The product was collected by vacuum filtration, washed successively with water and hexane to give Int-94-3 as an off-white solid (480 mg, 97% yield). LCMS: (M+1) m/z=320, 322.

Synthesis of Int-94-4.

To a mixture of Int-94-3 (100 mg, 0.31 mmol) in dichloromethane (1.5 ml) was added diethylaminosulfur trifluoride (0.25 ml, 1.88 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. Additional diethylaminosulfur trifluoride (0.21 ml, 1.58 mmol) was added at 0° C. and the reaction mixture continued to stir at room temperature for another 48 hours. The reaction mixture was slowly poured into saturated aqueous NaHCO ₃ . The organic layer was separated and the aqueous layer was extracted with dichloromethane (3x20 ml). The combined organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:EtOAc=80:20) to give Int-94-4 as a white solid (62.4 mg, 59% yield). LCMS: (M+1) m/z=342, 344.

Synthesis of Int-94-5.

To a suspension of Int-94-4 (40 mg, 0.12 mmol) in EtOH (0.5 ml) was added 1,4-dioxa-8-azaspiro[4,5]decane (0.030 ml, 0.24 mmol) and DIPEA (0.041 ml, 0.24 mmol). The reaction mixture was heated under microwave irradiation at 130°C for 40 min. The mixture was concentrated and purified by preparative TLC (hexane:EtOAc=80:20) to give Int-94-5 as a yellow solid (43 mg, 89% yield). LCMS: (M+1) m/z=449.

- 104 042282

Synthesis of Int-94-6.

To a solution of Int-94-5 (43 mg, 0.096 mmol) in THF (0.4 ml) was added 10% aq. H ₂ SO ₄ (0.8 ml) at room temperature. The mixture was then stirred at 45°C for 4 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous NaCO ₃ and was extracted with EtOAc (2x10 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. Ketone Int-94-6 (38 mg, 98%; yellow oil) was used in the next step without further purification. LCMS: (M+1) m/z=405.

Synthesis of compound 94.

A mixture of Int-94-6 (11 mg, 0.027 mmol), tetrahydro-2H-pyran-4-amine (5.5 mg, 0.054 mmol) in 1,2-dichloroethane (0.2 ml) was stirred at room temperature for 10 min. . NaBH(OAc) ₃ (11.4 mg, 0.054 mmol) and AcOH (3 μl, 0.054 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was directly purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 94 as an off-white solid (6.0 mg, 45% yield). LCMS: (M+1) m/z=490.

Synthesis of compound 95.

Mixture of Int-94-6 (11 mg, 0.027 mmol), (R)-tetrahydro-2H-pyran-3-amine hydrochloride (7.4 mg, 0.054 mmol) and DIPEA (9.4 µl, 0.054 mmol) in 1 ,2-dichloroethane (0.2 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (11.4 mg, 0.054 mmol) and AcOH (3 μl, 0.054 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was directly purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 95 as a white solid (6.0 mg, 45% yield). LCMS: (M+1) m/z=490.

Synthesis of compound 96.

A mixture of Int-94-b (11 mg, 0.027 mmol) and (R)-tetrahydrofuran-3-amine (4.7 mg, 0.054 mmol) in 1,2dichloroethane (0.2 ml) was stirred at room temperature for 10 min. . NaBH(OAc)3 (11.4 mg, 0.054 mmol) and AcOH (3 µl, 0.054 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was directly purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 96 as an off-white solid (2.0 mg, 16% yield). LCMS: (M+1) m/z=476.

Examples 97-98.

lnt-97-5 lnt-97-6 lnt-97-7

Compound 97

Compound 98

Synthesis of Int-97-3.

A mixture of Int-97-1 (1.37 g, 6.89 mmol) and tetrahydro-2H-pyran-4-amine Int-97-2 (1.395 g, 13.79 mmol) in 1,2-dichloroethane (20 ml ) was stirred at room temperature for 10 min. NaBH(OAc)3 (2.92 g, 3.79 mmol) and AcOH (0.78 ml, 13.79 mmol) were added to the mixture. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous Na2CO3 and EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc (2x40 ml). The combined organic phase was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The product was purified by column chromatography (CH ₂ C1 ₂ :MeOH=97:3) to give Int-97-3 as a yellow oil (1.716 g, 88% yield). LC-MS: (M+1) m/z=285.

Synthesis of Int-97-4.

Trifluoroacetic acid (9.2 ml, 120.67 mmol) was added dropwise to a solution of Int-97-3 (1.716 g, 6.03 mmol) in CH ₂ Cl ₂ (10 ml). The reaction mixture was stirred at room temperature for 1 hour, then the solvent and excess trifluoroacetic acid were evaporated under reduced pressure. The residue was partitioned between 2M NaOH solution and EtOAc. The organic phase was separated and the aqueous phase was back-extracted with EtOAc (3x20 ml). The combined organic phase was washed with water (2x5 ml), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give Int-97-4 as

- 105 042282 yellow oil which was used in the next step without further purification (1.1 g, quantitative yield). LCMS: (M+1) m/z=185.

Synthesis of Int-97-5.

Same as the synthesis of intermediate Int-94-3 described above for compounds 94-96.

Synthesis of Int-97-6.

Dimer dichloro(n-cymol)ruthenium(II) (0.38 mg, 0.6 µmol) and (1R,2R)-(-)-N-p-tosyl-1,2diphenylethylenediamine (0.55 mg, 1, 5 µmol) was suspended in water (0.25 ml). The mixture was degassed with nitrogen, then heated at 70° C. for 90 minutes under nitrogen. The resulting mixture was allowed to cool to room temperature. Ketone Int-97-5 (40 mg, 0.125 mg), sodium formate (42.5 mg, 0.625 mmol) and anhydrous THF (0.12 ml) were added and the reaction mixture was degassed with nitrogen. The reaction mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:EtOAc=70:30) to give the title compound as a white solid (33.0 mg, 82% yield, ee undetermined). LCMS: (M+1) m/z = 322, 324.

Synthesis of Int-97-7.

N-(Trimethylsilyl)morpholine (60 μl, 0.336 mmol) was added dropwise to a solution of DAST (43 μl, 0.328 mmol) in anhydrous CH ₂ Cl ₂ (0.2 ml) at -78°C. The resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was cooled at -78°C and a solution of (R)-1-(2-chloro-8-fluoro-4-methyl-3-(3- methyl-1,2,4-oxadiazol-5-yl)quinolin-6-yl)ethan-1-ol Int-97-6 (33 mg, 0.10 mmol) in anhydrous CH ₂ Cl ₂ (0.4 ml ). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then slowly poured into 10 ml of saturated NaHCO ₃ solution. The organic layer was separated and the aqueous phase was extracted with additional CH ₂ Cl ₂ (3x10 ml). The combined organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:EtOAc=80:20) to give the title compound as a yellow oil (14.6 mg, 45% yield, ee undetermined). LCMS: (M+1) m/z=324, 326.

Synthesis of compound 97.

A mixture of (S)-5-(2-chloro-8-fluoro-6-(1-fluoroethyl)-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-977 (13, 8 mg, 0.0426 mmol), N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine 4 (9 mg, 0.047 mmol) and DIPEA (8 µl, 0.047 mmol) in DMF (0.2 ml) was heated at 120°C overnight. The reaction mixture was diluted with brine and EtOAc. The organic phase was separated and washed with brine (2x5 ml). The organic phase was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=96:4) to give compound 97 as a yellow solid (5.0 mg, 25% yield, ee not determined). LCMS: (M+1) m/z=472.

Synthesis of Int-97-6.

F

Dimer dichloro(n-cymol)ruthenium(II) (1.13 mg, 1.8 µmol) and (1S,2S)-(+)-N-p-tosyl-1,2diphenylethylenediamine (1.63 mg, 4, 4 μmol) was suspended in water (0.74 ml). The mixture was degassed with nitrogen, then heated at 70° C. for 90 minutes under nitrogen. The resulting mixture was allowed to cool to room temperature. Ketone Int-97-5 (120 mg, 0.37 mmol), sodium formate (125.8 mg, 1.85 mmol) and anhydrous THF (0.37 ml) were added and the reaction mixture was degassed with nitrogen. The reaction mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography (hexane:EtOAc=70:30) to give the title compound as a white solid (109 mg, 91% yield, ee undetermined). LCMS: (M+1) m/z=322, 324.

- 106 042282

Synthesis of Int-97-7.

N-(Trumethylsilyl)morpholine (92 μl, 0.52 mmol) was added dropwise to a solution of DAST (67 μl, 0.508 mmol) in anhydrous CH ₂ Cl ₂ (0.2 ml) at -78°C. The resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was cooled at -78°C and a solution of (5)-1-(2-chloro-8-fluoro-4-methyl-3-(3- methyl-1,2,4-oxadiazol-5-yl)quinolin-6-yl)ethan-1-ol Int-97-6 (50 mg, 0.16 mmol) in anhydrous CH ₂ Cl ₂ (0.46 ml ). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then slowly poured into 10 ml of saturated NaHCO ₃ solution. The organic layer was separated and the aqueous phase was extracted with additional CH ₂ Cl ₂ (3x10 ml). The combined organic phase was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:EtOAc=80:20) to give the title compound as a yellow oil (20.5 mg, 41% yield) (ee not determined). LCMS: (M+1) m/z=324, 326.

Synthesis of compound 98.

A mixture of (R)-5-(2-chloro-8-fluoro-6-(1-fluoroethyl)-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-977 (8, 0 mg, 0.024 mmol), N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine Int-97-4 (6.8 mg, 0.036 mmol) and DIPEA (6 µl, 0.036 mmol) in DMF (0.2 ml) was heated at 120°C during the night. The reaction mixture was diluted with brine and EtOAc. The organic phase was separated and washed with brine (2x5 ml). The organic phase was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=96:4) to give compound 98 as a yellow solid (2.6 mg, 23% yield) (ee not determined). LCMS: (M+1) m/z=472.

Examples 99-101.

Reagents and conditions: i) Int-99-21 (1.0 eq.), Int-99-22 (1.1 eq.), PPh3 (0.06 eq.), PdCl ₂ ( _1/12 eq.) , CS2CO3 (3.0 equiv.), THF/H2O 85°C, 24 h, 69-72%; ii) Int-99-23 (1.0 equiv.), B^Me2S (2.06 equiv.), H2O2, NaOH, THF, 50°C, 2 h, 44-46%; iii) lnt-99-24 (1.0 eq.), DAST (1.1 eq.), C^Ck 0°C, 2.5 h; iv) Int-99-25 (1.0 eq.), 10% aq. H ₂ SO ₄ , THF, 45°C, 2 h, 54-57% (two stages); v) Int-99-26 (1.0 eq.), Amine (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.), AcOH (2.0 eq.), DIPEA (2, 0 equiv.), 1,2-dichloroethane, room. temp. during the night.

Synthesis of Int-99-23.

Suspension of Int-99-21 (1.0 eq.), potassium vinyl trifluoroborate (1.1 eq.), PPh ₃ (0.06 eq.), PdCl ₂ (1/12 eq.) and Cs ₂ CO ₃ (3 0 eq.) in THF/H2O (9/1) was heated at 85°C for 24 h. After cooling to room temperature, the crude material was filtered through celite. The filtrate was diluted with EtOAc and washed with brine and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:EtOAc) to give Int-99-23 as a pale yellow solid. LCMS: (M+1) m/z=411.

Synthesis of Int-99-24.

A solution of BH ₃ .Me ₂ S (2M, 2.06 equiv.) in THF was slowly added to a solution of Int-99-23 (1.0 equiv.) in THF at 0°C. The mixture was warmed to room temperature and stirred for 1 h. The solution was cooled to 0°C and quenched with 30% aqueous H ₂ O ₂ (7 eq.) and NaOH (1M, 1.4 eq.) and the mixture was heated at 50° C for 2 hours. The mixture was concentrated under reduced pressure and the product was purified by column chromatography (hexane:EtOAc). LCMS: (M+1) m/z=429.

Synthesis of Int-99-25.

To a solution of Int-99-24 (1.0 equiv.) in anhydrous CH ₂ Cl ₂ at 0°C was slowly added a solution of DAST (1.1 equiv.) in CH ₂ Cl ₂ and the reaction mixture was stirred for 2.5 h at 0-5°C. The mixture was diluted with EtOAc and washed with brine (2X). The organic phase was dried over

- 107 042282

Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was used without further purification (mixture of Int-99-25 and Int-99-23). LCMS: (M+1) m/z=431.

Synthesis of Int-99-26.

Solution of Int-99-25 and Int-99-23 in THF/10% aq. H ₂ SO ₄ was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous NaOH and the product was extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc to give Int-99-26 ketone as a pale yellowish solid (54-57% yield over two steps). LCMS: (M+1) m/z=387.

Synthesis of compound 99, compound 100 and compound 101.

A mixture of the ketone Int-99-26 (1.0 eq.), the appropriate amine (2.0 eq.), DIPEA (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) 0 eq.) in 1,2-dichloroethane was stirred at room temperature overnight. The mixture was filtered through Celite, concentrated under reduced pressure and purified by HPLC to give the title compounds. Compound 99 was obtained as an off-white solid in 91-92% yield (last step). LCMS: (M+1) m/z=472. Compound 100 was obtained as a pale yellow solid in 62-64% yield (last step). LCMS: (M+1) m/z=472. Compound 101 was obtained as a pale yellow solid in 81-83% yield (last step). LCMS: (M+1) m/z=458.

Example 102.

Int-102-1 Int-102-2 Int-102-3 lnt-102-4

lnt-102-8 Compound 102

Reagents and conditions: i) Int-102-1 (1.0 eq.), Br ₂ (1.2 eq.), Fe (15 mol.%), NaHCO ₃ (1.0 eq.), CH ₂ Cl ₂ , 50°C, overnight, 88%; ii) Int-102-2 (1.0 eq.), nBuLi (2.2 eq.), THF, -78°C, 1 h, then DMF (2.0 eq.), -78~0°C , 2 h, 11%; iii) Int-102-3 (1.0 eq.), ethyl cyanoacetate (2.0 eq.), NH ₄ OAc (5.0 eq.), 1,4-dioxane, 95°C, overnight, 90 %; iv) conc. HCl, 1,4-dioxane, 100°С, 2 h, 83%; v) 5 (1.0 eq.), POCl ₃ , 110° C., 2 h, then N-hydroxyacetamidine (1.2 eq.), DIPEA (3.0 eq.), 1,4-dioxane, 110° C, 1.5 h, 35%; vi) Int-102-6 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.), DIPEA (2.0 eq.), iPrOH, 110 °C, overnight, 62%; vii) 10% aq. H ₂ SO ₄ , THF, 45°C, 2 h, 90%; viii) Int-102-8 (1.0 eq.), Amine (2.0 eq.), NaBH(OAc) ₃ (3.0 eq.), AcOH (3.0 eq.), DIPEA (2, 0 equiv.), 1,2-dichloroethane, room. temp., during the night, 73% -83%.

Synthesis of Int-102-2.

To a suspension of aniline Int-102-1 (5.0 g, 27.9 mmol), iron powder (0.23 g, 4.2 mmol, 15 mol.%) and NaHCO ₃ (2.34 g, 27.9 mmol) in CH ₂ Cl ₂ (100 ml) was added Br ₂ (1.73 ml, 33.5 mmol) dropwise. The resulting mixture was refluxed at 50° C. overnight. The mixture was partitioned between 2N NaOH and CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-102-2 as a yellow solid (6.35 g, 88% yield).

Synthesis of Int-102-3.

To a solution of Int-102-2 (6.35 g, 24.6 mmol) in THF (30 ml) was added a 2.5 M solution of nBuLi in hexane dropwise at -78°C. After stirring for 1 h at -78°C, DMF (3.8 ml, 49.2 mmol) was added at the same temperature. The temperature was raised to 0°C and the mixture was stirred at 0°C for 2 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-102-3 as a yellow solid (0.56 d, 11% yield.

Synthesis of Int-102-4.

A mixture of Int-102-3 (560 mg, 2.68 mmol), ethyl cyanoacetate (605 mg, 5.36 mmol) and NH ₄ OAc (1.03 g, 13.4 mmol) in 1,4-dioxane (5 ml ) was stirred and heated at 95° C. overnight. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between H ₂ O and EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-102-4, a pale yellow solid, was used for the next reaction without further purification (620 mg, 90% yield).

- 108 042282

Synthesis of Int-102-5.

Suspension of compound Int-102-4 (620 mg, 2.41 mmol) in conc. HCl (5 ml) and 1,4-dioxane (5 ml) were heated at 100° C. for 2 h. After cooling to room temperature, H ₂ O (20 ml) was added.

The precipitated product was filtered and dried. The product Int-102-5, a pale yellow powder, was used for the next reaction without further purification (550 mg, 83% yield).

Synthesis of Int-102-6.

A mixture of Int-102-5 acid (550 mg, 2.0 mmol) and POCl ₃ (5 ml) was heated at 110° C. for 2 hours. After cooling to room temperature, excess POCl ₃ was removed in vacuo. The residue was dissolved in 1,4dioxane (5 ml) and N-hydroxyacetamidine (178 mg, 2.4 mmol) and DIPEA (1.04 ml, 6.0 mmol) were added. The resulting mixture was heated at 110°C for 1.5 h After cooling to room temperature, the mixture was concentrated in vacuo The residue was purified on a short silica gel column using 15% EtOAc in hexanes to give Int-102-6 as a pale yellow solid (232 mg, 35% yield).

Synthesis of Int-102-7.

1,4dioxa-8-azaspiro[4,5]decane ( 0.14 ml, 1.1 mmol) at room temperature. The mixture was then heated at 110° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give Int-102-7 as a yellow solid (150 mg, 62% yield). LCMS: (M+1) m/z=439.

Synthesis of Int-102-8.

To a solution of Int-102-7 (150 mg, 0.34 mmol) in THF (2 ml) was added 10% aq. H2SO4 (4 ml) at room temperature. The mixture was then stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc (x2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-102-8 as a yellow oil (128 mg, 90% yield). LCMS: (M+1) m/z=395.

Synthesis of compound 102.

A mixture of Int-102-8 (9.0 mg, 0.023 mmol), (S)-3-aminotetrahydropirane (6.3 mg, 0.046 mmol) and DIPEA (8 µl, 0.046 mmol) in 1,2-dichloroethane (1, 5 ml) was stirred at room temperature for 10 min. NaBH(OAc) ₃ (14.5 mg, 0.069 mmol) and AcOH (4 μl, 0.069 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated in vacuo. The residue was purified by HPLC (10-95% ACN in H ₂ O over 12 min) to give compound 102 as a pale yellow solid (8.0 mg, 73% yield). LCMS: (M+1) m/z=480.

Example 103.

lnt-103-10 lnt-103-11 lnt-103-12 lnt-103-13

lnt-103-14 lnt-103-15 lnt-103-16 lnt-103-17

Reagents and conditions: i) Int-103-10 (1.0 eq.), N,O-dimethylhydroxylamine HCl (1.8 eq.), EDCl (1.2 eq.), HOBt (1.2 eq.) , DIPEA (2.0 equiv.), DMF, room. temp., 18 h, 80%; ii) Int-103-11 (1.0 eq.), (CF ₃ CO) ₂ O (1.2 eq.), TEA (1.2 eq.), DCM, 0°C-room. temp., 5 h, 93%; iii) 12 (1.0 eq.), MeMgBr (4.0 eq.), THF, rt. temp., 6 h, 76%; iv) Int-103-13 (1.0 eq.), 2N NaOH (1.7 eq.), MeOH, 90° C., 1.5 h, 99%; v) Int-103-14 (1.0 eq.), PyICl (1.0 eq.), MeOH, 100° C., 18 h, 79%; vi) Int-103-15 (1.0 eq.), oxadiazole acid derivative (1.2 eq.), POCl ₃ , 110° C., 1 h; vii) Int-103-16 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1.2 eq.), DIPEA (1.2 eq.), EtOH, 120 °С, 18 h, 22% in two stages; viii) Int-103-17 (1.0 eq.), FO2SCF2CO2Me (5.0 eq.), CuI (2.0 eq.), DMF, 8%; ix) 10% aq. H ₂ SO ₄ , THF, 50°C, 1.5 h, quantitative yield; x) Int-103-19 (1.0 eq.), amine (2.0 eq.), NaBH(OAc) ₃ (3.0 eq.), AcOH (3.0 eq.), DIPEA (2, 0 equiv.), 1,2-dichloroethane, room. temp., 18 h, 82%.

Synthesis of Int-103-11.

- 109 042282

2-Amino-3-fluorobenzoic acid mixture 10 (10.3 g, 66.4 mmol), N,O-dimethylhydroxylamine-HCl (11.7 g, 119.5 mmol), EDCl (15.3 g, 79, 7 mmol), HOBt (12.2 g, 79.7 mmol) and DIPEA (23 ml, 132.8 mmol) in DMF (166 ml) were stirred at room temperature overnight. The mixture was diluted with EtOAc and washed successively with a solution of 1N NaOH, 10% aq. HCl and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-103-11 as a brown oil was used for the next reaction without further purification (10.48 g, 80% yield).

Synthesis of Int-103-12.

(CF ₃ CO) ₂ O (8.8 ml , 63.4 mmol) at 0°C. The resulting mixture was stirred at room temperature for 5 hours. The mixture was then washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-103-12 as a brown solid was used for the next reaction without further purification (14.47 g, 93% yield). LCMS: (M+1) m/z=295.

Synthesis of Int-103-13.

To a solution of Int-103-12 (14.47 g, 49.2 mmol) in anhydrous THF (200 ml) was added a 3M solution of MeMgBr in diethyl ether (66 ml, 196.7 mmol) at 0°C. The mixture was stirred at room temperature for 6 hours. The mixture was then poured onto crushed ice to quench the reaction and extracted with EtOAc. The organic layer was washed with 10% aqueous HCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-103-13 as a brown oil was used for the next reaction without further purification (9.36 g, 76% yield).

Synthesis of Int-103-14.

To a solution of Int-103-13 (9.36 g, 37.5 mmol) in MeOH (32 ml) was added 2N NaOH at room temperature. The mixture was then heated at 90° C. for 1.5 hours. After cooling to room temperature, the mixture was partitioned between brine and CH ₂ Cl ₂ . The aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-103-14 as a dark brown oil was used for the next reaction without further purification (5.70 g, 99% yield).

Synthesis of Int-103-15.

A mixture of Int-103-14 (5.7 g, 37.2 mmol) and PyICl (9.0 g, 37.2 mmol) in MeOH (125 ml) was heated at 100° C. overnight. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-103-15 as a yellow solid (7.91 g, 76% yield). LCMS: (M+1) m/z=280.

Synthesis of Int-103-16.

A mixture of Int-103-15 (2.20 g, 7.9 mmol), oxadiazole acid derivative (1.34 g, 9.5 mmol) and POC13 (10 ml) was stirred at 110°C for 1 hour. After cooling to room temperature, excess POC13 was removed in vacuo. The residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The organic layer was separated, washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The rest of Int-103-16 was used for the next reaction without further purification.

Synthesis of Int-103-l7.

To a suspension of crude Int-103-16 (2.70 g, 6.7 mmol) and DIPEA (1.4 ml, 8.0 mmol) in EtOH (50 ml) ,5]decane (1.0 ml, 8.0 mmol) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-103-17 as a brown solid (0.75 g, 22% yield over two steps). LCMS: (M+1) m/z=511.

Synthesis of Int-103-18.

To a suspension of 17 (200 mg, 0.39 mmol) and CuI (148 mg, 0.78 mmol) in DMF (4 ml) was added methylfluorosulfonyl difluoroacetate (0.24 ml, 1.95 mmol) at room temperature. The mixture was then heated at 80° C. for 1 hour. After filtration through celite, the filtrate was concentrated. The residue was purified by HPLC (50-95% ACN in H ₂ O over 15 min) to give Int-103-18 as an orange solid (14.8 mg, 8% yield). LCMS: (M+1) m/z=453.

Synthesis of Int-103-19.

To a solution of Int-103-18 (14.8 g, 0.033 mmol) in THF (1 ml) was added 10% aq. H2SO4 (2 ml) at room temperature. The mixture was then stirred at 50° C. for 1.5 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na2CO3 and extracted with EtOAc (x2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The ketone Int-103-19 as a yellow solid was used for the next reaction without further purification (13.3 mg, quantitative yield). LCMS: (M+1) m/z=409.

Synthesis of compound 103.

Mixture of Int-103-19 (13.3 mg, 0.033 mmol), 4-aminotetrahydropyran (6.6 mg, 0.066 mmol) and DIPEA

- 110 042282 (11 μl, 0.066 mmol) in 1,2-dichloroethane (1.5 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (20.8 mg, 0.099 mmol) and AcOH (6 μl, 0.099 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated in vacuo. The residue was purified by HPLC (10-95% ACN in H ₂ O for 12 min) to give compound 103 as a pale orange solid (13.2 mg, 82% yield). LCMS: (M+1) m/z=494.

Examples 104-107.

Compounds 104-107 were prepared according to the procedure described above for compound 103. Compound 104 was obtained as a pale yellow solid in quantitative yield (last step). LCMS: (M+1) m/z=494. Compound 105 was obtained as a pale yellow solid in quantitative yield (last step). LCMS: (M+1) m/z=494. Compound 106 was obtained as a pale yellow solid in 97% yield (last step). LCMS: (M+1) m/z=480. Compound 107 was obtained as a pale yellow solid in 84% yield (last step). LCMS: (M+1) m/z=480.

Examples 108-109.

Br

F ₃ C

VIII

IX lnt-108-35, R = Me lnt-108-36, R = H lnt-108-37, R = Me lnt-108-38, R=H

R-O-N

N lnt-108-29, R-Me lnt-108-30, R=H lnt-108-31, R=M lnt-108-32, R=H lnt-108-26, R=M lnt-108- 28, R= H

lnt-108-33, R=Me lnt-108-34, R=H

H Compound 108 , R = H Compound 109, R= Me

Reagents and conditions i) Int-36-4 (1.0 eq.), MeMgBr (4.0 eq.), THF, 0°C to room temperature, 2.5 h, 64-66%, ii) Int- 108-25 (1.0 eq.), NaOH (1.7 eq.), MeOH:H ₂ O 1:1, 90°C, 3 h, 90-93%, iii) Int-103-2 (1 .0 equiv.), BH3THF (3.0 equiv.), THF, room. temp., 18 h, iv) 27 (1.0 equiv.), MnO ₂ (6.0 equiv.), CH ₂ Cl ₂ , room. temp., overnight, 69-71% in two steps, v) B ₂ pin ₂ (1.2 eq.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (0.1 eq.), KOAc (3, 0 eq.), dioxane, 80°C, 18 h, 63-65%, vi) CF3CH2I (2.0 eq.), Pd2(dba)3 (0.1 eq.), XantPhos (0.2 eq. ), CS2CO3 (4.0 eq.), dioxane, H ₂ O (1.8 eq.), 80°C, 18 h, vii) 9 (1.0 eq.), POCl ₃ , 110°C, 1.5 h, viii) 1,4-dioxa-8azaspiro[4,5]decane (2.0 eq.), DIPEA (2.0 eq.), EtOH, 110°C, overnight, ix) 10% aq. H ₂ SO ₄ , THF, 45°C, 2 h, x) 4-aminotetrahydropyran (2.0 eq.), NaBH(OAc)3 (2.0 eq.), AcOH (2.0 eq.), 1 ,2-dichloroethane, room pace, 18 hours

Synthesis of Int-108-26.

