Compounds, compositions, and methods of use

Abstract

To provide CYP46A1 inhibitors.SOLUTION: There are provided compounds that act as CYP46A1 inhibitors, compositions comprising these compounds, and methods of their use into treating neurodegenerative diseases and the like, or a pharmaceutically active salt thereof. For example, there are provided compounds of Formula (I) designed to act as CYP46A1 inhibitors. In some embodiments, such compounds are useful as therapeutic agents for treating diseases associated with the inhibition of CYP46A1, for example, a neurodegenerative disease (e.g. Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, and multiple sclerosis), epilepsy, developmental and epileptic encephalopathies, psychiatric disorders (e.g. schizophrenia and autism spectrum disorder (ASD)), and spasm.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 852,565, filed on May 24, 2019, the entire contents of which are incorporated herein by reference.

Background Art

[0002] CYP46A1 is a gene expressed in the brain that encodes the enzyme cholesterol 24 - hydroxylase (also known as CYP46A1 and CH24H), which converts cholesterol to 24S - hydroxycholesterol (24 - HC), a positive allosteric modulator of the N - methyl - D - aspartic acid (NMDA) receptor. Inhibition of 24 - HC production in the brain by CYP46A1 inhibitors can negatively regulate glutamatergic over - activation in neurological diseases associated with NMDA hyperfunction such as epilepsy and autism spectrum disorder (ASD), or in diseases associated with elevated 24 - HC levels such as multiple sclerosis (MS). CYP46A1 inhibitors have also been suggested to be potential therapeutic agents for neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, cerebral infarction, traumatic brain injury, glaucoma, and amyotrophic lateral sclerosis. The present disclosure provides compounds that can modulate (e.g., inhibit) CYP46A1.

Summary of the Invention

Means for Solving the Problems

[0003] In part, for example, compounds designed to act as CYP46A1 inhibitors are provided herein. In some embodiments, such compounds are useful as therapeutic agents for treating diseases associated with inhibition of CYP46A1, such as neurodegenerative diseases (e.g., Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, and multiple sclerosis), epilepsy, developmental and epileptic encephalopathies, mental disorders (e.g., schizophrenia and autism spectrum disorder (ASD)), and seizures.

[0004] Accordingly, in one aspect, a compound of formula I

Chemical formula

[0005] In some embodiments, the compound of formula I is a compound of formula I-a [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the compound of formula I is a compound of formula I-b [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the compound of formula I is a compound of formula I-c

Chemical formula

[0008] In some embodiments, the compound of formula I is a compound of formula I-d

Chemical formula

[0009] In some embodiments, the compound of formula I is a compound of formula I-e

Chemical formula

[0010] In some embodiments, the compound of formula I is a compound of formula I-f

Chemical formula

[0011] Also provided herein are pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable excipients. In one embodiment, provided herein is a method of treating a disorder described herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound. In some embodiments, the disorder is a neurodegenerative disease (e.g., Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, and multiple sclerosis), epilepsy, developmental and epileptic encephalopathies, mental disorders (e.g., schizophrenia and autism spectrum disorder), and seizures.

Brief Description of the Drawings

Brief Description of the Drawings

[0012]

Figure 1

Mode for Carrying Out the Invention

[0013] As generally described herein, the present invention provides compounds designed to act as, for example, CYP46A1 inhibitors. In certain embodiments, such compounds are useful as therapeutic agents for treating neurodegenerative diseases (such as Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, and multiple sclerosis), epilepsy, developmental and epileptic encephalopathies, mental disorders (such as schizophrenia and autism spectrum disorder), and convulsions.

[0014] Compound Compounds of formula I are described herein. In embodiments, the compounds inhibit CYP46A1 and can be used for the treatment of neurodegenerative diseases, epilepsy, developmental and epileptic encephalopathies, mental disorders, and convulsions. For example, in one aspect, described herein are compounds of formula I

Chemical formula

[0015] Group R 1 In some embodiments, R 1 is substituted C6-C 10 aryl. In some embodiments, R 1 is unsubstituted C6-C 10 aryl.

[0016] In some embodiments, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0017] In some embodiments, R 1 is

Chemical formula

[0018] In an embodiment, R 1 is [Chemical formula] as follows. In a particular embodiment, R 1 is [Chemical formula] as follows. In an embodiment, R 1 is [Chemical formula] as follows. In some embodiments, R 1 is [Chemical formula] as follows. In some embodiments, R 1 is [Chemical formula] as follows. In some embodiments, R 1 is [Chemical formula] as follows. In some embodiments, R 1 is [Chemical formula] as follows. In one embodiment, R 1 is [Chemical formula] as follows. In one embodiment, R 1 is [Chemical formula] as follows. In one embodiment, R 1 is [Chemical formula] as follows.

[0019] In some embodiments, R 1 is [Chemical formula] as such. In an embodiment, R 1 is [Chemical formula] as such. In an embodiment, R 1 is [Chemical formula] as such. In an embodiment, R 1 is [Chemical formula] as such.

[0020] In an embodiment, R 1 is a substituted 5- to 10-membered heteroaryl. In an embodiment, R 1 is an unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R 1 is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, azocinyl, dithiazinyl, or oxazinyl. In some embodiments, R 1 is pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, pyridazinyl, or pyrazinyl.

[0021] In an embodiment, R 1 is [Chemical formula] and in the formula, each X is independently CH or N, and the H of CH is R 4 in one or more examples of can be substituted, each R 4 is independently halo, -CN, -OH, -NO2, -N(R 5 )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 aryl, C3-C7 cycloalkyl, or 3- to 7-membered heterocyclyl, and each R 5 is independently H or C1-C6 alkyl. In certain embodiments, R 1 is

Chemical formula

Chemical formula

[0022] In some embodiments, R 1 is substituted C3-C7 cycloalkyl. In some embodiments, R 1 is unsubstituted C3-C7 cycloalkyl. In certain embodiments, R 1 is cyclopropyl or cyclobutyl. In certain embodiments, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0023] Group R 4 In some embodiments, R 4 is independently substituted C1-C6 alkyl, substituted C1-C6 alkoxy, or substituted C3-C7 cycloalkyl. In embodiments, R 4 is independently unsubstituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, or unsubstituted C3-C7 cycloalkyl. In embodiments, R 4 is independently halo, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl. In some embodiments, R 4 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl. In certain embodiments, R 4 is independently halo, -CN, -CH3, -CH2CH3, -CF3, -OCH3, -OCF3, -C(CH3)2OH, or -C6H5. In embodiments, R 4 is independently Cl, F, Br, or I.

[0024] Group B In certain embodiments, B is

Chemical formula

[0025] In some embodiments, R 2 is halo, -CN, -OH, -NO2, -CH3, -CH2CH3, -CHF2, -CF3, -OCF3, -OCH3, -OCH2CH3, or -OCH2CF3. In embodiments, up to two R 6 may be N, and the other occurrences of R 6 are CH. In some embodiments, B is

Chemical formula

[0026] In certain embodiments, B is

Chemical formula

Chemical formula

[0027] Group R 2 In some embodiments, R 2 is halo, -CN, -OH, -NO2, -CH3, -CH2CH3, cyclopropyl, -CHF2, -CF3, -OCF3, -OCH3, -OCH2CH3, or -OCH2CF3.

[0028] Group A In certain embodiments, A is pyridinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazinyl, tetrazolyl, oxazolyl, isoxazolyl, or thiazolyl. In embodiments, A is pyridinyl oxazolyl, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl. In embodiments, A is

Chemical formula

Chemical formula

Chemical formula

[0029] n In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0. 1. In some embodiments, n is 1, R a is C1-C6 alkyl, and R b is H. In embodiments, n is 1, R a is ethyl, and R b is H. In embodiments, n is 1, R a is methyl, and R b is H. In some embodiments, n is 1, R a and R bTogether with the carbon to which they are attached, they form a cyclopropyl.

[0030] m In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 0.

[0031] o In some embodiments, o is 3. In some embodiments, o is 2. In some embodiments, o is 1. In some embodiments, o is 0.

[0032] p In some embodiments, p is 2. In some embodiments, p is 1. In some embodiments, p is 0.

[0033] In some embodiments, p is 1, and R c , R d , R e and R f are H. In some embodiments, p is 1, and R c is methyl, and R d , R e , and R f are H. In an embodiment, p is 1, and R c and R e are H, and R d and R f together with the carbon to which they are attached form a C1-C3 alkylene bridge. In some embodiments, p is 1, and R d and R f are H, and R c and R e together with the carbon to which they are attached form a C1-C3 alkylene bridge. In some embodiments, p is 0, and R c , R d , and R f are H.

[0034] q In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, q is 0.

[0035] In some embodiments, the compound is selected from the group consisting of the compounds specified in Table 1 below.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

[0036] Alternative Embodiments In alternative embodiments, the compounds of formula I may also contain one or more isotope substitutions. For example, hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium), and carbon may be, for example, 13 C or 14 C, oxygen may be, for example, 18 O, and nitrogen may be, for example, 15It may be N or the like. In other embodiments, a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotope abundance of the element occupying a particular site of the compound.

[0037] Pharmaceutical composition In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient). The compounds of formula I can be used for the treatment of the specific disorders described herein.

[0038] In certain embodiments, the compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In certain embodiments, the compounds of the present invention are provided in a prophylactically effective amount.

[0039] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0040] The pharmaceutical compositions provided herein can be administered by various routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0041] In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of relevant circumstances including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, among others.

[0042] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administering the compound or its pharmaceutical composition over a long period of time, such as for 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, for example, over the lifetime of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood within the therapeutic window, for example, over a long period of time.

[0043] The pharmaceutical compositions of the present invention can be further delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition can be administered as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient throughout the body. For example, intramuscular or subcutaneous bolus doses allow for a slow release of the active ingredient, while a bolus delivered directly into the vein (e.g., via an IV drip) allows for a much faster delivery that rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by an IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the body of the subject. Further, in still other embodiments, the pharmaceutical composition can be administered first as a bolus dose followed by a continuous infusion.

[0044] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosage forms for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), and the remainder consists of various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0045] For oral administration, oral administration 1 to 5 times a day, particularly 2 to 4 times a day, typically 3 times a day is a typical regimen. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of the compound provided by the present invention, and preferred doses provide from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg, respectively.

[0046] Transdermal dosages are generally selected to provide blood levels similar to or lower than those achieved using injection dosages, and generally range from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, more preferably from about 0.5 to about 15% by weight.

[0047] Injection dosage levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve an appropriate steady state level. The maximum total dose is not expected to exceed about 5 g / day for a human patient weighing 40 to 80 kg.

[0048] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle having a buffer, suspending and dispensing agents, coloring agents, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds of similar nature: binders such as crystalline cellulose, tragacanth gum, or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, primogel, or corn starch, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide, sweetening agents such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0049] Injectable compositions are typically based on sterile physiological saline for injection or phosphate-buffered saline or other injectable excipients known in the art. As described above, the active compounds in such compositions are typically minor components and are often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0050] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated, for example, in a cream having an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance skin penetration of the active ingredient or the stability of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0051] The compounds provided herein can also be administered by a transdermal device. Thus, transdermal administration can be achieved using either a reservoir type or a porous membrane type, or a patch of the solid matrix variety.

[0052] The above components of the orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, etc. are described in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0053] The compounds of the present invention can also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0054] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. The acids that can be used to prepare pharmaceutically acceptable salts are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.

[0055] In another aspect, the present invention provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable excipient, for example, a composition suitable for injection such as intravenous (IV) administration.

[0056] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion aids or suspending aids, surfactants, isotonic agents, preservatives, lubricants, etc. suitable for the particular dosage form desired, for example, an injectable. General considerations in the formulation and / or manufacture of pharmaceutical compositions are described, for example, in Remington’s Pharmac E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), Sixteenth Edition, and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005).

[0057] For example, injectable preparations such as sterile injectable aqueous suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate buffered saline, or Ringer's solution.

[0058] Injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injectable medium before use.

[0059] In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of relevant circumstances including the condition being treated, the route of administration selected, the compound actually being administered, the age, weight, response of the individual patient, and the severity of the patient's symptoms, among others.

[0060] The composition is presented in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as unit dosage forms for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include ampoules or syringes of pre-filled, pre-measured liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight, preferably from about 1% to about 40% by weight), and the remainder consists of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0061] The compounds provided herein can be administered as the sole active agent or in combination with other active agents. In one aspect, the invention provides a combination of a compound of the invention and another pharmaceutically active agent. The combined administration can be effected by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

[0062] The description of the pharmaceutical compositions provided herein relates primarily to pharmaceutical compositions suitable for administration to humans, although it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to render them suitable for administration to various animals are well understood, and those skilled in the art can design and / or effect such modifications by routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.

[0063] In one aspect, a kit is provided that includes a composition (e.g., a solid composition) comprising a compound of Formula I.

[0064] Method of Use and Treatment One feature of the present disclosure relates to compounds that may be useful as therapeutic agents for the treatment of diseases associated with the inhibition of CYP46A1 (e.g., epilepsy, neurodegenerative diseases, epilepsy, schizophrenia, and autism spectrum disorder). For example, in aspects of the present disclosure, provided herein is a method of treating a disorder in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound or composition described herein, including a compound of formula I as defined herein, to the subject. Examples of disorders that can be treated by the compounds include diseases associated with the inhibition of CYP46A1 (e.g., epilepsy, neurodegenerative diseases, epilepsy, and schizophrenia), neurodegenerative diseases, epilepsy, mental disorders (e.g., schizophrenia and autism spectrum disorder), epilepsy, and developmental and epileptic encephalopathies, but are not limited thereto. In some embodiments, the disease or disorder associated with the inhibition of CYP46A1 is a neurodegenerative disorder. In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, and multiple sclerosis. In certain embodiments, the disease or disorder associated with the inhibition of CYP46A1 is epilepsy. In certain embodiments, the disease or disorder associated with the inhibition of CYP46A1 is developmental and epileptic encephalopathy. In embodiments, the mental disorder is selected from the group consisting of schizophrenia, delusional disorder, schizoaffective disorder, depression, and autism spectrum disorder. In embodiments, the disease or disorder associated with the inhibition of CYP46A1 is epilepsy.

[0065] In some embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously. In some embodiments, the compound is administered by the oral route of administration.

[0066]

[0067] Neurodegenerative Diseases and Disorders​ The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the methods described herein, for example, in the treatment of neurodegenerative diseases and disorders.

[0068] The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of the structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including related symptoms of mild, moderate, or severe cognitive impairment), amyotrophic lateral sclerosis (ALS), anoxia and ischemic injury, ataxia and convulsion (including the treatment and prevention of seizures caused by drugs used in the treatment of bipolar affective disorder or schizophrenia), benign amnesia, cerebral edema, cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS), closed head injury, coma, contusion (e.g., spinal cord injury and head injury), dementia including multi-infarct dementia and senile dementia, disturbance of consciousness, Down syndrome, drug-induced or drug-treatment-induced parkinsonism (including neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-treatment-induced postural tremor), epilepsy, fragile X syndrome, Gilles de la Tourette syndrome, head trauma, hearing impairment and loss, Huntington's disease, Lennox syndrome, levodopa-induced dyskinesia, mental retardation, akinesia and akinesia (rigidity) syndrome (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS-dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy), chorea (including benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus), tremor (including resting tremor, postural tremor, and intention tremor), and dystonia (axial dystonia, dystonic cramp, hemiplegic dystonia, paroxysmal dystonia, and, for example, blepharospasm, oromandibular dystonia, spasmodicdystonia) and including local dystonia such as torticollis) including myoclonic jerks and disorders associated with myotonia or muscle weakness, ophthalmic injuries of the eye, nerve damage including retinopathy or macular degeneration, stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebrovascular spasm, hypoglycemia, memory loss, hypoxia, anoxia, perinatal asphyxia and neurotoxic injury following cardiac arrest, glaucoma (including symptoms associated with blindness, normal-tension glaucoma), Parkinson's disease, epileptic seizures, status epilepticus, stroke, tinnitus, tuberous sclerosis, and virus infection-induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy), but not limited thereto. Neurodegenerative diseases also include stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebrovascular spasm, hypoglycemia, memory loss, hypoxia, anoxia, perinatal asphyxia, and neurotoxic injury following cardiac arrest, but not limited thereto. The method for treating or preventing neurodegenerative diseases also includes treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0069] Mental disorders The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition composed of the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the methods described herein, for example, in the treatment of mental disorders.

[0070] The term "mental disorder" encompasses diseases and disorders associated with clinically significant disorders in behavior that reflect dysfunctions in the psychological, biological, or developmental processes underlying an individual's cognition, emotional regulation, or mental functions. Mental disorders include schizophrenia (including associated symptoms such as hallucinations, delusions, disorganized thinking, avolition, and reduced emotional expression), delusional disorder, schizoaffective disorder, dissociative identity disorder, depression also known as depressive disorder (including associated symptoms such as persistent anxiety, feelings of powerlessness, despair, pessimism, worthlessness, low energy, restlessness, sleep difficulties, insomnia, hypersensitivity, fatigue, motor problems, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, inadequate self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts), psychotic major depression (PMD), autism spectrum disorder, autism (including associated symptoms such as impairment in social interaction and impairment in verbal and non-verbal communication), bipolar disorder (including associated symptoms such as anxiety and mood instability), and attention deficit / hyperactivity disorder (including associated symptoms such as attention deficit, hyperactivity, and impulsivity), but are not limited to these.

[0071] Epilepsy The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the treatment of the disorders described herein, such as epilepsy, developmental and epileptic encephalopathies, status epilepticus, or seizures.

[0072] Epilepsy is a syndrome of paroxysmal brain dysfunction characterized by recurrent, unpredictable spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and is associated with the occurrence of seizures, movement disorders, and memory impairment. Types of epilepsy include generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, benign childhood focal epilepsy, but are not limited to these.

[0073] Epileptic encephalopathy The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the methods described herein, for example, in the treatment of developmental and epileptic encephalopathies.

[0074] Epileptic encephalopathy is a condition in which neurological deterioration is wholly or partly due to epileptic activity. This can be due to very frequent or severe seizures and / or semi - continuous interictal epileptic discharges. Developmental and epileptic encephalopathies represent a group of epileptic disorders that present early and are characterized by generalized or focal drug resistance, persistent severe electroencephalogram (EEG) abnormalities, and cognitive impairment or decline.

[0075] Epileptogenesis The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the methods described herein, for example, in the treatment of epileptogenesis.

[0076] Epileptogenesis is a step - wise process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from damage to nerve cells precipitated by an initial insult (e.g., status epilepticus).

[0077] Status epilepticus (SE) The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the methods described herein, for example, in the treatment of status epilepticus (SE).

[0078] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic discharges, and periodic lateralized epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive epileptic seizure states and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-choice therapy. Established status epilepticus is characterized by an epileptic seizure state that persists despite treatment with first-choice therapy, and second-choice therapy is administered. Refractory status epilepticus is characterized by an epileptic seizure state that persists despite first-choice and second-choice therapies, and general anesthetics are generally administered. Super-refractory status epilepticus is characterized by an epileptic seizure state that persists despite first-choice therapy, second-choice therapy, and treatment with general anesthetics for more than 24 hours.

[0079] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus, generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0080] Convulsion The compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, can be used in the methods described herein, for example, in the treatment of convulsions.

[0081] Spasm is a disease that occurs with abnormal electrical excitation of neurons in the brain, and it includes related symptoms such as muscle cramp, changes in the level of consciousness or weakness, nausea, severe headache, sudden numbness, and vomiting. Spasm is one of the characteristic clinical findings in Alzheimer's disease.

[0082] Combination therapy and treatment When applying the compounds of the present invention to each of the above-mentioned diseases, they can be administered in combination with pharmaceuticals or treatment methods generally used for the diseases. The combined administration can be carried out by any technique obvious to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

[0083] Examples of pharmaceuticals used in combination with the compounds of the present invention (hereinafter abbreviated as "combination drugs") include acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, xanapril, etc.), anti-dementia agents (e.g., memantine), inhibitors of the production, secretion, accumulation, aggregation and / or deposition of β-amyloid protein, β-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylaminomethyl)tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylaminomethyl)-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, and 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin), γ-secretase inhibitors, β-amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (JP-A-11-514333), and PPI-558 (JP-A-2001-500852)), β-amyloid vaccine, β-amyloid degrading enzyme, etc., brain function activators (e.g., aniracetam, nicergoline), other therapeutic agents for Parkinson's disease (e.g., dopamine receptor agonists), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline (l-deprenyl), rasagiline, riluzole), anticholinergic agents (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone), therapeutic agents for amyotrophic lateral sclerosis (e.g., riluzole, etc., neurotrophic factors), therapeutic agents for abnormal behaviors such as wandering due to the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), nerve differentiation or regeneration promoters (e.g., retapamulin, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-b-benzofuran-5-yl]isoindoline, and its optically active forms, salts, and hydrates), antidepressants (e.g., desipramine, amitriptyline, imipramine, tramadol), antiepileptic drugs (e.g., lamotrigine), anxiolytics (e.g., benzodiazepines), non-steroidal anti-inflammatory drugs (e.g., meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin), disease-modifying antirheumatic drugs (DMARD), anti-cytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), steroid drugs (e.g., dexamethasone, hexestrol, cortisone acetate), drugs for the treatment of incontinence or frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g., apomorphine, etc.), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), drugs for the treatment of osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, drugs for the treatment of insomnia (e.g., benzodiazepine drugs, non-benzodiazepine drugs, melatonin agonists), and drugs for the treatment of schizophrenia (e.g., typical antipsychotics such as haloperidol, atypical antipsychotics such as clozapine, olanzapine, risperidone, aripiprazole, drugs acting on metabotropic glutamate receptors or ion channel-linked glutamate receptors, phosphodiesterase inhibitors).

[0084] Also, it can be used in combination with a transplantation method of embryonic stem cells or neural tissues, or neural stem cells or neural progenitor cells prepared from fetal neural tissues, and in combination with pharmaceutical agents such as immunosuppressants after transplantation.

[0085] Furthermore, the compounds of the present invention can be used in combination with the following concomitant drugs.

[0086] 1. Therapeutic agents for diabetic complications For example, aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophic factors and their potentiators (e.g., NGF, NT-3, BDNF, neurotrophic factors and potentiators described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl-[oxazole])), nerve regeneration promoters (e.g., Y-128), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, pimagedine, pirtoxanthine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridoline, pyridoxamine), active oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), apoptosis signal-regulating kinase-1 (ASK-1) and the like can be mentioned.

[0087] 2. Therapeutic agents for hyperlipidemia For example, statin compounds (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or their salts (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., rapaquastatin acetate, or its salt), fibrate compounds (e.g., bezafibrate, clofibrate, cinfibrate, clinofibrate), ACAT inhibitors (e.g., avasimibe, eflusimibe), anion exchange resins (e.g., cholestyramine), probucol, nicotinic acid drugs (e.g., nicomol, nicertol), ethyl eicosapentaenoate, phytosterols (e.g., soy sterol, gamma oryzanol), etc.

[0088] 3. Diuretics For example, xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, pyritanide, bumetanide, furosemide, etc.

[0089] 4. Chemotherapeutic agents For example, alkylating agents (e.g., cyclophosphamide, ifosfamide), metabolic antagonists (e.g., methotrexate, 5-fluorouracil, or their derivatives), antitumor antibiotics (e.g., mitomycin, adriamycin), antitumor agents derived from plants (e.g., vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide, etc. Among these, fluturon and neofluturon, which are 5-fluorouracil derivatives, are preferred.

[0090] 5. Immunotherapeutic agents For example, microorganisms or bacterial components (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL)), colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin), etc., and interleukins such as IL-1, IL-2, IL-12 are preferred.

[0091] 6. Antithrombotic agents For example, heparin (e.g., sodium heparin, calcium heparin, dalteparin sodium), warfarin (e.g., potassium warfarin), antithrombin agents (e.g., argatroban), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitors (e.g., hydrochlorothiazide, cilostazol, ethyl eicosapentaenoate, sodium vera prost, sarpogrelate hydrochloride), and the like.

[0092] 7. Pharmaceutical for improving cachexia For example, cyclooxygenase inhibitors (e.g., indomethacin, etc.) [Cancer Research, Vol. 49, pages 5935 - 5939, 1989], progesterone derivatives (e.g., megestrol acetate) [Journal of Clinical Oncology, Vol. 12, pages 213 - 225, 1994], glucocorticoids (e.g., dexamethasone, etc.), metoclopramide agents, tetrahydrocannabinol agents (all publications are as described above), agents for improving lipid metabolism (e.g., eicosapentaenoic acid, etc.) [British Journal of Cancer, Vol. 68, pages 314 - 318, 1993], growth hormone, IGF - 1, or antibodies against cachexia - inducing factors such as TNF - α, LIF, IL - 6, oncostatin M.

[0093] The above - mentioned two or more combined drugs may be used in combination at appropriate ratios.

[0094] It is also possible to apply the compound of the present invention in combination with biological agents (e.g., antibodies, vaccine preparations, etc.) for each of the above - mentioned diseases, or in combination with gene therapy methods, etc., as a combined therapy.

[0095] Examples of antibody and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, TNFα antibodies and antibodies against other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., DIAPEP-277 manufactured by Peptor), anti-HIV antibodies, HIV vaccine preparations, etc., antibodies or vaccine preparations against cytokines, renin-angiotensin enzymes and their products, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines against enzymes or proteins involved in blood coagulation or fibrinolysis systems, antibodies or vaccine preparations against proteins involved in glucose metabolism or insulin resistance, etc.

[0096] Furthermore, it is also possible to use in combination with biological preparations involved in growth factors such as GH and IGF.

[0097] Examples of gene therapy methods include treatment methods using genes related to cytokines, renin-angiotensin enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes, treatment methods using DNA decoys such as NF.κB decoys, treatment methods using antisense, genes related to enzymes or proteins involved in blood lipid metabolism (e.g., genes involved in the metabolism, excretion or absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipids), treatment methods using enzymes or proteins (e.g., growth factors such as HGF and VEGF) involved in angiogenesis therapy targeting peripheral vascular occlusion, treatment methods using genes related to proteins involved in antisense against cytokines such as glucose metabolism or insulin resistance, TNF, etc. Examples include treatment methods using genes related to enzymes or proteins involved in the metabolism, excretion or absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipids, treatment methods using enzymes or proteins (e.g., growth factors such as HGF and VEGF) involved in angiogenesis therapy targeting peripheral vascular occlusion, treatment methods using genes related to proteins involved in antisense against cytokines such as glucose metabolism or insulin resistance, TNF, etc.

[0098] Furthermore, it is possible to use in combination with various organ regeneration methods such as heart regeneration, kidney regeneration, pancreas regeneration, blood vessel regeneration, etc., or cell transplantation therapy using bone marrow cells (bone marrow monocytes, bone marrow stem cells), or artificial organs (e.g., artificial blood vessels and cardiomyocyte sheets) using tissue engineering.

[0099] The administration times of the compounds of the present invention and the concomitant drugs are not limited, and they can be administered simultaneously or with a time difference to the administration subject. Furthermore, the compounds of the present invention and the concomitant drugs can be administered as two preparations each containing the respective active ingredient, or as a single preparation containing both active ingredients.

[0100] The dose of the concomitant drug can be appropriately determined based on the dose used in the clinical situation. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined according to the administration subject, administration route, target disease, symptoms, concomitant use, etc. When the administration subject is a human, for example, 0.01 to 100 parts by weight of the concomitant drug can be used with respect to 1 part by weight of the compound of the present invention.

[0101] Definition of chemical substances The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3 rdIt is described in Edition, Cambridge University Press, Cambridge, 1987.

[0102] Isomers, such as stereoisomers, can be isolated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers. mixtures.

[0103] Compounds that have the same molecular formula but differ in the nature or sequence of the bonds between their atoms, or in the spatial arrangement of those atoms, are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". If a compound has an asymmetric center, for example, bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the Cahn and Prelog R- and S-configuration rules, or by the manner in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as the (+) or (-)-isomer, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0104] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% by weight of the enantiomers. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound. As used herein, the term "diastereomeric purity" refers to the amount of the compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its diastereoisomers. The term "diastereomerically pure" means that the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% by weight of the diastereoisomers. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing the compound from its diastereoisomers, such as high performance liquid chromatography (HPLC).

[0105] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-position / center / carbon compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition can contain, for example, at least about 95% by weight of the R-compound, and up to about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound can contain, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition can contain, for example, at least about 95% by weight of the S-compound, and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain specific embodiments, the active ingredient can be formulated without using substantially or any excipient or carrier.

[0106] As used herein, the term "diastereomeric purity" refers to the amount of a compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its diastereoisomers. The term "diastereomerically pure" means that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% of diastereoisomers. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing a compound from its diastereoisomers, such as high performance liquid chromatography (HPLC).

[0107] The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "analog" means one analog, or more than one analog.

[0108] When a range of values is recited, each value and subrange within the range is intended to be included. For example, "C 1-6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0109] The following terms are intended to have the meanings presented below and are useful for understanding the specification and intended scope of the present invention.

[0110] "Alkyl" refers to a radical of a straight or branched chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). C1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 4 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). General abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0111] "Alkylene" refers to a divalent saturated hydrocarbon. Alkylene can be represented by - (CH2) n -, - (CH2)-, - (CH2)2-, - (CH2)3-, - (CH2)4-, - (CH2)5-, - (CH2)6-, - (CH2)7-, - (CH2)8-, - (CH2)9-, or - (CH2) 10 -. In some embodiments, the alkylene can be an alkylene of the indicated number of carbon atoms, e.g., C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. Unless otherwise specified, each example of an alkylene group , independently, optionally substituted, i.e., unsubstituted (“unsubstituted alkylene”) or substituted with one or more substituents (e.g., 1 to 4 substituents, 1 to 3 substituents, or 1 substituent) which can be halo, -NO2, -OH, C1-C6 alkoxy, C1-C6 alkyl, or C1-C6 cycloalkyl (“substituted alkylene”). Abbreviations for alkylene include -(CH(CH3))-, -(CH(CH2CH3))-, -(CH(CH2CH2CH3))-, -(CH(CH2CH2CH2CH3))-, -(CH2CH(CH2CH2CH2CH3))-, -(CH2CH2CH(CH2CH2CH2CH3))-, -(CH(CH3)CH2)-, -(CH(CH3)CH2CH2)-, -(CH(CH3)CH2CH2CH2)-, -(CH2CH(CH3)CH2)-, -(CH2CH(CH3)CH2CH2)-, and -(CH2CH2CH(CH3)CH2CH2)-.

[0112] “Aryl” has 6 to 14 ring carbon atoms and 0 heteroatoms provided in an aromatic ring system (“C 6ー14 aryl”) and refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared within a cyclic array). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”, e.g., phenyl). “Aryl” also includes a ring system where the aryl ring as defined herein is fused with one or more carbocyclic or heterocyclic groups where the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from benzene. Particularly, aryl groups include phenyl and indenyl. Unless otherwise specified, each example of an aryl group is independently, optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”).

[0113] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared within the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. The heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes the ring system, and the heteroaryl rings defined herein are fused with one or more carbocyclic or heterocyclic groups having the point of attachment on the heteroaryl ring, and in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system.

[0114] In some embodiments, the heteroaryl group is 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl").

[0115] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, fur Examples include, but are not limited to, nil and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.

[0116] Examples of representative heteroaryls include the following:

Chemical formula

[0117] "Alkylene bridge" refers to a straight-chain or branched-chain divalent hydrocarbon bridge that connects two different carbons of the same cyclic structure. The alkylene bridge can connect any two carbons within the cyclic structure. In some embodiments, the alkylene bridge can be an alkylene bridge having the indicated number of carbon atoms, e.g., a C1-C6 alkylene bridge, a C1-C5 alkylene bridge, a C1-C4 alkylene bridge, a C1-C3 alkylene bridge, or a C1-C2 alkylene bridge. Unless otherwise specified, each example of an alkylene bridge is independently optionally substituted, i.e., it is either unsubstituted ("unsubstituted alkylene bridge") or substituted with one or more substituents (e.g., 1 to 4 substituents, 1 to 3 substituents, or 1 substituent) that can be halo, -NO2, -OH, C1-C6 alkoxy, C1-C6 alkyl, or C1-C6 cycloalkyl ("substituted alkylene bridge"). Examples of alkylene bridges include, but are not limited to, methylene, ethylene, propylene, tetramethylene, and n-butylene.

[0118] "Nitrogen-containing heteroaryl" refers to a monocyclic aromatic heterocyclic group containing at least one nitrogen atom. Exemplary nitrogen-containing heteroaryl groups include, but are not limited to, pyrrolyl, thiazolyl, isoxazolyl, pyrazinyl, imidazolyl, oxazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl, triazolyl, triazinyl, tetrazolyl, azepinyl, azocinyl, dithiazinyl, and oxazinyl.

[0119] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero is, for example, 1 to 5, particularly 1 to 3 hetero It can be applied to any of the above-mentioned hydrocarbyl groups having an alkyl with an atom, such as a heteroalkyl, a cycloalkyl, such as a heterocyclyl, an aryl, such as a heteroaryl, a cycloalkenyl, such as a cycloheteroalkenyl, etc.

[0120] "Carbocyclic" or "carbocyclic ring" refers to a radical of a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 carbocyclic") and 0 heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclic"). Exemplary C 3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 carbocyclic groups include the aforementioned C 3-6 carbocyclic groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc., but are not limited to these. Exemplary C 3-10 carbocyclic groups include the aforementioned C 3-8 carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10) Octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decan-1-yl (C 10 ), and the like, but are not limited thereto. As shown in the foregoing examples, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or contains a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclic"), and can be saturated or partially unsaturated. "Carbocyclic" also includes a ring system, and the carbocyclic ring as defined herein is fused to one or more aryl or heteroaryl groups where the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to specify the number of carbons in the carbocyclic ring system. Unless otherwise specified, each example of a carbocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C 3-10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3-10 carbocyclic.

[0121] In some embodiments, "carbocyclic" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl"). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C 3-6 cycloalkyl groups include the aforementioned C5-6 Cycloalkyl groups, and cyclopropyl (C3) and cyclobutyl (C4) are included. C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, and cycloheptyl (C7), cyclooctyl (C8) are included. Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments the cycloalkyl group is unsubstituted C 3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3-10 cycloalkyl.

[0122] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. The heterocyclyl group can be any of a fused, bridged or spiro ring system such as monocyclic ("monocyclic heterocyclyl") or bicyclic system ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. The bicyclic heterocyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system, and the heterocyclic ring defined herein is fused to one or more carbocyclic groups, with the point of attachment being either a carbocyclic ring or a heterocyclic ring, or on the ring system, and the heterocyclic ring defined herein is fused to one or more aryl groups or heteroaryl groups, with the point of attachment being on the heterocyclic ring, and in such cases, the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0123] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0124] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, Examples include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6 bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6 bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0125] "Alkoxy" refers to an -OR 29 group, where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In particular, alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., alkoxy groups having 1 to 6 carbon atoms. Further certain alkoxy groups have 1 to 4 carbon atoms.

[0126] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10A group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, and particularly 1 to 3 substituents, especially 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl), and -O-(CH2) t (4- to 10-membered heterocyclyl), but are not limited thereto, wherein t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0127] "Haloalkoxy" refers to a haloalkyl group as defined herein bonded through an oxygen bridge (the oxygen of the alcohol radical).

[0128] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, the halo group is either fluorine or chlorine.

[0129] "Haloalkyl" refers to an alkyl radical in which one or more of the alkyl groups are substituted with a halogen. Exemplary haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0130] The alkyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen (e.g., a carbon or nitrogen atom) present on the group is replaced by an acceptable substituent, e.g., a substituent that results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, "substituted" groups have substituents at one or more substitutable positions of the group, and when two or more positions within any given structure are substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For the purposes of the present invention, a heteroatom such as nitrogen may have any suitable substituent described herein that satisfies the valence of the hydrogen substituent and / or heteroatom and results in the formation of a stable moiety.

[0131] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X -, -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb , -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3 - C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa、 -SC(=O)OR aa 、 -SC(=O)R aa 、 -P(=O)2R aa 、 -OP(=O)2R aa 、 -P(=O)(R aa )2、 -OP(=O)(R aa )2、 -OP(=O)(OR cc )2、 -P(=O)2N(R bb )2、 -OP(=O)2N(R bb )2、 -P(=O)(NR bb )2、 -OP(=O)(NR bb )2、 -NR bb P(=O)(OR cc )2、 -NR bb P(=O)(NR bb )2、 -P(R cc )2、 -P(R cc )3、 -OP(R cc )2、 -OP(R cc )3、 -B(R aa )2、 -B(OR cc )2、 -BR aa (OR cc )、 C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocycloyl, 3 - to 14 - membered heterocyclyl, C 6-14 Aryl, and 5 - to 14 - membered heteroaryl are included, but not limited thereto. Each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, or two geminal hydrogens on a carbon atom are substituted with group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc and Raa Each example of is independently selected from C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, R bb Each example of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two Rbb The base is bonded to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, R cc each example of which is independently selected from hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are bonded to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, R dd each example of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NRff ) OR ee 、 -OC(=NR ff ) R ee 、 -OC(=NR ff ) OR ee 、 -C(=NR ff ) N(R ff )2、 -OC(=NR ff ) N(R ff )2、 -NR ff C(=NR ff ) N(R ff )2、 -NR ff SO2R ee 、 -SO2N(R ff )2、 -SO2R ee 、 -SO2OR ee 、 -OSO2R ee 、 -S(=O) R ee 、 -Si(R ee )3、 -OSi(R ee )3、 -C(=S) N(R ff )2、 -C(=O) SR ee 、 -C(=S) SR ee 、 -SC(=S) SR ee 、 -P(=O)2R ee 、 -P(=O)(R ee )2、 -OP(=O)(R ee )2、 -OP(=O)(OR ee )2、 C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic, 3 - to 10 - membered heterocyclic, C 6-10 aryl, 5 - to 10 - membered heteroaryl, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd substituents can combine to form =O or =S, R ee Each example of which is independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, C 6-10 Selected from aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, carbocycloyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, R ff each example of which is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, each example of R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C1-6 (alkyl), -C(=O)(C 1-6 (alkyl), -CO2H, -CO2(C 1-6 (alkyl), -OC(=O)(C 1-6 (alkyl), -OCO2(C 1-6 (alkyl), -C(=O)NH2, -C(=O)N(C 1-6 (alkyl)2, -OC(=O)NH(C 1-6 (alkyl), -NHC(=O)(C 1-6 (alkyl), -N(C 1-6 (alkyl)C(=O)(C 1-6 (alkyl), -NHCO2(C 1-6 (alkyl), -NHC(=O)N(C 1-6 (alkyl)2, -NHC(=O)NH(C 1-6 (alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 (alkyl), -OC(=NH)(C 1-6 (alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 (alkyl)2, -C(=NH)NH(C 1-6 (alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 (alkyl)2, -OC(NH)NH(C 1-6 (alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 (alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 (alkyl), -SO2N(C 1-6 (alkyl)2, -SO2NH(C 1-6 (alkyl), -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 (alkyl)3, -OSi(C 1-6 (alkyl)3-C(=S)N(C 1-6 (alkyl)2, C(=S)NH(C 1-6 (alkyl), C(=S)NH2, -C(=O)S(C 1-6 (alkyl), -C(=S)SC 1-6Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycloyl, C 6-10 Aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg substituents can be joined to form =O or =S, and X - is a counterion.

[0132] Other definitions "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal government, a state government, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, more specifically humans.

[0133] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, carboxylic acid, 4-methylbicyclo-[2.2.2]-cycloene-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, tri Acid addition salts formed with organic acids such as methylacetic acid, tertiary butyric acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or coordinated by organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Examples of salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. are included. The term "pharmaceutically acceptable cation" refers to the acceptable cation counterion of the acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. See, for example, Berge, et al., J.Pharm.Sci. (1977) 66(1):1-79.

[0134] "Pharmaceutically acceptable carrier" refers to compositions, carriers, diluents, and reagents that are pharmaceutically acceptable materials that can be administered to or on a subject. A pharmaceutically acceptable carrier can be involved in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. The carrier can be in the form of a solid, semi-solid, or liquid diluent, cream, or capsule. The active ingredient can be mixed with pharmaceutically acceptable excipients in an amount that is pharmaceutically acceptable, compatible with the active ingredient, and suitable for use in the treatment methods described herein. Suitable excipients are, for example, water, physiological saline, dextrose, glycerol, ethanol, etc., and combinations thereof.

[0135] The "subjects" for which administration is contemplated include human subjects (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or elderly adults)), and / or non-human animals such as mammals including primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs, but are not limited thereto. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0136] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Examples of oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, but are not limited thereto, where R aa , R bb , and R cc are as defined herein. Oxygen protecting groups are well known in the art and are incorporated herein by reference, Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd including those described in detail in the 1999 edition, John Wiley & Sons.

[0137] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts). not limited thereto.

[0138] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocycloyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, and each alkyl, alkenyl, alkynyl, carbocycloyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd substituted with a radical, R aa , R bb , R cc , and R dd are as defined herein. Amino protecting groups are well known in the art and are incorporated herein by reference, as described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999.

[0139] Exemplary amino protecting groups include, but are not limited to, amide groups such as formamide and acetamide (e.g., -C(=O)R aa ), carbamate groups such as 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz) (e.g., -C(=O)OR aa ), and sulfonamide groups such as p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM) (e.g., -S(=O)2R aa ), among others.

[0140] Diseases, disorders, and conditions are used interchangeably herein.

[0141] As used herein and unless otherwise specified, the terms "treat," "treating," and "treatment" are intended to mean an action that reduces the severity of, or delays the progression or onset of, a disease, disorder, or condition that occurs while a subject is afflicted with the particular disease, disorder, or condition. In alternative embodiments, the invention contemplates administration of a compound of the invention as a prophylactic agent before a subject begins to suffer from a particular disease, disorder, or condition.

[0142] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. Effective amounts include therapeutic and prophylactic treatments.

[0143] As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a disease, disorder, or condition, either alone or in combination with other treatments. The term "therapeutically effective amount" can include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0144] As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent that provides a prophylactic benefit in the prevention of a disease, disorder, or condition, either alone or in combination with other agents. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0145] As used herein and unless otherwise specified, "pharmacokinetics" can be defined as the study of the absorption, distribution, metabolism, and excretion of a drug in the body. "Pharmacokinetics" can also be defined as the branch of pharmacology concerned with the characteristic interactions of a drug with the body, from the viewpoints of its absorption, distribution, metabolism, and excretion, or the ways in which a drug is taken up by, moves through, and is eliminated from the body.

Examples

[0146] In order for the invention described in this specification to be more fully understood, the following examples are described. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed in any way as limiting their scope.

[0147] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. When typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art through routine optimization.

[0148] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0149] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented along with details regarding the preparation of representative piperidines listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns that can be used for the separation / purification of enantiomers / diastereoisomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0150] Reported herein 1 1H-NMR (e.g., for the region between about 0.5 to about 10 ppm δ (ppm) is to be understood as an exemplary interpretation of the NMR spectrum of the compound (e.g., exemplary peak integrations).

[0151] Exemplary general method for LCMS / LC ELSD: 30 - 90 AB_2 min Lcm. (Mobile phase: 1.5 mL / 4 L of TFA in water (solvent A) and 0.75 mL / 4 L of TFA in acetonitrile (solvent B), using an elution gradient of 30% - 90% (solvent B) over 0.9 min, at a flow rate of 1.2 mL / min and held at 90% for 0.6 min. Column: Xtimate C18 2.1 * × 30 mm (3 μm), wavelength: UV 220 nm, column temperature: 50 °C, MS ionization: ESI, detector: PDA & ELSD)

[0152] Abbreviations ACN: Acetonitrile; AcOK or KOAc: Potassium acetate; AUC: Area under the curve; sec-BuLi: sec-Butyllithium; BSA: Bis(trimethylsilyl)acetamide; BuOH: Butanol; BPO: Benzoyl peroxide; n-BuLi: n-Butyllithium; CAN: Cerium(IV) ammonium nitrate; CYP46A1: Cholesterol 24-hydroxylase; DIPEA or DIEA: Diisopropylethylamine; DEA: Diethanolamine; DME: Dimethoxyethane; DMF: Dimethylformamide; DCM: Dichloromethane; DMA: Dimethylacetamide; DIPA: Diisopropylamine; DMSO: Dimethyl sulfoxide; EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOH: Ethanol; EtOAc: Ethyl acetate; HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HBSS: Hank's balanced salt solution; HOBt: Hydroxybenzotriazole; HSS: High force silica; IPA: Isopropyl alcohol; LC: Liquid chromatography; LDA: Lithium diisopropylamide; MeOD: Methanol-d4; MeCN: Acetonitrile; MS: Mass spectrometry; MDCK: Madin-Darby canine kidney cells; MDR1: Multidrug resistance mutation; MeOH: Methanol; NADPH: Nicotinamide adenine dinucleotide phosphate; NBS: N-Bromosuccinimide; NMR: Nuclear magnetic resonance; i-Pr2O: Diisopropyl ether; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0); Pd(OAc)2: Palladium(II) acetate; Pd(dppf)Cl2: (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride; PE: Petroleum ether; PET: Polyethylene film; PK: Pharmacokinetics; PO: Oral; RFU: Relative fluorescence unit; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; TQ: Triple quadrupole; UPLC: Ultra performance liquid chromatography.

[0153] Example 1. General synthetic scheme The compounds of the present invention can be prepared according to the following methods outlined in Schemes 1 and 2. As illustrated in Scheme 1, protected 4-cyanopiperidine A is treated with a sterically hindered base such as LDA, followed by addition of an alkyl halide or benzyl halide (or tosylate) to obtain 4,4-disubstituted protected piperidine B. Deprotection to obtain piperidine C and subsequent amide coupling with acid D provides the target compound E of the present invention.

Chemical formula

[0154] Alternatively, as shown in Scheme 2, amide G is obtained by amide coupling of 4-cyanopiperidine F and acid D. Treatment of cyano-piperidine G with a sterically hindered base such as LDA, followed by an alkylation reaction of amide G by addition of an alkyl halide or benzyl halide (or tosylate), provides the target compound E.

Chemical formula

[0155] Example 2. Synthesis of 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A6)

Chemical formula

[0156] Synthesis of A3 A solution of ethyl (E)-2-(3-(dimethylamino)acryloyl)nicotinate (3.3 g, 13.3 mmol) and acetic acid (9.96 g, 166 mmol) in n-BuOH (30 mL) was added with DIPEA (30 mL) at 25 °C in one portion. The mixture was stirred at 120 °C for 40 h to obtain a solution. The residue was poured into water (50 mL) and saturated NaHCO3 (18 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0 - 30% EtOAc in PE) to give ethyl 2-(pyrimidin-4-yl)nicotinate (2.3 g) as a red oil. 1 H NMR (400 MHz, CDCl3) δ H 9.29 - 9.12 (m, 1H), 9.01 - 8.86 (m, 1H), 8.83 - 8.68 (m, 1H), 8.17 - 7.94 (m, 2H), 7.58 - 7.38 (m, 1H), 4.34 - 4.20 (m, 2H), 1.64 (s, 3H).

[0157] Synthesis of A4 A suspension of ethyl 2-(pyrimidin-4-yl)nicotinate (2.3 g, 10.0 mmol) and LiOH·H2O (629 mg, 15.0 mmol) in THF (10 mL) and MeOH (10 mL) was stirred at 25 °C for 2 h to obtain a suspension. The mixture was concentrated, and the residue was dried in a vacuum drying oven at 70 °C for 2 h and then at 100 °C for 10 min to give 2-(pyrimidin-4-yl)nicotinic acid (2.48 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 9.16 - 9.03 (m, 1H), 8.84 - 8.72 (m, 1H), 8.55 - 8.41 (m, 1H), 7.97 - 7.84 (m, 1H), 7.76 - 7.67 (m, 1H), 7.44 - 7.32 (m, 1H).

[0158] Synthesis of A5 Step 1. To a solution of DIPA (642 mg, 6.3 mmol) in THF (4 mL) was added n-BuLi (2.53 mL, 2.5 M in hexane, 6.3 mmol) at -70 °C. The mixture was warmed to 0 °C and stirred for 1 h. To this cold (0 °C) LDA solution was added tert-butyl 4-cyanopiperidine-1-carboxylate (1.33 g, 6.3 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 0.5 h. Then 1-(bromomethyl)-4-fluorobenzene (1 g, 5.3 mmol) was added and the mixture was stirred at 75 °C for 5 h, poured into water (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the product was obtained as a solid (2 g). The residue was purified by silica gel flash chromatography using a gradient elution of 0 - 30% EtOAc and PE to give 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (1.6 g, 80% yield) as a solid. 1 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.19 (m, 2H), 7.03 (t), 4.25 - 4.05 (m, 2H), 3.10 - 2.90 (m, 2H), 2.83 (s, 3H), 1.87 - 1.77 (m, 2H), 1.55 - 1.42 (m, 11H).