To a solution of Int-36-4 (1.0 equiv.) in THF (200 ml) at 0°C was added a 1.4 M solution of MeMgBr (4.0 equiv.) in THF:toluene (1:3) and the resulting mixture stirred at room temperature for 2.5 hours Then the reaction mixture was poured onto ice, acidified with a solution of 2M HCl to pH 2 and was extracted with EtOAc (2x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 25 as a yellow oil (64-66% yield) which was used in the next step without further purification. LCMS: (M-1) m/z=325.327. To a solution of Int-108-25 (1.0 eq.) in MeOH was added an aqueous solution of 2 M NaOH (1.7 eq.) and the reaction mixture was heated at 90 °C for 3 hours. The reaction mixture was diluted with water and the solid was collected by filtration to give Int-108-26 as a yellow solid (90-93% yield) which was used in the next

- 111 042282 step without further purification by LCMS: (M+1) m/z=231, 233.

Synthesis of Int-108-28.

To a solution of Int-108-2 (1.0 equiv.) in THF (60 ml) was added dropwise a solution of BH3-THF complex (3.0 equiv.) at 0°C. The mixture was then stirred at room temperature for 18 hours. The reaction was quenched with MeOH at 0°C, concentrated, resuspended in EtOAc and washed with saturated aqueous NaHCO ₃ . The organic phase was dried over Na ₂ SO ₄ and concentrated to give alcohol Int-108-27, which was used in the next step without further purification. LCMS: (M+1) m/z=219.221. To a solution of alcohol 27 in CH ₂ Cl ₂ was added slowly activated MnO ₂ (6.0 eq.) and the mixture was stirred at room temperature overnight. The mixture was filtered through celite and the solvent removed under reduced pressure to give aldehyde Int-108-28 as a yellow solid (yield 69-71% over two steps) which was used in the next step without further purification. LCMS: (M+23) m/z=239, 241.

Synthesis of Int-108-29 and Int-108-30.

A mixture of Int-108-28 (1.0 eq.), bis(pinacolato)diboron (1.2 eq.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (0.1 eq.) and KOAc (3.0 eq.) in dioxane was heated at 80° C. for 18 h. The mixture was cooled to room temperature, filtered through celite, concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give boronate Int-108-30 as not quite white solid (yield 63-65%). LCMS: (M+1) m/z=266.

Boronate Int-108-29 was obtained using the same reaction conditions as a gray solid in 93-95% yield. LCMS: (M+1) m/z=280.

Synthesis of Int-108-31 and Int-108-32.

Boronate solution Int-108-30 was added to a suspension of Pd ₂ (dba) ₃ (0.1 equiv.), XantPhos (0.2 equiv.) and Cs ₂ CO ₃ (4.0 equiv.) in dioxane in a hermetically sealed vial. (1.0 eq.) and CF3CH2I (2.0 eq.) in dioxane. The reaction mixture was stirred at room temperature for 1 min, then H2O (1.8 eq.) was added. The mixture was stirred at 80° C. for 18 hours. After cooling, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (hexane/EtOAc) to give Int-108-32 as an orange solid (95-97% yield). LCMS: (M+1) m/z=222.

The ketone Int-108-31 was obtained in the same way as a pale yellow solid in 77-79% yield. LCMS: (M+1) m/z=236.

Synthesis of Int-108-33 and Int-108-34.

A mixture of aldehyde Int-108-32 (1.0 eq.), acid Int-108-9 (1.0 eq.) and POCl ₃ was stirred at 110°C for 1.5 h. Excess POCl ₃ was removed under reduced pressure . The residue was resuspended in saturated aqueous NaHCO ₃ and extracted with EtOAc (2x). The combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (hexane/EtOAc) to give Int-108-34 quinoline as a white solid (15-17% yield). LCMS: (M+1) m/z=346.

Quinoline Int-108-33 was obtained in the same way as a pale gray solid with a yield of 28-30%. LCMS: (M+1) m/z=360.

Synthesis of Int-108-35 and Int-108-36.

A mixture of Int-108-34 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.) and DIPEA (2.0 eq.) was heated at 110°C during the night. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give ketal 36 as a yellow solid (61-64% yield). LCMS: (M+1) m/z=453.

The ketal Int-108-35 was obtained in the same way as a pale yellow solid in 84-86% yield. LCMS: (M+1) m/z=467.

Synthesis of Int-108-37 and Int-108-38.

To a solution of ketal Int-108-36 (1.0 eq.) in THF was added 10% aq. _{H2SO4 .} The mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x). The combined organic layers were dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (hexane:EtOAc 7:3) to give Int-108-38 ketone as a yellow solid (54-56% yield), which was used in the next step without additional purification LCMS: (M+1) m/z=409.

Ketone Int-108-37 was obtained in the same way as a pale yellow solid with a yield of 88-90%. LCMS: (M+1) m/z=423.

Synthesis of compound 108 and compound 109.

A mixture of ketone Int-108-38 (1.0 eq.), 4-aminotetrahydropyran (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) in 1, 2-dichloroethane was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and purified by preparative TLC (95:5 EtOAc:iPrOH) to give compound 108 as a yellow solid (19-21% yield). LCMS: (M+1) m/z=494.

Compound 109 was obtained using the same procedure as a yellow solid

- 112 042282 with a yield of 22-24%. LCMS: (M+1) m/z=508.

Example 110.

Compound 110 was obtained according to the procedure for compound 109, starting from the ketone Int108-37 and the corresponding amine, as a pale yellow solid in 49-51% yield. HCMS:

(M+1) m/z=508.

Examples 111-115.

Reagents and conditions: i) Int-111-1 (1.0 eq.), B ₂ pin ₂ (1.2 eq.), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.03 eq.), KOAc (3.0 eq.), 1,4-dioxane, 90°C, overnight, 55%; ii) Int-111-2 (1.0 eq.), CF3CH2I (2.0 eq.), Pd ₂ (dba) ₂ (θ.1 eq.), XantPhos (0.1 eq.), Cs ₂ CO ₃ (4 eq.), H ₂ O (2.0 eq.), 1,4-dioxane, 80°C, overnight, 78%; iii) Int111-3 (1.0 eq.), PyICl (1.05 eq.), MeOH, 90°C, overnight, 67%; iv) 4 (1.0 eq.), oxadiazole acid derivative (1.2 eq.), POCl ₃ , 110° C., 1 h; v) Int-111-5 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1.2 eq.), DIPEA (2.0 eq.), EtOH, 120 °C, overnight, 26% (over two stages); vi) Int-111-6 (1.0 eq.), Zn(CN) ₂ (1.0 eq.), Zn (0.1 eq.), Pd(PPh3)4 (0.1 eq.), THF/DMF, 80°C, overnight, 84%; vii) 10% aq. H2SO4, THF, 50°С, 2 h, quantitative yield; viii) Int-111-8 (1.0 eq.), Amine (2.0 eq.), NaBH(OAc) ₃ (3.0 eq.), AcOH (3.0 eq.), DIPEA (2, 0 equiv.), 1,2-dichloroethane, room. temp., overnight, 89% ~ quantitative yield.

Synthesis of Int-111-2.

Mixture of Int-111-1 (6.42 g, 30.0 mmol), bis(pinacolato)diboron (9.14 g, 36.0 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(Π) CH ₂ Cl ₂ (0.73 g, 0.9 mmol) and KOAc (8.82 g, 90.0 mmol) in 1,4-dioxane (30 ml) were stirred at 90° C. overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-111-2 as a pale yellow solid (4.31 g, 55% yield).

Synthesis of Int-111-3.

Mixture Int-111-2 (1.70 g, 6.51 mmol), Pd ₂ (dba) ₂ (0.62 g, 0.65 mmol), XantPhos (0.38 g, 0.65 mmol), Cs ₂ CO ₃ (8.50 g, 26.04 mmol) and CF3CH2I (1.3 ml, 13.02 mmol) in 1,4-dioxane (32 ml) was stirred at room temperature for 1 min. H ₂ O (0.23 ml, 13.02 mmol) was added to the mixture and the resulting mixture was stirred at 80° C. overnight in a sealed vessel. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-111-3 as a yellow solid (1.11 g, 78% yield). LCMS: (M+1) m/z=218.

Synthesis of Int-111-4.

A mixture of Int-111-3 (1.11 g, 5.11 mmol) and PyICl ¹ (1.30 g, 5.36 mmol) in MeOH (20 ml) was stirred at 90° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-111-4 as a yellow solid (1.17 g, 67% yield). LCMS: (M+1) m/z=344.

Synthesis of Int-111-5.

A mixture of Int-111-4 (1.17 g, 3.41 mmol), oxadiazole acid derivative (0.58 g, 4.09 mmol) and POCl ₃ (7 ml) was stirred at 110° C. for 1 h. cooling to room temperature, excess POCl ₃ was removed under reduced pressure. H ₂ O was added to the residue at 0°C and the mixture was stirred at 0°C for 10 minutes. The precipitated crude chloroquinoline 5 was filtered, washed with H2O and dried under reduced pressure. The crude product Int-111-5 was used for the next reaction without further purification.

Synthesis of Int-111-6.

- 113 042282

To a suspension of crude chloroquinoline Int-111-5 (1.59 g, 3.41 mmol) and DIPEA (1.2 ml, 6.82 mmol) in EtOH was added 1,4-dioxa-8-azaspiro[4.5] decane (4.09 ml, 7.9 mmol) at room temperature. The mixture was then stirred at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give Int-111-6 as a dark brown foam (513 mg, 26% yield over two steps). LCMS: (M+1) m/z=575.

Synthesis of Int-111-7.

Mixture of Int-111-6 (513 mg, 0.89 mmol), Zn(CN)2 (105 mg, 0.89 mmol), Zn (6 mg, 0.09 mmol) and Pd(PPh ₃ ) ₄ (103 mg, 0.09 mmol) in THF/DMF (12 ml, 1:1, v/v) was stirred at 80° C. overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-111-7 as a yellow solid (356 mg, 84% yield). LCMS: (M+1) m/z=474.

Synthesis of Int-111-8.

To a solution of Int-111-7 (356 mg, 0.75 mmol) in THF (3 ml) was added 10% aq. H2SO4 (6 ml) at room temperature. The mixture was then stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc (x2). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated to dryness. The ketone Int-111-8 as a yellow solid was used for the next reaction without further purification. (322 mg, quantitative yield). LCMS: (M+1) m/z=430.

Synthesis of compound 111, compound 112, compound 113, compound 114, compound 115.

A mixture of Int-111-8 (11 mg, 0.026 mmol), the appropriate amine (0.052 mmol) and DIPEA (9 µl, 0.052 mmol) in 1,2-dichloroethane (1.5 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (16.3 mg, 0.078 mmol) and AcOH (5 μl, 0.078 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (10-95% ACN in H ₂ O for 12 min) to give the title compounds: compound 111, 11.8 mg, yellow solid, 89% yield. LCMS: (M+1) m/z=515; compound 112, 13.2 mg, yellow solid, 89% yield. LCMS: (M+1) m/z=515; compound 113, 13.2 mg, yellow solid, 89% yield. LCMS: (M+1) m/z=515; compound 114, 12.8 mg, yellow solid, 89% yield. LCMS: (M+1) m/z=501; and compound 115, 12.8 mg, yellow solid, 89% yield. LCMS: (M+1) m/z=501.

Examples 116-117.

Compound 30 Compound 116

Synthesis of compound 116.

Bis(triphenylphosphine )palladium(II) chloride (3.3 mg, 4.8 µmol) and the reaction mixture was heated under microwave learning conditions under nitrogen atmosphere at 100° C. for 45 min. The mixture was filtered and the solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 16 (5.0 mg, 18% yield) as a white solid. LCMS: (M+1) m/z=464; retention time: 2.50 min (method 1.).

Synthesis of compound 117.

Compound 117 was prepared in the same way as compound 116 except that 1-(6-bromo-8-fluoro-4methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2- yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine. Compound 30 was replaced by (R)-1-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)N-( tetrahydro-2H-pyran-3-yl)piperidin-4-amine. LCMS: (M+1) m/z=464; retention time: 2.55 min (method 1).

- 114 042282

Example 118.

Reagents and Conditions i) Int-118-14 (1.0 eq.), NBS (1.0 eq.), CH2C12, rt. temp., 18 h, 84-86%, ii) Int118-15 (1.0 eq.), (MeO)NH(Me) HCl (1.8 eq.), EDCI (1.2 eq.), HOBt (1.2 eq.), DIPEA (2.0 eq.), DMF, r.m. temp., 4 h, 84-86%, iii) Int-118-16 (1.0 equiv.), ^CO^O (1.3 equiv.), TEA (1.2 equiv.), CH2Q2, 0 °C to room temperature, overnight, 90-92%, iv) Int-118-17 (1.0 eq.), BEt ₃ (3.0 eq.), Cs ₂ CO ₃ (3.0 eq. ), Pd(dppf)Cl2 (0.02 eq.), THF, 70°C, 1.5 h, 45-47%, v) Int-118-18 (1.0 eq.), MeMgBr (5, 0 eq.), THF, 0°C to room temperature, 2.5 h, 85-87%, vi) Int-118-19 (1.0 eq.), NaOH (1.7 eq.), MeOH: H ₂ O 1:1, 90°C, 3 h, 80-82%, vii) Int-118-20 (1.0 eq.), 8 (2.0 eq.), p-TsOH (cat.) , 150°C, 2 h, 19-21%, viii) 21, POC13, 110°C, 2 h, 97-98%, ix) Int-118-22 (1.0 eq.), 1.4- dioxa-8-azaspiro[4,5]decane (2.0 eq.), DIPEA (2.0 eq.), EtOH, 110°C, overnight, 73-75%, x) 10% aq H2SO4, THF, 45°C, 2 h, 83-85%, xi) Int-118-24 (1.0 eq.), 4-aminotetrahydropyran (1.5 eq.), NaBH(OAc) ₃ (2.0 eq. .), AcOH (2.0 eq.), 1,2-dichloroethane, room. temp., during the night, 89-90%.

Synthesis of Int-118-2.

To a suspension of 2-amino-3-fluorobenzoic acid Int-118-1 (15.0 g, 96.7 mmol) in CH ₂ Cl ₂ (250 ml) was added N-iodosuccinimide (17.2 g, 96.7 mmol) and the mixture was stirred at room temperature overnight. The product was filtered, washed with CH ₂ Cl ₂ and dried under reduced pressure to give Int-118-2 as a pale brown solid (24.7 g, 91% yield).

Synthesis of Int-118-3.

Int-118-2 Mix (6.2 g, 22.06 mmol), N, O-dimethylhydroxylamine HCl (3.9 g, 39.71 mmol), EDCl (5.1 g, 26.47 mmol), HOBt (4.1 g, 26.47 mmol) and DIPEA (7.7 ml, 44.12 mmol) in DMF (110 ml) were stirred at room temperature overnight. The mixture was diluted with EtOAc and washed successively with 1N NaOH, 10% aq. HCl and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-118-3 as a brown oil was used for the next reaction without further purification (6.9 g, 96% yield).

Synthesis of Int-118-4.

₍ CF ₃ CO) _{2 O} (3 .9 ml, 27.7 mmol) at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was then washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-118-4 as a dark brown oil was used for the next reaction without further purification (8.8 g, 98% yield). LCMS: (M+1) m/z=421.

Synthesis of Int-118-5.

To a solution of Int-118-4 (4.47 g, 10.6 mmol) in anhydrous THF (100 ml) was added a 1.4 M solution of MeMgBr in diethyl ether (42 ml, 59.4 mmol) at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was then poured into crushed ice to quench the reaction and extracted with EtOAc. The organic layer was washed with 10% aqueous HCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-118-5 as a dark orange oil was used for the next reaction without further purification (1.68 g, 60% yield).

Synthesis of Int-118-6.

To a solution of Int-118-5 (1.22 g, 4.63 mmol) in MeOH (7 ml) was added 2N NaOH (4 ml) at room temperature. The mixture was then heated at 90° C. for 1.5 hours. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and brine. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-118-6 as a yellow solid was used for the next reaction without further purification (0.73 g, 94% yield).

Synthesis of Int-118-7.

- 115 042282

A mixture of Int-118-6 (371 mg, 2.22 mmol), oxadiazole acid derivative (380 mg, 2.67 mmol) and POCl ₃ (4.5 ml) was stirred at 110° C. for 1 h. After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. The residue was partitioned between CH ₂ Cl ₂ and H ₂ O. The organic layer was separated, washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-118-7 as a pale brown solid (0.25 g, 39% yield). LCMS: (M+1) m/z=292.

Synthesis of compound 118.

A mixture of Int-118-7 (30 mg, 0.103 mmol), amine (127 mg, 0.309 mmol) and 2,2,6,6-tetramethylpiperidine (18 µl, 0.103 mmol) in DMF (1 ml) was heated at 150°C during the night. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 118 as a pale yellow solid (23 mg, 51% yield). LCMS: (M+1) m/z=440.

Examples 119-120.

Connection 119 Connection 120

Synthesis of Int-119-12.

To the suspension of 8-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-1,4-dioxa8-azaspiro [4,5]decane (Int-83-2, 100 mg, 0.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 18 µmol) in dioxane (5 ml) was added dimethylzinc (10% wt ., in hexane, 0.50 ml) and the reaction mixture was stirred at 60°C for 1 h. The reaction was quenched with methanol and citric acid solution (5% aq.) and was extracted with ethyl acetate twice. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 8-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4oxadiazol-5-yl)quinolin-2-yl)-1,4-dioxa- 8-azaspiro[4,5]decane (Int-119-12) as a yellow solid (42 mg, 49% yield). LCMS (ESI): m/z 399 (M+H); retention time: 3.05 min (method 1).

Synthesis of Int-119-13.

Int-119-13 was synthesized using the general procedure used to prepare 1-(6bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2- yl)piperidin-4-one (Int-30-11f), replacing 8-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl) quinolin-2-yl)-1,4-dioxa-8azaspiro[4,5]decane (Int-1-1d) 8-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2 ,4-oxadiazol-5-yl)quinolin-2-yl)-1,4dioxa-8-azaspiro[4,5]decane (Int-119-12). LCMS (ESI) m/z 355 (M+H), retention time 2.60 min (method 1).

Synthesis of compound 119.

The same procedure was used as for the preparation of (R)-1-(6-bromo-8-fluoro-4-methyl-3-(3-methyl1,2,4-oxadiazol-5-yl)quinolin-2-yl) -N-(tetrahydro-2H-pyran-3-yl)piperidin-4-amine (compound 31) replacing 1-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2 ,4-oxadiazol-5-yl)quinolin-2-yl)piperidin-4-one (Int30-11f) 1-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4 -oxadiazol-5-yl)quinolin-2-yl)piperidin-4-one (Int119-13) to give compound 119 LCMS (ESI) m/z 440 (M+H), retention time 2.41 min (method 1 ).

Synthesis of compound 120.

The same procedure was used as for compound 119, replacing (R)-tetrahydro-2H-pyran-3-amine hydrochloride (2.0 eq.) with (S)-tetrahydro-2H-pyran-3-amine hydrochloride (2.0 eq. .) to give compound 120 LCMS (ESI) m/z 440 (M+H), retention time 2.44 min (method 1).

Examples 121-133.

Compounds 121-128 were prepared by the method disclosed below for compounds 134-137 using an amine with the appropriate stereochemistry and an appropriate ketone.

Compounds 129-133 were prepared by the method described below for compounds 147-152, or by the method described above for compounds 67-71.

- 116 042282

Examples 134-137.

lnt-134-44 lnt-134-45 lnt-134-46 lnt-134-47 „ ,,,

Compound 134

Reagents and conditions i) Int-134-44 (1.0 eq.), Int-134-45 (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.), AcOH (2.0 eq. .), 1,2-dichloroethane, room temp., overnight, ii) TFA (10 equiv.), CH ₂ Cl ₂ , room. temp., 2 h, iii) Int-13446 (2.0 eq.), Int-134-47 (1.0 eq.), DIPEA (4.0 eq.), EtOH, 110°C, overnight , 65-68% (3 stages).

Synthesis of Int-134-46.

A mixture of Int-134-44 (1.0 eq.), Int-134-45 (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) in DCE stirred at room temperature overnight. The mixture was quenched with saturated aqueous NaHCO ₃ and the product was extracted with CH ₂ Cl ₂ (3x). The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was used without further purification by LCMS (M+1) m/z=303. A mixture of the previous product and TFA (10.0 eq) in CH ₂ Cl ₂ was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the product was used without further purification by LCMS (M+1) m/z=203.

Synthesis of compound 134.

A mixture of Int-134-46 (2.0 eq.), Int-134-47 (1.0 eq.) and DIPEA (4.0 eq.) in EtOH was heated at 110° C. overnight. The mixture was concentrated under reduced pressure and the product was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=96:4) to give compound 134 in 65-68% yield (3 steps).

Synthesis of compound 135, compound 136 and compound 137.

Compound 135, Compound 136, and Compound 137 were prepared in the same manner as Compound 134, substituting the appropriate stereoisomers for starting material Int-134-44 Compound 135, pale gray solid, Compound 136, pale yellow solid, Compound 137, pale gray solid.

Example 138.

Reagents and Conditions i) Int-138-1 (1.0 eq.), NIS (1.0 eq.), CH ₂ Cl ₂ , rt. temp., 6 h, 76%, ii) Int-138-2 (1.0 eq.), BH3-THF (5.0 eq.), THF, room. temp., 6 h, quantitative yield, iii) Int-138-3 (1.0 eq.), MnO ₂ (6.0 eq.), CH ₂ Cl ₂ , room. temp., overnight, quantitative yield, iv) Int-138-4 (1.0 eq.), Zn(CN)2 (1.0 eq.), Zn (0.1 eq.), Pd(PPh3 )4 (0.05 equiv.), DMF, 80°C, overnight, 42%, v) Int-138-5 (1.0 equiv.), oxadiazole acid derivative (1.2 equiv.), POCl3 , 110°С, 1 h, 92%; vi) Int-138-6 (1.0 eq.), amine (2.0 eq.), DIPEA (2.0 eq.), CH3CN, 120°C, overnight, 17%.

Synthesis of Int-138-2.

To a suspension of 2-amino-3-chlorobenzoic acid Int-138-1 (17.16 g, 100 mmol) in CH ₂ Cl ₂ (250 ml) was added N-iodosuccinimide (17.80 g, 100 mmol). The mixture was stirred at room temperature for 6 hours. The product was filtered, washed with CH2Cl2 and dried under reduced pressure. The product Int-138-2, as an off-white solid, was used for the next reaction without further purification (22.61 g, 76% yield). LCMS: (M-1) m/z=296.

Synthesis of Int-138-3.

To a suspension of Int-138-2 (22.61 g, 76.0 mmol) in THF (100 ml) was added a solution of the BH3-THF complex (1M in THF, 380 ml, 380 mmol) dropwise at 0°C. The mixture was then stirred at room temperature for 6 hours. The reaction was quenched by slow addition of MeOH at 0° C. and the mixture was concentrated to dryness. The product Int-138-3 as a pink solid was used for the next reaction without further purification (21.54 g, quant.). LCMS: (M-1) m/z=282.

Synthesis of Int-138-4.

A mixture of Int-138-3 (21.54 g, 76.0 mmol) and activated MnO ₂ (40.0 g, 456.0 mmol) in CH ₂ Cl ₂ (500 ml) was stirred at room temperature overnight. The reaction mixture was filtered through celite to give Int-138-4 as a yellow solid (21.39 g, quant.).

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Synthesis of Int-138-5.

Mixture of Int-138-4 (9.95 g, 35.35 mmol), Zn(CN)2 (4.15 g, 35.35 mmol), Zn powder (0.23 g, 3.54 mmol) and Pd (PPh ₃ ) ₄ (2.04 g, 1.77 mmol) in DMF (70 ml) was heated at 80° C. overnight. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-138-5 as a pale yellow solid (2.68 g, 42% yield). LCMS: (M+1) m/z=181.

Synthesis of Int-138-6.

A mixture of Int-138-5 (180 mg, 1.00 mmol), oxadiazole acid derivative (175 mg, 1.23 mmol) and POCl ₃ (3 ml) was stirred at 110° C. for 1 h. After cooling to room temperature excess POCl ₃ was removed under reduced pressure. To the residue was added H ₂ O was added at 0°C. The mixture was partitioned between EtOAc and brine. The aqueous layer was separated and extracted with EtOAc (x2).

The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The product Int-1386 as a brown solid was used for the next reaction without further purification (281 mg, 92% yield).

Synthesis of compound 138.

A mixture of Int-138-6 (17 mg, 0.056 mmol), amine (33 mg, 0.112 mmol) and DIPEA (19 μl, 0.112 mmol) in CH3CN (1 ml) was heated at 120°C overnight. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5 to 90:10) to give compound 138 as a yellow oil (4.3 mg, 17% yield). LCMS: (M+1) m/z=453.

Example 139.

Synthesis of Int-139-28.

To a suspension of 2-amino-3-fluorobenzoic acid 25 (15.0 g, 96.7 mmol) in CH2Cl2 (250 mL) was added N-iodosuccinimide (17.2 g, 96.7 mmol). The mixture was stirred at room temperature overnight. The product was filtered, washed with CH ₂ Cl ₂ and dried under reduced pressure to give iodobenzoic acid 26 as an off-white solid. To a solution of Int-139-Int-139-26 (22.48 g, 80.0 mmol) in THF (200 ml) was added dropwise a solution of the BH3-THF complex (1M in THF, 400 ml, 400 mmol) at 0° WITH. The mixture was then stirred at room temperature overnight. The reaction was quenched by slow addition of MeOH at 0°C. After the solvent was removed by evaporation to dryness, the crude alcohol Int-139-Int-139-27 was dissolved in CH2Cl2 (500 ml) and activated MnO ₂ (41.7 g, 480 mmol) was added. The mixture was stirred at room temperature overnight. The crude product was purified on a short silica gel column (hexane:EtOAc, 1:1) to give aldehyde Int-139-Int-139-28 as a yellow solid (11.4 g, 45% yield over three steps). LCMS: (M-1) m/z=264.