[0159] Step 2. To a solution of tert-butyl 4-cyano-4-(4-fluorobenzyl)piperidine-1-carboxylate (300 mg, 0.9 mmol) in DCM (10 mL) was added TFA (527 mg, 4.7 mmol). The reaction was stirred at 10 °C for 3 h. Saturated NaHCO3 solution (10 mL) was added to adjust the pH to 8 and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-(4-fluorobenzyl)piperidine-4-carbonitrile (200 mg, 99%) as an oil.

[0160] Synthesis of A6 A solution of 2-(pyrimidin-4-yl)nicotinic acid (138 mg, 0.7 mmol) in DMF (5 mL) was added with HATU (208 mg, 0.5 mmol) and DIPEA (176 mg, 1.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, and then a solution of 4-(4-fluorobenzyl)piperidine-4-carbonitrile (100 mg, 0.5 mmol) in DMF (3 mL) was added. The reaction was stirred at 10 °C for 2 hours and then combined with the duplicate reaction. Water (30 mL) was added and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (CH2Cl2 / MeOH 10 / 1) gave 160 mg of an oil, which was further purified by preparative HPLC (column: Waters Xbridge 150 * 25 5 μm. Conditions; water (10 mM NH4HCO3)-ACN, starting B: 25, ending B: 55, flow rate of 25 mL / min to give 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (118.8 mg, 32% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6, t = 80 °C) δ H 9.10 (s, 1H), 8.97 (d), 8.79 (t), 8.20 - 8.18 (m, 1H), 7.86 (dd, 1H), 7.68 - 7.60 (m, 1H), 7.40 - 7.30 (m, 2H), 7.16 (t, 2H), 4.57 (d, 1H), 3.55 - 3.40 (m, 1H), 3.30 - 2.90 (m, 4H), 2.00 - 1.92 (m, 1H), 1.80 - 1.60 (m, 3H). LC-ELSD / MS purity ≥ 99%, C 23 H 21 FN5O [M + H] + Calculated value for MS ESI for 402, measured value 402.

[0161] Example 3. Synthesis of 1-([2,4'-bipyridine]-3-carbonyl)-4-(4-(trifluoromethoxy)benzyl)piperidine-4-carbonitrile (A10)

Chemical Structure

[0162] Synthesis of A10 A solution of 1-{[2,4'-bipyridin]-3-carbonyl}piperidine-4-carbonitrile (116.2 mg, 396 μmol) in THF (1.97 mL) was added with sec-BuLi (1.4 M in cyclohexane, 367 μL, 514 μmol) at -78 °C, and the reaction mixture was stirred for 30 minutes. Solid 1-(bromomethyl)-4-(trifluoromethoxy)benzene (131 mg, 514 μmol) was added in one portion, and the reaction mixture was stirred at -78 °C for 2 hours, then warmed to room temperature and stirred overnight. Water was added, and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMSO and purified on a 12 g C18 reverse-phase column using gradient elution. Solvent A was 0.1% ammonium carbonate in water, solvent B was acetonitrile, and the gradient was 20% solvent B (5 minutes), 20% - 100% solvent B (15 minutes), and 100% solvent B (5 minutes), and the product (30 mg, 77 μmol, 17.4%, 90%) was obtained as a solid. The material was further purified by HPLC to obtain 1-([2,4'-bipyridin]-3-carbonyl)-4-(4-(trifluoromethoxy)benzyl)piperidine-4-carbonitrile (11.2 mg, 32 μmol, yield 7.2%) as a solid. LCMS (ESI): [M+H] + Calculated value 467.2, measured value 467.1. 1 H NMR (400 MHz, CD3OD): δ 8.79 (m; 2H); 8.66 (s; 1H); 7.92 (s; 1H); 7.79 (s; 1H); 7.66 (s; 1H); 7.60 (s; 1H); 7.38 (s; 1H); 7.25 (m; 3H); 4.69 (s; 1.2H); 3.4 (m, 0.4H); 3.11 (s; 0.8H); 2.94 (s; 1.7H); 2.72 (m; 1.7H); 2.57 (m; 0.6H); 1.91 (d; 1H); 1. 63 (s; 1H); 1.45 (s; 0.5H); 1.29 (s; 0.6H); 0.10 (s; 0.5H).

[0163] Example 4. Synthesis of 1-{[2,4'-bipyridin]-3-carbonyl}-4-[(4-chloro-2-fluorophenyl)methyl]piperidine-4-carbonitrile (A11) [Chem.] A solution of 1-{[2,4'-bipyridin]-3-carbonyl}piperidine-4-carbonitrile (116 mg, 396 μmol) in THF (1.32 mL) was added with 2 M LDA in THF (217 μL, 435 μmol) at -78 °C, and the reaction mixture was stirred for 30 minutes. 1-(Bromomethyl)-4-chloro-2-fluorobenzene (56.6 μL, 407 μmol) was added in one portion, and the reaction mixture was stirred at -78 °C for 2 hours, then warmed to room temperature and stirred overnight. The mixture was diluted with EtOAc, filtered, and the organic phase was concentrated under reduced pressure. The residue was dissolved in DMSO and purified on a 12 g C18 reverse-phase column using gradient elution. Solvent A was 0.1% ammonium carbonate in water, solvent B was acetonitrile, and the gradient was 20% solvent B (5 minutes), 20% - 100% solvent B (15 minutes), and 100% solvent B (5 minutes), and the product (55 mg, purity 90%) was obtained as a solid. The material was further purified by HPLC to obtain 1-{[2,4'-bipyridin]-3-carbonyl}-4-[(4-chloro-2-fluorophenyl)methyl]piperidine-4-carbonitrile (35 mg, 80.4 μmol, yield 20%, purity 99%) as a solid. LCMS (ESI): [M+H] + Calculated values 435.1, 437.1, found values 435.1, 437.1. 1 H NMR (400 MHz, CD3OD): δ 8.80 (dd; 1H); 8.73 (m; 2H); 7.91 (m; 1H); 7.77 (s; 1H); 7.66 (s; 1H); 7.60 (t; 1H); 7.30 (m; 1H); 7.17 - 7.22 (m; 2H); 4.70 (s; 1.2H); 3.39 (s; 0.5H); 3.11 (m; 0.6H); 2.96 (s; 1.5H); 2.60 - 2.76 (m; 2.2H); 1.93 (s; 1H); 1.66 (m; 1.2H); 1.47 (m; 0.6H); 1.27 (s; 0.6H); 0.18 (s; 0.5H).

[0164] Example 5. Synthesis of 1-{[2,4'-bipyridine]-3-carbonyl}-4-[(2-fluorophenyl)methyl]piperidine-4-carbonitrile (A12) [ka] To a solution of 1-{[2,4'-bipyridine]-3-carbonyl}piperidine-4-carbonitrile (100 mg, 342 μmol) in THF (1.14 mL) was added LDA (2 M in THF, 188 μL, 376 μmol) at −78° C. The reaction mixture was stirred for 30 min and then 1-(bromomethyl)-2-fluorobenzene (66.5 mg, 352 μmol) was added. ol) was added in one portion and stirring was continued at -78 °C for 2 h, then warmed to room temperature and stirred overnight. The mixture was diluted with EtOAc, the solids were removed by filtration, and the organic phase was concentrated under reduced pressure. The residue was dissolved in DMSO and purified on a 12 g C18 reverse phase column using gradient elution. Solvent A was 0.1% ammonium carbonate in water, solvent B was acetonitrile, the gradient was 20% solvent B (5 min), 20% to 100% solvent B (15 min), and 100% solvent B (5 min) to give the product (50 mg, 90% purity) as a solid. The material was further purified by HPLC to give 1-{[2,4'-bipyridine]-3-carbonyl}-4-[(2-fluorophenyl)methyl]piperidine-4-carbonitrile (20 mg, 49.9 μmol, 14.7% yield, 99% purity) as a solid. LCMS (ESI): [M+H] + Calculated value: 401.2, actual value: 401.2. 1 H NMR(400MHz,CD3OD):δ8.80(d;1H);8.69(m;2H);7.91(m;1H);7.77(s;1H);7.6 6(s;1H);7.60(s;1H);7.30-7.33(br;2H);7.07-7.16(m;2H);4.70(br;1.2H);3 .10(m;0.7H);2.97(s;1.6H);2.73(m;1.6H);2.62-2.65(m;0.8H);1.93(s;1.2H );1.76(s;0.4H);1.66(s;0.7H);1.48(d;0.6H);1.29(s;0.6H);0.22(s;0.5H).

[0165] Example 6.1 - Synthesis of {[2,4'-bipyridine]-3-carbonyl}-4-[(3-fluorophenyl)methyl]piperidine-4-carbonitrile (A13)

Chemical Structure

[0166] Example 7.1 - Synthesis of ([2,4'-bipyridine]-3-carbonyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (A14)

Chemical formula

[0167] Synthesis of Example 8. 1-(2-(1H-imidazol-1-yl)nicotinoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (A16)

Chemical Structure

[0168] Synthesis of Example 9. 1-([2,3'-bipyridine]-3-carbonyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (A18)

Chemical Structure

[0169] Example 10. Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-1-([2,4'-bipyridine]-3-carbonyl)piperidine-4-carbonitrile (A19)

Chemical formula

[0170] Example 11. Synthesis of 1-([2,4'-bipyridine]-3-carbonyl)-4-(2-chlorobenzyl)piperidine-4-carbonitrile (A21)

Chemical Structure

[0171] Example 12. 1-([2,4'-Bipyridine]-3-carbonyl)-4-(2-chlorobenzyl)piperidine-4-carbonitrile (A22)

Chemical Structure

[0172] Example 13. Synthesis of 1-([2,4'-Bipyridine]-3-carbonyl)-4-(2-methylbenzyl)piperidine-4-carbonitrile (A25)

Chemical Structure

[0173] Example 14. Synthesis of 1-([2,4'-bipyridine]-3-carbonyl)-4-(4-cyanobenzyl)piperidine-4-carbonitrile (A27) [Chemical formula] A suspension of 4-(4-cyanobenzyl)piperidine-4-carbonitrile trifluoroacetate (104 mg, 0.31 mmol) and lithio[2,4'-bipyridine]-3-carboxylate (66.3 mg, 0.32 mmol) in a mixture of THF (0.3 mL) and DMF (2.7 mL) was added with potassium carbonate anhydrous (127 mg, 0.92 mmol), and the mixture was stirred at room temperature for 1 h. HATU (122 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (15 mL), filtered through glass wool, and the organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography using gradient elution (0% - 100% MeOH with 10% NH4OH / DCM) to give 1-([2,4'-bipyridine]-3-carbonyl)-4-(4-cyanobenzyl)piperidine-4-carbonitrile (89 mg, 0.21 mmol, 70% yield). LCMS (ESI): [M+H] + Calculated 408.2, found 408.2. 1 1H NMR, (400 MHz, DMSO-d6): mixture of rotamers. 8.79 (s; 1H); 8.70 (d; 2H); 7.90 (t; 1H); 7.82 (d; 2H); 7.53 - 7.61 (m; 4H); 7.40 (dd; 2H); 4.51 (t; 1H); 3.17 - 3.28 (m; 1.2H); 3.00 (s; 1.6H); 2.62 - 2.82 (m; 2.8H); 1.82 - 1.85 (m; 1.1H); 1.62 - 1.73 (m; 1H); 1.41 - 1.54 (m; 1H); 1.22 - 1.29 (m; 0.5H); 0.19 (t; 0.3H).

[0174] Example 15. Synthesis of 4-benzyl-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A31)

Chemical Structure

[0175] Synthesis of A30 To a solution of 4-benzyl-4-cyanopiperidine-1-carboxylate (10 g, 33.2 mmol) in EtOAc (40 mL) was added 40 mL of 4 M HCl in EtOAc. The mixture was stirred at 25 °C for 16 hours, concentrated under reduced pressure, and 4-benzylpiperidine-4-carbonitrile hydrochloride (5.5 g) was obtained as a solid. 1 H NMR (400 MHz, CDCl3) δ H 10.20 - 9.66 (m, 2H), 7.27 - 7.40 (m, 5H), 3.55 (d, 2H) 3.28 - 3.07 (m, 2H), 2.93 (s, 2H), 2.25 - 1.97 (m, 4H).

[0176] Synthesis of A31 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (203 mg, 1.00 mmol) and HATU (384 mg, 1.00 mmol) in DMF (10 mL), DIPEA (435 mg, 3.36 mmol) and 4-benzylpiperidine-4-carbonitrile-HCl (200 mg, 0.844 mmol) were added at 10 - 15 °C. The mixture was stirred at 10 - 15 °C for 12 h, poured into ice water (60 mL), and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (3 × 60 mL), the combined organic phases were washed with brine (3 × 60 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC (preparative HPLC method, equipment: Gilson GX-281 liquid handler, Gilson 322 pump, Gilson 156 UV detector, column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, mobile phase A: water (0.04% NH3.H2O + 10 mM NH4HCO3), mobile phase B: MeCN, gradient: B from 29% to 59% in 10 min, then hold at 100% B for 2.5 min, flow rate: 25 mL / min, column temperature: 30 °C, wavelength: 220 nm, 254 nm), to obtain 4-benzyl-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (115.1 mg, 0.3 mmol) as a solid. LC-MS purity 99%, C 23 H 22 N5O [M+H] + The calculated value of MS ESI for 384.2, the measured value 384.2. 1 1H NMR (400 MHz, DMSO-d6) δ H 9.17 (s, 0.5H), 8.98 - 8.95 (m, 1.5H), 8.79 (s, 1H), 8.24 - 8.19 (m, 1H), 7.87 (d, 1H), 7.66 (s, 1H), 7.37 - 7.32 (m, 5H), 4.62 - 4.56 (m, 1H), 3.52 - 3.49 (m, 0.5H), 3.29 (s, 1.5H), 3.00 - 2.88 (m, 3H), 1.95 (d, 1H), 1.75 - 1.67 (m, 3H).

[0177] Synthesis of Example 16.1 - ([2,4'-Bipyridine]-3-carbonyl)-4-benzylpiperidine-4-carbonitrile (A32)

Chemical Structure

[0178] Example 17. Synthesis of 4-(4-methylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A35)

Chemical Structure

[0179] Synthesis of A34 To a solution of tert-butyl 4-cyano-4-(4-methylbenzyl)piperidine-1-carboxylate (0.5 g, 1.59 mmol) in 2 mL of EtOAc was added 2 mL of 4 M HCl in EtOAc, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-(4-methylbenzyl)piperidine-4-carbonitrile HCl salt (0.3 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 7.17 (s, 4H), 3.53 (d, 2H), 3.15 (d, 2H), 2.89 (s, 2H), 2.34 (s, 3H), 2.18 - 1.99 (m, 4H), 1.35 - 1.17 (m, 1H).

[0180] Synthesis of A35 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (200 mg, 0.994 mmol) in DMF (5 mL) at 15 °C, HATU (452 mg, 1.19 mmol) and DIEA (384 mg, 2.98 mmol) were added. After stirring at 15 °C for 10 minutes, a solution of 4-(4-methylbenzyl)piperidine-4-carbonitrile (255 mg, 1.19 mmol) in DMF (3 mL) was added, and the mixture was stirred at 15 °C for 2 hours, treated with water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and 200 mg of the product was obtained as an oil. The residue was purified by HPLC (column: Waters Xbridge BEH C18 150 * 25 mm * 5 μm) using a gradient elution to 36% - 46% B over 9.5 minutes (condition A: 10 mM aqueous NH4HCO3 and condition B: acetonitrile), and 4-(4-methylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (72.4 mg, 36.3%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.3H), 8.88 (d, 1H), 8.75 (d, 1H), 8.73 - 8.70 (m, 1H), 8.72 (s, 0.7H), 8.30 - 8.18 (m, 1H), 7.71 - 7.60 (m, 1H), 7.46 (dd, 1H), 7.17 - 7.09 (m, 4H), 4.98 - 4.63 (m, 1H), 3.72 - 3.02 (m, 3H), 2.99 - 2.75 (m, 2H), 2.39 - 2.32 (m, 3H), 2.17 - 1.96 (m, 1H), 1.91 - 1.57 (m, 3H). LCMS purity > 99%, C 24 H 24 N5O [M - H] + The calculated value of MS ESI for 398.1, the measured value 398.1.

[0181] Example 18. Synthesis of 4-(4-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A37) [Chemical] Synthesis of A59 To a solution of DIPA (2.87 g, 28.4 mmol) in THF (20 mL) was added BuLi (11.3 mL, 2.5 M in hexane, 28.4 mmol) at -70 °C. The mixture was warmed to 0 °C and stirred for 30 minutes to obtain an LDA solution. To the cold (0 °C) LDA solution (28.4 mmol) was added tert-butyl 4-cyanopiperidine-1-carboxylate (5 g, 23.7 mmol) in THF (10 mL) dropwise over 0.5 hour at 0 °C. Then 1-chloro-4-(chloromethyl)benzene (4.57 g, 28.4 mmol) was added and the mixture was stirred at 75 °C for 5 hours, poured into water (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using gradient elution (0 - 10% EtOAc in PE) to give tert-butyl 4-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (6.7 g, 84.4%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 7.32 (d, 2H), 7.21 (d, 2H), 4.30 - 3.94 (m, 2H), 3.11 - 2.90 (m, 2H), 2.83 (s, 2H), 1.83 (d, 2H), 1.56 - 1.46 (m, 2H), 1.45 (s, 9H).

[0182] Synthesis of A36 To a solution of tert-butyl 4-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (0.5 g, 1.49 mmol) in 2 mL of EtOAc was added 2 mL of 4 M HCl in EtOAc. The mixture was stirred at 25 °C for 16 hours and then concentrated under reduced pressure to give 4-(4-chlorobenzyl)piperidine-4-carbonitrile (0.3 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ H7.34 (d, 2H), 7.25 - 7.21 (m, 2H), 3.60 - 3.45 (m, 2H), 3.23 - 3.10 (m, 2H), 2.91 (s, 2H), 2.21 - 2.01 (m, 4H).

[0183] Synthesis of A37 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (200 mg, 0.9941 mmol) in DMF (5 mL) was added HATU (452 mg, 1.19 mmol) and DIEA (384 mg, 2.98 mmol) at 15 °C, and the mixture was stirred at 15 °C for 10 minutes. A solution of 4-(4-chlorobenzyl)piperidine-4-carbonitrile (279 mg, 1.19 mmol) in DMF (3 mL) was added to the reaction mixture, and the mixture was stirred at 15 °C for 2 hours, then quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the product (200 mg) was obtained as an oil, which was purified by HPLC (column: Waters Xbridge BEH C18 150 * 25 mm * 5 um, conditions: water (10 mM NH4HCO3)-ACN, starting B: 37, ending B: 47), and 4-(4-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (61.9 mg, yield 31.1%) was obtained as a solid. 1 H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.4H), 8.96 (s, 0.6H), 8.91 (d, 0.6H), 8.87 (d, 0.4H), 8.76 (dd, 1H), 8.32 - 8.20 (m, 1H), 7.72 - 7.63 (m, 1H), 7.47 (dd, 1H), 7. 33 (d, 2H), 7.24 - 7.16 (m, 2H), 4.99 - 4.70 (m, 1H), 3.69 - 3.01 (m, 3H), 2.98 - 2.81 (m, 2H), 2.16 - 1.97 (m, 1H), 1.88 - 1.66 (m, 2H), 1.56 - 1.39 (m, 1H). LCMS purity 99.1%, C 23 H 21 ClN5O [M + H] +MS ESI calculated value for it is 418.0, measured value is 418.0.

[0184] Synthesis of Example 19.1-(2-(Pyrimidin-4-yl)nicotinoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4-carbonitrile (A40) [Chemical formula] Synthesis of A38 To a solution of DIPA (2.87 g, 28.4 mmol) in THF (20 mL), BuLi (11.3 mL, 2.5 M in hexane, 28.4 mmol) was added at -70 °C. The mixture was warmed to 0 °C and stirred for 30 minutes to obtain an LDA solution. To the cold (0 °C) LDA (28.4 mmol), tert-butyl 4-cyanopiperidine-1-carboxylate (5 g, 23.7 mmol) in THF (10 mL) was added dropwise at 0 °C over 0.5 hour. Then, 1-(chloromethyl)-4-(trifluoromethyl)benzene (5.52 g, 28.4 mmol) was added, and the mixture was stirred at 75 °C for 5 hours, poured into water (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using gradient elution (0 - 20% EtOAc in PE) to obtain tert-butyl 4-cyano-4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (5 g, yield 57.2%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 7.61 (d, 2H), 7.41 (d, 2H), 4.30 - 4.03 (m, 2H), 3.11 - 2.94 (m, 2H), 2.92 (s, 2H), 1.84 (d, 2H), 1.57 - 1.45 (m, 2H), 1.46 (s, 9H).

[0185] Synthesis of A39 To tert-butyl 4-cyano-4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.5 g, 1.35 mmol), 2 mL of 4 M HCl in EtOAc was added and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 4-(4-(trifluoromethyl)benzyl)piperidine-4-carbonitrile (0.3 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 9.8 (s, 1H), 7.64 (d, 2H), 7.43 (d, 2H), 3.57 (d, 2H), 3.26 - 3.10 (m, 2H), 3.00 (s, 2H), 2.27 - 2.02 (m, 4H), 1.38 - 1.13 (m, 1H).

[0186] Synthesis of A40 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (185 mg, 0.9195 mmol) in DMF (5 mL) was added HATU (418 mg, 1.10 mmol) and DIEA (354 mg, 2.75 mmol) at 15 °C and the mixture was stirred at 15 °C for 10 min. A solution of 4-(4-(trifluoromethyl)benzyl)piperidine-4-carbonitrile (295 mg, 1.10 mmol) in DMF (3 mL) was added and the reaction mixture was stirred at 15 °C for 2 h, quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product (200 mg) as an oil, which was purified by HPLC (column: Waters Xbridge BEH C18 150 * 25 mm * 5 um) using condition A: 10 mM aqueous NH4HCO3 and condition B: acetonitrile, gradient elution to 40% - 50% B over 9.5 min to give 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-(4-(trifluoromethyl)benzyl)piperidine-4-carbonitrile (96.4 mg, 48.4%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H9.21 (s, 0.4H), 9.05 (s, 0.6H), 8.96 - 8.82 (m, 1H), 8.77 (dd, 1H), 8.30 - 8.25 (m, 1H), 7.74 - 7.59 (m, 3H), 7.50 - 7.36 (m, 3H), 5.04 - 4.72 (m, 1H), 3.70 - 3.18 (m, 2H), 3.17 - 2.91 (m, 3H), 2.09 - 1.99 (m, 1H), 1.96 - 1.56 (m, 3H). LCMS purity > 99%, C 24 H 21 F3N5O [M + H] + The calculated value of MS ESI for it is 452.1, and the measured value is 452.1.

[0187] Example 20. Synthesis of (S)-4-(1-(4-fluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A44) and (R)-4-(1-(4-fluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A45)

Chemical Structure

[0188] Synthesis of A42 To a solution of tert-butyl 4-cyano-4-(1-(4-fluorophenyl)ethyl)piperidine-1-carboxylate (250 mg, 0.752 mmol) in EtOAc (10 mL) was added 10 mL of 4 M HCl in EtOAc. The mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure to afford 4-(1-(4-fluorophenyl)ethyl)piperidine-4-carbonitrile (200 mg) as a solid. 1 1H NMR (400 MHz, methanol-d4) δ H ppm 7.45 - 7.36 (m, 2H), 7.11 (m, 2H), 3.54 (m, 1H), 3.42 (m, 1H), 3.24 - 3.13 (m, 1H), 3.06 (m, 1H), 2.96 (q, 1H), 2.44 (dd, 1H), 1.94 - 1.82 (m, 1H), 1.78 (m, 1H), 1.74 - 1.65 (m, 1H), 1.51 (d, 3H).

[0189] Synthesis of A43 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (100 mg, 0.497 mmol) in DMF (5 mL) was added HATU (226 mg, 0.596 mmol) and DIEA (192 mg, 1.49 mmol) at 15 °C and the mixture was stirred at 15 °C for 10 min. A solution of 4-(1-(4-fluorophenyl)ethyl)piperidine-4-carbonitrile (160 mg, 0.596 mmol) in DMF (3 mL) was added and the reaction was stirred at 15 °C for 2 h, treated with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the product (200 mg) as a solid.

[0190] Synthesis of A44 and A45 Racemic 4-(1-(4-fluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (200 mg) was purified by SFC chromatography using DAICEL CHIRALCEL OD-H (250 mm * × 30 mm, 5 μm column and eluting with 25:75 0.1% NH3H2O:EtOH at a flow rate of 60 mL / min to obtain (peak 1, Rt = 2.82 min, 71.3 mg) as a solid and (peak 2, Rt = 3.13 min, 74.5 mg) as a solid. The product (54.5 mg, 0.1311 mmol) was diluted with EtOAc (30 mL), washed with saturated Na2CO3 (30 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain an enantiomerically pure compound as a solid. (S)-4-(1-(4-fluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.3H), 8.94 (s, 0.3H), 8.92 - 8.83 (m, 1.4H), 8.74 (m, 1H), 8.30 - 8.19 (m, 1H), 7.69 - 7.61 (m, 1H), 7.49 - 7.40 (m, 1H), 7.26 (m, 1.4H), 7.19 (m, 0.6H), 7.12 - 7.03 (m, 1H), 6.99 (t, 1H), 5.00 - 4.64 (m, 1H), 3.74 - 3.39 (m, 1H), 3.38 - 2.91 (m, 2H), 2.77 - 2.66 (m, 1H), 2.43 - 2.23 (m, 0.5H), 2.10 - 1.86 (m, 0.5H), 1.85 - 1.57 (m, 2H), 1.56 - 1.42 (m, 3H), 1.38 - 1.19 (m, 1H). 19 19F NMR (376.5 MHz, CDCl3) δ F -114.485. LC-ELSD / MS purity 99%, calculated MS ESI for C24H22FN5O [M+H]+ 416.2, found 416.3. Analyzed SFC 100% de value.

[0191] (R)-4-(1-(4-Fluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.3H), 8.95 (s, 0.3H), 8.92 - 8.84 (m, 1.4H), 8.75 (m, 1H), 8.24 (m, 1H), 7.65 (m, 1H), 7.50 - 7.41 (m, 1H), 7.32 - 7.26 (m, 1.4H), 7.22 - 7.15 (m, 0.6H), 7.12 - 7.03 (m, 1H), 6.99 (m, 1H), 4.82 (m, 1H), 4.99 - 4.63 (m, 1H), 3.71 - 3.39 (m, 1H), 3.37 - 2.93 (m, 2H), 2.81 - 2.62 (m, 1H), 2.44 - 2.19 (m, 0.5H), 2.11 - 1.85 (m, 0.5H), 1.84 - 1.72 (m, 0.7H), 1.71 - 1.67 (m, 0.3H), 1.60 - 1.55 (m, 1H), 1.54 - 1.43 (m, 3H), 1.41 - 1.22 (m, 1H). 19 19F NMR (376.5 MHz, CDCl3) δ F -114.485. LC - ELSD / MS purity 99%, calculated MS ESI value for C24H22FN5O [M + H]+ is 416.2, measured value is 416.1. Analytical SFC 100% de value.

[0192] Example 21. Synthesis of 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-carbonitrile (A48)

Chemical Structure

[0193] Synthesis of A47 To a solution of tert-butyl 4-cyano-4-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-1-carboxylate (300 mg, 0.973 mmol) in EtOAc (10 mL) was added 10 mL of 4 M HCl in EtOAc and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give 4-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-carbonitrile (218 mg) as a solid. 1 H NMR (400 MHz, MeOD-d4) δ H 3.92 (dd, 2H), 3.52 - 3.40 (m, 4H), 3.20 (td, 2H), 2.27 (d, 2H), 1.96 - 1.87 (m, 1H), 1.87 - 1.74 (m, 4H), 1.66 (d, 2H), 1.34 - 1.34 (m, 2H).

[0194] Synthesis of A48 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (150 mg, 0.7455 mmol) in DMF (5 mL) was added HATU (339 mg, 0.895 mmol) and DIEA (287 mg, 2.23 mmol) at 15 °C, and the mixture was stirred for 10 minutes. A solution of 4-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-carbonitrile (218 mg, 0.8946 mmol) in DMF (3 mL) was added, and the reaction mixture was stirred at 15 °C for 2 hours, treated with water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 17%, ending B: 47%) to give 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-carbonitrile (46.0 mg, yield 15.8%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 9.23 (s, 0.4H), 9.10 (s, 0.6H), 8.89 (d, 1H), 8.76 (dd, 1H), 8.32 - 8.17 (m, 1H), 7.67 (d, 1H), 7.52 - 7.42 (m, 1H), 4.87 (d, 0.6H), 4.75 (d, 0.4H), 4.02 - 3.89 (m, 2H), 3.66 - 3.55 (m, 0.5H), 3.51 - 3.35 (m, 3H), 3.34 - 3.23 (m, 0.5H), 3.21 - 3.10 (m, 1H), 2.19 (d, 0.4H), 2.12 (d, 0.6H), 1.92 - 1.61 (m, 5H), 1.60 - 1.30 (m, 5H). LC-MS purity 99%, C 22 H 26Calculated MS ESI value for N5O2[M+H]+ is 392.2, measured value is 392.3.

[0195] Synthesis of Example 22.4-(2,4-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A51)

Chemical Structure

[0196] Synthesis of A50 To a solution of tert-butyl 4-cyano-4-(2,4-difluorobenzyl)piperidine-1-carboxylate (2 g) in dioxane (15 mL), HCl / dioxane (20 mL) was added and the mixture was stirred at 25 °C for 16 h and concentrated to give 4-(2,4-difluorobenzyl)piperidine-4-carbonitrile (1.7 g). 1 H NMR (400 MHz, CDCl3) δ H9.5 - 9.0 (m, 2H), 7.53 - 7.43 (m, 1H), 7.31 (dt, 1H), 7.19 - 7.10 (m, 1H), 3.35 (s, 2H), 3.01 (s, 2H), 2.92 - 2.80 (m, 2H), 2.10 - 2.00 (m, 2H), 1.98 - 1.87 (m, 2H).

[0197] Synthesis of A51 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (221 mg) in DMF (5 mL) was added HATU (627 mg, 1.65 mmol) and DIPEA (0.575 mL) at 20 °C. The mixture was stirred for 30 minutes, and 4-(2,4-difluorobenzyl)piperidine-4-carbonitrile was added. The mixture was stirred at 20 °C for 1 hour, treated with water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC (column (Phenomenex Gemini-NX 150 * 30 mm * 5 μm), conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-CAN, starting B: 30%, ending B: 60%, flow rate 30 mL / min) to give 4-(2,4-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (146.3 mg, 31.6%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 9.24 - 8.94 (m, 1H), 8.92 - 8.85 (m, 1H), 8.76 (dd, 1H), 8.30 - 8.22 (m, 1H), 7.72 - 7.63 (m, 1H), 7.47 (dd, 1H), 7.41 - 7.37 (m, 1H), 6.97 - 6.80 (m, 2H), 5.00 - 4.72 (m, 1H), 3.68 - 3.20 (m, 2H), 3.11 (t, 1H), 2.99 - 2.91 (m, 2H), 2.15 - 1.98 (m, 1H), 1.97 - 1.61 (m, 3H). LC-MS purity 99%, C 23 1H 19 MS for C21H19F2N5O [M + H]+ 420.2, found 420.2.

[0198] Example 23. Synthesis of 4-((3,3-difluorocyclobutyl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A54) [Chemical formula] Synthesis of A52 To a solution of DIPA (1.72 g, 17.09 mmol) in THF (17 mL) was added BuLi (6.8 mL, 2.5 M in hexane, 17 mmol) at -70 °C. The mixture was warmed to 0 °C and stirred for 30 minutes to obtain an LDA solution. To the cold (0 °C) LDA solution was added tert-butyl 4-cyanopiperidine-1-carboxylate (1 g, 4.75 mmol) in THF (5 mL) over 0.5 hour. 3-(Bromomethyl)-1,1-difluorocyclobutane (1.05 g, 5.69 mmol) was added, and the mixture was stirred at 25 °C for 16 hours, quenched with saturated NH4Cl (20 mL), and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (5 mL) and dried over Na2SO4 dried, concentrated, and purified by flash chromatography using gradient elution (0 - 30% EtOAc in PE) to obtain tert-butyl 4-cyano-4-((3,3-difluorocyclobutyl)methyl)piperidine-1-carboxylate (900 mg, yield 60.8%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H = 4.27 - 4.00 (m, 2H), 3.13 - 2.92 (m, 2H), 2.89 - 2.74 (m, 2H), 2.47 - 2.22 (m, 3H), 1.88 (d, 2H), 1.81 (d, 2H), 1.46 (s, 9H), 1.44 - 1.36 (m, 2H). 19 F NMR (376.5 MHz, CDCl3) δ F -81.612, -82.127, -97.509, -98.025.

[0199] Synthesis of A53 To a solution of tert-butyl 4-cyano-4-((3,3-difluorocyclobutyl)methyl)piperidine-1-carboxylate (900 mg, 2.86 mmol) in dioxane (3 mL), dioxane / HCl (10 mL) was added at 25 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give 4-((3,3-difluorocyclobutyl)methyl)piperidine-4-carbonitrile (620 mg, yield 86.4%), which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ H = 8.96 (br s, 2H), 2.97 - 2.94 (m, 2H), 2.81 - 2.69 (m, 2H), 2.55 - 2.51 (m, 2H), 2.44 - 2.26 (m, 3H), 2.10 (d, 2H), 1.90 (d, 2H), 1.83 - 1.69 (m, 2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F -79.392, -79.898, -96.561, -97.067.

[0200] Synthesis of A54 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (250 mg, 1.24 mmol) and HATU (707 mg, 1.86 mmol) in DMF (6 mL) was added DIPEA (0.65 mL, 3.72 mmol) at 25 °C and the mixture was stirred for 30 minutes. 4-((3,3-Difluorocyclobutyl)methyl)piperidine-4-carbonitrile (310 mg, 1.24 mmol) was added and the mixture was stirred at 25 °C for 1 hour, quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (column: XBridge Shield RP18 2.1×50 mm×5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 32%, ending B: 52%, gradient time: 8 minutes) to give the product (87.6 mg, 17.8%) as a solid. The solid was washed with water (5 mL×2), filtered, the filter cake was triturated from i-Pr2O (2 mL) and 4-((3,3-difluorocyclobutyl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (19.2 mg, yield 22.2%) was obtained as a solid. 1 H NMR (400 MHz, CDCl3) δ H 9.32 - 9.06 (m, 1H), 8.94 - 8.86 (m, 1H), 8.77 (dd, 1H), 8.33 - 8.22 (m, 1H), 7.68 (d, 1H), 7.52 - 7.42 (m, 1H), 4.96 - 4.71 (m, 1H), 3.68 - 3.06 (m, 3H), 2.91 - 2.74 (m, 2H), 2.48 - 2.24 (m, 3H), 2.18 - 2.03 (m, 1H), 1.92 - 1.61 (m, 4.6H), 1.48 - 1.39 (m, 0.4H). 19 F NMR (400 MHz, CDCl3) δ F1 -81.575, -81.731, -82.090, -82.256, -97.270, -97.654, -97.786, -98.172. LC-MS purity 98%, C 21 H 22 Calculated for C H F2N5O [M+H]+ 398.4, found 398.4.

[0201] Example 24. Synthesis of 4-(4-fluorobenzyl)-1-(2-(oxazol-5-yl)nicotinoyl)piperidine-4-carbonitrile (A56)

Chemical formula

[0202] Example 25. Synthesis of 4-(cyclopropylmethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A58)

Chemical formula

[0203] Example 26. Synthesis of 4-(4-methoxybenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A63) [Chemical Formula] Synthesis of A61 To a solution of DIPA (2.87 g, 28.4 mmol) in THF (20 mL) was added n-BuLi (11.3 mL, 2.5 M in hexane, 28.4 mmol) at -70 °C. The mixture was warmed to 0 °C and stirred at 0 °C for 30 minutes to obtain an LDA solution. To LDA (28.4 mmol) was added tert-butyl 4-cyanopiperidine-1-carboxylate (5 g, 23.7 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred for 0.5 hour. Then, 1-(chloromethyl)-4-methoxybenzene (3.71 g, 23.7 mmol) was added, and the mixture was stirred at 75 °C for 5 hours, cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using gradient elution (0 - 30% EtOAc in PE) to obtain tert-butyl 4-cyano-4-(4-methoxybenzyl)piperidine-1-carboxylate (7.5 g, 95.7%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 7.19 (d, 2H), 6.87 (d, 2H), 4.12 (m, 2H), 3.80 (s, 3H), 2.98 (s, 2H), 2.80 (s, 2H), 1.83 (d, 2H), 1.51 - 1.42 (m, 11H).

[0204] Synthesis of A62 A mixture of tert-butyl 4-cyano-4-(4-methoxybenzyl)piperidine-1-carboxylate (0.5 g, 1.59 mmol) and 4 M HCl in EtOAc (2 mL) was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-(4-methoxybenzyl)piperidine-4-carbonitrile hydrochloride (0.3 g) as a solid. The residue was used directly in the next step.

[0205] Synthesis of A63 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (261 mg, 1.3 mmol) in DMF (5 mL) was added HATU (592 mg, 1.56 mmol) and DIEA (503 mg, 3.9 mmol) at 25 °C. The mixture was stirred at 15 °C for 10 min, and a solution of 4-(4-methoxybenzyl)piperidine-4-carbonitrile hydrochloride (300 mg, 1.3 mmol) in D MF (3 mL) was added. The reaction was stirred at 25 °C for 12 h, treated with water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic fractions were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 200 mg of an oil. Purification by HPLC (column: YMC Triart C18 150 * 25 mm * 5 μm, conditions: water (10 mM NH4HCO3)-CAN, start B: 42, end B: 52) afforded 4-(4-methoxybenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (87 mg, 43.7%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.3H), 8.89 (d), 8.80 (s, 0.7H), 8.75 (d), 8.08 - 8.40 (m, 1H), 7.82 - 7.58 (m, 1H), 7.49 - 7.43 (m, 1H), 7.22 - 7.12 (m, 2H), 6.88 (d, 2H), 4.96 - 4.70 (m, 1H), 3.88 - 3.74 (m, 3H), 3.61 (d), 3.47 - 3.35 (m, 1H), 3.26 - 3.03 (m, 1.4H), 2.96 - 2.80 (m, 2H), 2.14 - 1.96 (m, 1H), 1.64 (d), 1.54 - 1.39 (m, 1H), 1.25 (s, 1H). LC-MS purity > 97%, C 24 H 24 N5O2 [M + H] + Calculated MS ESI for 414.1, found 414.1.

[0206] Example 27.1 - ([2,4'-Bipyridine]-3-carbonyl)-4-(pyridin-4-ylmethyl)piperidine-4-carbonitrile (A65)

Chem.

[0207] Synthesis of Example 28. 4-(4-Fluorobenzyl)-1-(2-(pyridazin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A200)

Chem.

[0208] Synthesis of A73a 4-(Tributylstannyl)pyridazine (2.38 g, 6.44 mmol), Pd(PPh3)4 (563 mg, 0.54 mmol) and ethyl 2-chloropyridine-3-carboxylate (1 g, 5.38 mmol) in DMF (10 mL) were stirred at 120 °C for 16 h under N2. After cooling to 25 °C, the mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated to give the product, which was purified by flash chromatography (10 - 100% EtOAc in PE) to give ethyl 2-(pyridazin-4-yl)nicotinate (550 mg, 44.7%). 1 H NMR (400 MHz, CDCl3) δ H 9.40 - 9.17 (m, 2H), 8.86 (d, 1H), 8.33 (d, 1H), 7.72 - 7.59 (m, 1H), 7.51 (dd, 1H), 4.24 (q, 2H), 1.15 (t, 3H).

[0209] Synthesis of A74a Ethyl 2-(pyridazin-4-yl)nicotinate (300 mg, 1.3 mmol) and LiOH·H2O (163 mg, 3.9 mmol) were combined in THF (2 mL) and water (0.5 mL). The mixture was stirred at 15 °C for 2 h. The mixture was concentrated and EtOH (10 mL) was added. The suspension was stirred at 15 °C for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(pyridazin-4-yl)nicotinic acid (200 mg), which was used directly in the next step.

[0210] Synthesis of A200 Step 1: Oxalyl dichloride (127 mg, 1.0 mmol) was added to a solution of 2-(pyridazin-4-yl)nicotinic acid (100 mg, 0.50 mmol) and DMF (18.1 mg, 0.248 mmol) in DCM (5 mL) at 0 °C. After stirring at 20 °C for 1 h, the resulting acyl chloride was concentrated and used directly in the next step.

[0211] Step 2: 4-Piperidine-4-carbonitrile [methyl(4-fluorophenyl)] hydrochloride (126 mg, 0.50 mmol) and TEA (222 mg, 0.19 mL, 1.5 mmol) were added to the freshly prepared acyl chloride in DCM (5 mL) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was filtered and concentrated to give the product (180 mg), which was purified by HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm, conditions: water (0.225% FA)-ACN, start B: 25, end B: 55) to give 80 mg. The residue was dissolved in EtOAc (10 mL) and water (10 mL) was added at once. The pH of the mixture was adjusted to 7 - 8 with aqueous NaHCO3 solution (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and 4-(4-fluorobenzyl)-1-(2-(pyridazin-4-yl)nicotinoyl)piperidine-4-carbonitrile (29.2 mg, 14.6%) was obtained. 1 H NMR (400 MHz, CDCl3) δ H9.63 (s, 1H), 9.36 (s, 1H), 8.85 (dd, 1H), 8.10 - 7.960 (m, 1H), 7.79 (dd, 1H), 7.51 (dd, 1H), 7.21 - 7.55 (m, 2H), 7.05 - 6.95 (m, 2H), 4.82 (d, 1H), 3.26 - 2.42 (m, 5H), 1.93 (s, 1H), 1.73 - 1.59 (m, 1H), 1.46 - 1.19 (m, 2H), 0.14 - 0.16 (m, 1H). LC-MS purity ≥ 99%, C 23 H 20 FN5O [M + H] + The calculated MS ESI value for it is 402.2, and the measured value is 402.1.

[0212] Example 29. Synthesis of 4-((6-methylpyridin-3-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A201)

Chemical formula

[0213] Synthesis of A76 A mixture of tert-butyl 4-cyano-4-((6-methylpyridin-3-yl)methyl)piperidine-1-carboxylate (300 mg, 0.951 mmol) in HCl / dioxane (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give 4-((6-methylpyridin-3-yl)methyl)piperidine-4-carbonitrile hydrochloride (300 mg).

[0214] Synthesis of A201 A solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (49.9 mg, 0.248 mmol), 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (50 mg, 0.20 mmol), and HATU (141 mg, 0.372 mmol) in DMF (2 mL) was added with DIPEA (159 mg, 1.24 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (10 mL), and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain 40 mg, which was purified by preparative HPLC (column: YMC Triart C18 150*25mm*5um, condition: water (10 mM NH4HCO3)-ACN, starting B: 22%, ending 52%) to give 4-((6-methylpyridin-3-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (7.0 mg, 0.017 mmol, 8%). 1 H NMR (400 MHz, CDCl3) δ H , 7.25 - 8.84 (m, 2H), 8.79 - 8.73 (m, 1H), 8.34 (s, 1H), 8.30 - 8.22 (m, 1H), 7.72 - 7.64 (m, 1H), 7.64 - 7.50 (m, 1H), 7.50 - 7.44 (m, 1H), 7.20 - 7.15 (m, 1H), 4.97 - 4.72 (m, 1H), 3.67 - 3.00 (m, 3H), 2.96 - 2.81 (m, 2H), 2.60 - 2.51 (m, 3H), 2.14 - 1.97 (m, 1H), 1.87 - 1.44 (m, 4H). LC-ELSD / MS purity 99%, C 23 H 23 N6O [M + H] + The calculated value of MS ESI for 399.2, the measured value 399.2.

[0215] Example 30. Synthesis of 4-((6-methoxypyridin-3-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A202)

Chemical formula

[0216] Synthesis A78 A mixture of tert-butyl 4-cyano-4-((6-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (100 mg, 0.302 mmol) in HCl / dioxane (5 mL) was stirred at 25 °C for 1 h. The mixture was concentrated to give 4-((6-methoxypyridin-3-yl)methyl)piperidine-4-carbonitrile hydrochloride (100 mg), which was used directly in the next reaction.

[0217] Synthesis A202 A solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (93.8 mg, 0.467 mmol), 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (100 mg, 0.373 mmol), and HATU (266 mg, 0.700 mmol) in DMF (2 mL) was added with DIPEA (300 mg, 2.33 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (10 mL), and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain 100 mg, which was purified by HPLC (column: YMC Triart C18 150 * 25 mm * 5 μm, gradient: 28 - 58% and B: conditions: water (10 mM NH4HCO3)-ACN, flow rate: 30 mL / min) to obtain 4-((6-methoxypyridin-3-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (20.8 mg, 20.8%). 1 1H NMR (400 MHz, CDCl3) δ H 9.24 - 8.93 (m, 1H), 8.93 - 8.84 (m, 1H), 8.79 - 8.74 (m, 1H), 8.81 - 8.23 (m, 1H), 8.01 (s, 1H), 7.73 - 7.64 (m, 1H), 7.60 - 7.42 (m, 2H), 6.78 - 6.73 (m, 1H), 4.99 - 4.72 (m, 1H), 3.94 (m, 3H), 3.67 - 3.56 (m, 1H), 3.47 - 3.35 (m, 1H), 3.29 - 3.03 (m, 2H), 2.93 - 2.79 (m, 2H), 2.16 - 1.99 (m, 1H), 1.86 - 1.75 (m, 1H), 1.54 - 1.43 (m, 1H). LC-ELSD / MS purity 99%, C 23 H 23 N6O2 [M + H] + The calculated value of MS ESI for 415.2, the measured value 415.2.

[0218] Example 31. Synthesis of 4-((2-methylpyrimidin-5-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A203) [Chemical] Synthesis of A79 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (1.17 g, 5.60 mmol) in THF (10 mL), LDA (5.60 mL, 2 M) was added dropwise at -78 °C. After stirring at -78 °C for 1 hour, 5-(chloromethyl)-2-methylpyridine hydrochloride (400 mg, 2.80 mmol) was added at -78 °C. The mixture was warmed to 20 °C and stirred for 16 hours. The mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 10 mL). The organic layer was washed with sodium chloride solution (2 × 10 mL), dried, filtered, and concentrated to obtain the product, which was purified by column chromatography (0 - 50% EtOAc in PE) to give tert-butyl 4-cyano-4-((2-methylpyrimidin-5-yl)methyl)piperidine-1-carboxylate (150 mg). LC-ELSD / MS purity 99%, C 13 H 16 N4O2[M-C4H9+H] + MS for ESI calculated value 260.9, measured value 260.9.

[0219] Synthesis of A80 A mixture of tert-butyl 4-cyano-4-((2-methylpyrimidin-5-yl)methyl)piperidine-1-carboxylate (150 mg, 0.474 mmol) in HCl / dioxane (5 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated to obtain 4-((2-methylpyrimidin-5-yl)methyl)piperidine-4-carbonitrile hydrochloride (100 mg).

[0220] Synthesis of A203 A solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (99.4 mg, 0.495 mmol), 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (100 mg, 0.396 mmol), and HATU (255 mg, 0.593 mmol) in DMF (2 mL) was added with DIPEA (254 mg, 1.97 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (10 mL), and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain 50 mg, and purified by HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm, gradient: 12 - 42% B, conditions: water (0.04% NH3H2O)-ACN; flow rate: 25 mL / min) to obtain 4-((2-methylpyrimidin-5-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (27.6 mg, 0.069 mmol, 17%). 1 1H NMR (400 MHz, CDCl3) δ H , 9.23 - 9.00 (m, 1H), 8.93 - 8.85 (m, 1H), 8.80 - 8.74 (m, 1H), 8.61 - 8.54 (m, 2H), 8.30 - 8.25 (m, 1H), 7.71 - 7.64 (m, 1H), 7.51 - 7.44 (m, 1H), 4.98 - 4.77 (m, 1H), 3.70 - 3.40 (m, 2H), 3.40 - 3.04 (m, 2H), 3.01 - 2.82 (m, 2H), 2.82 - 2.70 (m, 3H), 2.15 - 2.00 (m, 1H), 1.90 - 1.70 (m, 2H). LC-ELSD / MS purity 99%, C 22 H 22 N7O [M + H] + The calculated value of MS ESI for 400.2, the measured value is 400.2.