Synthesis of Int-139-Int-139-30.

Mixture of aldehyde Int-139-Int-139-28 (5.74 g, 21.6 mmol), oxadiazole acid derivative Int139-Int-139-12 (3.69 g, 26.0 mmol) and POCl3 (22 ml) stirred at 110°C for 1 h After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. H ₂ O was added to this residue at 0°C and the mixture was stirred at 0°C for 10 minutes. The crude chloride 29 was filtered, washed with H ₂ O and dried under reduced pressure. To a suspension of 29 in EtOH (100 ml) was added 1,4-dioxa-8-azaspiro[4,5]decane (5.5 ml, 43.2 mmol) and DIPEA (7.5 ml, 43.2 mmol) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give quinoline Int-139-Int-139-30 as a yellow oil (2.50 g, 23% yield over two steps). LCMS: (M+1) m/z=497.

Synthesis of Int-139-31.

A mixture of Int-139-30 (2.50 g, 5.04 mmol), Zn(CN) ₂ (0.59 g, 5.04 mmol), Zn powder (33 mg, 0.50 mmol) and

- 118 042282

Pd(PPh ₃ ) ₄ (0.58 g, 0.50 mmol) in THF/DMF (50 ml, 1:1 (v/v)) was heated at 80°C for 5 h. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated.

The residue was purified by column chromatography (hexane/EtOAc gradient) to give cyanoquinoline

Int-139-31 as a yellow oil (0.93 g, 47% yield). LCMS: (M+1) m/z=396.

Synthesis of Int-139-32.

To a solution of Int-139-31 (0.47 g, 1.19 mmol) in THF (5 ml) was added 10% aq. H2SO4 (12 ml, v/v). The mixture was stirred at 45°C for 4 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x40 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column chromatography (hexane/EtOAc gradient) to give the ketone Int-139-Int-139-32 as a yellow solid (308 mg, 74% yield). LCMS: (M+1) m/z=352.

Synthesis of compound 139.

Mixture of ketone Int-139-32 (15.8 mg, 0.045 mmol), (S)-3-aminotetrahydropyran hydrochloride (12.4 mg, 0.09 mmol) and DIPEA (16 µl, 0.08 mmol) in 1, 2-dichloroethane (1.5 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (28.6 mg, 0.135 mmol) and AcOH (8 μl, 0.135 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 139 in LCMS (M+1) m/z=437.

Example 140.

as a yellow oil (18.1 mg, 92% yield).

Synthesis of Int-140-36.

Niodosuccinimide (17.1 g, 96.2 mmol) was added to a suspension of 2-aminobenzoic acid 33 (6.6 g, 48.1 mmol) in CH ₂ Cl ₂ (150 ml). The mixture was stirred at room temperature overnight. The product was filtered, washed with CH ₂ Cl ₂ and dried under reduced pressure to give iodobenzoic acid Int-140-34 as an off-white solid. To a solution of Int-140-34 (12.53 g, 32.2 mmol) in THF (100 ml) was added dropwise a solution of the BH ₃ -THF complex (1M in THF, 161 ml, 161 mmol) at 0°C. The mixture was then stirred at room temperature overnight. The reaction was quenched by slow addition of MeOH at 0°C. After the solvent was removed by evaporation to dryness, the crude alcohol Int-140-35 was dissolved in CH ₂ Cl ₂ (200 ml) and activated MnO ₂ (16.8 g, 193.2 mmol) was added. The mixture was stirred at room temperature overnight. The crude product was purified on a short silica gel column to give aldehyde Int-140-36 as a yellow solid (5.83 g, 32% yield over three steps). LCMS (M+1) m/z=374.

Synthesis of Int-140-38.

A mixture of aldehyde Int-140-36 (4.81 g, 12.9 mmol), oxadiazole acid derivative 12 (3.69 g, 15.5 mmol) and POCl ₃ (13 ml) was stirred at 110°C for 1 h After cooling to room temperature, excess POCl ₃ was removed under reduced pressure. To this residue was added H ₂ O was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The crude Int-140-37 chloride was filtered, washed with H2O and dried under reduced pressure. To a suspension of Int-140-37 in EtOH (65 ml) was added 1,4-dioxa-8-azaspiro[4,5]decane (3.3 ml, 25.8 mmol) and DIPEA (4.5 ml, 25. 8 mmol) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc gradient) to give quinoline Int-140-38 as a yellow oil (1.56 g, 20% yield over two steps). LCMS: (M+1) m/z=605.

Synthesis of Int-140-39.

A mixture of Int-140-38 (1.56 g, 2.58 mmol), Zn(CN) ₂ (0.61 g, 5.16 mmol), Zn powder (34 mg, 0.52 mmol) and Pd(PPh ₃ ) ₄ (0.60 g, 0.52 mmol) in THF/DMF (30 ml, 1:1 (v/v)) was heated at 80°C for 5 h. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give cyanoquinoline

- 119 042282

Int-140-39 as a yellow oil (0.62 g, 60% yield). LCMS: (M+1) m/z=403. Synthesis of Int-140-40.

To a solution of Int-140-39 (0.57 g, 1.42 mmol) in THF (5 ml) was added 10% aq. H ₂ SO ₄ (12 ml, v/v). The mixture was stirred at 45°C for 4 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x40 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The ketone Int-140-40 as an orange solid was used for the next reaction without further purification. (513 mg, quantitative yield). LCMS: (M+1) m/z=359.

Synthesis of compound 140.

Mixture of Int-140-40 ketone (13.0 mg, 0.036 mmol), (S)-3-aminotetrahydropyran hydrochloride (10.0 mg, 0.072 mmol) and DIPEA (13 µl, 0.072 mmol) in 1,2-dichloroethane ( 1.5 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (23.0 mg, 0.108 mmol) and AcOH (6 μl, 0.108 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 140 as a yellow oil (14.1 mg, 88% yield). LCMS: (M+1) m/z=444.

Example 141.

Synthesis of Int-141-2.

To a solution of Int-141-1 (2.04 g, 9.38 mmol) in EtOH (14 ml) was added diethyl malonate (1.99 ml, 13.1 mmol) and a catalytic amount of piperidine. The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and the resulting solid was collected by vacuum filtration, washing with EtOH to give Int-141-2 as a white solid (2.6 g, 88% yield). %). LCMS: (M-1) m/z=313.

Synthesis of Int-141-3.

A mixture of Int-141-2 (806 mg, 2.56 mmol) and phosphorus(V) oxychloride (5 ml) was heated at 110° C. for 1 hour. Phosphorus(V) oxychloride was removed under reduced pressure. Water was added to the residue and the precipitate was collected by vacuum filtration to give Int-141-3 as a white solid (850 mg, quant.).

Synthesis of Int-141-4.

To a solution of Int-141-3 (720 mg, 2.16 mmol) in THF (3.5 ml) was added NaOH (519 mg, 13.0 mmol) and water (7 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, then Amberlite IRN77 resin and MeOH (15 ml) were added. The resulting mixture was stirred at room temperature for 15 minutes, then the resin was filtered off. The filtrate was concentrated to dryness to give Int-141-4 as an off-white solid (660 mg, quant.). LCMS: (M-1) m/z=303.

Synthesis of Int-141-5.

A mixture of Int-141-4 (660 mg, 2.16 mmol) in dichloromethane (4 ml) and N,N-dimethylformamide (0.2 ml) was treated with oxalyl chloride (2M in dichloromethane, 4 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in dichloromethane (4 ml) and N,N-dimethylformamide (4 ml), then treated with Nhydroxyacetamide (160 mg, 2.16 mmol) and DIPEA (1.13 ml, 6.48 mmol). The reaction mixture was heated at 120°C for 2 h, then cooled to room temperature. Dichloromethane was removed in vacuo. EtOAc and water were added to the residue. The organic phase was separated and washed with brine (3x20 ml). The organic phase was dried over Na ₂ SO ₄ and concentrated to dryness, then purified

- 120 042282 column chromatography (hexane:EtOAc=92:8) to give Int-141-5 as a yellow solid (178 mg, 24% yield). LCMS: (M+1) m/z=342, 344.

Synthesis of Int-141-6.

A mixture of Int-141-5 (150 mg, 0.44 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (0.11 ml, 0.88 mmol) and DIPEA (0.15 ml, 0.88 mmol) in EtOH (3 ml) was heated under microwave conditions at 120° C. for 50 min. The reaction mixture was concentrated and purified by column chromatography (hexane:EtOAc=92:8) to give Int-141-6 as a yellow solid (190 mg, 96% yield). LCMS: (M+1) m/z=449, 451.

Synthesis of Int-141-7.

A mixture of Int-141-6 (190 mg, 0.42 mmol), triethylborane (1M in THF, 0.85 ml), K ₂ CO ₃ (117 mg, 0.85 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (34 mg, 0.041 mmol) in DMF (2 ml) was degassed with nitrogen and heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, filtered on celite and the product was partitioned between EtOAc and water. The organic phase was washed with brine (3x20 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The product was purified by column chromatography to give Int-141-7 as a yellow solid (45 mg, 27% yield). LCMS: (M+1) m/z=399.

Synthesis of Int-141-8.

To compound Int-141-7 (34 mg, 0.084 mmol) was added 10% aq. H ₂ SO ₄ (0.28 ml) at room temperature. The mixture was then stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x10 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness to give Int-141-8 as a yellow solid (29 mg, quant.). LCMS: (M+1) m/z=355.

Synthesis of compound 141.

Mixture of Int-141-8 (30 mg, 0.084 mmol), (R)-tetrahydro-2H-pyran-3-amine hydrochloride (15 mg, 0.11 mmol) and DIPEA (20 µl, 0.11 mmol) in 1 ,2-dichloroethane (0.4 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (27 mg, 0.13 mmol) and AcOH (7 μl, 0.13 mmol) were added to the mixture. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative TLC (CH ₂ Cl ₂ : MeOH=95:5) to give compound 141 as a yellow solid (32 mg, 87% yield). LCMS: (M+1) m/z=440.

Examples 142-146.

lnt-142-A lnt-142-9

Synthesis of Int-142-A.

Ethylmalonyl chloride (50 ml, 0.39 mol) was added dropwise to a suspension of N-hydroxyacetamidine (29 g, 0.39 mol) and DIPEA (102 ml, 0.58 mol) in 1,4-dioxane (200 ml) at 0 °C. The mixture was stirred at room temperature for 20 minutes, then heated at 100° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between brine and ether. The organic layer was washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The residue was purified on a short silica gel column eluting with 20% EtOAc in hexane to give Int-142-A as a light brown liquid (40.28 g, 61% yield).

Synthesis of Int-142-9.

To a solution of oxadiazole ester Int-142-A (10.0 g, 58.9 mmol) in THF (50 mL) was added 2M aq. NaOH (59 ml) at 0°C. The mixture was then stirred at room temperature for 1 hour. Amberlite IR 120 resin (H ⁺ ) was added to the mixture to adjust the pH to pH 4. The resin was removed by filtration and washed with H ₂ O. The filtrate was concentrated under reduced pressure. The residue was dried over P ₂ O ₅ in vacuo to give Int-142-9 and used in the next step without purification.

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Synthesis of Int-142-2.

To a suspension of 2-amino-3-fluorobenzoic acid 1 (20.0 g, 129 mmol) in CH ₂ Cl ₂ (300 ml) was added N-bromosuccinimide (22.9 g, 129 mmol). The mixture was stirred at room temperature overnight. The product was collected by vacuum filtration to give 2-amino-5-bromo-3-fluorobenzoic acid Int-142-2 as an off-white solid (27 g, 90% yield) which was used in the next step without further purification. LCMS: (M-1) m/z=232, 234.

Synthesis of Int-142-3.

Mixture of Int-142-2 (8.5 g, 36.3 mmol), N,O-dimethylhydroxylamine hydrochloride (6.4 g, 65.3 mmol), DIPEA (12.6 ml), EDCI (8.4 g , 43.6 mmol) and HOBt (6.7 g, 43.6 mmol) in DMF (90 mL) were stirred at room temperature for 4 h. brine to give Int-142-3 as a brown oil (8.6 g, 85% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=277, 279.

Synthesis of Int-142-4.

To a solution of Int-142-3 (8.6 g, 31 mmol) in CH ₂ Cl ₂ (100 ml) at 0°C was added TEA (5.2 ml, 37 mmol) followed by dropwise addition of trifluoroacetic anhydride (5, 6 ml, 40 mmol). The reaction mixture was stirred at room temperature overnight. Then a saturated aqueous solution of NaHCO ₃ was added and the organic phase was separated and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to give Int-142-4 as a yellow solid (9.4 g, 80% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=373, 375.

Synthesis of Int-142-5.

To a suspension of Int-142-4 (4.3 g, 11.5 mmol), Cs ₂ CO ₃ (11.0 g, 34.6 mmol) and Pd(dppf)Cl ₂ (170 mg, 0.23 mmol) in THF (25 ml) was added a 1M solution of BEt ₃ in THF (34.6 ml, 34.6 mmol) and the reaction mixture was heated at 70°C for 1.5 h. After cooling to room temperature, the crude material was filtered through celite and purified by column chromatography (hexane:EtOAc) to give Int-142-5 as a yellow solid (2.5 g, 54% yield). LCMS: (M+1) m/z=323.

Synthesis of Int-142-6.

To a solution of Int-142-5 (2.0 g, 6.2 mmol) in THF (40 ml) at 0°C was added a 1.4 M solution of MeMgBr in THF:toluene (22 ml, 31 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured onto ice, acidified to pH 2 with 2M HCl solution and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness to give Int-142-6 as a yellow oil which was used in the next step without further purification. LCMS: (M-1) m/z=276.

Synthesis of Int-142-7.

To a solution of Int-142-6 (2.0 g, 7.2 mmol) in MeOH (6 ml) was added an aqueous solution of 2 M NaOH (6 ml), the reaction mixture was heated at 90°C for 1.5 h. water and solid were collected by filtration to give Int-142-7 as a yellow solid (1.2 g, 92% yield) which was used in the next step without further purification. LCMS: (M+1) m/z=182.

Synthesis of Int-142-11.

Mixture of ketone Int-142-7 (250 mg, 1.38 mmol), 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid 9 (235 mg, 1.65 mmol) and POCl ₃ (2.5 ml) was stirred at 110°C for 1 h Excess POCl ₃ was removed in vacuum. Saturated aqueous NaHCO ₃ was added to the residue and the product was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was purified by column chromatography (hexane/EtOAc) to give 2-chloroquinoline Int-142-11 as a white solid (176 mg yield, 42%). LCMS: (M+1) m/z=306, 308.

Synthesis of Int-142-12.

To a suspension of Int-142-11 (220 mg, 0.72 mmol) in EtOH (5 mL) was added 1,4-dioxa-8azaspiro[4,5]decane (184 μL, 1.44 mmol) and DIPEA (250 μL , 1.44 mmol). The mixture was heated at 110° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced

- 122 042282 pressure and purified by column chromatography (hexane/EtOAc) to give Int-142-12 ketal as a yellow oil (278 mg, 93% yield). LCMS: (M+1) m/z=413.

Synthesis of Int-142-13.

To a solution of ketal Int-142-12 (278 mg, 0.67 mmol) in THF (1 ml) was added 10% aq. H ₂ SO ₄ (5 ml). The mixture was stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated to dryness to give the ketone Int-142-13 as a yellowish oil (224 mg, 90% yield) which was used in the next step without further purification by LCMS: (M+1) m/z=369.

Synthesis of compound 142.

A mixture of ketone Int-142-13 (160 mg, 0.43 mmol), 4-aminotetrahydropyran (66 mg, 0.65 mmol), NaBH(OAc) ₃ (182 mg, 0.86 mmol) and AcOH (50 µl, 1.05 mmol) in 1,2-dichloroethane (5.0 ml) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH, 95:5) to give compound 142 as a yellow solid (178 mg, 91% yield). LCMS: (M+1) m/z=454.

Synthesis of compound 143, compound 144, compound 145, compound 146.

The synthesis of compounds Nos. 143-146 was carried out in the same manner as the synthesis of compound 142 using reductive amination of intermediate 13 and the appropriate amine. Compound 143, pale yellow solid, for the last step (reductive amine): 89% yield. LCMS: (M+1) m/z=424; compound 144, pale yellow solid, for the last step (reducing amine): 59% yield. LCMS: (M+1) m/z=454; compound 145, pale yellow solid, for the last step (reduce, amine): 59% yield. LCMS: (M+1) m/z=440; compound 146, pale yellow solid, for the last step (reducing amine): 75% yield. LCMS: (M+1) m/z=440.

Example 147.

EtO ₂ (WCN

n

Compound 147

Synthesis of Int-147-11.

A mixture of ketone Int-147-7 (1.0 eq.), ethyl 2-cyanoacetate Int-147-8 (2.0 eq.) and NH4OAc (5.0 eq.) in dioxane was stirred at 90°C for 8 h. The mixture was concentrated under reduced pressure and the solid was washed successively with water and EtOAc/hexane (19) (2x). The pale yellow solid was used without further purification (83-85% yield). LCMS (M+1) m/z=231. A suspension of Int147-10 (1.0 eq.) in POCl ₃ was stirred at 110° C. for 1.5 h. Excess POCl ₃ was removed under reduced pressure. The crude material was quenched with ice and the mixture was stirred at room temperature for 15 min. The crude material was collected filtered and washed with water (3x). The product Int147-11 was obtained as a pale yellow solid in quantitative yield LCMS (M+1) m/z=249.

Synthesis of Int-147-12.

A mixture of Int-147-11 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1.5 eq.) and DIPEA (1.5 eq.) in EtOH was heated at 110 °C during the night. The mixture was concentrated under reduced pressure and the product was purified by column chromatography using hexane/EtOAc. The product Int-147-12 was obtained as a pale brown solid with a yield of 97-98% LCMS (M+1) m/z=356.

Synthesis of Int-147-13.

A mixture of Int-147-12 (1.0 eq.), NH2OH HCl (5.0 eq.) and Na ₂ CO ₃ (5.0 eq.) in anhydrous isopropanol was heated at 100° C. overnight. The mixture was cooled to room temperature and filtered. The organic phase was concentrated under reduced pressure and the product was used without further purification. LCMS: (M+1) m/z=389. A mixture of amidoxime (1.0 eq.), acetic anhydride (1.2 eq.) and DIPEA (1.2 eq.) in dioxane was stirred at room temperature for 40 minutes, then the mixture was heated

- 123 042282 at 100° C. for 8 hours. The mixture was concentrated under reduced pressure and the product was purified by column chromatography using hexane/EtOAc to give a pale brown solid in 64-66% yield (two steps). LCMS: (M+1) m/z=413. To a solution of ketal Int-147-13 (1.0 eq.) in THF (1 ml) was added 10% aq. H ₂ SO ₄ and the mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc (4x), dried over Na ₂ SO ₄ and concentrated to dryness to obtain pale brown ketone Int-147-14 in quantitative yield, which was used in the next step without further purification by LCMS: (M+1) m/z=369.

Synthesis of compound 147.

A mixture of ketone Int-147-14 (1.0 eq.), 4-aminotetrahydropyran (1.2 eq.), NaBH(OAc) ₃ (1.5 eq.) and AcOH (1.5 eq.) in 1, 2-dichloroethane was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH, 95:5) to give compound 147 as an off-white solid in 90-92% yield. LCMS: (M+1) m/z=454.

Example 148.

Synthesis 3

A mixture of Int-148-1 (500 mg, 2.53 mmol), (R)-tetrahydro-2H-pyran-3-amine hydrochloride 2 (384 mg, 2.79 mmol) and DIPEA (0.485 ml, 2.78 mmol ) in 1,2-dichloroethane (10 ml) was stirred at room temperature for 10 min. NaBH(OAc) ₃ (803 mg, 3.79 mmol) and AcOH (0.22 ml, 3.79 mmol) were added to the mixture. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between saturated aqueous Na ₂ CO ₃ and EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc (2x20 ml). The combined organic phase was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The product was purified by column chromatography (EtOAc:/PrOH=80:20) to give Int-148-13 as an amber oil (705 mg, 98% yield). LC-MS: (M+1) m/z=285.

Synthesis of Int-148-14.

Trifluoroacetic acid (3.78 ml, 49 mmol) was added dropwise to Int-148-13 (703 mg, 2.47 mmol) in CH ₂ Cl ₂ (5 ml). The reaction mixture was stirred at room temperature for 1 hour, then the solvent and excess trifluoroacetic acid were evaporated under reduced pressure to give Int-148-14 as a yellow oil, which was used in the next step without further purification (1.01 g, quantitative yield) . LCMS: (M+1) m/z=185.

Synthesis of compound 148.

To a solution of Int-148-15 (24.4 mg, 0.08 mmol) in EtOH (0.4 ml) and 2-propanol (0.2 ml) was added Int148-14 (R)-N-(tetrahydro-2H -pyran-3-yl)piperidin-4-amine bis trifluoroacetate (33 mg, 0.08 mmol) and DIPEA (55 μl, 0.32 mmol) The reaction mixture was heated under microwave irradiation at 140°C for 140 min, then cooled to room temperature and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=96:4) (2.6 g, 88% yield) to give compound 148 as a yellow solid (10.0 mg, 27% yield) . LCMS: (M+1) m/z=454.

Examples 149-152.

Compounds 149-152 were prepared according to the procedure described for compound 147, starting from the ketone Int-147-14 and the corresponding amine. Compound 149 was obtained as a pale yellow solid in 88-90% yield. LCMS: (M+1) m/z=440. Compound 150 was obtained as a pale brown solid in 89-90% yield. LCMS: (M+1) m/z=440. Compound 151 was obtained as a pale brown solid in 82-83% yield. LCMS: (M+1) m/z=454. Compound 152 was obtained as a pale yellow solid in 71-75% yield. LCMS: (M+1) m/z=454.

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Examples 153-155.

EtO ₂ C^CN

R = Br, 1PM53-1Y

R = Et. Int-153-19

H

Compound 153

Reagents and conditions i) Int-153-15 (1.0 eq.), Int-153-8 (2.0 eq.), NH4OAc (5.0 eq.), 90°C, 8 h, 95-97 %, ii) POCl ₃ , 110°C, 1.5 h, quantitative, iii) Int-153-17 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1 .1 equiv.), DIPEA (1.1 equiv.), iPrOH, 120°C, overnight, 96-98%, iv) Int-153-18 (1.0 equiv.), BEt3 (2.0 equiv.), Cs ₂ CO ₃ (2.0 equiv.), Pd(dppf)C12 CH ₂ C1 ₂ (0.05 equiv.), THF, 70°C, 1.5 h, 96-98%, v ) Int-153-19 (1.0 eq.), NH2OH HC1 (5.0 eq.), Na ₂ CO ₃ (5.0 eq.), iPrOH, 90°C, overnight, vi) (AcO) 2O (1.2 eq), DIPEA (1.2 eq), dioxane, rt to 90°C, 8 h, 28-30% two steps, vii) 10% aq H ₂ SO ₄ , THF, 45 °С, 2 h, 5254%, viii) 4-aminotetrahydropyran (1.2 eq.), NaBH(OAc) ₃ (1.5 eq.), AcOH (1.5 eq.), 1,2-dichloroethane, room temp., during the night, 78-80%.

Synthesis of Int-153-16.

A mixture of aldehyde Int-153-15 (1.0 eq.), ethyl 2-cyanoacetate Int-153-8 (2.0 eq.) and NH ₄ OAc (5.0 eq.) in dioxane was stirred at 90°C in for 8 h. The mixture was concentrated under reduced pressure and the solid was washed successively with water and EtOAc/hexane (1:9) (2x). The yellow solid Int-153-16 was used without further purification (95-97% yield). LCMS (M+1) m/z=266, 268.

Synthesis of Int-153-17.

A suspension of Int-153-16 (1.0 eq.) in POC13 was stirred at 110°C for 1.5 h Excess POC13 was removed under reduced pressure The crude material was quenched with ice and the mixture was stirred at room temperature for 15 min The crude material was collected by filtration and washed with water (SQ) to give Int-153-17 as a pale yellow solid in quantitative yield LCMS (M+1) m/z=284.286.

Synthesis of Int-153-18.

A mixture of 17 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1.1 eq.) and DIPEA (1.1 eq.) in iPrOH was heated at 120°C for night. The mixture was concentrated under reduced pressure and the product was purified by column chromatography using hexane/EtOAc. The product Int-153-18 was obtained as a pale brown solid in 96-98% yield. LCMS: (M+1) m/z=392, 394.

Synthesis of Int-153-19.

_{A 1M solution of} BEt ₃ in THF (2.0 eq.) and the reaction mixture was heated at 70°C for 1.5 h. After cooling to room temperature, the crude material was filtered through celite and purified by column chromatography (hexane:EtOAc) to obtain Int-153- 19 as a yellow solid (96-98% yield). LCMS: (M+1) m/z=342.

Synthesis of Int-153-20.

A mixture of Int-153-19 (1.0 eq.), NH ₂ OH.HC1 (5.0 eq.) and Na ₂ CO ₃ (5.0 eq.) in anhydrous isopropanol was heated at 90° C. overnight. The mixture was cooled to room temperature and filtered. The organic phase was concentrated under reduced pressure and the product was used without further purification. LCMS: (M+1) m/z=375. A mixture of amidoxime (1.0 eq.), acetic anhydride (1.2 eq.) and DIPEA (1.2 eq.) in dioxane was stirred at room temperature for 40 min, then the mixture was heated at 90°C for 8 h The mixture was concentrated under reduced pressure and the product was purified by column chromatography using hexane/EtOAc to give a pale yellow solid Int153-20 in 28-30% yield. LCMS: (M+1) m/z=399.

Synthesis of Int-153-21.

To a solution of ketal Int-153-20 (1.0 eq.) in THF was added 10% aq. H ₂ SO ₄ and the mixture was stirred at 45°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na2CO3 and extracted with EtOAc (4x), dried over Na2SO4 and concentrated to dryness. The product was purified by column chromatography using hexane:EtOAc to give the pale yellow ketone Int-153-21 in 52-54% yield. LCMS: (M+1) m/z=355.

- 125 042282

Synthesis of compound 153.

A mixture of ketone Int-153-21 (1.0 eq.), 4-aminotetrahydropyran (1.2 eq.), NaBH(OAc) ₃ (1.5 eq.) and AcOH (1.5 eq.) in 1, 2-dichloroethane was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH, 95:5) to give compound 153 as an off-white solid in 78-80% yield LCMS (M+1) m/z=440.

Synthesis of compound 154 and compound 155.

Compounds 154-155 were obtained in the same way from the ketone Int-153-21 Compound 155 was obtained as a pale yellow oil with a yield of 85-86% LCMS (M+1) m/z=426. Compound 154 was obtained as a pale yellow oil with a yield of 89-90% LCMS (M+1) m/z=426.