[0221] Example 32. Synthesis of 4-(4-(methylsulfonyl)benzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A204)

Chemical formula

[0222] Synthesis A82 To a mixture of tert-butyl 4-cyano-4-(4-(methylsulfonyl)benzyl)piperidine-1-carboxylate (550 mg, 1.45 mmol) in dioxane (10 mL), HCl / dioxane (4 M, 3.60 mL, 14.4 mmol) was added. After stirring at 20 °C for 16 hours, the reaction mixture was filtered and the filter cake was washed with 50 mL of EtOAc and dried to give 4-(4-(methylsulfonyl)benzyl)piperidine-4-carbonitrile hydrochloride (400 mg, 99.2%). 1 H NMR (400 MHz, CDCl3) δ H8.07 - 7.91 (m, 2H), 7.71 - 7.59 (m, 2H), 3.59 - 3.43 (m, 2H), 3.22 - 3.09 (m, 7H), 2.20 - 2.10 (m, 2H), 2.03 - 1.92 (m, 2H).

[0223] Synthesis of A204 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (72.2 mg, 0.359 mmol), 4-(4-(methylsulfonyl)benzyl)piperidine-4-carbonitrile hydrochloride (100 mg, 0.359 mmol), and HATU (204 mg, 0.538 mmol) in DMF (5 mL) was added DIPEA (360 mg, 1.79 mmol). After stirring at 20 °C for 3 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, evaporated under reduced pressure to give the product, which was purified by HPLC (Welch Xtimate C18 150×25 mm, 5 um, conditions: water (0.225% FA)-ACN, gradient: 52% - 82% of B in 8.5 min and hold 100% for 2 min, flow rate: 30 mL / min, injection: 8) to give 4-(4-(methylsulfonyl)benzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (69.7 mg, 42.2%). 1 H NMR (400 MHz, CDCl3) δ H 9.25 - 9.19 (m, 1H), 8.92 - 8.87 (m, 1H), 8.87 - 8.83 (m, 1H), 8.80 - 8.75 (m, 1H), 8.32 - 8.24 (m, 1H), 7.96 (d, 2H), 7.73 - 7.65 (m, 1H), 7.53 - 7.46 (m, 3H), 5.00 - 4.88 (m, 1H), 4.86 - 4.76 (m, 1H), 3.70 - 3.59 (m, 1H), 3.49 - 3.39 (m, 1H), 3.30 - 3.20 (m, 1H), 3.19 - 3.10 (m, 3H), 3.09 - 3.01 (m, 3H), 2.16 - 2.01 (m, 1H), 1.96 - 1.74 (m, 2H), 1.72 - 1.63 (m, 1H). LC-ELSD / MS purity 98.19%, C 24 H 23N5O3S[M+H] + The calculated value of MS ESI for it is 462.2, and the measured value is 462.3.

[0224] Synthesis of Example 33.4-(4-chloro-2-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A205) [Chemical formula] Synthesis of A83 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (1 g, 4.75 mmol) in THF (10 mL), LDA (3.56 mL, 7.12 mmol, 2 M in THF / n-hexane) was added dropwise at -78 °C. After stirring at -78 °C for 1 hour under nitrogen, 4-chloro-1-(chloromethyl)-2-fluorobenzene (1.01 g, 5.69 mmol) was added. The mixture was warmed to 20 °C and stirred for 16 hours. The reaction mixture was poured into saturated NH4Cl solution (30 mL), and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The product was purified by silica gel chromatography (PE:EtOAc from 5:1 to 4:1) to obtain tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-cyanopiperidine-1-carboxylate (1.3 g, 77.8%). 1 H NMR δ H 7.36 - 7.29 (m, 1H), 7.19 - 7.08 (m, 2H), 4.25 - 4.06 (m, 2H), 3.08 - 2.92 (m, 2H), 2.89 (s, 2H), 1.90 - 1.78 (m, 2H), 1.58 - 1.49 (m, 2H), 1.45 (s, 9H).

[0225] Synthesis of A84 A mixture of tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-cyanopiperidine-1-carboxylate (1.3 g, 3.68 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 15 °C for 16 h and concentrated to give 4-(4-chloro-2-fluorobenzyl)piperidine-4-carbonitrile hydrochloride (1.5 g). 1 H NMR δ H 7.34 - 7.27 (m, 1H), 7.21 - 7.12 (m, 2H), 3.61 - 3.52 (m, 2H), 3.25 - 3.09 (m, 2H), 2.97 (s, 2H), 2.30 - 2.00 (m, 4H).

[0226] Synthesis of A205 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (100 mg, 0.497 mmol) in DMF (3 mL) were added HATU (283 mg, 0.7455 mmol) and DIPEA (0.259 mL, 1.49 mmol) at 25 °C. After stirring at 25 °C for 30 min, 4-(4-chloro-2-fluorobenzyl)piperidine-4-carbonitrile hydrochloride (125 mg, 0.4970 mmol) was added to the solution and stirred at 25 °C for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the product, which was purified by preparative HPLC (Welch Xtimate C18 150 * 25 mm * 5 um, conditions: water (water (0.04% NH3H2O)-ACN, start B: 33, end B: 63, gradient time (min): 8.5, 100% B hold time (min): 2) to give 4-(4-chloro-2-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (23.7 mg, 10.9%). 1 H NMR δ H9.21 (s, 0.3H), 8.98 (s, 0.6H), 8.93 - 8.83 (m, 1H), 8.76 (dd, 1H), 8.36 - 8.18 (m, 1H), 7.75 - 7.60 (m, 1H), 7.50 - 7.43 (m, 1H), 7.37 - 7.29 (m, 1H), 7.19 - 7.10 (m, 2H), 4.95 - 4.85 (m, 0.6H) , 4.83 - 4.72 (m, 0.4H), 3.68 - 3.58 (m, 0.6H), 3.48 - 3.34 (m, 1H), 3.22 - 3.07 (m, 2H), 3.01 - 2.89 (m, 3.4H), 2.16 - 1.80 (m, 3H). LC - ELSD / MS purity 100%, C 23 H 19 ClFN5O [M + H] + The calculated MS ESI value for is 436, and the measured value is 436.

[0227] Example 34. Synthesis of 4-(3,4-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A206)

Chemical Structure

[0228] Synthesis of A86 A mixture of tert-butyl 4-cyano-4-(3,4-difluorobenzyl)piperidine-1-carboxylate (1.3 g, 3.86 mmol) in HCl / dioxane (4M, 10 mL) was stirred at 15 °C for 16 h. The mixture was concentrated to give 4-(3,4-difluorobenzyl)piperidine-4-carbonitrile hydrochloride (1.5 g). 1 H NMR δ H 7.22 - 7.10(m, 2H), 7.06 - 6.99(m, 1H), 3.63 - 3.51(m, 2H), 3.26 - 3.09(m, 2H), 2.90(s, 2H), 2.23 - 1.99(m, 4H).

[0229] Synthesis of A206 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (100 mg, 0.497 mmol) in DMF (3 mL) was added HATU (283 mg, 0.745 mmol) and DIPEA (0.259 mL, 1.49 mmol) at 15 °C. After stirring at 25 °C for 30 min, 4-(3,4-difluorobenzyl)piperidine-4-carbonitrile hydrochloride (150 mg, 0.572 mmol) was added. The mixture was stirred at 25 °C for 10 h and then purified directly by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 um, conditions: water (0.04% NH3H2O)-ACN, start B: 33, end B: 63, gradient time (min): 8.5, hold time at 100% B (min): 2, flow rate (ml / min): 30, injection: 9) and freeze-dried, triturated from DCM / n-hexane (1:2, 5 mL) to give 4-(3,4-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (13.2 mg, 6%). 1 ​1H NMR δ H 9.15 (s, 0.4H), 8.95 (s, 0.6H), 8.89 - 8.77 (m, 1H), 8.70 (dd, 1H), 8.24 - 8.17 (m, 1H), 7.64 - 7.57 (m, 1H), 7.43 - 7.36 (m, 1H), 7.13 - 6.99 (m, 2H), 6.98 - 6.88 (m, 1H), 4.89 - 4.80 (m, 0.6H), 4.78 - 4.68 (m, 0.4H), 3.62 - 3.51 (m, 0.5H), 3.43 - 3.26 (m, 1H), 3.22 - 2.96 (m, 1.5H), 2.89 - 2.73 (m, 2H), 2.08 - 1.90 (m, 1H), 1.82 - 1.66 (m, 1.5H), 1.63 - 1.53 (m, 1H), 0.84 - 0.72 (m, 0.5H). LC-ELSD / MS purity 100%, C 23 H 20 F2N5O [M+H] + The calculated value of MS ESI for it is 420, and the measured value is 420.

[0230] Example 35. Synthesis of 4-(2,6-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A207)

Chemical formula

[0231] Synthesis of A88 To a mixture of tert-butyl 4-cyano-4-(2,6-difluorobenzyl)piperidine-1-carboxylate (1.2 g, 3.56 mmol) in dioxane (12 mL) was added HCl / dioxane (4 M, 8.90 mL, 35.6 mmol), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL) and dried to give 4-[(2,6-difluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (800 mg, 95.1%). 1 1H NMR (400 MHz, CDCl3) δ H 7.51 - 7.35 (m, 1H), 7.12 - 7.00 (m, 2H), 3.58 - 3.45 (m, 2H), 3.24 - 3.12 (m, 4H), 2.31 - 2.15 (m, 2H), 2.08 - 1.91 (m, 2H).

[0232] Synthesis of A207 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (127 mg, 0.634 mmol), 4-[(2,6-difluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (150 mg, 0.634 mmol), and HATU (361 mg, 0.951 mmol) in DMF (5 mL) was added DIPEA (637 mg, 3.17 mmol). After stirring at 20 °C for 3 h, the reaction mixture was poured into water (150 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the product, which was purified by HPLC (Phenomenex Gemini-NX 150 × 30 mm, 5 um, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, gradient: 33% - 57% of B in 8 min and hold 100% for 2 min, flow rate: 30 mL / min, injection: 7) to give 4-(2,6-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (79.1 mg, 27.0%). 1 H NMR (400 MHz, CDCl3) δ H 9.26 - 9.20 (m, 1H), 8.90 - 8.84 (m, 1H), 8.79 - 8.73 (m, 1H), 8.54 - 8.49 (m, 1H), 8.30 - 8.20 (m, 1H), 7.71 - 7.63 (m, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.30 (m, 1H), 7.03 - 6.91 (m, 2H), 4.97 - 4.87 (m, 1H), 4.84 - 4.75 (m, 1H), 3.69 - 3.60 (m, 1H), 3.52 - 3.39 (m, 1H), 3.32 - 3.21 (m, 1H), 3.20 - 3.04 (m, 3H), 2.23 - 2.06 (m, 1H), 2.01 - 1.81 (m, 2H), 1.80 - 1.72 (m, 1H). LC-ELSD / MS purity 100%, C 23 H 19 F2N5O [M + H] + The calculated value of MS ESI for C

[0233] Example 36. Synthesis of 4-(4-Ethylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A208) [Chemical formula] Synthesis of A89 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (1 g, 4.75 mmol) in THF (10 mL), LDA (3.56 mL, 7.12 mmol, 2 M in THF / n-heptane) was added dropwise at -70 °C. After stirring at -70 °C for 1 hour under nitrogen, 1-(chloromethyl)-4-ethylbenzene (734 mg, 4.75 mmol) was added and the mixture was kept at 25 °C for 16 hours. The reaction mixture was poured into saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The residue was purified by flash chromatography (0 - 30% EtOAc in PE) to give 1.5, and further purified by chromatography (0 - 30% EA in PE) to give tert-butyl 4-cyano-4-(4-ethylbenzyl)piperidine-1-carboxylate (1.16 g, 77.8%). 1 1H NMR (400 MHz, CDCl3) δ H 7.17 (s, 4H), 4.25 - 3.90 (m, 2H), 2.99 (s, 2H), 2.83 (s, 2H), 2.64 (d, 2H), 1.84 (d, 2H), 1.45 (s, 11H), 1.23 (t, 3H).

[0234] Synthesis of A90 To a mixture of tert-butyl 4-cyano-4-(4-ethylbenzyl)piperidine-1-carboxylate (1.16 g, 3.53 mmol) in dioxane (12 mL), HCl / dioxane (4 M, 8.82 mL, 35.3 mmol) was added and the mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated to give 4-(4-ethylbenzyl)piperidine-4-carbonitrile hydrochloride (895.8 mg, 95.8%). 1 1H NMR (400 MHz, CD3OD) δ H6.94 (d, 4H), 3.20 (d, 2H), 3.03 - 3.01 (m, 1H), 3.01 (s, 1H), 2.89 - 2.78 (m, 2H), 2.69 (s, 2H), 2.40 - 2.30 (m, 2H), 1.84 (d, 2H), 1.6 - 1.55 (m, 2H), 0.93 (t, 3H).

[0235] Synthesis of A208 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (143 mg, 0.71 mmol), 4-(4-ethylbenzyl)piperidine-4-carbonitrile hydrochloride (189.4 mg, 0.71 mmol) and HATU (406 mg, 1.07 mmol) in DMF (5 mL) was added DIEA (459 mg, 3.56 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated and purified by HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, start B: 45, end B: 61, gradient time: 8 min, hold time at 100% B: 3.5 min, flow rate: 30 mL / min) to give 4-(4-ethylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (89.3 mg, 32%). 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (s, 1H), 8.88 (d, 1H), 8.75 (s, 1H), 8.30 - 8.19 (m, 1H), 7.71 - 7.62 (m, 1H), 7.45 (d, 1H), 7.23 - 7.10 (m, 4H), 4.91 - 4.73 (m, 1H), 3.61 (d, 1H), 3.47 - 3.36 (m, 1H), 3.29 - 3.01 (m, 2H), 2.95 - 2.85 (m, 2H), 2.66 (d, 2H), 2.12 - 1.99 (m, 1H), 1.92 - 1.73 (m, 2H), 1.29 - 1.20 (m, 3H). LC-ELSD / MS purity 98%, C 25 H 26 Calculated MS ESI for C24H27N5O [M + H]: 412, found 412.

[0236] Example 37. Synthesis of 4-(2,3-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A209)

Chemical Structure

[0237] Synthesis of A92 To a solution of tert-butyl 4-cyano-4-(2,3-difluorobenzyl)piperidine-1-carboxylate (1.1 g, 3.27 mmol) in MeOH (10 mL), HCl / dioxane (0.817 mL, 3.27 mmol, 4 M) was added. The mixture was stirred at 25 °C for 12 hours under nitrogen and concentrated to give 4-(2,3-difluorobenzyl)piperidine-4-carbonitrile hydrochloride (800 mg). 1 1H NMR (400 MHz, CDCl3) δ H7.39 - 7.14 (m, 3H), 3.58 - 3.48 (m, 2H), 3.24 - 3.10 (m, 4H), 2.21 (br d, 2H), 2.06 - 1.94 (m, 2H).

[0238] Synthesis of A209 To a solution of 4-(2,3-difluorobenzyl)piperidine-4-carbonitrile hydrochloride (150 mg, 0.550 mmol) in DMF (1 mL) were added HATU (313 mg, 0.825 mmol) and DIPEA (0.287 mL, 1.65 mmol) at 25 °C. After stirring at 25 °C for 30 minutes, 2-(pyrimidin-4-yl)nicotinic acid (110 mg, 0.55 mmol) was added. The mixture was stirred at 25 °C for 10 hours, concentrated, and purified directly by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 um, conditions: water (0.04% NH3H2O + 10 mM of NH4HCO3)-ACN, start B: 22, end B: 52, gradient time (min): 3, hold time at 100% B (min): 2, flow rate (ml / min): 30, injection: 7) to give 4-(2,3-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (20.7 mg, 9.0%). 1 H NMR (400 MHz, CDCl3) δ H 9.26 - 8.74 (m, 2H), 8.73 - 8.12 (m, 2H), 7.68 - 7.35 (m, 2H), 7.14 - 7.00 (m, 3H), 4.95 - 4.65 (m, 1H), 3.63 - 3.12 (m, 2H), 3.09 - 2.90 (m, 3H), 2.11 - 1.93 (m, 1H), 1.91 - 1.82 (m, 1H), 1.81 - 1.55 (m, 2H). LC-MS purity >99%, C 23 H 19 F2N5O [M + H] + The calculated value of MS ESI for 420.3, the measured value 420.3.

[0239] Example 38. Synthesis of 4-(3-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A210) [Chemistry] Synthesis of A93 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (1 g, 4.75 mmol) in THF (15 mL), LDA (4.01 mL, 2 M, 8.02 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 1 hour, 1-(bromomethyl)-3-chlorobenzene (1.16 g, 5.69 mmol) was added. The mixture was warmed to 20 °C and stirred for 16 hours. The mixture was poured into water (25 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromatography (10 - 30% EtOAc in PE) to give tert-butyl 4-(3-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (1.0 g, 62.8%). 1 H NMR (400 MHz, CDCl3) δ H 7.32 - 7.28 (m, 2H), 7.26 - 7.17 (m, 2H), 4.31 - 4.04 (m, 2H), 3.15 - 2.92 (m, 2H), 2.84 (s, 2H), 1.85 (br d, 2H), 1.55 - 1.40 (m, 11H).

[0240] Synthesis of A94 To a solution of tert-butyl 4-(3-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (1.0 g, 2.98 mmol) in MeOH (10 mL), HCl / dioxane (5.95 mL, 23.8 mmol, 4 M) was added. The mixture was stirred at 25 °C for 12 hours under nitrogen and concentrated to give 4-(3-chlorobenzyl)piperidine-4-carbonitrile hydrochloride (800 mg). 1 H NMR (400 MHz, CDCl3) δ H 7.49 - 7.26 (m, 4H), 3.52 (br d, 2H), 3.18 (br t, 2H), 3.04 (s, 2H), 2.16 (br d, 2H), 2.01 - 1.83 (m, 2H).

[0241] Synthesis of A210 To a solution of 4-(3-chlorobenzyl)piperidine-4-carbonitrile hydrochloride (150 mg, 0.553 mmol) in DMF (1 mL), HATU (315 mg, 0.827 mmol) and DIPEA (0.287 mL, 1.65 mmol) were added at 25 °C. After stirring at 25 °C for 30 minutes, 2-(pyrimidin-4-yl)nicotinic acid (111 mg, 0.553 mmol) was added to the solution. The mixture was stirred at 25 °C for 10 hours, concentrated, and purified directly by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, start B: 22, end B: 52, gradient time (min): 3, hold time at 100% B (min): 2, flow rate (ml / min): 30, injection: 7) to obtain 4-(3-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (30.4 mg, 13.1%). 1 1H NMR: (400 MHz, CDCl3) δ H 9.27 - 8.74 (m, 3H), 8.31 - 8.21 (m, 1H), 7.73 - 7.60 (m, 1H), 7.48 (dd, 1H), 7.38 - 7.28 (m, 2H), 7.26 - 7.13 (m, 2H), 4.97 - 4.74 (m, 1H), 3.72 - 3.07 (m, 3H), 3.00 - 2.84 (m, 2H), 2.21 - 1.96 (m, 1H), 1.91 - 1.61 (m, 3H). LC-MS purity > 99%, C 23 H 20 ClN5O [M + H] + for MS 418.3, found 418.3.

[0242] Example 39. Synthesis of 4-((6-cyclopropylpyridin-3-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A211)

Chemical Structure

[0243] Synthesis of A97 To a mixture of methyl 6-cyclopropylnicotinate (2 g, 11.2 mmol) in THF (30 mL) was added LiAlH4 (1.27 g, 33.5 mmol) in one portion at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was diluted with THF (10 mL), and water (1.3 g) was added. After stirring at 15 °C for 5 min, 15% NaOH (1.3 g) was added. After stirring at 15 °C for 5 min, water (3.9 g) was added. Anhydrous sodium sulfate was added, and the mixture was filtered and concentrated to give (6-cyclopropylpyridin-3-yl)methanol (1.5 g). 1 H NMR (400 MHz, CDCl3) δ H 8.45 - 8.35 (m, 1H), 7.53 - 7.58 (m, 1H), 7.09 - 7.01 (m, 1H), 4.60 - 4.53 (m, 2H), 2.05 - 1.96 (m 1H), 1.03 - 0.90 (m, 4H).

[0244] Synthesis of A98 A mixture of (6-cyclopropylpyridin-3-yl)methanol (1.5 g, 10.0 mmol) in SOCl2 (5.95 g, 50.0 mmol) was stirred at 70 °C for 12 h. The reaction was cooled and poured into NaHCO3 solution (50 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), the combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the product. The product was purified by flash chromatography (0 - 10% of EA in PE) to give 5-(chloromethyl)-2-cyclopropylpyridine (1.1 g, 65.8%). 1 H NMR (400 MHz, CDCl3) δ H 8.42 - 8.41 (m, 1H), 7.68 - 7.58 (m, 1H), 7.09 - 7.01 (m, 1H), 4.60 - 4.53 (m, 2H), 2.05 - 1.96 (m, 1H), 1.09 - 0.93 (m, 4H).

[0245] Synthesis of A99 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (626 mg, 2.98 mmol) in THF (10 mL) was added dropwise LDA (5 mL, 4.47 mmol) at -78 °C, and the mixture was stirred at -78 °C for 1 h under nitrogen. 5-(Chloromethyl)-2-cyclopropylpyridine (500 mg, 2.98 mmol) was added and the mixture was warmed to 20 °C for 16 h. The reaction mixture was poured into saturated NH4Cl solution (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL), the combined organic layers were washed with brine (20 mL), and dried over Na2SO4. The product was purified by silica gel chromatography (PE:EtOAc from 5:1 to 4:1) to give tert-butyl 4-cyano-4-((6-cyclopropylpyridin-3-yl)methyl)piperidine-1-carboxylate (460 mg, 45.5%). 1 H NMR (400 MHz, CDCl3) δ H8.35 - 8.25 (m, 1H), 7.59 - 7.48 (m, 1H), 7.09 - 7.01 (m, 1H), 4.25 - 4.05 (m, 2H), 3.05 - 2.95 (m, 2H), 2.85 - 2.75 (m, 2H), 2.09 - 1.85 (m, 1H), 1.82 - 1.75 (m, 2H), 1.72 - 1.55 (m, 2H), 1.55 - 1.45 (m, 9H), 1.09 - 0.93 (m, 4H).

[0246] Synthesis of A100 To a mixture of tert-butyl 4-cyano-4-((6-cyclopropylpyridin-3-yl)methyl)piperidine-1-carboxylate (200 mg, 0.5857 mmol), HCl / dioxane (4 M, 10 mL, 40 mmol) was added, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to give 4-((6-cyclopropylpyridin-3-yl)methyl)piperidine-4-carbonitrile hydrochloride (170 mg), which was used directly in the next step.

[0247] Synthesis of A211 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (142 mg, 0.7073 mmol) in DMF (3 mL), HATU (403 mg, 1.06 mmol) and DIPEA (273 mg, 2.12 mmol) were added at 25 °C. After stirring at 25 °C for 30 min, 4-((6-cyclopropylpyridin-3-yl)methyl)piperidine-4-carbonitrile hydrochloride (170 mg, 0.7073 mmol) was added and the mixture was stirred at 25 °C for 10 h. The mixture was concentrated and purified by preparative HPLC (Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH₃H₂O + 10 mM of NH₄HCO₃)-ACN, start B: 30, end B: 50, gradient time (min): 8, 100% B hold time (min): 3.5, flow rate (ml / min): 30, injection: 6) to give 4-((6-cyclopropylpyridin-3-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (52.5 mg, 17.5%). 11H NMR (400 MHz, CDCl3) δ H 9.25 - 9.15 (m, 1H), 8.93 - 7.83 (m, 1H), 8.76 - 8.66 (m, 1H), 8.30 - 8.20 (m, 2H), 7.70 - 7.60 (m, 1H), 7.55 - 7.43 (m, 2H), 7.18 - 7.08 (m, 1H), 4.95 - 4.75 (m, 2H), 3.65 - 3.35 (m, 2H), 3.25 - 3.05 (m, 1H), 2.85 - 2.75 (m, 2H), 2.22 - 1.95 (m, 2H), 1.75 - 1.65 (m, 3H), 1.09 - 0.95 (m, 4H). LC - ELSD / MS purity 97%, C 25 H 25 N6O [M + H] + The calculated value of MS ESI for C

[0248] Example 40. Synthesis of 4-(4 - cyclopropylbenzyl)-1-(2-(pyrimidin - 4 - yl)nicotinoyl)piperidine - 4 - carbonitrile (A212)

Chemical Structure

[0249] Synthesis of A102 A mixture of tert-butyl 4-(4-bromobenzyl)-4-cyanopiperidine-1-carboxylate (2 g, 5.27 mmol), cyclopropylboronic acid (1.35 g, 15.8 mmol), Pd(dppf)Cl2 (430 mg, 0.527 mmol) and DIPEA (3.39 g, 26.3 mmol) in toluene (30 mL) / H2O (5 mL) was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography (0 - 10% of EA in PE) to give tert-butyl 4-cyano-4-(4-cyclopropylbenzyl)piperidine-1-carboxylate (1.2 g). 1 H NMR (400 MHz, methanol-d4) δ H ppm 7.15 - 7.13 (d, 2H), 7.04 - 7.02 (d, 2H), 4.22 - 4.00 (m, 2H), 3.05 - 2.90 (m, 2H), 2.81 (s, 2H), 1.91 - 1.86 (m, 1H), 1.85 - 1.78 (m, 2H), 1.50 - 1.46 (m, 2H), 1.45 (s, 9H), 0.98 - 0.93 (m, 2H), 0.70 - 0.66 (m, 2H).

[0250] Synthesis of A103 To a mixture of tert-butyl 4-cyano-4-(4-cyclopropylbenzyl)piperidine-1-carboxylate (1.2 g, 3.52 mmol) in dioxane (15 mL) was added HCl / dioxane (4 M, 17.6 mL, 70.4 mmol), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with 5 mL of EtOAc and dried to give 4-(4-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (800 mg, yield 82.1%). 1 H NMR (400 MHz, CD3OD) δ H ppm 7.23 - 7.19 (d, 2H), 7.09 - 7.04 (d, 2H), 3.52 - 3.45 (m, 2H), 3.18 - 3.08 (td, 2H), 2.95 (s, 2H), 2.17 - 2.04 (m, 2H), 1.96 - 1.80 (m, 3H), 0.98 - 0.93 (m, 2H), 0.67 - 0.63 (m, 2H).

[0251] Synthesis of A212 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (159 mg, 0.7947 mmol), 4-(4-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (200 mg, 0.7225 mmol), and HATU (410 mg, 1.08 mmol) in DMF (5 mL) was added DIPEA (465 mg, 3.61 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into H2O (50 mL), and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 42%, ending 64%) to give 4-(4-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (60.6 mg, yield 19.8%). 1 H NMR (400 MHz, CDCl3) δ H9.21 (s, 0.4H), 8.89 - 8.88 (m, 1H), 8.81 (s, 0.6H), 8.75 - 8.74 (m, 1H), 8.26 - 8.21 (m, 1H), 7.66 - 7.64 (m, 1H), 7.47 - 7.45 (m, 1H), 7.13 - 7.11 (m, 2H), 7.05 - 7.03 (m, 2H), 4.88 - 4.85 (m, 0.7H), 4.77 - 4.73 (m, 0.3H), 3.62 - 3.58 (m, 0.7H), 3.44 - 3.37 (m, 1H), 3.25 - 3.21 (m, 0.3H), 3.14 - 3.11 (m, 1H), 2.89 - 2.87 (m, 2H), 2.10 - 2.06 (m, 1H), 1.85 - 1.75 (m, 2H), 1.74 - 1.65 (m, 0.5H), 1.64 - 1.60 (m, 1H), 1.50 - 1.40 (m, 0.5H), 0.97 - 0.95 (m, 2H), 0.69 - 0.65 (m, 2H). LC - ELSD / MS purity 100%, calculated MS ESI value for C26H25N5O [M + H]+ is 424.2, measured value is 424.3.

[0252] Example 41. Synthesis of 4-(3,5-difluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A213)

Chemical Structure

[0253] Synthesis of A105 To a mixture of tert-butyl 4-cyano-4-[(3,5-difluorophenyl)methyl]piperidine-1-carboxylate (2.4 g, 7.13 mmol) in dioxane (30 mL) was added HCl / dioxane (4 M, 35.5 mL, 142 mmol), and the mixture was stirred at 20 °C for 16 hours. The reaction mixture was filtered, and the filter cake was washed with 10 mL of EtOAc and dried to obtain 4-[(3,5-difluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (600 mg). 1 H NMR (400 MHz, CDCl3) δ H 7.13 - 7.01 (m, 2H), 7.95 - 7.85 (m, 1H), 3.58 - 3.42 (m, 2H), 3.28 - 3.18 (m, 2H), 3.08 - 3.01 (m, 2H), 2.18 - 2.08 (m, 2H), 2.05 - 1.95 (m, 2H).

[0254] Synthesis of A213 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (200 mg, 0.9941 mmol), 4-[(3,5-difluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (243 mg, 0.8946 mmol), and HATU (566 mg, 1.49 mmol) in DMF (5 mL) was added DIPEA (641 mg, 4.97 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into water (50 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 38%, ending 58%) to give 4-[(3,5-difluorophenyl)methyl]-1-[2-(pyrimidin-4-yl)pyridine-3-carbonyl]piperidine-4-carbonitrile (54.1 mg, 15%). 1 H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.34H), 8.97 (s, 0.56H), 8.96 - 8.86 (m, 1H), 8.78 - 8.68 (m, 1H), 8.30 - 8.20 (m, 1H), 7.70 - 7.60 (m, 1H), 7.49 - 7.39 (m, 1H), 6.80 - 6.68 (m, 3H), 4.95 - 4.85 (m, 0.60H), 3.65 - 3.55 (m, 0.61H), 3.50 - 3.35 (m, 1H), 3.32 - 3.21 (m, 0.39H), 3.20 - 3.05 (m, 1H), 2.95 - 2.75 (m, 2H), 2.21 - 2.01 (m, 1H), 1.85 - 1.75 (m, 1.6H), 1.71 - 1.59 (m, 1H), 1.55 - 1.45 (m, 0.43H). 19 F NMR (376.5 MHz, CDCl3) δ F -108.921, δ F -108.986. LC-ELSD / MS purity 99%, C 23 H 20F2N5O[M+H] + The calculated MS ESI value for it is 420.3, and the measured value is 420.3.

[0255] Synthesis of Example 42.4-(2-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A214)

Chemical formula

[0256] Synthesis of A107 A mixture of tert-butyl 4-(2-bromobenzyl)-4-cyanopiperidine-1-carboxylate (1 g, 2.63 mmol), cyclopropylboronic acid (677 mg, 7.89 mmol), Pd(dppf)Cl2 (214 mg, 0.263 mmol) and DIPEA (2.27 mL, 13.1 mmol) in toluene (15 mL) / H2O (2.5 mL) was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was poured into H2O (50 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated to give the product, which was purified by flash chromatography (0 - 10% of EtOAc in PE) to give tert-butyl 4-cyano-4-(2-cyclopropylbenzyl)piperidine-1-carboxylate (1 g). 1 1H NMR (400 MHz, CDCl3) δ H 7.30 (dd, 1H), 7.25 - 7.12 (m, 2H), 7.04 - 6.98 (m, 1H), 4.33 - 4.01 (m, 2H), 3.16 (s, 2H), 3.02 (br s, 2H), 2.09 - 1.99 (m, 1H), 1.94 (br d, 2H), 1.63 (br d, 1H), 1.56 (br d, 1H), 1.46 (s, 8H), 1.04 - 0.94 (m, 2H), 0.73 - 0.65 (m, 2H).

[0257] Synthesis of A108 To a solution of tert-butyl 4-cyano-4-(2-cyclopropylbenzyl)piperidine-1-carboxylate (1 g, 2.93 mmol) in MeOH (10 mL) was added HCl / dioxane (5.85 mL, 4 M, 23.4 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h under nitrogen. The mixture was concentrated to give 4-(2-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (900 mg). 1 1H NMR (400 MHz, CDCl3) δ H7.37 - 7.30 (m, 1H), 7.27 - 7.15 (m, 2H), 7.03 (d, 1H), 3.52 (br d, 2H), 3.30 (s, 2H), 3.19 (br t, 2H), 2.25 (br d, 2H), 2.18 - 2.10 (m, 1H), 2.09 - 1.94 (m, 3H), 1.12 - 0.99 (m, 2H), 0.76 - 0.63 (m, 2H).

[0258] Synthesis of A214 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (100 mg, 0.3612 mmol) in DMF (1 mL), HATU (206 mg, 0.5418 mmol) and DIPEA (0.187 mL, 1.08 mmol) were added at 25 °C. After stirring at 25 °C for 30 minutes, 4-(2-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (72.6 mg, 0.3612 mmol) was added to the solution. The mixture was stirred at 25 °C for 10 hours, concentrated, and purified directly by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, start B: 37, end B: 67, gradient time (min): 3, hold time at 100% B (min): 2, flow rate (ml / min): 30, injection: 7) to obtain 4-(2-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (30.2 mg, 19.8%). 1 H NMR (400 MHz, CDCl3) δ H9.22 (s, 1H), 8.89 - 8.82 (m, 1H), 8.75 (br d, 1H), 8.50 (s, 1H), 8.27 (br d, 1H), 8.21 (d, 1H), 7.71 - 7.62 (m, 1H), 7.46 (dd, 1H), 7.32 - 7.26 (m, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.11 (m, 1H), 7.01 (br d, 1H), 4.91 (br d, 1H), 4.79 (br d, 1H), 3.67 - 3.55 (m, 1H), 3.52 - 3.36 (m, 1H), 3.32 - 3.04 (m, 3H), 2.23 - 2.07 (m, 1H), 2.05 - 1.83 (m, 3H), 1.80 - 1.68 (m, 1H), 1.05 - 0.88 (m, 2H), 0.73 - 0.58 (m, 2H). LC-MS purity 100%, C 26 H 25 N5O [M + H] + The calculated value of MS ESI for it is 424.3, and the measured value is 424.3.

[0259] Example 43. Synthesis of (R)-4-(1-(4-fluorophenyl)propyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A215) and (S)-4-(1-(4-fluorophenyl)propyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A216)

Chemical formula

[0260] Synthesis of A110 To a mixture of 1-(4-fluorophenyl)propan-1-ol (1 g, 6.48 mmol) in DCM (15 mL) was added thionyl chloride (1.03 mL, 14.2 mmol) at 0 °C. The mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was concentrated to give 1-(1-chloropropyl)-4-fluorobenzene (1 g). 1 H NMR (400 MHz, CDCl3) δ H ppm 7.36 - 7.32 (dd, 2H), 7.05 - 7.01 (td, 2H), 4.79 - 4.75 (t, 1H), 2.15 - 2.02 (m, 2H), 1.01 - 0.97 (t, 3H).

[0261] Synthesis of A111 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (1 g, 4.75 mmol) in THF (20 mL) was added LDA (3.56 mL, 7.12 mmol, 2 M in THF / n-heptane) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h under nitrogen, and 1-(1-chloropropyl)-4-fluorobenzene (982 mg, 5.69 mmol) was added. The mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was poured into saturated NH4Cl solution (100 mL), and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4. The product was purified by flash chromatography (0 - 10% EA in PE) to give tert-butyl 4-cyano-4-(1-(4-fluorophenyl)propyl)piperidine-1-carboxylate (700 mg, yield 42.6%). 1 H NMR (400 MHz, CDCl3) δ Hppm 7.25 - 7.21 (dd, 2H), 7.05 - 7.01 (t, 2H), 4.25 - 3.90 (m, 2H), 3.10 - 2.75 (td, 2H), 2.38 - 2.34 (dd, 2H), 2.05 - 1.97 (m, 2H), 1.91 - 1.81 (m, 1H), 1.43 (s, 9H), 1.39 - 1.30 (m, 2H), 0.74 - 0.70 (t, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ F - 114 .911.

[0262] Synthesis of A112 To a mixture of tert-butyl 4-cyano-4-(1-(4-fluorophenyl)propyl)piperidine-1-carboxylate (700 mg, 2.02 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 10.1 mL, 40.4 mmol), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to afford 4-(1-(4-fluorophenyl)propyl)piperidine-4-carbonitrile hydrochloride (550 mg). 1 1H NMR (400 MHz, CDCl3) δ H ppm 7.40 - 7.36 (dd, 2H), 7.15 - 7.10 (t, 2H), 3.59 (s, 1H), 3.54 - 3.50 (m, 1H), 3.41 - 3.37 (m, 1H), 3.21 - 3.15 (td, 1H), 3.10 - 3.02 (td, 1H), 2.70 - 2.66 (dd, 1H), 2.51 - 2.46 (m, 1H), 2.13 - 2.03 (m, 1H), 1.96 - 1.62 (m, 4H), 0.78 - 0.74 (t, 3H).

[0263] Synthesis of A113 and SFC Separation A solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (500 mg, 2.48 mmol), 4-(1-(4-fluorophenyl)propyl)piperidine-4-carbonitrile hydrochloride (525 mg, 1.86 mmol), and HATU (1.41 g, 3.72 mmol) in DMF (15 mL) was added with DIPEA (1.58 g, 12.3 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to obtain the product. The product was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 38%, ending 68%) to give racemic-4-(1-(4-fluorophenyl)propyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (300 mg, yield 28.3%). 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.4H), 8.93 - 8.85 (m, 1.6H), 8.76 - 8.72 (m, 1H), 8.27 - 8.22 (m, 1H), 7.66 - 7.62 (m, 1H), 7.47 - 7.41 (m, 1H), 7.29 - 7.19 (m, 1.4H), 7.19 - 7.14 (m, 0.6H), 7.11 - 7.07 (m, 1H), 7.02 - 6.98 (m, 1H), 4.93 - 4.65 (m, 1H), 4.05 - 3.95 (m, 0.1H), 3.75 - 3.65 (m, 0.3H), 3.50 - 3.25 (m, 1.6H), 3.20 - 2.80 (m, 1.4H), 2.50 - 2.25 (m, 1.6H), 2.20 - 1.75 (m, 3H), 1.55 - 1.45 (m, 1H), 1.35 - 1.15 (m, 2H), 0.80 - 0.70 (m, 3H), and further purified by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm), conditions: 0.1% NH3H2O ETOH, starting B: 25%) to give (R)-4-(1-(4-Fluorophenyl)propyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (87.0 mg, 29%) was obtained. 1 H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.4H), 8.93 - 8.85 (m, 1.6H), 8.76 - 8.72 (m, 1H), 8.27 - 8.22 (m, 1H), 7.66 - 7.62 (m, 1H), 7.47 - 7.41 (m, 1H), 7.29 - 7.19 (m, 1.4H), 7.19 - 7.14 (m, 0.6H), 7.11 - 7.07 (m, 1H), 7.02 - 6.98 (m, 1H), 4.93 - 4.65 (m, 1H), 4.05 - 3.95 (m, 0.1H), 3.75 - 3.65 (m, 0.3H), 3.50 - 3.25 (m, 1.6H), 3.20 - 2.80 (m, 1.4H), 2.50 - 2.25 (m, 1.6H), 2.20 - 1.75 (m, 3H), 1.55 - 1.45 (m, 1H), 1.35 - 1.15 (m, 2H), 0.80 - 0.70 (m, 3H). 19 F NMR (376.5 MHz, CDCl3) δ F -114.475. LC-ELSD / MS purity 100%, C 25 H 24 Calculated MS ESI for C24H24FN5O [M + H]+ 430.2, found 430.3. Analytical SFC 98% de value.

[0264] (S)-4-(1-(4-Fluorophenyl)propyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (102.5 mg, 34%). 1 H NMR (400 MHz, CDCl3) δ H9.21 (s, 0.4H), 8.93 - 8.85 (m, 1.6H), 8.76 - 8.72 (m, 1H), 8.27 - 8.22 (m, 1H), 7.66 - 7.62 (m, 1H), 7.47 - 7.41 (m, 1H), 7.29 - 7.19 (m, 1.4H), 7.19 - 7.14 (m, 0.6H), 7.11 - 7.07 (m, 1H), 7.02 - 6.98 (m, 1H), 4.93 - 4.65 (m, 1H), 4.05 - 3.95 (m, 0.1H), 3.75 - 3.65 (m, 0.3H), 3.50 - 3.25 (m, 1.6H), 3.20 - 2.80 (m, 1.4H), 2.50 - 2.25 (m, 1.6H), 2.20 - 1.75 (m, 3H), 1.55 - 1.45 (m, 1H), 1.35 - 1.15 (m, 2H), 0.80 - 0.70 (m, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ F -114.466. LC-ELSD / MS purity 98%, C 25 H 24 Calculated MS ESI for C19H15FN5O [M+H]+ 430.2, found 430.3. Analytical SFC 99% de.

[0265] Example 44.1-(2-(Pyrimidin-4-yl)nicotinoyl)-4-(4-(trifluoromethoxy)benzyl)piperidine-4-carbonitrile (A217) Synthesis

Chemical Structure

[0266] Synthesis of A115 To a solution of tert-butyl 4-cyano-4-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (6 g, 15.8 mmol) in dioxane (63 mL) was added HCl / dioxane (4 M, 50 mL, 200 mmol) at 20 °C. After stirring at 20 °C for 16 h, the reaction was concentrated to give 4-(4-(trifluoromethoxy)benzyl)piperidine-4-carbonitrile hydrochloride (3.28 g, 64.8%). 1 H NMR (400 MHz, CDCl3) δ H 10.04 - 9.60 (m, 2H), 7 .33 (d, 2H), 7.22 (d, 2H), 3.61 - 3.52 (m, 2H), 3.21 - 3.09 (m, 3H), 2.95 (s, 2H), 2.22 - 2.12 (m, 2H), 2.10 - 2.02 (m, 2H).19 19F NMR (377 MHz, CDCl3) δ F -57.86

[0267] Synthesis of A217 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (200 mg, 0.994 mmol), 4-(4-(trifluoromethoxy)benzyl)piperidine-4-carbonitrile hydrochloride (287 mg, 0.894 mmol), and HATU (566 mg, 1.49 mmol) in DMF (5 mL) was added DIPEA (641 mg, 4.97 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 40%, ending 60%) to give 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-(4-(trifluoromethoxy)benzyl)piperidine-4-carbonitrile (95 mg, 20%). 1 H 1H NMR (400 MHz, CDCl3) δ H 9.25 - 9.17 (m, 1H), 9.04 (s, 1H), 8.91 (br d, 1H), 8.76 (dd, 1H), 8.26 (br d, 1H), 7.72 - 7.62 (m, 1H), 7.47 (dd, 1H), 7.34 - 7.28 (m, 2H), 7.21 (s, 2H), 4.94 - 4.86 (m, 1H), 4.83 - 4.74 (m, 1H), 3.68 - 3.56 (m, 1H), 3.49 - 3.35 (m, 1H), 3.30 - 3.18 (m, 1H), 3.10 (br d, 1H), 2.92 (br d, 2H), 2.01 (br d, 1H), 1.83 (br d, 2H), 1.66 (br s, 1H), 1.49 (br d, 1H). 19 19F NMR (377 MHz, CDCl3) δ F -57.84. LC-ELSD / MS purity 100%, C24 H 20 The calculated MS ESI value for F3N5O2[M+H] is 467.4, and the measured value is 467.4.

[0268] Synthesis of Example 45.4-(3-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A218)

Chemical Structure

[0269] Synthesis of A117 A mixture of tert-butyl 4-(3-bromobenzyl)-4-cyanopiperidine-1-carboxylate (2 g, 5.27 mmol), cyclopropylboronic acid (1.35 g, 15.8 mmol), Pd(dppf)Cl2 (430 mg, 0.527 mmol) and DIPEA (3.39 g, 26.3 mmol) in toluene (30 mL) / water (5 mL) was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 10% EA in PE) to give tert-butyl 4-cyano-4-(3-cyclopropylbenzyl)piperidine-1-carboxylate (1.21 g, 67.5%). 1 H NMR (400 MHz, CDCl3) δ H 7.24 - 7.18 (m, 1H), 6.97 (br s, 3H), 4.23 - 4.02 (m, 2H), 3.05 - 2.91 (m, 2H), 2.81 (s, 2H), 1.81 (br s, 1H), 1.65 (s, 2H), 1.45 (s, 12H), 1.01 - 0.92 (m, 2H), 0.74 - 0.66 (m, 2H).

[0270] Synthesis of A118 To a mixture of tert-butyl 4-cyano-4-(3-cyclopropylbenzyl)piperidine-1-carboxylate (1.19 g, 3.52 mmol) in dioxane (15 mL) was added HCl / dioxane (4 M, 17.6 mL, 70.4 mmol) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was filtered. The filter cake was washed with EtOAc (5 mL) and dried to give 4-(3-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (1.2 g, 77.4%). 1 H NMR (400 MHz, CDCl3) δ H9.81 (br s, 2H), 7.25 - 7.20 (m, 1H), 7.08 - 6.97 (m, 3H), 3.55 (br d, 2H), 3.16 (br d, 2H), 2.89 (s, 2H), 2.19 - 1.95 (m, 4H), 1.87 (dt, 1H), 1.01 - 0.91 (m, 2H), 0.76 - 0.63 (m, 2H).

[0271] Synthesis of A218 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (200 mg, 0.994 mmol), 4-(3-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (247 mg, 0.892 mmol), and HATU (566 mg, 1.49 mmol) in DMF (5 mL) was added DIPEA (641 mg, 4.97 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into water (5 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN, starting B: 37%, ending 67%) to give 4-(3-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (20 mg, 4.76%). 1 H NMR (400 MHz, CDCl3) δ H 8.87 (d, 1H), 8.75 (br d, 1H), 8.60 (s, 1H), 8.22 (br s, 1H), 7.64 (s, 1H), 7.46 (dd, 1H), 7.22 (br d, 1H), 7.07 - 6.91 (m, 3H), 4.93 - 4.73 (m, 1H), 3.69 - 3.56 (m, 1H), 3.49 - 3.35 (m, 1H), 3.11 (br d, 1H), 2.95 - 2.84 (m, 2H), 2.00 (br d, 1H), 1.86 (br d, 3H), 1.66 (br s, 1H), 0.95 (br d, 2H), 0.73 - 0.65 (m, 2H). LC-ELSD / MS purity 100%, C 26 H 25Calculated MS ESI value for N5O[M+Na] is 446.3, measured value is 446.3.

[0272] Synthesis of Example 46.1-(4-Fluoro-2-(pyrimidin-4-yl)benzoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (A220)

Chemical Structure

[0273] Synthesis of A121 A mixture of methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500 mg, 1.78 mmol), 4-chloropyrimidine hydrochloride (241 mg, 1.60 mmol), Pd(dppf)Cl2·DCM (205 mg, 0.1780 mmol) and K2CO3 (1.22 g, 8.90 mmol) in dioxane (10 mL) / water (2.5 mL) was stirred at 100 °C for 3 h under nitrogen. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The product was purified by flash chromatography (0 - 10% EA in PE) to give methyl 4-fluoro-2-(pyrimidin-4-yl)benzoate (330 mg, 82.7%). 1 H NMR (400 MHz, CDCl3) δ H 10.42 - 10.33 (m, 1H), 8.93 - 8.65 (m, 1H), 8.42 - 7.82 (m, 1H), 7.37 - 7.27 (m, 1H), 7.24 - 7.06 (m, 2H), 3.78 - 3.52 (m, 3H).

[0274] Synthesis of A122 To a solution of methyl 4-fluoro-2-(pyrimidin-4-yl)benzoate (330 mg, 1.42 mmol) in MeOH (10 mL) was added LiOH.H2O (65.5 mg, 1 .56 mmol) at 25 °C. The mixture was warmed to 60 °C and stirred for 12 h under nitrogen. The reaction mixture was concentrated to give 4-fluoro-2-(pyrimidin-4-yl)benzoic acid (310 mg). 1 H NMR (400 MHz, CDCl3) δ H 9.19 - 9.16 (m, 1H), 8.75 - 8.72 (m, 1H), 7.82 - 7.76 (m, 1H), 7.74 - 7.68 (m, 1H), 7.45 - 7.39 (m, 1H), 7.26 - 7.20 (m, 2H).

[0275] Synthesis of A220 To a solution of 4-fluoro-2-(pyrimidin-4-yl)benzoic acid (100 mg, 0.458 mmol) in DMF (1 mL) was added HATU (261 mg, 0.687 mmol) and DIPEA (0.239 mL, 1.37 mmol) at 25 °C. After stirring at 25 °C for 30 minutes, 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (116 mg, 0.458 mmol) was added and the mixture was stirred at 25 °C for 10 hours. The mixture was concentrated and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30 mm * 5 μm, conditions: water (0.225% FA)-ACN, start B: 35, end B: 65, gradient time (min): 3, hold time at 100% B (min): 2, flow rate (ml / min): 30, injection: 7), and freeze-dried to obtain 1-(4-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (20.3 mg, 10%). 1 H NMR (400 MHz, CDCl3) δ H 9.23 (s, 0.34H), 9.01 (s, 0.58H), 8.87 - 8.72 (m, 1H), 7.62 - 7.51 (m, 1H), 7.50 - 7.40 (m, 1H), 7.39 - 7.30 (m, 1H), 7.26 - 7.13 (m, 3H), 7.05 - 6.95 (m, 2H), 4.80 - 4.60 (m, 1H), 3.66 - 3.60 (m, 0.63H), 3.55 - 3.45 (m, 0.38H), 3.45 - 3.25 (m, 0.52H), 3.13 - 2.95 (m, 1H), 2.90 - 2.72 (m, 2H), 2.05 - 1.95 (m, 1H), 1.75 - 1.65 (m, 1H), 1.50 - 1.43 (m, 3H). 19 F NMR (376.5 MHz, CDCl3) δ F -110.204, δ F -114.432. LC-ELSD / MS purity 99%, C 24 H 21 F2N4O [M + H] + The calculated value of MS ESI for 419.3, the measured value is 419.3.