Examples 156-158.

Synthesis of Int-156-28.

To a suspension of 2-amino-3,4-difluorobenzoic acid 27 (1.0 eq) in CH ₂ Cl ₂ was added N-bromosuccinimide (1.01 eq) and the mixture was stirred at room temperature for 48 h. The product was collected by filtration to give the acid Int-156-28 as a white solid (9295% yield) which was used in the next step without further purification by LCMS (M-1) m/z=251.253.

Synthesis of Int-156-29.

A mixture of Int-156-28 (1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (1.2 eq.), DIPEA (1.2 eq.), EDCI (1.5 eq.) and HOBt (1.2 eq.) 5 eq.) in DMF was stirred at room temperature for 4 h. The reaction mixture was diluted with water and the product was collected by filtration as a white solid, which was used in the next step without further purification. LCMS: (M+1) m/z=294, _296. Trifluoroacetic anhydride ₍ 1.2 eq.). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the crude material was diluted with water. The solid was collected by filtration and used in the next step without further purification. LCMS: (M-1) m/z=388, 390.

Synthesis of Int-156-30.

A solution of 1M Et ₃ B (3.0 eq.) in THF was added to a suspension of Int-156-29 (1.0 eq.), Cs ₂ CO ₃ (3.0 eq.) and Pd(dppf)Cl2 (0.0 eq.) 1 eq.) in THF and the reaction mixture was heated at 50°C overnight. After cooling to room temperature, the crude material was filtered through celite and purified by column chromatography (hexane:EtOAc) to give the appropriate product in 9-11% yield. LCMS: (M+1) m/z=341. MeMgBr (1.4 M) in THF:toluene (4.0 eq.) was added to a solution of the indicated product (1.0 eq.) in THF at 0°C and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was poured onto ice, acidified to pH 2 with 2M HCl solution and the product was extracted with EtOAc (2x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the corresponding ketone, which was used in the next step without further purification. LCMS: (M-1) m/z=294. To a solution of the ketone (1.0 equiv.) in MeOH was added 2 M aq. NaOH solution (2.0 equiv.) and the reaction mixture was heated at 90°C for 1.5 hours, the Reaction mixture was concentrated and acidified with a solution of 1M HCl. The product was extracted with EtOAc (3x) and the organic phase was concentrated under reduced pressure. The crude material was purified by column chromatography using hexane:EtOAc to give Int-156-30 as a pale yellow solid (50-54% yield, two steps). LCMS: (M+1) m/z=200.

- 126 042282

Synthesis of Int-156-31.

A mixture of ketone Int-156-30 (1.0 eq.), 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid 2 (1.0 eq.) and

POCl ₃ (2.5 ml) was stirred at 80°C for 1 h Excess POCl ₃ was removed under reduced pressure.

Ice/water was added to the residue and the solid was collected by filtration. The crude material was used without further purification. LCMS: (M+1) m/z=324, 326.

Synthesis of Int-156-32.

A suspension of Int-156-31 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (1.2 eq.) and DIPEA (1.2 eq.) in iPrOH was heated at 125 °C during the night. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane:EtOAc) to give Int-156-32 ketal as a yellow solid (47-49% yield, two steps). LCMS: (M+1) m/z=431.

Synthesis of Int-156-33.

A suspension of ketal Int-156-32 (1.0 eq.) in 10% aq. H2SO4 was stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with Na ₂ CO ₃ and the product was extracted with EtOAc (3x). The organic phase was dried over Na ₂ SO ₄ and concentrated to give the ketone Int-156-33 as a yellowish solid which was used in the next step without further purification. LCMS: (M+1) m/z=387.

Synthesis of compound 156, compound 157 and compound 158.

A mixture of the ketone Int-156-33 (1.0 eq.), the appropriate amine (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) in 1.2 -dichloroethane was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by HPLC to give the title compounds. Compound 156 was obtained as a pale brown solid in 96-97% yield (last step). LCMS: (M+1) m/z=472. Compound 157 was obtained as a pale brown solid in 79-81% yield (last step). LCMS: (M+1) m/z=472. Compound 158 was obtained as a pale yellow oil in 94-96% yield (last step). LCMS: (M+1) m/z=458.

Examples 159-160.

Synthesis of Int-159-2.

To a solution of Int-159-1 (1.23 g, 5 mmol) in THF (25 ml) was added a solution of n-BuLi (2.5 M in hexane, 6 ml, 15 mmol) at -78°C and the mixture was stirred at -78°C for 1 hour Added acetaldehyde (1.1 ml, 20 mmol) at -78°C and the mixture was stirred at -78°C for 0.5 hour. The reaction was quenched with saturated aqueous NH ₄ Cl and the product was extracted with EtOAc (3x). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to give Int-159-2 as a yellow liquid which was used in the next step without further purification. LCMS: (M+1) m/z=290.

Synthesis of Int-159-3.

To a solution of Int-159-2 in CH ₂ Cl ₂ (30 ml) was added DMP (3.18 g, 7.5 mmol) and NaHCO ₃ (0.84 g, 10 mmol) at room temperature and the mixture was stirred for 2 h. To the mixture was added hexane (30 ml) and the combined suspension was filtered through a short column of silica gel. The column was washed with hexane/EtOAc (4:1, 50 ml x3). The combined organic solution was concentrated to give Int-159-3 as a yellow solid (1.34 g, 93% yield over 2 steps) which was used in the next step without further purification. LCMS: (M+23) m/z=312.

Synthesis of Int-159-7.

To a solution of Int-159-3 (288 mg, 1 mmol) in THF (4 ml) was added Pd(OAc) ₂ (6.7 mg, 0.03 mmol), XPhos (28.6 mg, 0.06 mmol) , Et ₃ B (1.0 M in THF, 3 ml, 3 mmol) and Cs ₂ CO ₃ (975 mg, 3 mmol). The reaction mixture was stirred at 80° C. overnight. After cooling to room temperature, the crude material was filtered through celite and purified by column chromatography (hexane:EtOAc) to give Int-159-7 as a yellow liquid (176 mg, 51% yield). LCMS: (M+23) m/z=304.

Synthesis of Int-159-8.

A mixture of Int-159-7 (150 mg, 0.53 mmol) and TFA (1 ml) in CH ₂ Cl ₂ (4 ml) was stirred at room

- 127 042282 temperature for 4 hours. The reaction was quenched with saturated aqueous Na2CO3 and the product was extracted with CH ₂ Cl ₂ . The combined organic layer was dried over Na ₂ SO ₄ and concentrated to give Int-159-8 as a yellow liquid which was used in the next step without further purification. LCMS: (M+1) m/z=182.

Synthesis of Int-159-9.

A mixture of Int-159-8, 2-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid (110 mg, 0.77 mmol) and POCl ₃ (1.5 ml) was stirred at 110° C during the night. Excess POCl ₃ was removed in vacuo. Saturated aqueous NaHCO ₃ was added to the residue and the product was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was purified by column chromatography (hexane/EtOAc) to give Int-159-9 as a yellow solid (60 mg, 39% yield over 2 steps). LCMS: (M+1) m/z=306.

Synthesis of Int-159-10.

To a suspension of Int-159-9 (50 mg, 0.16 mmol) in EtOH (1.6 mL) was added 1,4-dioxa-8azaspiro[4,5]decane (41 μL, 0.32 mmol) and DIPEA ( 56 µl, 0.32 mmol). The mixture was heated at 110° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-159-10 ketal as a yellow solid (60 mg, 91% yield). LCMS: (M+1) m/z=413.

Synthesis of Int-159-11.

To a solution of Int-159-10 (1.0 eq.) in acetone was added aq. 2M HCl solution and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with EtOAc and washed successively with aqueous Na ₂ CO ₃ and brine to give Int159-11 as a pale brown solid in 91-93 yield %, which was used in the next step without further purification. LCMS: (M+1) m/z=369.

Synthesis of compound 159.

A mixture of ketone Int-159-11 (1.0 eq.), 4-aminotetrahydropyran (1.2 eq.), NaBH(OAc) ₃ (1.5 eq.) and AcOH (1.5 eq.) in 1, 2-dichloroethane was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by HPLC to give compound 159 as an off-white solid in 91-93% yield. LCMS: (M+1) m/z=454.

Synthesis of compound 160.

Compound 160 was prepared in the same manner as compound 159 using the ketone intermediate Int-159-11 and the corresponding amine as a pale yellow oil; yield 81%. LCMS: (M+1) m/z=454.

Examples 161-165.

Compound 161

Synthesis of Int-161-2.

To a suspension of aniline Int-161-1 (1.0 eq.) in CH ₂ Cl ₂ (100 ml) was added NBS (1.05 eq.) and the reaction mixture was stirred at room temperature overnight. The mixture was partitioned between saturated aqueous NaHCO ₃ and CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give Int-161-2 as a yellow solid (57-59% yield). LCMS (M+1) m/z=223, 225.

Synthesis of Int-161-3.

To a solution of Int-161-2 (1.0 eq.) in THF at -78°C was added dropwise a solution of 2.0 M nBuLi (2.2 eq.) in hexane. After stirring at -78° C. for 1 hour, DMF (1.4 eq.) was added at the same temperature. The temperature was raised to 0° C. and the mixture was stirred at 0° C. for 2 hours. The mixture was quenched with saturated aqueous NH ₄ Cl and the product was extracted with EtOAc (2x). The organic phase was washed with brine (3x), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-161-3 as a yellow solid (53-55% yield). LCMS (M+1) m/z=174.

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Synthesis of Int-161-5.

A mixture of Int-161-3 (1.0 eq.) and 4 (1.2 eq.) in POCl ₃ was stirred at 110° C. for 1.5 h. The excess POCl ₃ was concentrated under reduced pressure. The crude material was quenched with ice and stirred for 15 minutes at room temperature. The solid was collected by vacuum filtration and washed with water (2x). The solid was purified on a short silica gel column using hexane/EtOAc to give Int-161-5 in 17-19% yield as a yellow solid. LCMS: (M+1) m/z=397, 399.

Synthesis of Int-161-6.

A solution of Int-161-5 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.) and DIPEA (2.0 eq.) in PrOH was heated at 110 °C during the night. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (hexane/EtOAc) to give Int-161-6 as a yellow solid (82-84% yield). LCMS: (M+1) m/z=405.

Synthesis of Int-161-7.

To a solution of Int-161-6 (1.0 eq.) in THF was added 10% aq. H ₂ SO ₄ at room temperature. The mixture was then stirred at 45° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc (x3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc gradient) to give Int-161-7 as a pale yellow solid (63-65% yield). LCMS: (M+1) m/z=361.

Synthesis of compound 161.

A mixture of Int-161-7 (1.0 eq.), amine (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.) and AcOH (2.0 eq.) in 1,2 dichloroethane was stirred at room temperature overnight. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC using CH ₂ Cl ₂ /MeOH. Compound 161 was obtained as a pale yellow solid in 71-73% yield. LCMS: (M+1) m/z=446.

Synthesis of compound 162, compound 163, compound 164, compound 165.

The title compounds were prepared according to the procedure described for compound 160 starting from the ketone Int-161-14 and the corresponding amine. Compound 162 was obtained as a pale yellow solid in 65-67% yield. LCMS: (M+1) m/z=446. Compound 163 was obtained as a pale yellow solid in 66-68% yield. LCMS: (M+1) m/z=446. Compound 164 was obtained as a pale yellow solid in 59-61% yield. LCMS: (M+1) m/z=432. Compound 165 was obtained as a pale yellow solid in 72-74% yield. LCMS: (M+1) m/z=432.

Example 166.

Compounds 166 were prepared using the Int-33-14k ketone described above for the synthesis of compounds 33-35. Mixture of ketone Int-33-14k (15 mg, 0.040 mmol), oxetan-3-ylmethanamine (5.3 mg, 0.060 mmol) and AcOH (5 µl, 0.081 mmol) in 1,2-dichloroethane (0.1 ml) stirred at room temperature for 30 min, then NaBH(OAc) ₃ (17.2 mg, 0.081 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH, 95:5) to give compound 166 as a yellow solid (2.3 mg, 12.9% yield). LCMS: (M+1) m/z=442.

Examples 167-169.

Compound 167 Compound 168 Compound 169

Compounds 167-169 were prepared as described above for compounds 40-59 and compounds 134-137 using the appropriate amines with the appropriate stereochemistry and Int-36-14h described above for the preparation of compounds 36-39.

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Examples 170-171.

Synthesis of Int-170-1a.

Intermediate Int-170-1a was prepared starting from Int-91-22 described above for the synthesis of compound 91 and as disclosed for Int-33-14j described above for the synthesis of compounds 33-35.

Synthesis 1b.

Intermediate Int-170-1b was prepared as disclosed for Int-33-14k described above for the synthesis of compounds 33-35.

Synthesis of compound 170 and compound 171.

Compound 170 and compound 171 were prepared from Int-170-1b and the appropriate amine as described above for the synthesis of compounds 33-35.

Example 172.

Reagents and Conditions (Int-172-4 and Int-172-13 as examples) i) Int-172-1 (1.0 eq.), Amine (Int-1722, 1.2 eq.), NaBH(OAc) ₃ (1.5 eq.), AcOH (1.5 eq.), 1,2-dichloroethane, rt. temp., 18 h, 87-97%, ii) Int-1723 (1.0 eq.), TFA (20 eq.), CH2Cl2, room. temp., 40 min, iii) Int-172-1 (1.0 eq.), Int-172-11 (2.0 eq.), DIPEA (3.0 eq.), CH3CN, 95°C, 48 h, 68-95%.

Synthesis of (2R,4R)-tert-butyl 2-methyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate Int-172-3.

NaBH(OAc) ₃ (59 mg, 0 .28 mmol) and AcOH (15.5 μl, 0.28 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with 1M NaOH solution and extracted with EtOAc (4x). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH gradient) to give Int-172-3 as a pale gray solid (54 mg, 97% yield). LCMS: (M+1) m/z=299.

Synthesis of (2R,4R)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amune Int-172-4.

A mixture of Int-172-3 (54 mg, 0.18 mmol) and TFA (277 μl, 3.61 mmol) in CH2Cl2 (2 ml) was stirred at

- 130 042282 room temperature for 40 min. The mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and concentrated aq.

NaOH. H2O was removed by adding anhydrous MgSO ₄ and the solid was filtered off and washed with EtOAc (3x). The filtrate was concentrated and the product was used without further purification (quantitative yield). Int-172-4 was obtained as a pale yellow oil. LCMS: (M+1) m/z=199.

Synthesis of tert-butyl (2R,4S)-2-methyl-4-((tetrahydro-2H-pyran-4-yl)amino)piperidine-1-carboxylate Int-172-6.

NaBH(OAc) ₃ (59 mg, 0 .28 mmol) and AcOH (15.5 μl, 0.28 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with a 1M NaOH solution and extracted with EtOAc (4x). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH gradient) to give Int-172-6 as a pale gray solid (53 mg, 97% yield). LCMS: (M+1) m/z=299.

Synthesis of (2R,4S)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine Int-172-7.

A mixture of Int-172-6 (53 mg, 0.18 mmol) and TFA (277 μl, 3.61 mmol) in CH ₂ Cl ₂ (2 ml) was stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and concentrated aq. NaOH. H ₂ O was removed by adding anhydrous MgSO ₄ and the solid was filtered off and washed with EtOAc (3x). The filtrate was concentrated and the product was used without further purification (quantitative yield). Int-172-7 was obtained as a pale yellow oil. LCMS: (M+1) m/z=199.

Synthesis of (2S,4S)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine Int-172-10.

The compound (2S,4S)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine Int-172-10 was synthesized in the same way in 94% yield (in two steps) and obtained in as a pale yellow oil. LCMS: (M+1) m/z=199.

Synthesis of (2R,4R)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172-13.

A mixture of Int-172-1 (1.0 g, 4.6 mmol), Int-172-11 (3.3 g, 14 mmol) and DIPEA (2.44 ml, 14 mmol) in acetonitrile (10 ml) was heated 95° C. for 48 hours. The mixture was concentrated under reduced pressure and purified by column chromatography using CH2Cl2/MeOH as mobile phase to give 1.0 g of a pale gray solid (76% yield). LCMS: (M+1) m/z=285.

A mixture of Int-172-12 (1 g, 3.51 mmol) and TFA (5.38 ml, 70.3 mmol) in CH2Cl2 was stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and concentrated aq. NaOH. H ₂ O was removed by adding anhydrous MgSO ₄ and the solid was filtered off and washed with EtOAc (3x). The filtrate was concentrated and the product was used without further purification (640 mg, quantitative yield). LCMS: (M+1) m/z=185.

Synthesis of (2R,4R)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172-16.

A mixture of Int-172-1 (1.0 g, 4.6 mmol), Int-172-14 (3.3 g, 14 mmol) and DIPEA (2.44 ml, 14 mmol) in acetonitrile (10 ml) was heated 95° C. for 48 hours. The mixture was concentrated under reduced pressure and purified by column chromatography using CH2Cl2/MeOH as the mobile phase. 1.26 g of a pale gray solid were obtained (95% yield). LCMS: (M+1) m/z=285.

A mixture of Int-172-15 (1260 mg, 4.43 mmol) and TFA (6.78 ml, 88.6 mmol) in CH ₂ Cl ₂ (20 ml) was stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and concentrated aq. NaOH. H ₂ O was removed by adding anhydrous MgSO ₄ and the solid was filtered off and washed with EtOAc (3x). The filtrate was concentrated and the product was used without further purification (810 mg, quantitative yield). LCMS: (M+1) m/z=185.

Synthesis of (2R,4S)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172-18.

The compound (2R,4S)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172-18 was synthesized in the same way. The product was obtained as a pale yellow oil in 46% yield (two steps). LCMS: (M+1) m/z=185.

Synthesis of (2S,4S)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172-20.

The compound (2S,4S)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172-20 was synthesized in the same way. The product was obtained as a pale yellow oil in 33% yield (two steps). LCMS: (M+1) m/z=185.

- 131 042282

Reagents and conditions (Int-172-26 as an example): i) Int-172-21 (1.0 eq.), NIS (1.05 eq.), AcOH, r.m. temp., 67-74%; ii) Int-172-22 (1.0 eq.), Int-172-23 (6.0 eq.), K ₂ CO ₃ (1.2 eq.), DPPP (0.05 eq.), Pd (OAc) ₂ (0.01 eq.), toluene/H ₂ O (1:9) 90°C, 24-40 h, 10-37%; iii) Int-172-24 (1.0 eq.), Int-172-25 (1.2 eq.), POC13, 80°C, 1 h, 17-95%; iv) Int-172-42 (1.0 eq.), NBS (1.05 eq.), CHCh, room. temp., 18 h, 56%; v) Int172-38 (1.0 eq.), Benzophenoneimine (1.2 eq.), Pd ₂ (dba) ₃ (0.025 eq.), XantPhos (0.1 eq.), NaOtBu (1.2 eq. ), 1,4-dioxane, 100°С, 18 h; then HCl (1 M aq.), THF, room. temp., 1 h, 30%.

Synthesis of 5-(2,8-dichloro-4,6-dimethylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-172-26.

Synthesis of 2-chloro-6-iodo-4-methylaniline Int-172-22.

To a mixture of Int-172-21 (5.0 g, 35.3 mmol) in acetic acid (50 mL) was added NIS (8.34 g, 37.1 mmol) in one portion and the mixture was stirred at room temperature for 1 h The mixture was diluted with EtOAc (500 ml) and washed with brine (3x) and saturated aqueous NaHCO ₃ (2x). The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc (0-30% EtOAc in hexane) as the mobile phase. The product was obtained as a pale red solid in 74% yield (7 g). LCMS: (M+1) m/z=267.

Synthesis of 1-(2-amino-3-chloro-5-methylphenyl)ethanone Int-172-24.

Blend Int-172-22 (7 g, 26.17 mmol), 23 (14.09 ml, 157 mmol), K2CO3 (4.34 g, 31.4 mmol), DPPP (521 mg, 1.3 mmol) and Pd(OAc) ₂ (59 mg, 0.26 mmol) in 60 ml H ₂ O/toluene (9:1) were heated at 90°C for 24 h. After the mixture was cooled to room temperature, concentrated HCl (15 ml) and the mixture was stirred at room temperature for 1 h. The product was extracted with EtOAc (3x). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) to give a pale yellow solid (1.3 g) in 27% yield. LCMS: (M+1) m/z=184.

Synthesis of 5-(2,8-dichloro-4,6-dimethylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-172-26.

A mixture of Int-172-24 (1.3 g, 7.08 mmol) and 25 (1.2 g, 8.5 mmol) in POCl ₃ (5 ml) was stirred at 80°C for 1 h. The mixture was concentrated at reduced pressure and quenched with ice/H ₂ O. The mixture was stirred at room temperature for 30 min and the product was filtered. The solid was purified by column chromatography using hexane/EtOAc (0-30% EtOAc in hexanes) and the product was obtained as a pale yellow solid in 19% yield (430 mg). LCMS: (M+1) m/z=308.

Synthesis of 5-(2,6-dichloro-8-fluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole 29.

Synthesis of 1-(2-amino-5-chloro-3-fluorophenyl)ethan-1-one Int-172-28.

Mixture Int-172-27 (5 g, 18.4 mmol), 23 (9.9 ml, 110.5 mmol), K2CO3 (3.05 g, 22.1 mmol), DPPP (366

- 132 042282 mg, 0.92 mmol) and Pd(OAc) ₂ (41 mg, 0.18 mmol) in 60 ml H ₂ O/toluene (9:1) were heated at 90°C for 24 h. After cooling mixture to room temperature was slowly added concentrated HCl (14 ml) and the mixture was stirred at room temperature for 1 h, the Product was extracted with EtOAc (3x). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc (020% EtOAc in hexane) to give a pale brown solid (1.3 g) in 37% yield. LCMS: (M+1) m/z=188.

Synthesis of 5-(2,6-dichloro-8-fluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-172-29.

A mixture of Int-172-28 (1.25 g, 6.66 mmol) and 25 (1.04 g, 7.33 mmol) in POC13 (5 ml) was stirred at 80°C for 1 h. The mixture was concentrated under reduced pressure and quenched with ice/H ₂ O. The mixture was stirred at room temperature for 30 min and the product was filtered. The solid was purified by column chromatography using hexane/EtOAc (0-30% EtOAc in hexanes) and the product was obtained as a pale brown solid in 17% yield (350 mg). LCMS: (M+1) m/z=312.

Synthesis of 5-(2-chloro-8-fluoro-4-methyl-6-(trifluoromethoxy)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int172-33.

Synthesis of 2-fluoro-6-iodo-4-(trifluoromethoxy)aniline Int-172-31.

A mixture of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene Int-172-38 (12.8 g, 49.4 mmol), benzophenoneimine (10 ml, 59.3 mmol), pd ₂ (dba) ₃ ( 1.1 g, 1.23 mmol), XantPhos (2.8 g, 4.9 mmol) and NaOtBu (5.7 g, 59.3 mmol) in 1,4-dioxane (100 ml) were stirred and heated at 100°C overnight. After cooling to room temperature, the mixture was concentrated. The residue was then partitioned between EtOAc and H ₂ O and the organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using hexane/EtOAc (0-5% EtOAc in hexane). The product was dissolved in THF (100 ml) and 1M aqueous HCl solution (50 ml) was added. After stirring at room temperature for 1 h, the mixture was partitioned between EtOAc and H ₂ O. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane). Product 30 was obtained as a pale brown oil in 30% yield (5.4 mg). LCMS: (M+1) m/z=196.

To a mixture of Int-172-30 (310 mg, 1.58 mmol) in acetic acid (5 ml) was added NIS (373 mg, 1.66 mmol) in one portion and the mixture was stirred at room temperature for 2.5 h. diluted with EtOAc and washed with brine (3x) and saturated aqueous Na ₂ CO ₃ (2x). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as the mobile phase. The product was obtained as a red oil in 67% yield (340 mg).

Synthesis of 1-(2-amino-3-fluoro-5-(trifluoromethoxy)phenyl)ethanone Int-172-32.

Mixture of Int-172-31 (340 mg, 1.06 mmol), Int-172-23 (0.5 ml, 5.30 mmol), K2CO3 (176 mg, 1.27 mmol), DPPP (22 mg, 0.053 mmol) and Pd(OAc) ₂ (2.4 mg, 0.0106 mmol) in 1,4-dioxane/H ₂ O (2 ml, 9:1 v/v) heated at 90° C. overnight . After the mixture was cooled to room temperature, concentrated HCl (1 ml) was added slowly and the mixture was stirred at room temperature for 1 hour. The product was extracted with EtOAc (3x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as the mobile phase. The product was obtained as a pale yellow solid (128 mg) in 51% yield. LCMS: (M+1) m/z=238.

Synthesis of 5-(2-chloro-8-fluoro-4-methyl-6-(trifluoromethoxy)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int172-33.

A mixture of Int-172-32 (128 mg, 0.54 mmol) and Int-172-25 (92 mg, 0.65 mmol) in POC13 (2 mL) was stirred at 100°C for 1 h. temperature, excess POC13 was removed in vacuo. H ₂ O was added to the residue at 0°C and the mixture was stirred at 0°C for 10 minutes. The precipitated crude chloroquinoline Int-172-33 was filtered, washed with H ₂ O and dried under reduced pressure. The residue as a dark brown solid was used without further purification (185 mg, 95% yield). LCMS: (M+1) m/z=362.

Synthesis of 2-chloro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinoline-8-carbonitrile Int-172-37.

Synthesis of 2-amino-3-iodo-5-methylbenzonitrile Int-172-35.

To a mixture of Int-172-34 (5.0 g, 37.8 mmol) in acetic acid (50 ml) was added NIS (8.9 g, 39.7 mmol) in one portion and the mixture was stirred at room temperature for 1 h The mixture was diluted with EtOAc (500 mL) and washed with brine (3x) and saturated NaHCO3 (2x). The organic phase was dried over Na2CO3 and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc (0-30% EtOAc in hexane) as the mobile phase. 35 was obtained as a pale brown solid in 71% yield (6.9 g). LCMS: (M+1) m/z=258.

Synthesis of 3-acetyl-2-amino-5-methylbenzonitrile Int-172-36.

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Mixture of Int-172-35 (2 g, 7.75 mmol), Int-172-23 (4.17 ml, 46.5 mmol), K ₂ CO ₃ (1.28 g, 9.3 mmol), DPPP (154 mg, 0.39 mmol) and Pd(OAc)2 (17 mg, 0.08 mmol) in 40 ml H ₂ O/toluene (9:1) were heated at 90°C for 24 hours. After cooling the mixture to room temperature was slowly added concentrated HCl (8 ml) and the mixture was stirred at room temperature for 1 h. The product was extracted with EtOAc (3x). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane/EtOAc (030% EtOAc in hexane) to give a pale yellow solid (203 mg) in 15% yield. LCMS: (M+1) m/z=175.

Synthesis of 2-chloro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinoline-8-carbonitrile Int-172-37.

A mixture of Int-172-36 (408 mg, 2.3 mmol) and Int-172-25 (400 mg, 2.8 mmol) in POCl ₃ (4 ml) was stirred at 80° C. for 1 h. The mixture was concentrated at reduced pressure and quenched with ice/H ₂ O. The mixture was stirred at room temperature for 30 min and the product was filtered. The solid was purified by column chromatography using hexane/EtOAc (0-40% EtOAc in hexanes) and the product was obtained as a pale yellow solid in 28% yield (190 mg). LCMS: (M+1) m/z=299.

Synthesis of 5-(2-chloro-6,8-difluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-172-41.

Synthesis of 1-(2-amino-3,5-difluorophenyl)ethanone Int-172-40.

Mixture Int-172-39 (3.02 g, 11.84 mmol), 23 (5.3 ml, 59.20 mmol), K2CO3 (2.0 g, 14.20 mmol), DPPP (0.24 g , 0.59 mmol) and Pd(OAc) ₂ (27 mg, 0.12 mmol) in 1,4-dioxane/H ₂ O (25 ml, 9:1, v/v) were heated at 90°C within 2 days. After the mixture was cooled to room temperature, concentrated HCl (6 ml) was added slowly and the mixture was stirred at room temperature for 1 hour. The product was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The product was purified by column chromatography using hexane/EtOAc (020% EtOAc in hexane) as the mobile phase. The product was obtained as a yellow solid in 28% yield (0.56 g). LCMS: (M+1) m/z=172.

Synthesis of 5-(2-chloro-6,8-difluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int-172-41.

A mixture of Int-172-40 (0.56 g, 3.28 mmol) and Int-172-25 (0.56 g, 3.94 mmol) in POCl ₃ (10 ml) was stirred at 100°C for 1 h After cooling to room temperature, excess POCl ₃ was removed in vacuo. H ₂ O was added to the residue at 0°C and the mixture was stirred at 0°C for 10 minutes. The precipitated crude chloroquinoline Int-172-41 was filtered, washed with H ₂ O and dried under reduced pressure.

The solid was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as the mobile phase. The product was obtained as a pale brown solid in 25% yield (0.25 g). LCMS: (M+1) m/z=296.

Synthesis of 5-(2-chloro-8-fluoro-4-methyl-6-(trifluoromethyl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int172-45.

Synthesis of 2-bromo-6-fluoro-4-(trifluoromethyl)aniline Int-172-43.

To a solution of Int-172-42 (8.5 g, 47.45 mmol) in CH ₂ Cl ₂ (100 ml) was added NBS (8.9 g, 49.83 mmol) in one portion and the mixture was stirred at room temperature for night. After concentration in vacuo, the mixture was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as the mobile phase. The product was obtained as a red oil in 56% yield (6.8 g).

Synthesis of 1-(2-amino-3-fluoro-5-(trifluoromethyl)phenyl)ethanone Int-172-44.

A mixture of Int-172-43 (6.8 g, 26.35 mmol), Int-172-23 (12 ml, 131.75 mmol), K2CO3 (4.4 g, 31.62 mmol), DPPP (0. 55 g, 1.32 mmol) and Pd(OAc) ₂ (59 mg, 0.26 mmol) in 1,4-dioxane/H ₂ O (60 ml, 9:1, v/v) were heated at 95 °C for 40 h. After the mixture was cooled to room temperature, concentrated HCl (14 ml) was added slowly and the mixture was stirred at room temperature for 1 h. The product was extracted with EtOAc (3x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as the mobile phase. The product was obtained as a yellow solid in 10% yield (0.58 g). LCMS: (M+1) m/z=222.

Synthesis of 5-(2-chloro-8-fluoro-4-methyl-6-(trifluoromethyl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole Int172-45.

A mixture of Int-172-44 (0.58 g, 2.64 mmol) and Int-172-25 (0.45 g, 3.17 mmol) in POCl ₃ (5 ml) was stirred at 100°C for 1 h After cooling to room temperature, excess POCl ₃ was removed in vacuo. H ₂ O was added to the residue at 0°C and the mixture was stirred at 0°C for 10 minutes. The precipitated crude chloroquinoline Int-172-45 was filtered, washed with H ₂ O and dried under reduced pressure. The solid was purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as the mobile phase. The product was obtained as a pale brown solid in 26% yield (0.24 g). LCMS: (M+1) m/z=346, 348.

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Reagents and conditions i) Int-172-46 (1.0 eq.), amine (1.5 eq.), KF (2.5 eq.), DMF, 125°C, 18 h, 10-21%.

Synthesis of (2R,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2- methyl N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 172).

A mixture of Int-172-46 (10 mg, 0.033 mmol), 7 (9.7 mg, 0.049 mmol) and KF (4.7 mg, 0.08 mmol) in DMF (150 µl) was heated at 125°C for night. The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with a solution of 1M NaOH (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 172 was obtained as a pale brown oil in 21% yield (3.2 mg). LCMS (M+1) m/z=468 (2S,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl )quinolin2-yl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine. Compound 173 was obtained as a pale yellow oil with the yield of Examples 174-176.

10% (4.1 mg). LCMS (M+1) m/z=468.

Reagents and conditions i) Int-174-26 (1.0 eq.), amine (1.5 eq.), KF (2.5 eq.), DMSO, 125°C, 14 h, 17-20%.

Synthesis of (2R,4S)-1-(8-chloro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl- N(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 174).

A mixture of Int-174-26 (20 mg, 0.062 mmol), Int-174-4 (19 mg, 0.097 mmol) and KF (9.4 mg, 0.163 mmol) in DMSO (200 µl) was heated at 125°C for 14 hours The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with a solution of 1M NaOH (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 174 was obtained as a pale yellow oil in 17% yield (5.3 mg). LCMS: (M+l) m/z=470.

(2R,4S)-1-(8-chloro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N -((R)tetrahydrofuran-3-yl)piperidin-4-amine (compound 175) was obtained as a pale yellow oil in 20% yield (5.8 mg). LCMS: (M+1) m/z=456.

(2R,4S)-1-(8-chloro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N -((S)tetrahydrofuran-3-yl)piperidine-4-amine. Compound 176 was obtained as a pale yellow oil in 20% yield (5.8 mg). LCMS: (M+1) m/z=456.

Examples 177-179.

Reagents and conditions: i) Int-177-29 (1.0 eq.), amine (2.0 eq.), KF (2.5 eq.), DMSO, 125°C, 14 h, 1433%.

Synthesis of (2R,4R)-1 -(6-chloro-8-fluoro-4-methyl-3 -(3-methyl-1,2,4-oxadiazol-5 -yl)quinolin-2-yl)-2- methylN-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 177).

A mixture of Int-177-29 (20 mg, 0.064 mmol), Int-177-4 (25 mg, 0.127 mmol) and KF (9.3 mg, 0.159 mmol) in DMSO (200 µl) was heated at 125°C for night. The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with 1 M NaOH solution (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 177 was obtained as a pale brown oil in 14% yield (4.3 mg). LCMS: (M+1) m/z=474.

(2R,4R)-1-(6-chloro-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N-((S)tetrahydrofuran-3-yl)piperidin-4-amine (compound 178) was obtained as a pale brown oil in 33% yield (9.7 mg). LCMS: (M+1) m/z=460.

(2R,4R)-1-(6-chloro-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N-((R)tetrahydrofuran-3-yl)piperidin-4-amine (compound 179) was obtained as a pale brown oil in 30% yield (8.7 mg). LCMS: (M+1) m/z=460.

Example 180.

Reagents and conditions: i) Int-180-33 (1.0 eq.), Int-180-13 (1.5 eq.), KF (2.0 eq.), DIPEA (3.0 eq.), DMSO, 140°С, 18 h, 10%.

Synthesis of (2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-(trifluoromethoxy)quinolin2-yl)-2- methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 180).

Mixture of Int-180-33 (15 mg, 0.041 mmol), Int-180-13 (11 mg, 0.062 mmol), KF (4.7 mg, 0.082 mmol) and DIPEA (21 µl, 0.123 mmol) in DMSO (1 ml) was heated at 140°C overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 and washed with brine. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (96:4) followed by EtOAc:/PrOH (95:5). Compound 180 was obtained as a yellow solid in 10% yield (2.0 mg). LCMS: (M+1) m/z=510.

Examples 181-183.

Reagents and conditions: i) Int-181-37 (1.0 eq.), amine (2.0 eq.), KF (2.5 eq.), DMSO, 125°C, 14 h, 1417%.

Synthesis of 4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-((tetrahydro-2Н-pyran4- yl)amino)piperidin-1-yl)quinoline-8-carbonitrile (compound 181).

A mixture of Int-181-37 (20 mg, 0.066 mmol), Int-181-4 (18.4 mg, 0.1 mmol) and KF (9.6 mg, 0.165 mmol) in DMSO (200 µl) was heated at 125 °C for 14 hours. The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with a solution of 1M NaOH (3x). The organic phase was dried over Na2SO4, concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 181 was obtained as a pale yellow oil in 14% yield (4.3 mg). LCMS: (M+1) m/z=461.

4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-(((S)-tetrahydrofuran-3yl )Amino)piperidin-1-yl)quinolin-8-carbonitrile (compound 182) was obtained as a pale brown oil in 17% yield (5.1 mg). LCMS: (M+1) m/z=447.

4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-(((R)-tetrahydrofuran-3yl )Amino)piperidin-1-yl)quinolin-8-carbonitrile (compound 183) was obtained as a pale brown oil in 15% yield (4.3mg). LCMS: (M+1) m/z=447.

Examples 184-186.

Reagents and conditions: i) Int-184-41 (1.0 eq.), amine (1.5 eq.), KF (2.0 eq.), DIPEA (3.0 eq.), DMSO,

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125°C, 18 h, 6-22%.

Synthesis of (2R,4R)-1-(6,8-difluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl- N((R)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 184).

Mixture of Int-184-41 (25 mg, 0.084 mmol), Int-184-16 (23 mg, 0.126 mmol), KF (10 mg, 0.168 mmol) and DIPEA (44 µl, 0.252 mmol) in DMSO (1 ml) heated at 125° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 and washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative TLC using EtOAc:/PrOH (97:3) followed by CH ₂ Cl ₂ /MeOH (95:5). Compound 184 was obtained as a pale yellow solid in 6% yield (2.1 mg). LCMS: (M+1) m/z=444.

(2R,4R)-1-(6,8-difluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N -((S)tetrahydrofuran-3-yl)piperidin-4-amine (compound 185) was obtained as a pale yellow solid in 12% yield (4.5 mg). LCMS: (M+1) m/z=444.

(2R,4R)-1-(6,8-difluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N (Tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 186) was obtained as a pale yellow solid in 22% yield (7.5 mg). LCMS: (M+1) m/z=458.

Examples 187-189.

Reagents and conditions: i) Int-187-45 (1.0 eq.), amine (1.5 eq.), KF (2.0 eq.), DIPEA (3.0 eq.), DMSO, 125° C, 18 h, 14-33%.

Synthesis of (2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)quinolin-2yl)-2- methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 187).

Mixture of Int-187-45 (25 mg, 0.072 mmol), Int-187-16 (20 mg, 0.108 mmol), KF (8.4 mg, 0.144 mmol) and DIPEA (38 µl, 0.216 mmol) in DMSO (1 ml) was heated at 125°C overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 and washed with brine. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by preparative TLC using EtOAc:/PrOH (98:2) followed by CH ₂ Cl ₂ /MeOH (97:3). Compound 187 was obtained as a pale orange solid in 14% yield (4.8 mg). LCMS: (M+1) m/z=494.

(2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)quinolin-2-yl)-2methyl -N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 188) was obtained as a pale orange solid in 31% yield (11.1 mg). LCMS: (M+1) m/z=494.

(2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)quinolin-2-yl)-2methyl -N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 189) was obtained as a pale orange solid in 33% yield (12.2 mg). LCMS: (M+1) m/z=508.

Examples 190-192.

Reagents and conditions i) Int-190-47 (1.0 eq.), amine (2.0 eq.), KF (2.5 eq.), DMSO, 125°C, 14 h, 23-24%.

Synthesis of (2R,4R)-1-(8-chloro-6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2- methyl N-(tetrahydro-2H-n-piran-4-yl)-n-piperidin-4-amine (compound 190).

A mixture of Int-190-47 (20 mg, 0.062 mmol), Int-190-4 (15 mg, 0.074 mmol) and KF (9 mg, 0.155 mmol) in DMSO (200 μl) was heated at 125° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with a solution of 1M NaOH (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5) compound 190 was obtained as a pale orange oil with a yield of 23% (7 mg). LCMS (M+1) m/z=484.

(2R,4R)-1-(8-chloro-6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N-((S)- 137 042282 tetrahydrofuran-3-yl)piperidin-4-amine (compound 191) was obtained as a pale brown oil in 23% yield (6.8 mg). LCMS (M+1) m/z=470.

(2R,4R)-1-(8-chloro-6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N-((R)tetrahydrofuran-3-yl)piperidin-4-amine (compound 192) was obtained as a pale orange oil in 24% yield (7.1 mg). LCMS (M+1) m/z=470.

Examples 193-194.

Reagents and conditions i) Int-193-48 (1.0 eq.), amine (2.0 eq.), KF (2.5 eq.), DMSO, 125°C, 14 h, 18-21%.

Synthesis of (2R,4R)-1-(6-cyclopropyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)2-methyl -N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 193).

A mixture of Int-193-48 (10 mg, 0.031 mmol), Int-193-4 (7.4 mg, 0.037 mmol) and KF (4.5 mg, 0.078 mmol) in DMSO (200 µl) was heated at 125°C during the night. The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with a solution of 1M NaOH (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 193 was obtained as a pale orange oil in 21% yield (3.2 mg). LCMS: (M+1) m/z=480.

(2R,4R)-1-(6-cyclopropyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2methyl-N -((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 194) was obtained as a pale yellow oil in 18% yield (3.9 mg). LCMS: (M+1) m/z=466.

Examples 195-197.

Reagents and conditions: i) Int-195-46 (1.0 eq.), amine (1.5 eq.), KF (2.5 eq.), DMF, 125°C, 18 h, 10-22% .

Synthesis of (2R,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2- methyl N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 195).

A mixture of Int-195-46 (15 mg, 0.049 mmol), Int-195-13 (15.6 mg, 0.074 mmol) and KF (7 mg, 0.123 mmol) in DMSO (200 µl) was heated at 125°C for nights. The mixture was cooled to room temperature, diluted with EtOAc (100 ml) and washed with 1M NaOH solution (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 195 was obtained as a pale brown oil in 22% yield (4.9 mg). LCMS: (M+1) m/z=454.

(2R,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N-((R)tetrahydrofuran-3-yl)piperidin-4-amine (compound 196) was obtained as a pale brown oil in 12% yield (2.6 mg). LCMS: (M+1) m/z=454.

(2R,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 197) was obtained as a pale yellow oil in 10% yield (3.2 mg). LCMS: (M+1) m/z=468.

Examples 198-203.

Reagents and conditions:

i) Int-198-49 (1.0 eq.), amine (1.5 eq.), KF (2.0 eq.), DIPEA (3.0 eq.), DMSO, 125°C, 18 hours , 50-56%;

ii) Int-198-50 (1.0 equiv.), NaB(OCH3) ₄ (4.0 equiv.), Pd2(dba)3 (2.5% equiv.), tBuXPhos (5.5% equiv. .), 1,4dioxane, 125°С, 2 h, 6-10%.

- 138 042282

Synthesis of Int-198-50.

A mixture of Int-198-49 (100 mg, 0.28 mmol), Int-195-13 amine in Example 195-197 (77 mg, 0.42 mmol), KF (33 mg, 0.56 mmol) and DIPEA ( 150 μl, 0.84 mmol) in DMSO (1 ml) was heated at 125° C. overnight. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and washed with brine. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by column chromatography (0~50% EtOAc in hexanes, then 0~10% MeOH in CH ₂ Cl ₂ ). The product was obtained as a green oil in 54% yield (77 mg). LCMS: (M+1) m/z=504. 506.

Interaction with Int-187-16 in example 187-189; 79 mg, green oil, 56% yield. LCMS: (M+1) m/z=504, 506.

Interaction with Int-187-4 in example 193-194; 73 mg, green solid, 50% yield. LCMS: (M+1) m/z=518, 520.

Obtaining NaB(OMe)4 before the synthesis of Int-198-51.

A solution of NaBH4 (0.5 g) in MeOH (25 ml) was refluxed for 30 min. After cooling to room temperature, the mixture was concentrated to dryness in vacuo and used without further purification.

Synthesis of Int-198-51 (a: Compound 198, b: Compound 199, c: Compound 200) and 52 (a: Compound 201, b: Compound 202, c: Compound 203).

A mixture of Int-198-50 (77 mg, 0.15 mmol), NaB(OMe)4 (96 mg, 0.61 mmol), Pd ₂ (dba) ₃ (3.5 mg, 2.5 mol%) and tBuXPhos (3.6 mg, 5.5 mol.%) in 1,4-dioxane (1.5 ml) was stirred at 125°C for 2 h. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and saturated saline solution. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:PrOH (97:3). (2R,4R)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N -((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 198) was obtained as a yellow solid in 6% yield (4.2 mg). LCMS: (M+1) m/z=456; by-product, (2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methylN- ((S)-tetrahydrofuran-3-yl)-piperidin-4-amine (compound 201) was obtained as a yellow oil in 3% yield (2.4 mg). LCMS: (M+1) m/z=426.

(2R,4R)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N((R)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 199) was obtained as a yellow solid in 10% yield (7.1 mg). LCMS: (M+1) m/z=456.

(2R,4R)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl -N(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 200) was obtained as a yellow solid in 6% yield (4.2 mg). LCMS: (M+1) m/z=470.

(2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-( (R)tetrahydrofuran-3-yl)piperidin-4-amine (compound 202) was obtained as a yellow oil in 5% yield (3.2 mg). LCMS: (M+1) m/z=426.

(2R,4R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-( tetrahydro2H-pyran-4-yl)piperidin-4-amine (compound 203) was obtained as a yellow oil in 0.8% yield (0.5 mg). LCMS: (M+1) m/z=440.

Example 204.

Int-172-18 Connection 204

Reagents and conditions: i) Int-204-49 (1.0 eq.), Int-172-18 (1.0 eq.), KF (2.0 eq.), DIPEA (2.0 eq.), DMSO, 125°C, 18 h, 38%, ii) Int-204-53 (1.0 eq.), NaB(OCH ₃ ) ₄ (4.0 eq.), Pd2(dba) ₃ (2.5 % equiv.), tBuXPhos (5.5% equiv.), 1,4-dioxane, 125°C, 2 h, 8%.

Synthesis of (2R,4S)-1-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2- methyl N-((S)-tetrahydrofuran-3-yl)-piperidin-4-amine Int-204-53.

A mixture of Int-204-49 (45.2 mg, 0.127 mmol), Int-172-18 amine in Example 172 (23.4 mg, 0.127 mmol), KF (15 mg, 0.254 mmol) and DIPEA (44 µl, 0.254 mmol) in DMSO (1 ml) was heated at 125° C. overnight. After cooling to room temperature, the mixture was diluted with CH2Cl2 and washed with brine. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography using hexane/EtOAc (0-50% EtOAc in hexane) and then CH ₂ Cl ₂ /MeOH (0-10% MeOH in CH ₂ Cl ₂ ) as the mobile phase. Product Int-204-53 was obtained as a green oil in 38% yield (24 mg). LCMS (M+1) m/z=505.

Synthesis of (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2methyl- N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 204).

A mixture of Int-204-53 (24 mg, 0.047 mmol), NaB(OMe)4 (30 mg, 0.19 mmol), Pd2(dba)3 (1 mg, 2.5 mol%) and tBuXPhos (1 mg , 5.5 mol %) in 1,4-dioxane (1 ml) was stirred at 125°C for 2 hours. After cooling to room temperature, the mixture was partitioned between CH2C12 and brine.

The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative

TLC using EtOAc/PrOH (97:3). Compound 204 was obtained as a yellow solid in 8% yield (1.7 mg). LCMS (M+1) m/z=456.

Example 205.

Reagents and conditions: i) Int-205-49 (1.0 eq.), Int-172-20 (1.0 eq.), KF (2.0 eq.), DIPEA (2.0 eq.), DMSO, 125°С, 18 h, 51%; ii) Int-205-54 (1.0 equiv.), NaB(OCH ₃ ) ₄ (4.0 equiv.), Pd ₂ (dba) ₃ (2.5% equiv.), tBuXPhos (5.5% equiv.), 1,4-dioxane, 125°С, 2 h, 4%.

Synthesis of (2S,4S)-1-(6-bromo-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2- methyl N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-205-54.

A mixture of Int-205-49 (33.2 mg, 0.093 mmol), Int-172-20 amine in Example 172 (17.2 mg, 0.093 mmol), KF (11 mg, 0.186 mmol) and DIPEA (32 µl, 0.186 mmol) in DMSO (1 ml) was heated at 125° C. overnight. After cooling to room temperature, the mixture was diluted with CH2Cl2 and washed with brine. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by column chromatography (0~50% EtOAc in hexane followed by 0~10% MeOH in CH2Cl2). Product Int-205-54 was obtained as a green oil in 51% yield (24 mg). LCMS: (M+1) m/z=504, 506.

Synthesis of (2S,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2methyl- N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 205).

A mixture of Int-205-54 (24 mg, 0.047 mmol), NaB(OMe) ₄ (30 mg, 0.19 mmol), Pd ₂ (dba) ₃ (1 mg, 2.5 mol%) and tBuXPhos (1 mg, 5.5 mol.%) in 1,4-dioxane (1 ml) was stirred at 125°C for 2 hours After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:/PrOH (97:3). Compound 205 was obtained as a yellow solid in 4% yield (0.9 mg). LCMS: (M+1) m/z=456.

Examples 206-208.

Reagents and conditions: i) Int-206-50 (1.0 equiv.), NaB(OCD ₃ ) ₄ (4.0 equiv.), Pd ₂ (dba) ₃ (2.5% equiv.), tBuXPhos ( 5.5% eq.), 1,4-dioxane, 125°C, 18 h, 1-11%.

С synthesis -2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 206).

A solution of NaBH ₄ (0.1 g) in CD3OD (5 ml) was refluxed for 30 minutes. After cooling to room temperature, the mixture was concentrated to dryness in vacuo and used without purification. A mixture of Int-206-50 (70.5 mg, 0.14 mmol), NaB(OCD ₃ ) ₄ (95 mg, 0.56 mmol), Pd ₂ (dba) ₃ (3.2 mg, 2.5 mol .%) and tBuXPhos (3.2 mg, 5.0 mol.%) in 1,4-dioxane (1.5 ml) was stirred at 125°C overnight. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:/PrOH (97:3). Compound 206 was obtained as a yellow oil in 4% yield (2.7 mg). LCMS: (M+1) m/z=459.

(2R,4R)-1-(8-fluoro-6-(methoxy-d3)-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl) -2-methylN-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 207) was obtained as a yellow oil in 1% yield (0.6 mg). LCMS: (M+1) m/z=459.

(2R,4R)-1-(8-fluoro-6-(methoxy-d3)-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl) -2-methylN-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 208) was obtained as a yellow oil in 11% yield (6 mg). LCMS: (M+1) m/z=473.

- 140 042282

Examples 209-211.

Reagents and conditions: i) Int-209-50 (1.0 eq.), iPrMgCl (3.0 eq.), Pd(OAc)2 (0.1 eq.), P(tBu) ₃ HBF ₄ (0 , 12 equiv.), ZnBr2 (0.5 equiv.), THF, 25°C, 2 h, 8-13%.

Synthesis of (2R,4R)-1-(8-fluoro-6-isopropyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2methyl- N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 209).

To a suspension of Int-209-50 (70.5 mg, 0.14 mmol), Pd(OAc) ₂ (3.1 mg, 0.014 mmol), P(tBu) ₃ HBF4 (4.9 mg, 0.017 mmol), ZnBr ₂ (70 µl, 1 M in THF) in THF (1.5 ml) was added a 2 M solution of PrMgCl (0.21 ml, 0.42 mmol) and the mixture was stirred at room temperature for 2 h. water and product were extracted with EtOAc (3x). The combined organic layers were washed with 1% aq. HCl solution and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:iPrOH (97:3) and CH ₂ Cl ₂ :MeOH (96:4). Compound 209 was obtained as a yellow solid in 8% yield (5.4 mg). LCMS: (M+1) m/z=468.

(2R,4R)-1-(8-fluoro-6-isopropyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methylN -((R)-tetrahydrofuran-3-yl)piperidin-4-amine (compound 210) was obtained as a yellow solid, 8% yield (5.2 mg). LCMS: (M+1) m/z=468.

(2R,4R)-1-(8-fluoro-6-isopropyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methylN -(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 211) was obtained as a yellow oil, 13% yield (7.4 mg). LCMS: (M+1) m/z=482.

Examples 212-213.

Reagents and Conditions i) Int-212-55 (1.0 eq.), Int-172-16 (1.5 eq.), KF (2.0 eq.) DIPEA (3.0 eq.), DMSO, 125°C, 18 h, 48%, ii) Int-212-56(l.0 eq.), Zn(CN) ₂ (1.0 eq.), Zn (0.1 eq.), Pd(PPh ₃ ) ₄ (0.1 equiv.), THF/DMF (1:1, v/v), 80°C, 18 h, 2% (for compound 212) and 58% (for Int-212-57 ), iii) Int-21-57 (1.0 eq.), EtB(OH) ₂ (1.4 eq.), PCy ₃ (0.1 eq.), K ₃ PO ₄ (3.6 eq. ), Pd(OAc) ₂ (5% equiv.), Toluene, H ₂ O, 100°C, 18 h, 18%.

Synthesis of (2R,4R)-1-(6-bromo-8-iodo-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2- methyl N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine Int-212-56.

A mixture of Int-212-55 (150 mg, 0.32 mmol), Int-172-16 amine of Example 172 (89 mg, 0.48 mmol), KF (37 mg, 0.64 mmol) and DIPEA (0.17 ml, 0.96 mmol) in DMSO (2 ml) was heated at 125° C. overnight. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and washed with brine. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by column chromatography using hexane/EtOAc (0-50% EtOAc in hexane) and then CH ₂ Cl ₂ /MeOH (0-10% MeOH in CH ₂ Cl ₂ ) as mobile phase. The product was obtained as a dark green oil in 48% yield (94.3 mg). LCMS (M+1) m/z=612, 614.