[0276] Example 47. Synthesis of 1-(2-Fluoro-6-(pyrimidin-4-yl)benzoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (A221)

Chemical Structure

[0277] Synthesis of A125 A mixture of ethyl 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500 mg, 1.69 mmol), 4-chloropyrimidine hydrochloride (229 mg, 1.52 mmol), Pd(dppf)Cl2 (124 mg, 0.169 mmol) and K2CO3 (1.16 g, 8.45 mmol) in dioxane (10 mL) / water (2.5 mL) was stirred at 100 °C for 3 h under nitrogen. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 10% EA in PE) to afford ethyl 2-fluoro-6-(pyrimidin-4-yl)benzoate (170 mg, 40.8%). 1 H NMR (400 MHz, CDCl3) δ H 9.21 (s, 1H), 8.80 (d, 1H), 7.59 (d, 1H), 7.48 (s, 2H), 7.26 (s, 1H), 4.30 (d, 2H), 1.24 (d, 2H), 1.20 (s, 1H).

[0278] Synthesis of A126 To a mixture of ethyl 2-fluoro-6-(pyrimidin-4-yl)benzoate (170 mg, 0.69 mmol) in MeOH (5 mL) / water (0.5 mL) was added LiOH·H2O (31.8 mg, 0.759 mmol). After stirring at 60 °C for 16 h, the reaction mixture was concentrated to afford 2-fluoro-6-(pyrimidin-4-yl)benzoic acid (140 mg, 93.3%). 1 H NMR (400 MHz, CDCl3) δ H 13.13 (s, 1H), 12.71 (d, 1H), 12.01 - 11.85 (m, 1H), 11.57 (s, 1H), 11.66 - 11.52 (m, 1H), 11.43 - 11.31 (m, 1H), 11.21 (s, 1H).

[0279] Synthesis of A221 A solution of 2-fluoro-6-(pyrimidin-4-yl)benzoic acid (130 mg, 0.595 mmol), 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (136 mg, 0.535 mmol), and HATU (338 mg, 0.892 mmol) in DMF (5 mL) was added with DIPEA (383 mg, 2.97 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Venusil ASB Phenyl 150 * 30 mm * 5 μm, condition: water (0.05% HCl)-ACN, starting B: 50%, ending 80%) to give 1-(2-fluoro-6-(pyrimidin-4-yl)benzoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (9.7 mg, 3.9%). 1 H NMR (400 MHz, CDCl3) δ H 9.33 - 9.20 (m, 1H), 9.08 (br s, 1H), 8. 88 (br s, 1H), 7.76 (br s, 1H), 7.52 (br s, 2H), 7.50 - 7.26 (m, 2H), 7.05 (br t, 2H), 4.88 - 4.65 (m, 1H), 3.67 (s, 1H), 3.52 - 3.27 (m, 1H), 3.19 - 2.95 (m, 1H), 2.95 - 2.80 (m, 2H), 1.86 (br d, 2H), 1.78 - 1.54 (m, 2H). LC-ELSD / MS purity 100%, calculated MS ESI for C24H20F2N4O [M+H]+ 419.0, found 419.0. 19 F NMR (376.5 MHz, CDCl3) δ F -113.89.

[0280] Example 48. Synthesis of 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-4-carbonitrile (A222)

Chemical Structure

[0281] Synthesis of A129 To a solution of tert-butyl 4-cyano-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylate (200 mg, 0.54 mmol) in dioxane (2 mL) was added HCl / dioxane (3 mL, 4 M, 12.0 mmol) at 25 °C, and the mixture was stirred under nitrogen for 12 hours. The mixture was concentrated to give 4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-4-carbonitrile hydrochloride (200 mg), which was used without further purification.

[0282] Synthesis of A222 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (78.9 mg, 0.39 mmol) in DMF (2 mL), HATU (186 mg, 0.49 mmol) and DIPEA (0.17 mL, 0.981 mmol) were added at 25 °C. After stirring at 25 °C for 30 minutes, 4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-4-carbonitrile hydrochloride (100 mg, 0.33 mmol) was added to the solution. The mixture was stirred at 25 °C for 2 hours, poured into water (20 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column Welch Xtimate C18 150 * 25 mm * 5 μm, conditions water (0.05% NH3H2O)-ACN, start B: 30 , end B: 60, gradient time (min) 8, 100% B hold time (min): 2), and freeze-dried to obtain 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-4-carbonitrile (21.1 mg, 14%). 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.4H), 9.12 (s, 0.6H), 8.97 - 8.85 (m, 1H), 8.80 - 8.73 (m, 1H), 8.60 (s, 1H), 8.32 - 8.24 (m, 1H), 7.98 - 7.82 (m, 1H), 7.76 - 7.63 (m, 2H), 7.52 - 7.43 (m, 1H), 4.99 - 4.89 (m, 0.5H), 4.87 - 4.76 (m, 0.5H), 3.69 - 3.57 (m, 0.5H), 3.53 - 3.32 (m, 1H), 3.29 - 3.18 (m, 0.5H), 3.17 - 2.88 (m, 3H), 2.18 - 1.99 (m, 1H), 1.92 - 1.61 (m, 3H). LC-ELSD / MS purity 100%, C 23 H 20 F3N6O [M + H] + Calculated MS ESI value for 453, found 453 for

[0283] Example 49. Synthesis of 4-(4-(2-Hydroxypropan-2-yl)benzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A223) [Chemical formula] Synthesis of A131 To a solution of methyl 4-methylbenzoate (5 g, 33.2 mmol) in MeOH (80 ml) was added NBS (11.8 g, 66.4 mmol) and BPO (1.6 g, 6.64 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NaHCO3 (200 mL), treated with water (100 mL), and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and methyl 4-(bromomethyl)benzoate (7 g) was obtained.

[0284] Synthesis of A132 To a solution of bromo(methyl)magnesium (30.5 mL, 3 M in diethyl ether, 91.5 mmol) was added methyl 4-(bromomethyl)benzoate (7 g, 30.5 mmol) in THF (100 mL) at 25 °C in one portion. The mixture was stirred at 25 °C for 2 h. The mixture was poured into NH4Cl solution (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and 2-(4-(bromomethyl)phenyl)propan-2-ol (6.9 g) was obtained.

[0285] Synthesis of A133 tert-Butyl 4-cyanopiperidine-1-carboxylate in THF (30 mL) To a mixture of toluene (2.73 g, 13 mmol) was added dropwise LDA (6.5 mL, 2 M, 13 mmol) at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 2-(4-(bromomethyl)phenyl)propan-2-ol (2 g, 8.72 mmol) was added, the mixture was warmed to 20 °C and stirred for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and tert-butyl 4-cyano-4-(4-(2-hydroxypropan-2-yl)benzyl)piperidine-1-carboxylate (1.5 g) was obtained.

[0286] Synthesis of A134 To a solution of tert-butyl 4-cyano-4-(4-(2-hydroxypropan-2-yl)benzyl)piperidine-1-carboxylate (1.5 g, 4.18 mmol) in dioxane (30 mL) was added HCl (4 M in dioxane, 2.09 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to give 4-(4-(2-hydroxypropan-2-yl)benzyl)piperidine-4-carbonitrile hydrochloride (1.2 g).

[0287] Synthesis of A223 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (508 mg, 2.53 mmol) in DMF (15 mL) was added HATU (962 mg, 2.53 mmol) and DIPEA (653 mg, 5.06 mmol) at 15 °C. After stirring at 15 °C for 10 minutes, 4-(4-(2-hydroxypropan-2-yl)benzyl)piperidine-4-carbonitrile hydrochloride (500 mg, 1.69 mmol) was added to the above reaction mixture. The mixture was stirred at 15 °C for 2 hours. Water (100 mL) was added and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated to give the product (300 mg). The residue was purified by HPLC (column: Phenomenex Gemini-NX 80 * 30 mm* (3 μm), Condition: water (10 mM NH4HCO3)-ACN, starting B: 21%, ending B: 51%). It was purified to obtain 4-(4-(2-hydroxypropan-2-yl)benzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (92.5 mg, 31%). 1 1H NMR (400 MHz, CDCl3) δ H 8.65 - 8.74 (m, 2H), 8.22 (d, 1H), 7.61 (d, 1H), 7.55 (d, 2H), 7.46 - 7.41 (m, 1H), 7.03 - 7.12 (m, 3H), 4.97 - 4.90 (m, 1H), 4.84 (s, 1H), 3.42 - 3.57 (m, 2H), 3.06 - 3.21 (m, 3H), 2.05 - 1.95 (m, 1H), 1.79 - 1.94 (m, 2H), 1.70 (s, 3H), 1.59 - 1.63 (m, 1H), 1.54 (s, 3H). LCMS purity 99%, C 26 H 25 N5O [M - H2O + H] + The calculated value of MS ESI for it is 424.2, and the measured value is 424.2.

[0288] Example 50. Synthesis of 4-(naphthalen-2-ylmethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A224)

Chemical Structure

[0289] Synthesis of A137 To a mixture of tert - butyl 4 - carboxyimidoyl - 4 - [(naphthalen - 2 - yl)methyl]piperidine - 1 - carboxylate (630 mg, 1.78 mmol) in dioxane (20 mL), HCl / dioxane (4 M, 4.45 mL, 17.8 mmol) was added and the mixture was stirred at 20 °C. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was filtered and the filter cake was washed with 50 mL of EtOAc and dried to give 4-(naphthalen - 2 - ylmethyl)piperidine - 4 - carbonitrile hydrochloride (247 mg, 48%). 1 H NMR (400 MHz, CD3OD) δ H 7.94 - 7.80 (m, 4H), 7.55 - 7.45 (m, 3H), 3.49 (br d, 2H), 3.23 - 3.09 (m, 4H), 2.18 (br d, 1H), 2.23 - 2.12 (m, 1H), 1.98 (br dd, 2H).

[0290] Synthesis of A224 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (247 mg, 1.23 mmol) and HATU (703 mg, 1.85 mmol) in DMF (50 mL) was added DIPEA (478 mg, 3.71 mmol). The mixture was stirred at 15 °C for 10 minutes, then 4-(naphthalen-2-ylmethyl)piperidine-4-carbonitrile hydrochloride (247 mg, 0.8673 mmol) was added. The mixture was stirred at 15 °C for 16 hours. The reaction mixture was poured into water (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by HPLC to give 4-(naphthalen-2-ylmethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (160.6 mg, 30%). 1 1H NMR (400 MHz, CDCl3) δ H 8.93 (br d, 2H), 8.80 (br d, 1H), 8.41 (br s, 1H), 7.93 - 7.79 (m, 3H), 7.78 - 7.69 (m, 2H), 7.58 - 7.53 (m, 1H), 7.50 (dd, 2H), 7.41 (br d, 1H), 4.84 (br s, 1H), 3.68 - 3.54 (m, 1H), 3.43 (br s, 1H), 3.21 - 3.03 (m, 3H), 2.10 (br s, 1H), 1.96 - 1.69 (m, 3H), 1.54 - 1.44 (m, 1H). LC - ELSD / MS purity 95%, C 27 H 23 N5O [M + H] + The calculated value of MS ESI for C

[0291] Example 51. Synthesis of 4-(naphthalen-1-ylmethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A225)

Chemical Structure

[0292] Synthesis of A140 To a mixture of tert-butyl 4-cyano-4-[(naphthalen-1-yl)methyl]piperidine-1-carboxylate (1.89 g, 5.39 mmol) in dioxane (40 mL) was added HCl / dioxane (4 M, 13.4 mL, 53.9 mmol), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL) and dried to give 4-(naphthalen-1-ylmethyl)piperidine-4-carbonitrile hydrochloride (660 mg, 49.2%). 1 H NMR (400 MHz, CD3OD) δ H (d, 1H), 7.90 (m, 2H), 7.61 - 7.46 (m, 4H), 3.58 (s, 2H), 3.47 (d, 2H), 3.21 - 3.09 (m, 2H), 2.24 - 2.14 (m, 2H), 2.07 - 1.96 (m, 2H).

[0293] Synthesis of A225 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (301 mg, 1.50 mmol) and HATU (855 mg, 2.25 mmol) in DMF (50 mL) was added DIPEA (580 mg, 4.50 mmol). The mixture was stirred at 15 °C for 10 minutes, then 4-(naphthalen-1-ylmethyl)piperidine-4-carbonitrile hydrochloride (300 mg, 1.05 mmol) was added. The mixture was stirred at 15 °C for 16 hours. The reaction mixture was poured into water (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 um, conditions: water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN, start: B33, end: B57, gradient time (min): 9, 100% B hold time (min): 4, flow rate (ml / min): 30, injection: 7) to give 4-(naphthalen-1-ylmethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (84.7 mg, 13%). 1 H NMR (400 MHz, CDCl3) δ H 9.20 (s, 1H), 8.86 (d, 1H), 8.73 (d, 1H) , 8.47 (s, 1H), 8.30 - 8.14 (m, 1H), 8.09 - 7.96 (m, 1H), 7.94 - 7.79 (m, 2H), 7.71 - 7.59 (m, 1H), 7.57 - 7.38 (m, 5H), 4.94 - 4.67 (m, 1H), 3.63 - 3.31 (m, 4H), 3.27 - 2.95 (m, 1H), 2.07 (d, 1H), 1.96 - 1.84 (m, 1H), 1.79 (d, 1H), 1.67 (d, 1H) LCMS: purity 99%, C 27 H 23 N5O [M+Na] + Calculated value for MS ESI 456.2 for C 27 H 23 N5O [M+H] +The calculated value by MS ESI is 434.2, and the measured value is 434.0.

[0294] Synthesis of Example 52. 4-((5-Cyclopropylpyridin-2-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A226)

Chemical formula

[0295] Synthesis of A143 To a mixture of tert-Butyl 4-cyanopiperidine-1-carboxylate (1.11 g, 5.30 mmol) in THF (10 mL) under nitrogen, LDA (3.98 mL, 2 M, 7.96 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 1 hour, 5-Bromo-2-(bromomethyl)pyridine (1.6 g, 6.37 mmol) in THF (30 mL) was added. After stirring at 25 °C for 16 hours, the mixture was poured into water (25 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (10 - 30% of EtOAc in PE) to obtain tert-Butyl 4-((5-bromopyridin-2-yl)methyl)-4-cyanopiperidine-1-carboxylate (1.1 g, 55%). 1 H NMR (400 MHz, CDCl3) δ H8.64 - 8.62 (m, 1H), 7.83 - 7.79 (m, 1H), 7.28 - 7.25 (m, 1H), 4.25 - 4.00 (m, 3H), 3.10 - 2.92 (m, 3H), 1.91 - 1.86 (m, 2H), 1.65 - 1.56 (m, 2H), 1.45 (s, 9H).

[0296] Synthesis of A144 A mixture of tert-butyl 4-((5-bromopyridin-2-yl)methyl)-4-cyanopiperidine-1-carboxylate (1.1 g, 2.89 mmol), cyclopropylboronic acid (744 mg, 8.67 mmol), Pd(t-Bu2P)2(dppf)Cl2 (188 mg, 0.289 mmol) and Cs2CO3 (1.19 g, 8.67 mmol) in dioxane (30 mL) was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was filtered and the filtrate was extracted with EtOAc (2 × 50 mL). The combined organic layers were concentrated and the residue was purified by flash chromatography (0 - 15% of EtOAc in PE) to give tert-butyl 4-cyano-4-((5-cyclopropylpyridin-2-yl)methyl)piperidine-1-carboxylate (780 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ H 8.37 (s, 1H), 7.32 - 7.23 (m, 2H), 4.20 - 4.00 (m, 2H), 3.13 - 2.90 (m, 4H), 1.90 - 1.84 (m, 3H), 1.69 - 1.60 (m, 1H), 1.58 - 1.52 (m, 1H), 1.45 (s, 9H), 1.03 (d, 2H), 0.73 - 0.70 (m, 2H).

[0297] Synthesis of A145 To a mixture of tert-butyl 4-cyano-4-((5-cyclopropylpyridin-2-yl)methyl)piperidine-1-carboxylate (300 mg, 0.879 mmol) in dioxane (5 mL) was added HCl / dioxane (4 M, 4.37 mL, 17.5 mmol) at 25 °C. After stirring for 1 h, the reaction mixture was filtered. The filter cake was washed with EtOAc (5 mL) and dried, and 4-((5-cyclopropylpyridin-2-yl)methyl)piperidine-4-carbonitrile hydrochloride (200 mg, 82%) was obtained for direct use in the next step. 1 H NMR (400 MHz, CD3OD) δ H 8.72 (s, 1H), 8.37 - 8.18 (m, 1H), 8.09 - 7.90 (m, 1H), 4.20 (d, 1H), 3.58 (d, 1H), 3.48 (s, 1H), 3.36 (s, 1H), 3.27 - 3.13 (m, 1H), 2.99 (br s, 1H), 2.32 - 2.09 (m, 3H), 1.96 - 1.90 (m, 2H), 1.78 - 1.71 (m, 1H), 1.30 (d, 2H), 1.08 - 0.94 (m, 2H).

[0298] Synthesis of A226 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (200 mg, 0.994 mmol), HATU (566 mg, 1.49 mmol) in DMF (5 mL) was added DIPEA (641 mg, 4.97 mmol) at 25 °C. After stirring for 30 min, 4-((5-cyclopropylpyridin-2-yl)methyl)piperidine-4-carbonitrile hydrochloride (193 mg, 0.696 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (30 mL), and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 * 40 mm *Purified with 3 μm, condition: water (0.05% NH₃H₂O + 10 mM NH₄HCO₃)-ACN, starting B: 22%, ending 48%), and 4-((5-cyclopropylpyridin-2-yl)methyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (31 mg, 7%) was obtained. 1 H NMR (400 MHz, CDCl₃) δ H 9.22 - 8.93 (m, 1H), 8.87 (s, 1H), 8.77 - 8.84 (m, 1H), 8.36 (s, 1H), 8.25 - 8.21 (m, 1H), 7.65 - 7.63 (m, 1H), 7.48 - 7.42 (m, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 4.96 - 4.65 (m, 1H), 3.63 - 3.61 (m, 1H), 3.50 - 3.33 (m, 1H), 3.50 - 3.33 (m, 1H), 3.31 - 2.94 (m, 4H), 2.22 - 2.02 (m, 1H), 1.92 - 1.75 (m, 2H), 1.03 (d, 2H), 0.73 (s, 2H). LCMS purity 97.8%, C 25 H 24 N6O [M + H] + The calculated value of MS ESI for 425, the measured value 425.

[0299] Example 53. Synthesis of 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)-5-(trifluoromethyl)benzoyl)piperidine-4-carbonitrile (A227)

Chemical formula

[0300] Synthesis of A148 A mixture of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (600 mg, 1.74 mmol), 4-chloropyrimidine hydrochloride (235 mg, 1.56 mmol), Pd(dppf)Cl2 (128 mg, 0.174 mmol) and K2CO3 (1.2 g, 8.70 mmol) in dioxane (20 mL) / H2O (2 mL) was stirred at 100 °C for 3 h under nitrogen. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (20 - 25% of EA in PE) to give ethyl 2-(pyrimidin-4-yl)-5-(trifluoromethyl)benzoate (330 mg, 64.0%). 1 H NMR (400 MHz, CDCl3) δ H 9.27 (s, 1H), 8.83 (d, 1H), 8.17 (s, 1H), 7.89 - 7.83 (m, 1H), 7.67 (d, 1H), 7.49 (dd, 1H), 4.22 (d, 2H), 1.15 (t, 3H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.92.

[0301] Synthesis of A149 To a mixture of ethyl 2-(pyrimidin-4-yl)-5-(trifluoromethyl)benzoate (340 mg, 1.14 mmol) in MeOH / water (5 / 1, 6 mL) was added LiOH H2O (52.5 mg, 1.25 mmol) and the mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated to give 2-(pyrimidin-4-yl)-5-(trifluoromethyl)benzoic acid (340 mg). 1 H NMR (400 MHz, CD3OD) δ H 9.19 (d, 1H), 8.76 (d, 1H), 7.93 (s, 1H), 7.85 - 7.72 (m, 3H). 19 F NMR (376.5 MHz, CD3OD) δ F -64.35.

[0302] Synthesis of A227 To a solution of 2-(pyrimidin-4-yl)-5-(trifluoromethyl)benzoic acid (190 mg, 0.708 mmol), 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (180 mg, 0.708 mmol), and HATU (402 mg, 1.05 mmol) in DMF (3 mL) was added DIPEA (456 mg, 3.54 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 * 30 mm * 3 um, conditions: water (10 mM NH4HCO3)-ACN, starting B: 38%, ending 68%) to give 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)-5-(trifluoromethyl)benzoyl)piperidine-4-carbonitrile (35.9 mg, yield 10.8%). 1 H NMR (400 MHz, CDCl3) δ H 9.42 - 8.96 (m, 1H), 8.86 (s, 1H), 7.93 - 7.76 (m, 2H), 7.72 - 7.59 (m, 2H), 7.22 (d, 2H), 7.05 (m, 2H), 4.91 - 4.59 (m, 1H), 3.66 - 3.33 (m, 2H), 3.17 - 2.99 (m, 1H), 2.92 - 2.80 (m, 2H), 2.06 - 1.87 (m, 1H), 1.70 - 1.58 (m, 2H), 1.52 - 1.44 (m, 1H). LC / MS purity 99%, C 25 H 20 Calculated MS ESI for C24H22F4N4O [M + H]+ 469.0, found 469.0. 19 F NMR (376.5 MHz, CDCl3) δ F -62.86, -62.95, -114.37.

[0303] Example 54. Synthesis of 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-4-carbonitrile (A228)

Chem.

[0304] Synthesis of A152 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (656 mg, 3.12 mmol) in THF (10 mL) at -78 °C, LDA (1.56 mL, 2 M, 3.12 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 h, then 2-(bromomethyl)-5-(trifluoromethyl)pyridine (500 mg, 2.08 mmol) was added. The mixture was warmed to 20 °C and stirred for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (0 - 30% EtOAc in PE) to give tert-butyl 4-cyano-4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-1-carboxylate (0.3 g, 39%). 1 H NMR (400 MHz, CDCl3) δ H8.85 (singlet, 1H), 7.93 (doublet, 1H), 7.50 (doublet, 1H), 4.23 - 4.06 (multiplet, 2H), 3.15 - 3.10 (multiplet, 2H), 3.07 - 2.97 (multiplet, 2H), 1.95 - 1.86 (multiplet, 2H), 1.68 - 1.59 (multiplet, 2H), 1.4 - 1.45 (multiplet, 9H).

[0305] Synthesis of A153 To a solution of tert-butyl 4-cyano-4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-1-carboxylate (0.18 g, 0.49 mmol) in dioxane (5 mL) under nitrogen, HCl / dioxane (0.12 mL, 4 M HCl in dioxane) was added at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to afford 4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-4-carbonitrile hydrochloride (140 mg).

[0306] Synthesis of A228 A solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (128 mg, 0.64 mmol), HATU (242 mg, 0.64 mmol), DIPEA (0.37 mL, 2.12 mmol) and 4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-4-carbonitrile hydrochloride (130 mg, 0.43 mmol) in DMF (10 mL) was stirred at 0 °C for 2 h. The mixture was poured into saturated NH4Cl solution (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 295 mg, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 * 30 mm * 3 μm, conditions: water (10 mM NH4HCO3)-ACN, starting B: 28%, ending B: 58%) to afford 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-4-carbonitrile (166.5 mg, 56%). 11H NMR (400 MHz, CDCl3) δ H 9.32 - 9.02 (m, 1H), 8.94 - 8.85 (m, 1H), 8.85 - 8.80 (m, 1H), 8.79 - 8.73 (m, 1H), 8.30 - 8.24 (m, 1H), 7.98 - 7.91 (m, 1H), 7.71 - 7.64 (m, 1H), 7.55 - 7.40 (m, 2H), 4.97 - 4.69 (m, 1H), 3.68 - 3.59 (m, 1H), 3.48 - 3.34 (m, 0.5H), 3.26 - 3.12 (m, 3H), 2.25 - 2.06 (m, 1H), 2.02 - 1.93 (m, 1H), 1.90 - 1.73 (m, 1.5H), 1.71 - 1.61 (m, 0.5H), 1.39 - 1.20 (m, 0.5H). 19 19F NMR (376.5 MHz, CDCl3) δF - 62.430. LCMS purity 99%, C 23 H 19 F3N6O [M + H] + Calculated value for 453.2, measured value 453.2.