Synthesis of 4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-(((R)-tetrahydrofuran-3yl) amino)piperidin-1-yl)quinolin-6,8-dicarbonitrile (compound 212) and 57.

Mixture of Int-212-56 (94.3 mg, 0.154 mmol), Zn(CN) ₂ (18.0 mg, 0.154 mmol), Zn powder (1.0 mg, 0.0154 mmol) and Pd(PPh ₃ ) ₄ (17.8 mg, 0.0154 mmol) in THF/DMF (2 ml, 1:1, v/v) was stirred at 80° C. overnight. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC using EtOAc/PrOH (98:2) to give compound 212 as a yellow solid (1.4 mg, 2% yield) and 57 as a yellow solid with 58% (45.6 mg). LCMS (M+1) m/z=511, 513.

- 141 042282

Synthesis of 6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-(((R)tetrahydrofuran -3-yl)amino)piperidin-1-yl)quinoline-8-carbonitrile (compound 213).

A mixture of Int-212-57 (45.6 mg, 0.089 mmol), EtB(OH) ₂ (9.2 g, 0.125 mmol), P(Cy)3 (2.5 mg, 0.0089 mmol), Pd( OAc) ₂ (1.0 mg, 0.0045 mmol) and K3PO4 (68 mg, 0.32 mmol) in toluene (2 ml) and H ₂ O (40 μl) were stirred and heated at 100°C overnight. After cooling to room temperature, the mixture was filtered through celite. Filtered, concentrated in vacuo and purified by preparative TLC using EtOAc:iPrOH (98:2) followed by CH ₂ Cl ₂ /MeOH (973). The product, compound 213, was obtained as a yellow solid in 18% yield (7.4 mg). LCMS (M+1) m/z=461.

Examples 214-215.

Reagents and conditions i) Int-214-58 (1.0 eq.), Et ₃ B (1.5 eq.), K ₂ CO ₃ (2.0 eq.), Pd(PPh ₃ ) ₄ (5% equiv.), THF/DMF (1:1, v/v), 80°C, 1.5 h, 66%, ii) Int-214-59 (1.0 equiv.), NIS (1, 05 equiv.), AcOH, room. temp., 1.5 h, 88%, iii) Int-214-60 (1.0 eq.), POCl ₃ , 100°C, 1 h, 44%, iv) Int-214-61 (1.0 equiv.), amine (1.5 equiv.), KF (2.0 equiv.) DIPEA (3.0 equiv.), DMSO, 125°C, 18 h, 32-41%, v) Int-214-62 (1.0 equiv.) Zn(CN) ₂ (1.5 equiv.), Zn (0.1 equiv.), Pd(PPh3) ₄ (0.1 equiv.), DMF, 80°C, 18 h , 13-17%.

Synthesis of Int-214-59.

To a mixture of Int-214-58 (6.0 g, 28.0 mmol), K2CO3 (7.7 g, 56.0 mmol) and Pd(PPh ₃ ) ₄ (1.6 g, 1.4 mmol) in THF/DMF (60 ml, 1:1 v/v) was added a 1M solution of Et ₃ B in THF (42 ml, 42.0 mmol) at room temperature The mixture was then heated at 80°C for 1.5 h. After cooling to room temperature, the mixture was filtered through celite. The filter material was concentrated in vacuo and purified by column chromatography using hexane/EtOAc (0-20% EtOAc in hexane) as mobile phase. Product Int-214-59 was obtained as a yellow solid in 66% yield (3.0 g). LCMS: (M+1) m/z=164.

Synthesis of Int-214-60.

To a mixture of Int-214-59 (2.5 g, 15.6 mmol) in acetic acid (50 ml) was added NIS (3.7 g, 16.4 mmol) in one portion and the mixture was stirred at room temperature for 1, 5 hours The mixture was diluted with EtOAc (500 ml) and washed with brine (3x) and sat. NaHCO3 solution (2x). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by column chromatography using hexane/EtOAc (0-30% EtOAc in hexane) as the mobile phase. The product was obtained as a red oil in 88% yield (4.0 g). LCMS: (M+1) m/z=290.

Synthesis of Int-214-61.

A mixture of Int-214-60 (2.09 g, 7.23 mmol) and Int-214-25 (1.13 g, 7.95 mmol) in POCl ₃ (14 ml) was stirred at 100°C for 1 h After cooling to room temperature, excess POCl ₃ was removed in vacuo. H2O was added to the residue at 0°C and the mixture was stirred at 0°C for 10 min. The precipitated crude chloroquinoline Int-214-61 was filtered, washed with H ₂ O and dried under reduced pressure. The solid was purified by column chromatography (0-20% EtOAc in hexane) as mobile phase. The product was obtained as a yellow solid in 44% yield (1.33 g).

Synthesis of Int-214-62.

A mixture of Int-214-61 (75 mg, 0.18 mmol), Int-214-13 (50 mg, 0.27 mmol), KF (21 mg, 0.36 mmol) and DIPEA (94 µl, 0.54 mmol) in DMSO (2 ml) was heated at 125°C overnight. After cooling to room temperature, the mixture was diluted with CH2Cl2 and washed with brine. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by column chromatography using hexane/EtOAc (0-50% EtOAc in hexane) and then CH ₂ Cl ₂ /MeOH (010% MeOH in CH ₂ Cl ₂ ) as the mobile phase. Product Int-214-62a was obtained as a dark brown oil in 41% yield (41.4 mg). LCMS: (M+1) m/z=562.

Reaction with the amine Int-214-4 gave Int-214-62b (33.1 mg, 32% yield) as a dark brown oil. LCMS: (M+1) m/z=576.

Synthesis of 6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-(((S)- 142 042282 tetrahydrofuran-3-yl)amino)piperidin-1-yl)quinolin-8-carbonitrile (compound 214).

Mixture of Int-214-62 (41.4 mg, 0.074 mmol), Zn(CN) ₂ (13.0 mg, 0.111 mmol), Zn powder (0.5 mg, 0.0074 mmol) and Pd(PPh ₃ ) ₄ (8.6 mg, 0.0074 mmol) in DMF (2 ml) was stirred at 80° C. overnight. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:/PrOH (98:2) then CH ₂ Cl/MeOH (97:3). The product, compound 214, was obtained as a yellow solid in 17% yield (6.0 mg). LCMS: (M+1) m/z=461.

6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-((tetrahydro-2H-pyran -4yl)amino)piperidin-1-yl)quinolin-8-carbonitrile (compound 215) was obtained as a yellow solid in 29% yield (7.9mg). LCMS: (M+1) m/z=475.

Example 216.

Reagents and conditions: i) Int-216-66 (1.0 eq.), amine (1.2 eq.), TMP/DMSO (1:1, v/v), 150°C, 18 h, 8%.

Synthesis of (2R,4S)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N( tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 216).

A mixture of Int-216-66 (30 mg, 0.104 mmol) and 7 (23 mg, 0.125 mmol) in 2,2,6,6tetramethylpiperidine/DMSO (1.5 ml, 1:1 v/v) was heated at 150 °C during the night. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using CHCl/MeOH (96:4). The product, compound 216, was obtained as a brown oil in 8% yield (3.7 mg). LCMS: (M+1) m/z=450.

Example 217.

Reagents and conditions: i) Int-217-66 (1.0 eq.), amine (1.2 eq.), TMP/DMSO (1:1, v/v), 150°C, 18 h, 6%.

Synthesis of (2R,4R)-1-(6-ethyl-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N( tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 217).

A mixture of Int-217-66 (30 mg, 0.104 mmol) and Int-217-4 (23 mg, 0.125 mmol) in 2,2,6,6tetramethylpiperidine/DMSO (1.5 ml, 1:1 v/v) ) was heated at 150° C. overnight. After cooling to room temperature, the mixture was partitioned between CH2Cl2 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (96:4). The product, compound 217, was obtained as a brown oil in 6% yield (2.7 mg). LCMS: (M+1) m/z=450.

Examples 218-220.

Reagents and conditions: i) Int-218-67 (1.0 eq.), amine (1.2 eq.), KF (2.5 eq.), DIPEA (2.0 eq.), DMF, 125° C, 18 h, 13%.

Synthesis of (2R,4R)-1-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl- N(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (compound 218).

A mixture of Int-218-67 (15 mg, 0.051 mmol) and Int-172-4 (12.3 mg, 0.062 mmol), KF (7.4 mg, 0.128 mmol) and

- 143 042282

DIPEA (18 μl, 0.102 mmol) in DMF (200 μl) was heated at 125° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc (60 ml) and washed with a solution of 1M NaOH (3x).

The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 218 was obtained as a pale yellow oil in 13% yield (3.1 mg). LCMS: (M+1) m/z=454.

(2R)-1-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-( (S)tetrahydrofuran-3-yl)piperidin-4-amine (compound 219) was obtained as a pale yellow oil in 15% yield (3.3 mg). LCMS: (M+1) m/z=440.

(2R)-1-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-( (R)tetrahydrofuran-3-yl)piperidin-4-amine (compound 220) was obtained as a pale yellow oil in 13% yield (3.0 mg). LCMS: (M+1) m/z=440.

Compounds 219a and 220a were prepared according to the procedure described for compounds 219220, replacing the amine Int-218-4 with an amine with suitable stereochemistry and functionality.

Examples 221-223.

Reagents and conditions: i) Int-221-29 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.), DIPEA (2.0 eq.) , iPrOH, 120°C, overnight, 23%; ii) Int-221-69 (1.0 eq.), H ₂ SO ₄ (10% aq.), THF, 40° C., 2 h, 62%; iii) Int-221-70 (1.0 eq.), Amine (2.0 eq.), NaBH(OAc) ₃ (2.0 eq.), AcOH (2.0 eq.), DIPEA (2, 0 equiv.), 1,2dichloroethane, room. temp., during the night, 76-95%.

Synthesis of Int-221-69.

Suspension of Int-221-29 (210 mg, 0.669 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (190 mg, 1.33 mmol) and DIPEA (233 µl, 1.33 mmol) in iPrOH (4 ml) was heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc) to give Int-221-69 ketal as a yellow solid in 23% yield (65 mg). LCMS: (M+1) m/z=419.

Synthesis of Int-221-70.

A solution of Int-221-69 ketal (60 mg, 0.143 mmol) in THF/10% aq. H2SO4 (1:1, 1.5 ml) was stirred at 40° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous NaOH and extracted with EtOAc (2x). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give Int-221-70 ketone as a yellow solid in 62% yield (33 mg) which was used in the next step without further purification by LCMS (M+1) m /z=367.

Synthesis of compounds 221-223.

Mixture of ketone Int-221-70 (8 mg, 0.021 mmol), 4-aminotetrahydropyran (4.3 mg, 0.043 mmol), DIPEA (7.4 µl, 0.043 mmol), NaBH(OAc)3 (9 mg, 0.043 mmol ) and AcOH (2.4 μl, 0.043 mmol) in 1,2-dichloroethane was stirred at room temperature overnight. The mixture was filtered through Celite, concentrated under reduced pressure and purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5) to give 1-(6-chloro-8-fluoro-4-methyl-3-(3-methyl- 1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro2H-pyran-4-yl)piperidin-4-amine (compound 221) as a pale yellow solid in 91% yield (8.9 mg). LCMS (M+1) m/z=460.

(S)-1-(6-chloro-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydrofuran3- yl)piperidine-4-amine (compound 222) was obtained as a pale yellow solid in 95% yield (9.0 mg). LCMS (M+1) m/z=446.

(S)-1-(6-chloro-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro- 2Hpyran-3-yl)piperidin-4-amine (compound 223) was obtained as a pale yellow oil in 76% yield (7.4 mg). LCMS (M+1) m/z=460.

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Examples 224-225.

Reagents and Conditions i) Int-224-67 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.), DIPEA (2.0 eq.), EtOH, 120°C, overnight, 84%, ii) Int-224-71 (1.0 eq.), H2SO4 (10% aq.), THF, 50°C, 2 h, 87%, iii) Int -224-72 (1.0 eq.), amine (1.2 eq.), NaBH(OAc) ₃ (2.0 eq.), AcOH (2.0 eq.), DIPEA (2.0 eq. ), 1,2dichloroethane, room temp., during the night, 50-62%.

Synthesis of Int-224-71.

To a suspension of chloroquinoline Int-224-67 (210 mg, 0.75 mmol) and DIPEA (0.26 ml, 1.50 mmol) in EtOH (5 ml) was added 1,4-dioxa-8-azaspiro[4.5 ]decane (0.20 ml, 1.50 mmol) at room temperature. The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (0-20% EtOAc in hexane) as the mobile phase. The product Int-224-71 was obtained as a pale yellow solid in 84% yield (251 mg). LCMS: (M+1) m/z=399.

Synthesis of Int-224-72.

To a solution of Int-224-71 (246 mg, 0.62 mmol) in THF (2.5 ml) was added 10% aq. H ₂ SO ₄ (5 ml) at room temperature. The mixture was then stirred at 50° C. for 1 h. After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and extracted with EtOAc (2x20 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by column chromatography (0-66% EtOAc in hexane as mobile phase). The product Int-224-72 was obtained as a yellow solid in 87% yield (189 mg). LCMS: (M+1) m/z=355.

Synthesis of (R)-1-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N(tetrahydrofuran-3- yl) piperidine-4-amine (compound 224).

A mixture of Int-224-72 (10.0 mg, 0.028 mmol), (R)-3-aminotetrahydrofuran hydrochloride (4.2 mg, 0.034 mmol) and DIPEA (10 µl, 0.056 mmol) in 1,2-dichloroethane (1 ml) was stirred at room temperature for 10 min. NaBH(OAc) ₃ (12.0 mg, 0.056 mmol) and AcOH (3 μl, 0.056 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (96:4). The product, compound 224, was obtained as a yellow solid in 62% yield (7.4 mg). LCMS: (M+1) m/z=426.

(S)-1-(8-fluoro-4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydrofuran-3yl) piperidine-4-amine (compound 225) was obtained as a yellow solid in 50% yield (5.9 mg). LCMS: (M+1) m/z=426.

Examples 226-227.

H Connection 226 Connection 227

Reagents and Conditions i) Int-226-33 (1.0 eq.), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 eq.), DIPEA (2.0 eq.), EtOH, 120°C, overnight, 77%, ii) Int-226-73 (1.0 eq.), H2SO4 (10% aq.), THF, 50°C, 2 h, 59%, iii) Int-226-74 (1.0 eq.), Amine (1.2 eq.), NaBH(OAc)3 (2.0 eq.), AcOH (2.0 eq.), DIPEA (2.0 eq. .), 1,2dichloroethane, room temp., during the night, 67-79%.

Synthesis of Int-226-73.

To a suspension of chloroquinoline Int-226-33 (170 mg, 0.47 mmol) and DIPEA (0.16 ml, 0.94 mmol) in EtOH (5 ml) was added 1,4-dioxa-8-azaspiro[4.5 ]decane (0.12 ml, 0.94 mmol) at room temperature The mixture was then heated at 120° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (0-20% EtOAc in hexane) as mobile phase.

The product Int-226-73 was obtained as a red oil in 77% yield (170 mg). LCMS (M+1) m/z=469.

Synthesis of Int-226-74.

To a solution of Int-226-73 (170 mg, 0.36 mmol) in THF (2 ml) was added 10% aq H ₂ SO ₄ (3 ml) at room temperature. The mixture was then stirred at 50°C for 2 hours After cooling to room temperature, the mixture was neutralized with saturated aqueous Na ₂ CO ₃ and was extracted with EtOAc (2x20 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by column chromatography (0-66% EtOAc in hexanes) as mobile phase. The product Int-226-74 was obtained as a red oil in 59% yield (91 mg). LCMS (M+1) m/z=425.

Synthesis of 1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-(trifluoromethoxy)quinolin-2-yl)-N(tetrahydro-2Н- pyran-4-yl)piperidine-4-amine (compound 226).

A mixture of Int-226-74 (15.0 mg, 0.035 mmol), 4-aminotetrahydropyran (4.2 mg, 0.042 mmol) and DIPEA (12 μl, 0.070 mmol) in 1,2-dichloroethane (1 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (14.8 mg, 0.070 mmol) and AcOH (4 μl, 0.070 mmol) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (96:4). The product, compound 226, was obtained as a brown solid in 67% yield (11.9 mg). LCMS: (M+1) m/z=510.

(R)-1-(8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-(trifluoromethoxy)quinolin-2-yl)-N(tetrahydrofuran -3-yl)piperidin-4-amine (compound 227) was obtained as a yellow solid in 79% yield (13.9 mg). LCMS: (M+1) m/z=496.

Example 228.

Compound 228

Synthesis of (R)-1-(8-fluoro-6-(methoxy-d3)-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)- N(tetrahydrofuran-3-yl)piperidin-4-amine (compound 228).

Step 1: Following the preparation of Int-33-14j in which KB(OCH ₃ ) ₄ was replaced with KB(OCD ₃ ) ₄ , Int228-1 was obtained as a white solid after purification by silica gel chromatography (0-60% EtOAc/ hexane). LCMS: m/z 418 (M+H).

Step 2-3: Following the procedure described above for compound 34 and using the appropriate deuterium-substituted intermediate(s), compound 228 was obtained as a white solid. LCMS: m/z 445 (M+H); retention time: 3.55 min (method 2).

Example 229

Following the general procedure for the synthesis of compound 197, using the appropriate chiral amine, compound 229 was obtained as a white solid; LCMS: m/z 468 (M+H).

Examples 230-235.

Compounds 230-235 were prepared using the methods disclosed in Examples 195-197 or 236237 using amines and alkylating agents with suitable stereochemistry.

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Examples 236-237.

Compound 236b

Compound 236a

Compound 237a Compound 237b

236a and 236b: mixture of (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin2-yl)- 2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine and (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl3-(3-methyl-1 ,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4 amine, and

237a and 237b: mixture of (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin2-yl)- 2-methyl-N-((8)-tetrahydrofuran-3-yl)piperidin-4-amine and (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl3-(3-methyl-1 ,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((8)-tetrahydrofuran-3-yl)piperidin-4 amine.

Reagents and conditions i) KB(OMe) ₄ (3 equiv.), Pd2(dba)3 (0.05 equiv.), tBuXphos (0.1 equiv.), dioxane, 100°C, 2 h, ii) KF (2.5 eq), DMSO, 130°C, iii) TFA, DCM, iv) DIPEA (4 eq), CH3CN, microwave, 120°C, iv) DIPEA (4 eq), CH3CN, microwave, 120° WITH.

Int-236-1 was synthesized from Int-1-1c according to the general procedure for the synthesis of Int-33-14j.

Synthesis of tert-butyl 1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)trans-2-methylpiperidin- 4-yl)carbamate (Int-236-3).

A microwave vessel was charged with 5-(2-chloro-8-fluoro-6-methoxy-4-methylquinolin-3yl)-3-methyl-1,2,4-oxadiazole (Int-236-1) (0.143 mg, 0.45 mmol), racemic tert-butyl N-[(trans)-2methylpiperidin-4-yl]carbamate (Int-236-2, 0.199 g, 0.929 mmol), potassium fluoride (67.5 mg, 1.16 mmol ), anhydrous DMSO (1.2 ml) and diisopropylethylamine (0.21 ml, 1.16 mmol). The mixture was placed under a nitrogen atmosphere and heated at 130° C. for 15 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic extract was washed successively with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to 300 mg. The crude product was purified by column chromatography eluting from 12 g silica gel with a 0-40% EA/hexane gradient to give the title product as a yellow oil (140 mg, 61% yield). LCMS: (M+1) m/z=486.1.

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Synthesis of 1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-trans-2methylpiperidin-4-amine ( Int-236-4).

To a cooled 0°C solution of tert-butyl 1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4oxadiazol-5-yl)quinolin-2-yl)-trans- 2-methylpiperidin-4-yl)carbamate (Int-236-3, 135 mg, 0.278 mmol) in 5 ml DCM was added 2.5 ml TFA. The mixture was stirred for 1.5 h at room temperature, concentrated to an orange foam and partitioned between equal volumes of half-saturated Na ₂ CO ₃ solution and EtOAc. The organic solution was washed with Na ₂ CO 3 solution twice, dried over sodium sulfate and concentrated to give Int-236-4 as a yellow solid (99 mg, 94% yield). LCMS: (M+1) m/z=386.2.

Synthesis of compounds 236а methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine and 236b (2S,4R)-1-(8-fluoro-6methoxy-4-methyl-3-(3-methyl-1, 2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3yl)piperidin-4-amine.

1-(8-Fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4oxadiazol-5-yl)quinolin-2-yl)-trans-2-methylpiperidine was loaded into a microwave treatment vessel -4-amine (Int-236-4, 55 mg, 0.14 mmol), (3S)oxolan-3-yl 4-methylbenzene-1-sulfonate (Int-172-14, 140 mg, 0.56 mmol) , diisopropylethylamine (97 µl, 0.56 mmol) and CH3CN (0.9 ml). The mixture was heated at 120°C in a microwave for 12 hours. The mixture was partitioned between EtOAc and aqueous Na ₂ CO ₃ , the organic layer over sodium sulfate and concentrated to 225 mg of an orange oil. The crude product was purified by column chromatography eluting from silica gel with a 0-60% EtOAc/hexane gradient followed by a 0-10% MeOH/DCM gradient to give a mixture of diastereoisomers as a yellow solid (40 mg, 63% yield). The mixture can be separated to obtain individual diastereomers using a phenomenex Lux 5 µm cellulose-2 column (250 mm x 4.6 mm, hexane:ethanol:DEA (80:20:1), 1 ml/min, retention time: 15.7 min, 17.5 min LCMS: (M+1) m/z=356.1.

Synthesis of compound 237a methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine and compound 237b (2S,4R)1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl- 1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((S)tetrahydrofuran-3-yl)piperidin-4-amine.

1-[8-Fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4oxadiazol-5-yl)quinolin-2-yl]-trans-2-methylpiperidine was loaded into a microwave treatment vessel -4-amine (Int-236-4, 58 mg, 0.15 mmol), (3R) oxolan-3-yl 4-methylbenzene-1-sulfonate (Int-172-11, 146 mg, 0.56 mmol) , DIPEA (0.105 ml, 0.56 mmol) and CH ₃ CN (0.9 ml). The mixture was heated for 12 hours at 120° C. in a microwave reactor. The mixture was partitioned between EtOAc and aqueous Na2CO3, the organic layer was dried over sodium sulfate and concentrated to 170 mg of an orange oil. The crude product was purified by column chromatography eluting with a 0-60% EtOAc/hexane gradient followed by a 0-10% MeOH/DCM gradient to give a mixture of diastereoisomers as a yellow solid (38 mg, 56% yield). The mixture can be separated to obtain individual diastereomers using a phenomenex Lux 5 µm cellulose-4 column (250 mm x 4.6 mm, hexane:ethanol:DEA (73:27:0.1), 1 ml/min, retention time: 7 .2 min, 8.9 min LCMS: (M+1) m/z=356.1.

Example 238-239.

Compound 238 Compound 239

Compounds 238 and 239 were prepared according to the procedure described above for compound 228 and the appropriate amines were used in step 3. Compound 238: yellow solid; LCMS: m/z 459 (M+H); retention time: 3.71 min (method 2). Compound 239: white solid; LCMS: m/z 429 (M+H); retention time: 3.90 min (method 2).

Example 240.

I OD__ DI O' ¹ ^__ DI O'N_ ^Bf TYj ^N -i^rvGDj Ji! ^Nlnt -172-4

Y^N^CI Pd(PPh ₃ ) ₂ CI ₂ KF, DMSO ψΉ lnt-240-1 lnt-240-2 ^H

Compound 240

Step 1: To a suspension of 5-(6-bromo-2-chloro-8-fluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole (357 mg, 1.00 mmol) and bis(triphenylphosphine)palladium(II) chloride (68 mg, 88 µmol) in THF (2 ml) was added a suspension of (methyl-d3)zinc(II) iodide (7.0 ml, ref: DOI: 10.1039/c7cc06106d) and the reaction mixture was stirred at 60° C. for 4 hours. The reaction was quenched with a solution of citric acid (5% aq.) and was extracted with ethyl acetate two times. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/Hex) to give the title product as a white solid (153 mg, 52% yield). LCMS (ESI): m/z 295 (M+H).

Step 2: Similar to the preparation of compound 174, replacing 5-(2,8-dichloro-4,6-dimethylquinolin-3yl)-3-methyl-1,2,4-oxadiazole with 5-(2-chloro-8-fluoro- 4-methyl-6-(methyl-c13)quinolin-3-yl)-3-methyl-1,2,4oxadiazole gave compound 240 as a white solid. LCMS: m/z 457 (M+H).

Example 241-242.

Following the procedure for the preparation of compound 240, compound 241 was obtained as a white solid; LCMS: m/z 443 (M+H); retention time: 3.62 min (method 2). Compound 242 was obtained as a white solid; LCMS: m/z 443 (M+H); retention time: 3.74 min (method 2).

Example 243.

Following the general synthetic procedure for compound 197, using the appropriate chiral amine, compound 243 was obtained as a white solid; LCMS: m/z 468 (M+H).

Example 244.

Compound 244

Compound 244 was prepared using the methods disclosed in Examples 259-260 using the appropriate chiral amine Int-259-13 and Int-36-14h.

Examples 245-248.

Synthesis of 4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-(((tetrahydro-2Hpyran-4 -yl)methyl)amino)piperidin-1-yl)quinoline-8-carbonitrile (compound 245).

A mixture of Int-245-1 (200 mg, 0.67 mmol), Int-245-2 (172 mg, 0.804 mmol) and KF (97 mg, 1.67 mmol) in DMSO (2 ml) was heated at 125°C during the night. The mixture was cooled to room temperature, diluted with EtOAc (150 ml) and washed with brine (3x). The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was purified column

- 149 042282 chromatography using hexane/EtOAc (7:3). The product was obtained as a yellow solid in 56% yield (180 mg). LCMS: (M+1) m/z=477.

A mixture of Int-245-3 (170 mg, 0.356 mmol) and TFA (550 μl, 7.13 mmol) in CH ₂ Cl ₂ (5 ml) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and washed with 2M NaOH solution (2x). The aqueous phase was extracted with EtOAc (2x). The combined organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the product was used without further purification. Int-245-4 was obtained as a yellow solid in 95% yield. LCMS: (M+1) m/z=377.

A mixture of amine Int-245-4 (10 mg, 0.026 mmol) and Int-245-5 (3 mg, 0.026 mmol) in DCE (200 µl) was stirred at room temperature for 1 h followed by the addition of NaBH(OAc) ₃ ( 11 mg, 0.052 mmol) and AcOH (2.9 µl, 0.052 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (50 ml) and washed with 2M NaOH solution (1x). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 245 was obtained as a yellow solid in 49% yield (6.1 mg). LCMS: (M+1) m/z=475.

Synthesis of 4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-((((R)tetrahydrofuran- 2-yl)methyl)amino)piperidin-1-yl)quinolin-8-carbonitrile (compound 246).

A mixture of Int-245-4 (10 mg, 0.026 mmol), Int-245-6 (13.3 mg, 0.052 mmol) and DIPEA (9.1 µl, 0.052 mmol) in acetonitrile (150 µl) was heated at 80° C. during the night. The mixture was concentrated under reduced pressure and purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 246 was obtained as a yellow oil in 53% yield (6.3 mg). LCMS: (M+1) m/z=461.

Synthesis of 4,6-dimethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-2-((2R,4R)-2-methyl-4-((((S)tetrahydrofuran- 2-yl)methyl)amino)piperidin-1-yl)quinolin-8-carbonitrile (compound 247).

Compound 247 was synthesized in the same manner and was obtained as a yellow oil in 50% yield (6.0 mg). LCMS: (M+1) m/z=461.

Synthesis of 2-((3S,4R)-3-fluoro-4-((tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)-4,6-dimethyl-3-(3methyl-1, 2,4-oxadiazol-5-yl)quinoline-8-carbonitrile (compound 248).

A mixture of Int-245-1 (20 mg, 0.067 mmol), Int-245-8 (34.4 mg, 0.08 mmol) and DIPEA (47 µl, 0.268 mmol) in EtOH (250 µl) was heated at 125°C during the night. The mixture was concentrated under reduced pressure and purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5). Compound 248 was obtained as a yellow solid in 46% yield (14.3 mg). LCMS: (M+1) m/z=465.

Example 249.

lnt-85-43

Compound 249

Synthesis of (R)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(4-((tetrahydro-2H-pyran-3-yl)amino)piperidin-1yl)-6 -(trifluoromethoxy)quinoline-8-carbonitrile (compound 249).

Mixture of ketone Int-85-43 (5 mg, 0.012 mmol), 3-(R)-aminotetrahydropyran HCl (3.3 mg, 0.024 mmol), DIPEA (4.2 µl, 0.024 mmol), NaBH(OAc)3 ( 5 mg, 0.024 mmol) and AcOH (1.3 μl, 0.024 mmol) in 1,2 dichloroethane were stirred at room temperature overnight. The mixture was filtered through celite, concentrated under reduced pressure and purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 249 (4.1 mg, 69% yield) as a yellow solid. LCMS: (M+1) m/z=503.

Example 250.

lnt-141-8 N

Compound 250

Synthesis of 1-(6-ethyl-8-fluoro-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran4-yl)piperidine -4-amine (compound 250).

A mixture of Int-141-8 (8 mg, 0.022 mmol), 4-aminotetrahydropyran (3.4 mg, 0.034 mmol), NaBH(OAc) ₃ (7.2 mg, 0.034 mmol) and AcOH (1.9 µl, 0 ,13 mmol) in 1,2-dichloroethane (0.4 ml) was stirred at room temperature for 3 h. The reaction mixture was directly purified by preparative TLC (CH ₂ Cl ₂ : MeOH=95:5) to give compound 250 as a yellow solid (8.1 mg, 82% yield). LCMS: (M+1) m/z=440.

- 150 042282

Example 251.

Synthesis of (R)-1-(6-ethyl-8-fluoro-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydrofuran3-yl)piperidine -4-amine (compound 251).

Mixture of Int-141-8 (10 mg, 0.028 mmol), (R)-tetrahydrofuran-3-amine hydrochloride (4.2 mg, 0.034 mmol) and DIPEA (5.9 µl, 0.11 mmol) in 1.2 -dichloroethane (0.4 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (8.9 mg, 0.042 mmol) and AcOH (2.3 μl, 0.042 mmol) were added to the mixture. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative TLC (CH ₂ Cl ₂ :MeOH=95:5) to give compound 251 as a yellow solid (8.1 mg, 68% yield). LCMS: (M+1) m/z=426.

Example 252-253.

(S)-1-(6-ethyl-8-fluoro-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydrofuran-3yl)piperidine- 4-amine (compound 252) was synthesized in the same manner as compound 251 and was obtained as a yellow solid in 82% yield (9.8 mg). LCMS: (M+1) m/z=426.

Synthesis of (S)-1-(6-ethyl-8-fluoro-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2Hpyran-3 -yl)piperidin-4-amine (compound 253) was carried out in the same manner as the synthesis of compound 251, and the product was obtained as a yellow solid in 84% yield (10.4 mg). LCMS: (M+1) m/z=440.

Example 254.

Synthesis of compounds 254.

Compound 254 (7.6 mg, 40% yield at final step) was obtained as a white solid following the procedure for the synthesis of compound 170, replacing 6-bromo-4-methyl-3-(5-methyl-1,2,4- oxadiazol-3-yl)-2(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)quinoline-8-carbonitrile on 6-bromo-3-(3-methyl-1,2, 4-oxadiazol-5yl)-2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)quinoline-8-carbonitrile. LCMS (ESI): m/z 435 (M+H); retention time: 1.86 min (method 1).

Example 255.

Compound 255 was prepared according to the procedure described for compound 85, replacing the starting aldehyde Int-85-38 with the appropriate methyl ketone.

Example 256-258.

Compounds 256-258 were prepared according to the procedure described for compounds 174-176, replacing the amine Int-174-4 with an amine with suitable stereochemistry.

- 151 042282

Example 259 and 260.

Synthesis of (3S,4R)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine Int-259-13.

A mixture of Int-259-10 (100 mg, 0.46 mmol), Int-259-11 (86 µl, 0.93 mmol), NaBH(OAc) ₃ (197 mg, 0.93 mmol) and AcOH (51, 6 μl, 0.93 mmol) in DCE (2 ml) was stirred at room temperature overnight. The mixture was quenched with a 1M NaOH solution and extracted with EtOAc (4x). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography eluting with a CH ₂ Cl ₂ /MeOH gradient to give Int-259-12 as a white solid (122 mg, 89% yield). LCMS (M+1) m/z=299.

A mixture of Int-259-12 (120 mg, 0.402 mmol) and TFA (615 μl, 3.61 mmol) in CH ₂ Cl ₂ (2 ml) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The product, Int-259-13, was used without further purification (white solid). LCMS (M+1) m/z=199.

Synthesis of (3R,4S)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine, Int-259-16.

Int-259-16 was synthesized in the same manner as Int-259-13, replacing Int-259-10 with Int-259-14, and obtained as a white solid (87% yield, two steps). LCMS: (M+1) m/z=199.

Synthesis of (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-3- methylN-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine, compounds 259.

A mixture of Int-142-11 (15 mg, 0.049 mmol), Int-259-13 (31 mg, 0.074 mmol) and DIPEA (42 μl, 0.245 mmol) in iPrOH (250 μl) was heated at 125° C. overnight. The mixture was concentrated under reduced pressure and purified by preparative TLC using CH ₂ Cl ₂ /MeOH (95:5) as eluent. Compound 259 was obtained as a yellow solid in 31% yield (7.1 mg). (M+1) m/z=468.

Synthesis of (3R,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-3- methylN-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine, compound 260.

Compound 260 was synthesized from Int-142-11 and Int-259-16 using the same conditions used to synthesize compound 259 and was obtained as a yellow solid in 36% yield (8.3 mg). LCMS: (M+1) m/z=468.

Examples 261-265.

Compounds 261-265 were prepared using the general procedures detailed for compounds 33-39 and 198-203, using cyclopropanol to replace KB(OMe) ₄ in the esterification step and the appropriate amine to give the desired products.

Example B-1.

Activity in vitro.

In the experimental data below, 1-(6-ethyl-3-(3-methyl-1,2,4-oxadiazol-5yl)quinolin-2-yl)-N-((3-methyloxetan-3-yl) methyl)piperidine-4-amine (compound A), PF-04455242 and LY2456302 were used as reference compounds. Compound A was prepared using the synthetic procedure described in US Pat. No. 9,682,966. PF-04455242 is a known KOR antagonist disclosed in WO 2009/156889. LY2456302 is a known KOR antagonist disclosed in WO 2009/094260.

Analysis of KOR antagonists.

The OPRK1 antagonist cell line stably expresses the following elements:

- 152 042282 The carboxy-terminus of the OPRK1 receptor contains a 7-amino acid linker followed by a TEV protease cleavage site and a GAL4-VP16 fusion protein. The cell line also expresses the b-arrestin-2-TEV protease fusion protein and contains a reporter construct consisting of a UAS response element and a b-lactamase (bla) reporter gene. Upon receptor activation, the g-protein coupled receptor kinase (GRK) phosphorylates specific intracellular residues and this induces recruitment of the Warrestin2-TEV protease. The TEV protease recognizes and cleaves the TEV site, releasing the GAL4-VP16 fusion protein, which is then translocated to the nucleus. GAL4-V16 binds to the UAS element that controls the expression of the b-lactamase gene. Detection of β-lactamase expression is carried out using the cell-penetrating fluorescent substrate CCF4-AM. This substrate consists of coumarin bound to fluorescein via a b-lactam ring. In the absence of β-lactamase, excitation of the dye with 405 nm light results in FRET from coumarin to fluorescein and emission of green (525 nm maximum) light. Cleavage of the substrate with B-lactamase releases the coumarin fluorophore from the fluorescein and 405 nm excitation results in blue (460 nm maximum) emission. The analysis is controlled by the blue/green emission ratio.

OPRK1 TANGO U2OS cells are cultured in growth medium (McCoy's 5A medium, 10% dialyzed FBS, non-essential amino acids, 25mM FIEPES, 1mM sodium pyruvate, penicillin/streptomycin). Two million cells are added to a T175 flask in 30 ml growth medium and incubated at 37° C./5% CO ₂ for four days, at which time they become ~70-90% confluent. The culture medium is removed by aspiration, 5 ml of 0.25% Trypsin/EDTA is added to the flask and washed gently over the cell surface. The trypsin is then removed by aspiration. The cells are allowed to adhere and are separated by gentle tapping of the flask. Cells are suspended in assay medium (high glucose DMEM with 1% charcoal-purified dextran FBS, non-essential amino acids, 25 mM HEPES, 1 mM sodium pyruvate, penicillin/streptomycin), triturated, counted and pelleted by centrifugation. Cells are resuspended at 1.6 million cells per ml and Jucl is added to each well of a black 384 well clear bottom assay plate (Greiner part number 788092). The assay plates are placed in a humid chamber and incubated for 16-24 hours at 37°C/5% CO ₂ . Compounds dissolved in DMSO are serially diluted in DMSO in a 384-well polypropylene plate. 50 nl of each compound dilution is added to the assay plate wells using needle instruments. 50 nl DMSO is added to the control wells. The plates are returned to the incubator for 30 minutes. After pre-incubation with 50 nl compound, 600 nM (−)-U-50.488 (agonist challenge) is added to the wells of the assay plate containing the compound. Control wells were supplemented with 50 nL 5.6 μM (-)-U-50.488 (100% response control), 50 nL 600 nM (-)-U-50.488 (EC80 control), or 50 nL DMSO (0% response control). ). The assay plates are returned to the incubator for 4 hours at 37°C/5% CO ₂ . The assay plates are then removed from the incubator and 2.5 μl of LiveBlazer CCF4-AM dye substrate (Invitrogen) is added to each well. The assay plates are then placed on a rack for two hours at room temperature covered from light with foil.

The plates are then read on a fluorescent plate reader with an excitation wavelength of 405 nm and emission wavelengths of 460 nm and 525 nm. The results are calculated using the blue/green emission ratio. Percent inhibition is calculated using the following equation, where IC ₅₀ is the compound concentration required to achieve 50% inhibition: / , well with „„ \

- connection ~ well with 0% response \\ % Inhibition = 100 - I 100 I-------------------------------- ---------1 I

I \ £ C80 moons ^ ° ^{LNA - well with 0% response} ' /

In order for a peripheral kappa antagonist to be effective with minimal side effects, it is desirable that it does not interact to any significant extent with other opioid receptors. Thus, delta and mu opioid receptor antagonist assays were used to assess activation at mu or delta receptors.

Analysis of OPR Antagonists Delta.

The Delta OPR antagonist cell line stably expresses the following elements: The carboxy terminus of the OPR Delta receptor contains a 7-amino acid linker followed by a TEV protease cleavage site and a GAL4-VP16 fusion protein. The cell line also expresses the b-arrestin-2-TEV protease fusion protein and contains a reporter construct consisting of a UAS response element and a b-lactamase (bla) reporter gene. Upon receptor activation, the g protein-coupled receptor kinase (GRK) phosphorylates specific intracellular residues and this induces recruitment of the B-arrestin2-TEV protease. The TEV protease recognizes and cleaves the TEV site, releasing the GAL4-VP16 fusion protein, which is then translocated to the nucleus. GAL4-V16 binds to the UAS element that controls the expression of the b-lactamase gene. Detection of β-lactamase expression is carried out using the cell-penetrating fluorescent substrate CCF4-AM. This substrate consists of coumarin bound to fluorescein via a b-lactam ring. In the absence of b-lactamase, excitation of the 405 nm dye leads to FRET from coumarin to fluorescein and green emission.

- 153 042282 (525 nm maximum) light. Cleavage of the substrate with B-lactamase releases the coumarin fluorophore from the fluorescein and 405 nm excitation results in blue (460 nm maximum) emission. The analysis is controlled by the blue/green emission ratio.

OPR DELTA TANGO U2OS cells are cultured in growth medium (McCoy's 5A medium, 10% dialyzed FBS, non-essential amino acids, 25mM HEPES, 1mM sodium pyruvate, penicillin/streptomycin). Two million cells are added to a T175 flask in 30 ml growth medium and incubated at 37° C./5% CO ₂ for four days, at which time they become ~70-90% confluent. The culture medium is removed by aspiration, 5 ml of 0.25% Trypsin/EDTA is added to the flask and washed gently over the cell surface. The trypsin is then removed by aspiration. The cells are allowed to adhere and are separated by gentle tapping of the flask. Cells are suspended in assay medium (high glucose DMEM with 1% charcoal-purified dextran FBS, non-essential amino acids, 25 mM HEPES, 1 mM sodium pyruvate, penicillin/streptomycin), triturated, counted and pelleted by centrifugation. Cells are resuspended at 1.6 million cells per ml and 10 μl are added to each well of a black 384 well clear bottom assay plate (Greiner part number 788092). The assay plates are placed in a humid chamber and incubated for 16-24 hours at 37°C/5% CO ₂ . Compounds dissolved in DMSO are serially diluted in DMSO in a 384-well polypropylene plate. 50 nl of each compound dilution is added to the assay plate wells using needle instruments. 50 nl DMSO is added to the control wells. The plates are returned to the incubator for 30 minutes. After pre-incubation with 50 nl compound, 35 μM SNC80 (agonist challenge) is added to the wells of the assay plate containing the compound. Control wells are supplemented with 50 nl 2 mM (100% response control), 50 nl 35 μM SNC80 (EC80 control) or 50 nl DMSO (0% response control). The assay plates are returned to the incubator for 4 hours at 37°C/5% CO ₂ . The assay plates are then removed from the incubator and 2.5 μl of LiveBlazer CCF4-AM dye substrate (Invitrogen) is added to each well.

The assay plates are then placed on a rack for two hours at room temperature covered from light with foil. The plates are then read on a fluorescent plate reader with an excitation wavelength of 405 nm and emission wavelengths of 460 nm and 525 nm. The results are calculated using the blue/green emission ratio. Percent inhibition is calculated using the equation above, where IC ₅₀ is the compound concentration required to achieve 50% inhibition.

Representative compounds listed in table. 2 below, all showed an IC50 value greater than 3000 nM on MU DOR.

Analysis of MU OPR antagonists.

The purpose of this assay is to confirm the activity and selectivity of compounds synthesized as OPRK1 antagonists. This assay monitors the activation of OPRMu1 by recruiting βarrestin in the membrane. The assay controls the affinity of GPCR-β-arrestin using complementation of a low-affinity fragment of beta-galactosidase (beta-gal). It uses U20S cells that express OPRMu1 fused to a complementary beta-gal fragment (enzyme acceptor). As expected, compounds that act as antagonists will prevent receptor activation resulting in a decrease in luminescence in the wells. Compounds were tested in triplicate using 10-point 1:3 dilution series starting at a nominal concentration of 10 μM.

The Discover X OPRMul-U20S cell line was routinely cultured in T175 flasks at 37°C, 5% CO ₂ and 95% relative humidity (RH). Culture media consisted of DMEM/F12 1:1 Media supplemented with 10% v/v heat-inactivated fetal bovine serum, 25mM HEPES, non-essential amino acids, 1mM sodium pyruvate, 1X penicillin/streptomycin antibiotic mixture) plus 500 µg/mL Geneticin and 300 µg/ ml Hygromycin (selected antibiotics).

On Assay Day 1, 5000 cells in 20 µl of assay buffer (Cell Growth Reagent 5 from Discover X) were plated in each well of a 384 Corning 3570 standard white plate and incubated for 16-24 hours at 37°C, 5% CO2 and 95% (RH ). On Day 2, 100 nl of test compound in DMSO was added to the appropriate wells, 100 nl of DMSO was added to the control wells and the plates were incubated for ZOmin at 37°C, 5% CO ₂ and 95% (RH). Then 100 nl DAMGO OPRMul or DMSO in assay medium (EC80 Challenge consists of 100 nl 50 μM DAMGO, final assay concentration = 250 nM, 100 nl 200 μM DAMGO is added to wells with 100% response). After incubation for 3 hours at 37° C., 5% CO ₂ and 95% (RH), 10 µl of Path Hunter Detection Mix was added to each well, the plate was placed on a plate shaker/mixer for ~10 min and then incubated at room temperature in the dark for 1 hour Luminescence in the wells was measured on Perkin Elmer's Envision.

Percent inhibition was calculated from the mean ratio as follows: , compound well ^- 0% response well. £C80 control - 0% response well well where compound well is defined as the well containing the test compound;

% Inhibition = 100 - I 100

- 154 042282

EC80 control well is defined as the well containing DAMGO stimulant (final concentration 250 nM) = 0% inhibition; and a 0% response well is defined as a well containing DMSO=100% inhibition.

IC ₅₀ is defined as the concentration of a compound required to achieve 50% inhibition.

Activity, expressed as IC ₅₀ representative compounds against the kappa-opioid receptor (KOR) and mu-opioid receptor (MOR), is presented in table. 2 below. With respect to KOR activity: ++++ means IC ₅₀ less than 1 nM; +++ means IC ₅₀ from 1 nM to less than 10 nM; ++ means IC ₅₀ from 10 nM to less than 100 nM; and + means IC ₅₀ of 100 nM or more. With respect to MOR activity: ++++ means IC ₅₀ less than 1 nM; +++ means IC ₅₀ from 1 nM to less than 10 nM; ++ means IC ₅₀ from 10 nM to less than 100 nM; + means IC ₅₀ from 100 nM to less than 1,000 nM; and - means IC ₅₀ greater than 1000 nm.

The kappa specificity of representative compounds is also shown in Table 1. 2 (i.e. MOR IC50/KOR IC ₅₀ ). The selectivity range is indicated as follows: ++++ means more than 1000 times more selective than the mu-opioid receptor (MOR), +++ means 100-1000 times more selective, ++ means 10-100 times more selective greater, and + means selectivity 10 times less.

table 2

- 155 042282

- 156 042282

- 157 042282

- 158 042282

- 159 042282

Dynorphin A-induced activation of the β-arrestin pathway.

Compound 142 was also evaluated for biased signaling activity on OPRK1 using the PathHunter® β-arrestin assay (DiscoverX, Fremont CA). In this assay, cells were pre-incubated with Compound 142 (5.1 μM followed by agonist challenge using Dynorphin A (0.0498 μM) at an EC ₈₀ concentration (performed in five replicates). Compound 142 blocked dynorphin A-induced activation of the β- arrestin (IC ₅₀ = 3.1 nM), suggesting balanced antagonistic properties, and antagonized dynorphin A-induced receptor internalization (IC ₅₀ = 6.1 nM).

Radioligand binding assay.

Compound 142 showed strong inhibition at the human kappa 1 opioid receptor (hOPRK1; Ki=1.5 nM) and showed >300-fold selectivity over the human mu 1 opioid receptor (hOPRM1; Ki=0.45 μM) in binding assays radioligand using [3H]diprenorphine (600 pM) (tested in triplicate, N=3). Mean value ±SEM. Fig. 8.

Example B-2.

Activity in vivo.

Tail flick test in mice.

The efficacy of systemic administration of compound 142 to block (-)-U-50,488 induced acute antinociception was tested in previously unexperimented ICR mice using the tail-flick test. Briefly, mice were tested at baseline to determine their tail-flick latencies when immersed in hot 50° C. water (limited to 15 sec to prevent tissue damage). Administration of OPRK1 agonist (-)-U-50,488 (15 mg/kg, i/p), test compound (1 mg/kg, i/p), or vehicle (10% DMSO/10% Tween 80/80% saline, 5 ml/kg, i/p) was administered by injection 1 or 24 h later, (-)-U-50.488 (15 mg/kg, i/p) was administered to all mice. Separate groups of mice were treated at different pretreatment time points. Tail-flick latencies were assessed again 30 minutes after administration of (-)-U-50,488. In this trial, (-)-U-50.488 provided strong analgesia in previously unexperimented mice, which was blocked by compound 142 administered 1 hour but not 24 hours to (-)U-50.488. Compound 142 had no effect when administered in the absence of (-)-U-50,488.

Adult male CD-1 mice were treated with compound 142 (30 mg/kg, po) or vehicle (10% DMSO/10% Tween 80/80% saline followed by (-)-U-50,488 (20 mg/kg ,

- 160 042282 i / p, in saline) after 1 or 24 hours in separate cohorts of mice. Tail flick latency was measured from a 50° C. water bath. In this trial, Compound 142 (30 mg/kg, po) given hr but not 24 hr prior to (-)-U-50,488 blocked the analgesic effect induced by (-)-U-50,488 in a withdrawal assay mouse tail, demonstrating the reversible action of this OPRK1 antagonist in vivo.

Fig. 9.

Study of prolactin levels in mice.

The kappa opioid antagonists were solubilized in water at a concentration of 0.5 mg/ml. 8-10 week old male C57BL/6J mice were treated intraperitoneally with 10 mg/kg bw of a kappa opioid antagonist or vehicle water for one hour. U-69593 kappa opioid agonist (Sigma) was solubilized in 45% 2-hydroxypropylcyclodextrin at a concentration of 10 mg/ml.

One hour after antagonist treatment, 0.3 mg/kg U-69593 or vehicle, 0.3% 2hydroxypropylcyclodextrin, was administered subcutaneously at the back of the neck. 30 minutes after agonist treatment, mice were sacrificed with CO ₂ and cardiac puncture was performed. Blood was collected and placed in a K2EDTA-coated microcontainer and stored in the cold. Blood was centrifuged at 4°C, 1000xg for 10 min. Plasma was removed and 10 μl was used to determine prolactin levels using the Milliplex Mouse Pituitary Magnetic Bead Panel (MPTMAG-49K). 50 prolactin analytes were collected from each replicate using Milliplex Analyzer Luminex 200 and pg/ml prolactin was determined using Milliplex Analyst 5.1 software.

Compound 142 was tested for antagonistic properties in vivo using an OPRK1 agonist-induced prolactin stimulation approach in 8-10 week old male C57BL/6J mice (n=3-4/group). In particular, after administration to mice of compound 142 (0.01-3.0 mg/kg, ip; water [vehicle]; 1 h PTT) or compound 142 (3, 10, or 30 mg/kg, po; water [vehicle]; 2 h PTT) were injected with OPRK1 agonist U69593 (0.3 mg/kg, sc; 5% cyclodextran [vehicle]; 0.5 h PTT) and plasma samples were collected via cardiac puncture in the final procedure after 0.5 hours. In these studies, U69593 significantly increased plasma prolactin concentration (p<0.05 vs vehicle), and compound 142 suppressed the increase in prolactin in a dose-dependent manner (p<0.05 vs U69593 alone). As shown in FIG. 1, after intraperitoneal (i/p) injection, compound 142 effectively blocked the U69593-induced rise in prolactin with a minimum effective dose (MED) of <0.01 mg/kg (see FIG. 1A); and after oral (po) administration, compound 142 significantly suppressed the agonist-induced increase in prolactin at 10 mg/kg (see Fig. 1B).

Additional compounds were tested in the same way. Tab. 3 shows the results of oral administration of selected compounds on plasma prolactin levels. The results were evaluated based on the reduction in prolactin levels compared to the results of the U69593-stimulated group and the vehicle control group: NA means no significant decrease, + means partial decrease (<50%), ++ means decrease (>50%), +++ means a reduction to the levels in the control group of the introduction of the vehicle. Fig. 2 shows the results after ip injection (FIG. 2A) or PO (FIG. 2B) of Compound 141. FIG. 3 shows the results after ip injection (FIG. 3A) or po administration (FIG. 3B) of Compound 145. FIG. 4 shows the results after ip injection (FIG. 4A) or PO administration (FIG. 4B) of Compound 146. FIG. 5 shows the results after ip injection (FIG. 5A) or PO (FIG. 5B) of Compound 147. FIG. 6 shows the results after i/p injection of Compound A tartrate salt.

- 161 042282

Table 3

Oral prolactin levels (mouse)

Connection No. 1 mg/kg 3 mg/kg 10mg/kg ZOmg/kg Time 34 + 2h 109 NA NA NA 2h 110 NA NA NA 2h 134 ++ + ++ 2h 136 + ++ + + + 2h 141 + ++ + + + 2h 142 ++ + + + + + + 2h 145 + + ++ 2h 146 ++ ++ + + + 2h 147 NA NA ++ 2h 175 + NA ++ 1 hour 176 NA NA + 1 hour 181 + + + + + + 1 hour 182 ++ + + + 1 hour 183 NA + + + 1 hour 196 ++ 1 hour 197 ++ NA ++ 2h 214 NA + + + 1 hour 215 ++ ++ 1 hour 219 + + + + + + + + + 1 hour 220 NA ++ 1 hour 250 NA NA NA 2h Connection No. 1 mg/kg 3 mg/kg 10mg/kg ZOmg/kg Time 251 NA ++ + 2h

NA: no significant decrease.

Study of prolactin in rats.

Compound 142 was tested for antagonistic properties in vivo using the OPRK1 agonist-induced prolactin stimulation approach. In this trial, after administration of compound 142 (10 and 30 mg/kg, po; water [vehicle]; 1 h PTT) to male Sprague-Dawley rats; n=8-10) were injected with the OPRK1 agonist spiradoline (0.32 mg/kg, sc; 5% cyclodextran [vehicle]; 0.08 h PTT). Blood samples were taken 5 minutes before oral administration (B1) and 5 minutes before spiradoline administration (B2), and then 5, 30 and 60 minutes after spiradoline administration by tail vein cannulation. In these studies, spiradoline significantly increased plasma prolactin concentration, and compound 142 suppressed the increase in prolactin with a MED of 10 mg/kg at time points of 5 and 60 minutes. The OPRK1 antagonist LY-2345302 (10 mg/kg, PO; 1 h PTT) was used as a reference drug and suppressed the spiradolin-induced increase in prolactin at time points of 5, 30 and 60 minutes. Fig. 10.

Stress-induced skin allodynia in rats (an animal model of migraine).

The efficacy of compound 142 after systemic administration on the ability to block bright light stress (BLS)-induced periorbital and hindpaw allodynia in rats with sumatriptan-induced latent sensitization was evaluated. In this model, sumatriptan (0.6 mg/kg/day, sc) was administered to rats for 7 days using osmotic minipumps. On Days (D) 20 and 21, a one-hour BLS procedure was applied daily after sumatriptan infusion for 2 consecutive days. Compound 142 (1 mg/kg, i/p) or vehicle (10% DMSO/10% Tween-80/80% saline, 5 ml/kg, i/p) was administered 30 min before each BLS session. Baseline periorbital and hindpaw tactile threshold was assessed at D21 prior to the 2nd administration of compound 142. Periorbital and hindpaw tactile threshold was assessed hourly for 5 hours after the 2nd stress. Baseline data and area under the time-effect curve (AOC calculated from baseline and hourly tactile threshold) were calculated. Compound 142 (1 mg/kg, ip) administered 30 min before each BLS treatment blocked the development of allodynia in rats pretreated with sumatriptan. Compound 34 (5 mg/kg, po) and compound 196 (5 mg/kg, po) were tested similarly and blocked the development of allodynia in rats pretreated with sumatriptan.

Study of penetration into the brain.

Compound 142 was evaluated for brain penetration properties using an in vivo microdialysis procedure in which the striatum and jugular vein of rats were cannulated and samples were collected every 30 minutes. In the striatum, exposures of compounds 142 were approximately 4 times higher than those observed in jugular vein samples taken from the same animals. Surgical

- 162 042282 operation: Adult male Sprague Dawley rats were anesthetized and implanted with a MetaQuant (MQ) probe (3 mm membrane) in the jugular vein (JV). The animals were then placed in a stereotaxic frame and a second MQ microdialysis probe (3 mm membrane) was inserted into the striatum: (AP) = +0.9 mm from the bregma, lateral (L) = +3.0 mm from the midline and ventrally (V ) = -6.5 mm from the dura mater. The studies were carried out 1 day after the operation. Sample collection and analysis: Probes were perfused with artificial CSF solution at a flow rate of 0.15 μl/min. Samples were collected every 30 minutes and analyzed by LC/MS. Experiments were performed at Brains On-Line, LLC (Brisbane, CA). Fig. eleven.

Electrophysiological study of sections of whole cells.

In previously unexperimented rats, the selective KOR agonist, U69593, induces postsynaptic hyperpolarizations in a subpopulation of dopamine ventral tegmental area (VTA DA) neurons, but not non-DA neurons, via activation of G protein-coupled K+ internal rectifying channels (GIRKs). ). The EC ₅₀ for this U69593 effect is 42 nM. The activity, selectivity and reversibility of Compound 142, Compound A, PF-04455242 and LY2456302 were evaluated in native tissue using horizontal sections of brain tissue (~150 μm) containing VTA from male Sprague-Dawley rats. Fig. 12.

In this study, whole cell recordings were made at 33° C. using a 2.5-4 μΩ pipette in potential clamp mode (Vm = -60 mV) to provide measurement of pulse rate and/or membrane potential. Fig. 13. Dose-response data were obtained after bath application of various concentrations of Compound 142, Compound A, PF-04455242 and LY2456302 (0.1-100 nM) to cells followed by administration of OPRK1 agonist U69593 (1 μM) delivered through a pressurized ejector placed in a 300 μM registration site. Each application consisted of a 60 s agonist ejection followed by a 30 s flush with control artificial cerebrospinal fluid (aCSF).

Data are presented as % inhibition of U69593-induced outward current provided by the respective antagonist in each responding cell. In control experiments, repeated application of U69593 to VTA neurons resulted in the same magnitude of responses. In validation experiments, each cell was calibrated with at least one application of a base concentration of U69593, and cells that showed a time-fixed response were used to characterize the antagonist.

In this study, compound 142 showed full antagonist properties and an IC ₅₀ =1.3 nM. Both concentrations of 10 and 100 nM of compound 142 completely blocked the U69593 response. This is very similar to the effective concentration in the heterologous rat KOR expressing system where compound 142 has an IC ₅₀ of 3.2 nM for blocking compound (-)-U50.488 (3 nM) adenylyl cyclase inhibition. Fig. 14A.

A related compound, compound A, showed an IC ₅₀ =4.6 nM. A 100 nM dose of Compound A almost completely blocked U69593 responses. Fig. 14V.

The known KOR antagonist, PF-04455242, was also evaluated in this assay. Surprisingly, PF04455242 only partially blocked U69593's response. There was a maximum blockade of 60% of the U69593 response at both 100 nM and 1 μM PF-04455242, with an absolute IC ₅₀ value of 19.6 nM. The relative IC ₅₀ value was 4.3 nM. Fig. 14C.

The dose-response of LY2456302 was also determined. An absolute IC ₅₀ value of 0.3 nM was determined for LY2456302, but the dose-response form was unusual and did not fit the Hill equation. Fig. 14D. Another unexpected feature of these experiments was that at 100 nM and 1 μM doses of LY2456302, a subgroup of cells responded to U69593 with incoming currents.

Compound 142 effectively blocks KOR activity in VTA DA neurons in the prefrontal cortex.

Compound 142's ability to block U69593-induced responses was also measured, particularly in VTA DA neurons that protrude into the medial prefrontal cortex (mPFC). Retrograde indicator DiI was injected into mPFC neurons 7 days prior to whole cell recordings made specifically in retrograde labeled neurons from mPFC to VTA. In these selected neurons, the IC ₅₀ of compound 142 was 2.2 nM, within the variance of the IC ₅₀ among non-selected neurons. Fig. 15.

KOR selectivity of compound 142 compared to LY2456302.

To assess the selectivity of Compound 142 and LY2456302 for KOR over MOR and DOR, the ability to block selective agonist-induced responses at these two receptor types in VTA neurons was tested. The selective MOR agonist, DAMGO, or the selective DOR agonist, DPDPE, was pressurized into VTA neurons, and in responsive neurons, the agonist was reapplied after application of 10 nM of either antagonist in the bath for at least 4 minutes. This dose of Compound 142, which completely blocked the KOR response with U69593, did not affect the response to DAMGO or DPDPE. In contrast, 10 nM LY2456302 consistently reduced the response to DAMGO. Fig. 16.

- 163 042282

One time wash.

NorBNI is the most widely used preclinical KOR antagonist. One of the main disadvantages of NorBNI, for many experimental paradigms, is the evidence of persistent biological activity even after a single dosing without a measurable amount of the compound in the body. A selective short-acting (reversible) antagonist is not only useful for clinical development, but also for experimental projects that require ligands to be cleared from the brain within hours. This study tested whether KOR antagonists dissociated from KOR quickly enough in brain VTA slices to observe washout when recorded in whole cell format.

In each experiment, the baseline U69593 response was measured, then the antagonist was applied to the section for 5-10 min. This interval was sufficient to completely block U69593 responses as observed in dose-response experiments. U69593 responses were then examined 10 and/or 20 minutes after the onset of antagonist washout. As expected, a typical ex vivo dose of NorBNI showed no washout at 20 min (-27.13±17.41% of baseline U69593 response, n=4). On the other hand, a 10 nM dose of compound 142, sufficient to completely block the actions of U69593, showed complete washout within 10 min. Interestingly, Compound A did not show significant reversion on washout up to 20 minutes. These data suggest that there may be differences in the reversible action of compounds within the same chemical series. PF-04455242 showed some washout, with the U69593 response recovering after 20 min but not after 10 min. LY2456302 showed no significant reversion after 10 or 20 minutes. Fig. 17.

The results of these studies with additional KOR antagonists suggest that PF04455242 exhibits partial antagonistic activity and also generates an outward current in a subset of neurons via an unknown receptor. Compound A did not show washout of the KOR blockade during the sectioning experiment. In addition, LY2456302 may have more than one binding site, and a subset of cells responded to U69593 with incoming currents in the presence of 100 nM and 1 μM, indicating that it is not a neutral antagonist. Together, these data provide electrophysiological evidence that compound 142 is a potent, selective, and short-acting KOR antagonist in neurons that modulate brain circuits commonly deregulated in neurobehavioral disorders.

The various embodiments described above may be combined to provide additional embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification and/or listed in the application information sheet are incorporated herein by reference in their entirety. Aspects of the embodiments may be modified, if necessary, to use the concepts of various patents, applications, and publications to provide other additional embodiments. These and other changes are possible in the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed as limiting the claims to the particular embodiments disclosed in the specification and claims, but should be construed as including all possible embodiments together with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited to the present disclosure.

Claims (52)

1. A compound having the structure of formula (I), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: where X is O when Y is N, or X is N when Y is O; R ¹ is H or F; R ² is H or C1- _C8 alkyl; R ⁴ and R ⁸ are each independently C ₁ -C ₈ alkyl, halo or cyano; R ⁵ and R ⁷ are both H; R ⁶ is C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halogen or cyano, and R ⁶ is not C1-C8- 164 042282 alkyl when R ⁸ is C ₁ -C ₈ alkyl; R ¹¹ is -(CH ₂ ) _o . ₁ R ¹² where R ¹² is n is an integer having a value of 1-5. 2. The compound according to claim 1 or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt, where R ⁴ represents H or C ₁ -C ₈ -alkyl; R ⁵ and R ⁷ are both H; R ⁸ is C ₁ -C ₈ alkyl, halo or cyano; and n is 1 or 2. 3. A compound according to claim 1 having the structure of formula (II), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 4. The compound according to claim 1 having the structure of formula (III), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 5. A compound according to claim 1 having the structure of formula (IV), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 6. A compound according to claim 1 having the structure of formula (V), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 7. A compound according to claim 1 having the structure of formula (VI), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 8. A compound according to claim 1 having the structure of formula (VII), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: - 165 042282 9. A compound according to claim 1 having the structure of formula (VIII), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 10. A compound according to claim 1 having the structure of formula (IX), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 11. A compound according to claim 1 having the structure of formula (X), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 12. The compound according to claim 1, having the structure of formula (XI), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 13. The compound according to claim 1, having the structure of formula (XII), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 14. The compound according to claim 1, having the structure of formula (XIII), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 15. The compound according to claim 1, having the structure of formula (XIV), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: - 166 042282 16. The compound according to claim 1, having the structure of formula (XV), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 17. The compound according to claim 1, having the structure of formula (XVI), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 18. The compound according to claim 1, having the structure of formula (XVII), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 19. The compound according to claim 1, having the structure of formula (XVIII), or its pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt: 20. A compound according to claim 1 having the structure of formula (XIX), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 21. A compound according to claim 1 having the structure of formula (XX), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate or solvate, isotope or salt thereof: 22. The compound according to claim 1, having the structure: - 167 042282 1 У Yd nN beat ^w 2 ^N I Ο,Χ Η 3 ι ι Ο'Ν A /O. γ^N Ν % Ζ > + -^N-abs ⁴⁴ -^ Η 4 ι ι Ο'Ν -+03+ γ'χ ν ^ "D ^F An—Ν abs Η 5 ι ι Ο'Ν HCol ^Ν γΉ yy |\| _a bs Η 6 DAS ^F 7 n V 7 ι ι O'N γ^N N X F H\D 8 . O'N SPIRIT γ^Ν N^i ^F dd _N '^Y ₇ η V 9 A 1 °dv DD Y^n nA ^F ^---+^1---^0^- h \D 10 A^DD'D Till, l γ^ N N y C > Nab++ Η - 168 042282 eleven l 1 Υχ Η 12 A 1 erN__ VCXD γ^ ν ν η Up to ^F <Α _Ν Α> Η 13 1 Ο' ^Ν χγτ ⁴ ^ γ^Ν νΥ r^Q Ν abs Η 14 -πΥΥ Ul A 15 ah oh H 16 ___ 1 θ'Νξ tOlX^ ^nX γ^Ν f~Q abs Η 17 Λ^ιΧΛ ςΧι D γ Ν Ν >< Ο ^F <ΑΑ> Η - 169 042282 - 170 042282 35 i O'N 'ΧάΛ τCV? H 36 1 O'N 'Χά+ν ^F H 37 ^F <a _n aj H 38 'X/A X-αχ H 39 F η V 40 1 ^z w ⁿ V -φ,χ 41 i ?'V xL r- ςχο - 171 042282 42 I О'Ч__ γ^Ν ^F F ^Η 43 1 θ^χ 'θΧΧΧ^ Υγ^Ν ν'Ύ rQ ^F CHA^ β ^Η 44 V^jO 45 '°ό+^ τ γΌ 46 π· ^Λ α,Ό 1 ^Η 47 r ^N WO F ^H 48 1 θΟν Χά+ g- φγ - 172 042282 49 i °Ά χάθ ι QX F ^Η 50 °Q 1 O ^{- w} ° \ 51 _β —Q ^F F ^Η 52 ssDde Υ^Ρι ^Ν '' 9-Ρ 53 χ/Χ XX F ^Η 54 XX ΙΖ' 9 55 ι ?'V 'ΧϊΥ· ϊ - 173 042282 56 Q i ZT / ^l Ζ^ _ζ / \—η oD AU O \ 57 1 rrN 'X1Y' ^A ί F ^Η 58 ^F Dy%7 59 F Η V 60 7 1 61 -π......ς y z z 1 IZ' 1 67 1 ^N '°\ Ύϊ5 ^λ i iXO H - 174 042282 68 1 N'Q A ¹ 'Au- Η 69 '°νάΑ _Γ Η 70 Ου b 71 1 ^Ν '°\ -χΑ· A αζ Η 77 1 Ο' ^Ν +α.η Η 78 ι °b\ ^F Η 79 4, ) - 175 042282 - 176 042282 88 ίΎ Η 89 γ^Ν and °\ ^CN <Λ _Ν ΥΖ η 91 νΧΧ Η 94 Q Υ -^ζ A/ ^w 95 Υ 1 Γγ [ϊ] ^Ν τ αχ Η 96 700 ΙΖ' 0 97 Q, Xό - 177 042282 98 τ 1 ^Ν Η 99 άό -nH, LL 100 O > \..........( । ζι Ar 101 r 1 ^ZI -PP PP ^w 103 O 0 ΙΖ ' ъ 104 νΧχΰ n 105 I Ο-Ν__ γόο. F <a _n aj n - 178 042282 106 1 ^ZI 40 o LL 107 q 0p O LL 109 1 O' ^N Y^n'^n'W. H 110 O 0% 0 111 Q 1 ^ZI 40 O LL 112 -=^00+ 0 ' 0.0 H 113 0 < O LL - 179 042282 114 i O'N ν'α,η Η 115 1 _____________ Y'U^N'''^ H 116 ^ύύΜ^ GSE Η 117 ^YyLXy ¥ ^l o, o Η 118 I Ο'Ν__ ΟίΧΪ Ν ><Ο ^F Η 119 1 Ο'Ν Υ"' ι'CuO Η 120 1 Ο'Ν yyV^ ΐ ^ _n aJ Η - 180 042282 121 Q 122 ⁿ 123 1 Z^ / \—lL 124 Ά? yr Ar 1Z* ' b 125 rA Wr A F AA F ^H 126 •Q ZT ^za yf O / z=/ ^X _Z A ~w ^z - 181 042282 127 Ao ^F 4W F ^H 128 ύΧγ ^f CHAA> F ^H 129 ΧόνΟ H 130 χάΑ γ ^Λ Ν ^Λ ΝΥ "A FH 131 1 ^N '°\ xAC Y ^< n ^a nA Ao ^f <a _n aj h 132 I A. Yli ^N f <a _n aj H 133 1 r°>Yja ⁿ Y^n'^n'A r°\ ^F kA _N A? H - 182 042282 - 183 042282 145 ι O'N x+V y'x m'X rQ ^f <α _ν λχ H 146 1 ^N y^N'^N'A X°>. ^F 4Α _ν ΛΧ Η 147 1 N'Q 1 /A AH1D Ν Ν η Up to ^F < Α _ν ΑΧ Η 148 /γγΧΑΧ Vwx Η 149 1 ^Ν '°\ /4 /X Λ l 'ΎχΛ ^Ν γ^Ν ^χ ^Ν' ^ΧΧ > s^Q. ^F ^--''X'''' ⁴ / Η 150 1 ^N '°\ Α/λ'^OljL ^Ν γ^Ν'^Ν'Α ^F Η 151 1 ^Ν '°\ Ν Υ^ν^ν'Α Α ^ο > ^f Η - 184 042282 152 1 ^N '°\ V-xvO H 166 167 i °A AChl ^{N F} Μ-ν-Αλ J n Co 168 i °А ΑγΑ ⁿ An A ^F ν^Ν-Ά^ f H Co 169 1 °A ΑΧ ^F C^uA% f n Co 170 χΧ o-οχ Η 171 ι °Ά /°хх\DххАг АХД Α^ ^νν Α ^CN Ν n Co - 185 042282 - 186 042282 179 1 O' ^N LI J T JCW H 180 1 θ^χ ΪΠΚ ^F rO f AA _n A/ H 181 i °Ά f _r ° ON AA.AA H 182 i °Ά ^CN AAA H 183 O'N τάΤ . γ^ nn η ^CN AA> _n Az H 184 A 1 ZI Ά AA LL. 185 1 Vv and F AA> _n Az H - 187 042282 - 188 042282 - 189 042282 200 Lo ^F Η 204 I O'N__ yN nA ^F η 205 1 Α Ж Λ ^f xkA _N A/ Η 206 ^F ΑΑ* _ν Α/ Η 207 ^D D ^0 F ΑΑ* _ν -Χζ Η 208 Q Α' st ^w // 209 1 I Ο'Ν ΛΑ γΆ Ν^Α f Η - 190 042282 210 ^F ζ\Α _ν Ύ η 211 bfxbb γ^ Ν Ν D [ ° ^F αα _ν α> Η 212 ? pp ΙΖ' b 213 1 Ο' ^Ν 'χν> Η 214 ί Ο'Ν__ Αθυό ^{Ν CN} AL^A/ Η 215 1 Ο'Ν XXXI /γ γ^Ν νΥ γΌ CN ΛΑ^ Η 218 ;· ΙΖ 1 - 191 042282 - 192 042282 224 1 O'N__ Huiy t O.g> n 225 And IZ' b 226 G. ^f UA N 227 1 ON ^F bA _N A/ Η 228 ^D γ^Ν'^Ν'Υ Η 229 1 °Ύ /Y ' AOOL ^Ν f Ab> _N A Η 230 ι °Ά τ-XXG Η - 193 042282 231 ABOUT IZ'bo 232 Vpo H 233 A Py~b 234 A b 235 Q A \ 236a ^F AAL? H 236b 1 °'\ 'ΠΓ r ,a.r> H - 194 042282 237a 1 °0\ XT γΝ N0 =Y ^F AW H 237b ι °Λ γ^Ν N0 =γ ^F AW H 238 I O'N__ ^D Wo H 239 o σ—Y 00 IZ ' 3 240 γ-ΎΎγ γο ^F /Y» _n AX H 241 DJ O' ^N ^__ Y^N^nY *Y f AA _n A2 H 242 0 x 0 Q - 195 042282 - 196 042282 256 7 Afi 257 CHOOA ^N Υή νΎ ^Cl H 258 ^iXV 4OlX ^N γX ^Cl H 259 Q 1 ^ZI 260 v °A -γΑ-ν- Foy i H 261 v ^zi V 262 τχάίΓ ,Α ^F Η 263 ⁴¹ ~o pF b 264 1 °P\ %ΎχΡ ^N ₀ γ^+γ^Ύ _f o ^F H 265 τ 0.0 Η 23. A compound having the structure of formula (XI), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt thereof: where R ¹ represents H, F or C ₁ -C ₈ -alkyl; R ² represents H or C ₁ -C ₈ -alkyl; - 197 042282 R ⁴ and R ⁸ each independently represents H, C ₁ -C ₈ -alkyl, halogen or cyano; R ⁵ and R ⁷ are both H; And R ⁶ is C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halogen or cyano. 24. The compound according to claim 23, having the structure: 1 1 1 °A (OOL ^Ν ϊ ΥΑ Η 12 Λ I Ο'Ν__ ΑΑ νΥ γο F Η 17 1 Ο'Ν Λ- — γ Ν Ν > γ ο F Η thirty ύυΑ^ Α^ν^νΑ a f AA-AL Η 36 1 °2\ ΑΆΑα α° F <Α _ν Α2 Η 54 1 Ο'Ν__ ΑΑΑα α° ί ΑΑ F ^Η 55 1 Ο'Ν jαα 56 Ύ% + φ.ρ - 198 042282 57 i °Λ Oli OW F ^H 80 i °A ϊAU H 88 =4 00 0 94 woo h 97 FI O'N ΧύΫχ N Ν'η [ O ^F <a _n aj H 98 1/ 0 99 1 O'N ϊ ⁿ ax? H 103 0 00 o LL - 199 042282 109 LHho Η 111 1 Ο-Ν f ₃ c ^z γ ψηρ ^Ν Ϊν Η 116 \ 1 °Α CT% ^N 1 ^Ν Ο _ν Ό° Η 118 Q 1 ^ΖΙ + 0 121 τζ' 0 122 vbTo F ^Η 127 i °'V- VXy,£j 128 ΞΕΖ' - 200 042282 134 1 °X -χΧ ^Ν ι ux 135 -pDD ........<Qj> Day 1 ΙΖ' 0 136 Horch 137 1 °'\ XIX*· g αχ F ^Η 142 1 Ο'Ν ναχ Η 172 1 ^xxV uHiH Χ^ο F Η 173 ι Ο'Ν χΧΧΑ Ν Ν'η <^ο η 174 χό^ χ-Οci Η - 201 042282 177 1 O'N__ ^c, vA r- Η 181 WbY A^o CN H 186 ,^αΑΆ ΧΙλ D γΉ Ν'η Ao F Z >, . H 189 fsc^^zYAn^ νογ _Г o F aa _n a H 190 i °A 'AOA y^N Ν^ί A^O ^Cl xY-Yj-Yb H 193 O'N AAA yy n nA Ao f AA _n A> H 197 O'N AA Y^N n^AA^o F Ζν> _Ν ^Α H 200 1PPIZ' 0 - 202 042282 208 + F _g . Η 211 1 1 τΎΧ7 _ Ν Ν η < ο ^F Ζ ^ν Η 215 ι Ο'Ν γάχ γ^Ν Ν η <ό CN Α-λ _Ν Α> Η 218 Χ7 _Γ . Η 221 °х7У ΓΟ.Ο Η 226 ^Ff χ αχ Η 229 ι Ο'Ν γ^Ν Ν% <Ο ^f Η 232 ι °Α ΧΙχ;^ ^F x'k^" _N AX Η - 203 042282 25. A compound having the structure of formula (XIII-A), or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt thereof: where R ¹ represents H, F or C ₁ -C ₈ -alkyl; R ⁴ and R ⁸ each independently represents H, C ₁ -C ₈ -alkyl, halogen or cyano; R ⁵ and R ⁷ are each independently H, halogen, or cyano; where when R ⁴ and R ⁸ are H, R ⁷ is halogen or cyano; And R ⁶ is C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halo or cyano. 26. The compound according to claim 25, having the structure: - 204 042282 - 205 042282 27. A compound having the structure of formula (XIII-B), or a pharmaceutically acceptable thereof - 206 042282 enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt: where R ² represents C ₁ -C ₈ -alkyl; R ⁴ and R ⁸ each independently represents H, C ₁ -C ₈ -alkyl, halogen or cyano; R ⁵ and R ⁷ are each independently H, halogen or cyano; R ⁶ is C ₁ -C ₈ alkyl, haloalkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, cycloalkoxy, propynyl, cyclopropyl, cyclobutyl, halogen or cyano. 28. The compound according to claim 27, having the structure: - 207 042282 - 208 042282 29. A pharmaceutical composition containing a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 30. A method of antagonizing a kappa opioid receptor (KOR), comprising contacting the KOR with an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope, or salt thereof, or a composition comprising such connections. 31. A method for reducing serum prolactin levels, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition, including such a connection, with a frequency and duration sufficient to provide a beneficial effect for the subject. 32. A method of treating a neuropsychiatric or behavioral condition, organic, stress-induced or iatrogenic, which is characterized by elevated levels of prolactin in serum - 209 042282 in which administration of a kappa opioid receptor (KOR) antagonist reduces serum prolactin, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate thereof , solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 33. A method of treating substance abuse or dependence disorders, wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 -28 or a pharmaceutically acceptable enantiomer, diastereomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 34. A method of treating a CNS-related disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer thereof , diastereomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 35. A method of treating an anxiety disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer, diastereomer thereof , racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 36. The method of claim 35 wherein the anxiety disorder is social anxiety. 37. The method of claim 35 wherein the anxiety disorder is a phobia. 38. The method of claim 35 wherein the anxiety disorder is a stress-related disorder. 39. The method of claim 35 wherein the anxiety disorder is PTSD. 40. The method of claim 35 wherein the anxiety disorder is GAD. 41. A method of treating a depressive disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer, diastereomer thereof , racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 42. The method of claim 41 wherein the depressive disorder is major depression. 43. The method of claim 41 wherein the depressive disorder is MDD. 44. A method of treating a mood disorder wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer, diastereomer, racemate thereof , hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 45. The method of claim 44 wherein the mood disorder is anhedonia. 46. The method of claim 44 wherein the mood disorder is major depression. 47. The method of claim 44 wherein the mood disorder is MDD. 48. A method of treating schizophrenia or schizoaffective disorder, wherein kappa-opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer, diastereomer thereof , racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 49. A method of treating obesity or an eating disorder, wherein kappa-opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer thereof, a diastereomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject. 50. A method of treating migraine, wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 28, or a pharmaceutically acceptable enantiomer thereof, - 210 042282 diastereomer, racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, with a frequency and duration sufficient to provide a beneficial effect to the subject. 51. The method of claim 50, wherein the method of treating migraine is for the prevention of migraine. 52. A method of treating postpartum depression, wherein kappa opioid receptor (KOR) antagonism is medically indicated or beneficial, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable enantiomer, diastereomer thereof , racemate, hydrate, solvate, isotope or salt, or a pharmaceutical composition comprising such a compound, at a frequency and duration sufficient to provide a beneficial effect to the subject.