[0307] Example 55. Synthesis of 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)benzoyl)piperidine-4-carbonitrile (A229)

Chemical Structure

[0308] Synthesis of A156 A mixture of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1 g, 3.62 mmol), 4-chloropyrimidine hydrochloride (490 mg, 3.25 mmol), Pd(dppf)Cl2 (267 mg, 0.3620 mmol) and K2CO3 (2.50 g, 18.1 mmol) in dioxane (15 mL) / water (2 mL) was stirred at 100 °C for 3 h under nitrogen. The reaction mixture was poured into water (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (0 - 30% EA in PE) to give ethyl 2-(pyrimidin-4-yl)benzoate (800 mg). 1 1H NMR (400 MHz, CDCl3) δ H 9.21 (S, 1H), 8.80 - 8.72 (m, 1H), 7.90 - 7.84 (m, 1H), 7.60 - 7.56 (m, 1H), 7.54 - 7.52 (m, 2H), 7.46 - 7.44 (m, 1H), 4.20 - 4.10 (m, 2H), 2.00 (s, 2H), 1.26 - 1.20 (m, 3H).

[0309] Synthesis of A157 To a mixture of ethyl 5-fluoro-2-(pyrimidin-4-yl)benzoate (400 mg, 1.75 mmol) in MeOH (10 mL) / water (1 mL) was added LiOH·H2O (80.6 mg, 1.92 mmol). The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated to dryness to give 5-fluoro-2-(pyrimidin-4-yl)benzoic acid (300 mg). 1 1H NMR (400 MHz, CD3OD) δ H9.13 (s, 1H), 8.72 - 8.66 (m, 1H), 7.80 - 7.74 (m, 1H), 7.66 - 7.60 (m, 2H), 7.50 - 7.46 (m, 2H).

[0310] Synthesis of A229 A solution of ethyl 2-(pyrimidin-4-yl)benzoate (350 mg, 1.74 mmol), HOBt (469 mg, 3.48 mmol), EDCI (664 mg, 3.48 mmol), DIPEA (0.908 mL, 5.22 mmol) and 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (443 mg, 1.74 mmol) in DMF (5 mL) was stirred at 0 °C for 2 h. The mixture was filtered, concentrated, and purified by preparative HPLC (column: Xtimate C18 150 * 40 mm * 5 μm, conditions: water (10 mM NH4HCO3)-ACN, starting B: 25, ending B: 35, gradient time (min): 8, hold time at 100% B (min): 2), to give 4-(4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)benzoyl)piperidine-4-carbonitrile (49.1 mg, 7%). 1 1H NMR (400 MHz, CDCl3) δ H 9.40 - 9.02 (br s, 1H), 8.80 (s, 1H), 7.80 - 7.58 (m, 2H), 7.58 - 7.50 (m, 2H), 7.38 - 7.32 (m, 1H), 7.24 - 7.18 (m, 2H), 7.04 (s, 2H), 4.86 - 4.66 (m, 1H), 3.68 - 3.24 (m, 2H), 3.10 - 2.74 (m, 4H), 2.05 - 1.88 (m, 1H), 1.86 - 1.58 (m, 2H). 19 19F NMR (376.5 MHz, CDCl3) δ F -114.52. LC-ELSD / MS purity 98%, C 24 H 21 FN4O [M + H] + The calculated value of MS ESI for C

[0311] Example 56. Synthesis of 4-(2-Cyclopropyl-4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A230) [Chemical formula] Synthesis of A159 A mixture of methyl 2-bromo-4-fluorobenzoate (3 g, 12.8 mmol), cyclopropylboronic acid (1.53 g, 17.9 mmol), palladium(II) bis(di-tert-butyl(cyclopenta-1,3-dien-1-yl)phosphane) iron dichloride (834 mg, 1.28 mmol) and Cs2CO3 (2.64 g, 19.2 mmol) in dioxane (40 mL) was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (0 - 30% of EtOAc in PE) to give methyl 2-cyclopropyl-4-fluorobenzoate (1.2 g, yield 48.3%). 1 H NMR (400 MHz, CDCl3) δ H 7.85 (m, 1H), 6.86 (m, 1H), 6.66 (m, 1H), 3.90 (s, 3H), 2.80 - 2.71 (m, 1H), 1.09 - 0.98 (m, 2H), 0.72 - 0.65 (m, 2H). 19 F NMR (376.5 MHz, CDCl3) δ F -107.49.

[0312] Synthesis of A160 To a solution of methyl 2-cyclopropyl-4-fluorobenzoate (500 mg, 2.57 mmol) in THF (10 mL) was added LiAlH4 (195 mg, 5.14 mmol) in one portion. After stirring, the mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into water (20 mL), and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated, and (2-cyclopropyl-4-fluorophenyl)methanol (330 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ H 7.30 (m, 1H), 6.85 (m, 1H), 6.67 (m, 1H), 4.82 (s, 2H), 2.09 - 1.98 (m, 1H), 1.83 (ms, 1H), 1.06 - 0.91 (m, 2H), 0.74 - 0.59 (m, 2H). 19 F NMR (376.5 MHz, CDCl3) δ F -114.77.

[0313] Synthesis of A161 To a solution of (2-cyclopropyl-4-fluorophenyl)methanol (100 mg, 0.601 mmol) in DCM (20 mL) was added PBr3 (243 mg, 0.901 mmol) with stirring under nitrogen at 25 °C. The reaction was stirred at 25 °C for 2 hours. The mixture was cooled in an ice bath, and saturated NH4Cl solution (30 mL) was added. The mixture was extracted with DCM (2 × 30 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (0 - 5% EA in PE) to give 1-( bromomethyl)-2-cyclopropyl-4-fluorobenzene (110 mg, yield 80.2%). 1 H NMR (400 MHz, chloroform-d) δ H 7.29 (m, 1H), 6.89 - 6.81 (m, 1H), 6.70 (m, 1H), 4.74 - 4.66 (m, 2H), 1.54 (s, 1H), 1.11 - 1.02 (m, 2H), 0.78 - 0.69 (m, 2H).

[0314] Synthesis of A162 To tert-butyl 4-cyanopiperidine-1-carboxylate (175 mg, 0.833 mmol) in THF (30 mL), LDA (0.63 mL, 1.25 mmol, 2 M in THF / n-heptane) was added dropwise at -78 °C, and the mixture was stirred at 78 °C under nitrogen for 1 h. Then 1-(bromomethyl)-2-cyclopropyl-4-fluorobenzene (230 mg, 1.0 mmol) was added at -78 °C, and the mixture was warmed to 20 °C and stirred under nitrogen for 16 h. The reaction mixture was poured into saturated NH4Cl solution (50 mL), and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated. The product was purified by column chromatography (0 - 10% EtOAc in PE) to give tert-butyl 4-cyano-4-(2-cyclopropyl-4-fluorobenzyl)piperidine-1-carboxylate (110 mg, yield 36.9%). 1 H NMR (400 MHz, CDCl3) δ H 7.24 (d, 1H), 6.86 (m, 1H), 6.67 (m 1H), 4.14 (m, 2H), 3.09 (s, 2H), 3.05 - 2.90 (m, 2H), 2.06 - 1.97 (m, 1H), 1.91 (m, 2H), 1.46 (s, 10H), 1.07 - 0.99 (m, 2H), 0.67 (q, 2H).

[0315] Synthesis of A163 To a mixture of tert-butyl 4-cyano-4-(2-cyclopropyl-4-fluorobenzyl)piperidine-1-carboxylate (110 mg, 0.306 mmol) in dioxane (20 mL), HCl / dioxane (4 M, 0.77 mL, 3.06 mmol) was added, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to give 4-(2-cyclopropyl-4-fluorobenzyl)piperidine-4-carbonitrile hydrochloride (120 mg), which was used without further purification.

[0316] Synthesis of A230 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (117 mg, 0.584 mmol) and HATU (332 mg, 0.876 mmol) in DMF (20 mL) was added DIEA (225 mg, 1.75 mmol). The mixture was stirred at 25 °C for 10 minutes, then 4-(2-cyclopropyl-4-fluorobenzyl)piperidine-4-carbonitrile hydrochloride (120 mg, 0.409 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (50 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, and concentrated. The product was purified by HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 um, conditions: water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN, start: B40, end: B56, gradient time (min): 8, 100% B hold time (min): 2.6, flow rate (ml / min): 30, injection: 5) to give 4-(2-cyclopropyl-4-fluorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (9.3 mg, 3.61%). 1 H NMR (400 MHz, CDCl3) δ H 9.22 (s, 1H), 8.88 (d, 1H), 8.83 - 8.72 (m, 2H), 8.24 (d, 1H), 7.66 (d, 1H), 7.47 (m, 1H), 7.23 (d, 1H), 6.91 - 6.80 (m, 1H), 6.68 (d, 1H), 4.92 (d, 1H), 4.80 (d, 1H), 3.62 (d, 1H), 3.51 - 3.36 (m, 1H), 3.17 (d, 3H), 2.20 - 2 .05 (m, 1H), 2.04 - 1.81 (m, 3H), 1.70 (d, 1H), 1.57 (s, 3H), 1.25 (s, 1H), 1.08 - 0.92 (m, 2H), 0.67 (br s, 2H). LCMS purity 100%, C 26 H 24 FN5O [M+Na] + The calculated value of MS ESI for 464.2, the measured value 464.2.

[0317] Synthesis of Example 57. 4-(4-Chloro-2-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A231) and 4-(2-Bromo-4-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A232)

Chemical formula

[0318] Synthesis of A166 tert-Butyl 4-(2-bromo-4-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (400 mg, 0.97 mmol), cyclopropylboronic acid (165 mg, 1.93 mmol), Pd(OAc)₂ (125 mg, 0.19 mmol) and K₃PO₄ (331 g, 1.93 mmol) were mixed in toluene (10 mL) and water (1 mL), and stirred at 100 °C for 16 h under nitrogen. Ice water (10 mL) was added and the mixture was extracted with EtOAc (15 mL × 2). The combined organic layers were dried over Na₂SO₄, concentrated and purified twice by flash chromatography (0 - 90% of EtOAc in PE) to obtain tert-butyl 4-(4-chloro-2-cyclopropylbenzyl)-4-cyanopiperidine-1-carboxylate (150 mg). 1 H NMR (400 MHz, CDCl₃) δ H 7.62 (d, 0.5H), 7.47 - 7.42 (m, 0.5H), 7.34 - 7.29 (m, 0.5H), 7.24 - 7.20 (m, 0.5 H), 7.16 - 7.11 (m, 1H), 6.96 (d, 1H), 4.14 (s, 2H), 3.13 - 2.87 (m, 4H), 2.02 - 1.82 (m, 2H), 1.71 - 1.57 (m, 1H), 1.46 (s, 9H), 1.31 - 1.24 (m, 1H), 1.06 - 0.93 (m, 2H), 0.91 - 0.81 (m, 2H).

[0319] Synthesis of A167 To a solution of tert-butyl 4-(4-chloro-2-cyclopropylbenzyl)-4-cyanopiperidine-1-carboxylate (150 mg, 0.4 mmol) was added HCl / dioxane (10 mL, 4 M, 40.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h under nitrogen. The mixture was concentrated to obtain 4-(4-chloro-2-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (100 mg). The product was used directly in the next step.

[0320] Synthesis of A231 and A232 A solution of 2-(pyrimidin-4-yl)nicotinic acid (87.8 mg, 0.45 mmol), HOBt (98.2 mg, 0.73 mmol), EDCI (139 mg, 0.73 mmol), DIPEA (0.314 mL, 1.81 mmol) and 4-(4-chloro-2-cyclopropylbenzyl)piperidine-4-carbonitrile hydrochloride (100 mg, 0.36 mmol) in DMF (2 mL) was stirred at 15 °C for 16 h. The mixture was filtered, concentrated, and purified by preparative HPLC (column: Xtimate C18 150 * 40 mm * 5 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 50, end B: 80, gradient time (min): 8.5, hold time at 100% B (min): 2) to give 4-(4-chloro-2-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (30 mg, 12.0%) and 4-(2-bromo-4-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (30 mg, 16.6%).

[0321] SFC purification 4-(4-chloro-2-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (20 mg, 0.045 mmol) was further purified by SFC (column DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm), conditions 0.1% NH3H2O IPA, start B 40, end B 40) to give 4-(4-chloro-2-cyclopropylbenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (12.1 mg, 60.8%). 1 1H NMR (400 MHz, CDCl3) δ H9.22 (s, 0.3H), 8.91 - 8.82 (m, 1.7H), 8.79 - 8.74 (m, 1H), 8.33 - 8.19 (m, 1H), 7.74 - 7.61 (m, 1H), 7.51 - 7.40 (m, 1H), 7.24 - 7.18 (m, 1H), 7.17 - 7.11 (m, 1H), 7.02 - 6.94 (m, 1H), 5.01 - 4.72 (m, 1H), 3.67 - 3.58 (m, 0.5H), 3.53 - 3.35 (m, 1H), 3.32 - 3.00 (m, 3.5H), 2.21 - 2.04 (m, 1H), 2.01 - 1.82 (m, 3H), 1.79 - 1.65 (m, 1H), 1.08 - 0.92 (m, 2H), 0.77 - 0.60 (m, 2H). LCMS purity 100%, C 26 H 24 ClN5ONa [M+Na] + The calculated MS ESI value for it is 480, and the measured value is 480 for + .

[0322] 4-(2-Bromo-4-chlorobenzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (30 mg, 0.06 mmol) was further purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm * × 30 mm, 5 μm), condition: 0.1% NH3H2O IPA, start B 40, end B 40), and 4-(2-bromo-4-chlorobenzyl)-1-(2-(pyrimidin-4-yl)ni cotinoyl)piperidine-4-carbonitrile (20.6 mg, 68.8%) was obtained. 1 H NMR (400 MHz, CDCl3) δ H 9.21 (s, 0.3H), 9.09 (s, 0.7H), 8.90 (d, 1H), 8.76 (d, 1H), 8.26 (d, 1H), 7.74 - 7.58 (m, 2H), 7.46 (d, 2H), 7.33 (d, 1H), 5.05 - 4.62 (m, 1H), 3.63 (d, 1H), 3.50 - 3.33 (m, 1H), 3.29 - 3.01 (m, 3H), 2.19 - 1.95 (m, 3H), 1.88 - 1.76 (m, 1H), 1.64 (d, 1H). LCMS purity 98%, C 23 H 20Calculated MS ESI value for BrClN5ONa[M + H + Na] is 520, measured value is 520.

[0323] Example 58. Synthesis of 4-(4-Fluorobenzyl)-1-(2-(5-fluoropyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A233)

Chemical Structure

[0324] Synthesis of A170 To a solution of 5-fluoro-4-(trimethylstannyl)pyrimidine (500 mg, 1.91 mmol) in DMF (20 mL) were added ethyl 2-chloropyridine-3-carboxylate (0.53 g, 2.86 mmol), λ 2 -iron(II) bis(cyclopenta-2,4-dien-1-yl)diphenyl-λ 4-Phosphane) Palladium (II) dichloride (138 mg, 0.19 mmol) and CuI (36.3 mg, 0.19 mmol) were added at 25 °C under nitrogen. The mixture was stirred at 110 °C for 2 h. The mixture was poured into saturated NH4Cl solution (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and ethyl 2-(5-fluoropyrimidin-4-yl)nicotinate (0.3 g) was obtained, which was used directly in the next step.

[0325] Synthesis of A171 To a solution of ethyl 2-(5-fluoropyrimidin-4-yl)nicotinate (0.3 g, 1.21 mmol), MeOH (1 mL) and water (0.2 mL) in THF (3 mL), LiOH·H2O (91.9 mg, 2.42 mmol) was added in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 30 min. The mixture was concentrated and 2-(5-fluoropyrimidin-4-yl)nicotinic acid (180 mg) was obtained, which was used directly in the next step.

[0326] Synthesis of A233 To a solution of 2-(5-fluoropyrimidin-4-yl)nicotinic acid (150 mg, 0.68 mmol) in DMF (5 mL) at 0 °C, HATU (387 mg, 1.02 mmol) and DIPEA (442 mg, 3.42 mmol) were added. After stirring at 0 °C for 10 min, 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (226 mg, 0.89 mmol) was added. The mixture was stirred at 15 °C for 2 h. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by HPLC (column: Phenomenex Gemini-NX 80 * 40 mm *Purified by (3 μm), conditions: water (0.05% NH₃H₂O + 10 mM NH₄HCO₃)-ACN, starting B: 34%, ending B: 54%) to obtain 4-(4-fluorobenzyl)-1-(2-(5-fluoropyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (10.2 mg, 10%). 1 H NMR (400 MHz, CDCl₃) δ H 8.82 - 8.78 (m, 1H), 8.75 - 8.73 (m, 1H), 7.75 - 7.70 (m, 1H), 7.51 - 7.46 (m, 1H), 7.29 - 7.26 (m, 1H), 7.26 - 7.20 (m, 2H), 7.09 - 7.02 (m, 2H), 4.77 - 4.64 (m, 1H), 3.77 - 3.59 (m, 1H), 3.53 - 3.33 (m, 1H), 3.13 - 2.98 (m, 1H), 2.98 - 2.83 (m, 2H), 2.13 - 2.10 (m, 0.5H), 2.03 - 1.95 (m, 1H), 1.84 - 1.76 (m, 1H), 1.67 - 1.59 (m, 1.5H). 19 F NMR (376.5 MHz, CDCl₃) δF - 114.337. LCMS purity 99%, C 23 H 19 F₂N₅O [M + H] + For 5 - 95AB_1.5min_220&254 calculated value 420.2, measured value 420.2.

[0327] Example 59. Synthesis of 1-(5-chloro-2-(pyrimidin-4-yl)benzoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (A234)

Chemical Structure

[0328] Synthesis of A174 A mixture of ethyl 5 - chloro - 2-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzoate (1.2 g, 3.86 mmol), 4 - chloropyrimidine hydrochloride (523 mg, 3.47 mmol), Pd(dppf)Cl2 (284 mg, 0.3860 mmol), and K2CO3 (2.66 g, 19.3 mmol) in dioxane (15 mL) / water (2 mL) was stirred at 100 °C for 3 hours under nitrogen. The reaction mixture was poured into water (20 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The product was purified by flash chromatography (0 - 25% EtOAc in PE) to give ethyl 5 - chloro - 2-(pyrimidin - 4 - yl)benzoate (740 mg, yield 73.2%). 1 1H NMR (400 MHz, CDCl3) δ H9.23 (d, 1H), 8.78 (d, 1H), 7.85 (d, 1H), 7.59 - 7.54 (m, 1H), 7.51 - 7.47 (m, 1H), 7.45 (m, 1H), 4.19 (d, 2H), 1.13 (t, 2H), 1.10 - 1.10 (m, 1H).

[0329] Synthesis of A175 To ethyl 5-chloro-2-(pyrimidin-4-yl)benzoate (740 mg, 2.81 mmol) in MeOH (5 mL) / water (1 mL), LiOH·H2O (176 mg, 4.21 mmol) was added and the mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated to give 5-chloro-2-(pyrimidin-4-yl)benzoic acid (1 g). 1 H NMR (400 MHz, CD3OD) δ H 9.14 (s, 1H), 8.72 (d, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 7.61 (d, 1H), 7.46 (m, 1H).

[0330] Synthesis of A234 5-Chloro-2-(pyrimidin-4-yl)benzoic acid (100 mg, 0.4261 mmol), HOBt (190 mg, 0.8509 mmol), EDCI (171 mg, 0.8522 mmol), DIPEA (274 mg, 2.13 mmol) and 4-[(4-fluorophenyl)methyl]piperidine-4-carbonitrile hydrochloride (130 mg, 0.5113 mmol) were mixed in DMF (5 mL) and stirred at 20 °C for 2 h. The mixture was filtered, concentrated and purified by preparative HPLC (column: Phenomenex Gemini-NX 80 * 30 mm * 3 um, condition: water (10 mM NH4HCO3)-ACN, start B: 42, end B: 72) to give 1-(5-chloro-2-(pyrimidin-4-yl)benzoyl)-4-(4-fluorobenzyl)piperidine-4-carbonitrile (20 mg, 10.8%). 1 H NMR (400 MHz, CDCl3) δ H9.24 - 8.75 (m, 2H), 7.75 - 7.48 (m, 3H), 7.35 (d, 1H), 7.26 - 7.17 (m, 2H), 7.04 (s, 2H), 4.82 - 4.63 (m, 1H), 3.69 - 3.57 (m, 1H), 3.52 - 3.28 (m, 1H), 3.14 - 2.98 (m, 1H), 2.87 (s, 2H), 2.21 (s, 1H), 2.13 - 1.73 (m, 2H), 1.61 (s, 1H), 1.54 - 1.45 (m, 1H). LC - ELSD / MS purity 99%, C 24 H 20 The calculated MS ESI value for C1815ClF4N4O[M + H]+ is 435.2, and the measured value is 435.2. 19 19F NMR (376.5 MHz, CDCl3) δ F - 62.86, - 62.95, - 114.40.

[0331] Example 60. Synthesis of (S) - 4 - (1 - (2,4 - difluorophenyl)ethyl) - 1 - (2 - (pyrimidin - 4 - yl)nicotinoyl)piperidine - 4 - carbonitrile (A241) and (R) - 4 - (1 - (2,4 - difluorophenyl)ethyl) - 1 - (2 - (pyrimidin - 4 - yl)nicotinoyl)piperidine - 4 - carbonitrile (A242)

Chemical Structure

[0332] Synthesis of A178 To a solution of 1-(2,4-difluorophenyl)ethan-1-ol (5 g, 31.6 mmol) in CHCl3 (80 mL), tribromophosphane (8.98 ml, 94.8 mmol) was added in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 2 h. The mixture was slowly poured into ice water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, concentrated to give 1-(1-bromoethyl)-2,4-difluorobenzene (5.5 g). 1 H NMR (400 MHz, CDCl3) δ H 7.60 - 7.40 (m, 1H), 6.94 - 9.86 (m = 2.0 Hz, 1H), 6.86 - 6.74 (s, 1H), 5.48 - 5.36 (m, 1H), 2.10 - 1.98 (m, 3H).

[0333] Synthesis of A179 To a mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (7.12 g, 33.9 mmol) in THF (50 mL), LDA (16.9 mL, 2 M, 33.9 mmol) was added dropwise at -78 °C and the mixture was stirred at -78 °C for 1 h. Then 1-(1-bromoethyl)-2,4-difluorobenzene (5 g, 22.6 mmol) was added and stirring was continued at -78 °C for 2 h. The mixture was poured into water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 30% of EtOAc in PE) to give tert-butyl 4-cyano-4-(1-(2,4-difluorophenyl)ethyl)piperidine-1-carboxylate (5 g, 63.2%). 1 H NMR (400 MHz, CDCl3) δ H7.56 - 7.46 (m, 1H), 6.98 - 6.88 (m, 1H), 6.84 - 6.76 (m, 1H), 4.30 - 4.14 (m, 1H), 4.08 - 3.88 (m, 1H), 3.20 - 3.10 (m, 1H), 3.06 - 2.80 (m, 2H), 2.22 - 2.10 (m, 1H), 1.48 (s, 3H), 1.46 - 1.44 (m, 2H), 1.44 (s, 9H).

[0334] Synthesis of A180 (including SFC separation) To tert-butyl 4-cyano-4-(1-(2,4-difluorophenyl)ethyl)piperidine-1-carboxylate (3 g, 8.56 mmol) in dioxane (5 mL) was added HCl / dioxane (4 M, 21.4 mL, 85.6 mmol), and the mixture was stirred at 20 °C for 16 h. The mixture was concentrated to give 4-(1-(2,4-difluorophenyl)ethyl)piperidine-4-carbonitrile hydrochloride (2 g). The residue was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δH 7.54 - 7.42 (m, 1H), 7.02 - 6.88 (m, 1H), 6.86 - 6.76 (m, 1H), 3.66 - 3.42 (m, 2H), 3.30 - 2.96 (m, 3H), 2.44 - 2.30 (m, 1H), 2.26 - 2.04 (m, 2H), 1.76 - 1.64 (m, 1H), 1.50 - 1.46 (m, 3H), 1.44 - 1.42 (m, 1H).

[0335] Synthesis of A181 2-(Pyrimidin-4-yl)pyridine-3-carboxylic acid (400 mg, 1.99 mmol), HOBt (888 mg, 3.98 mmol), EDCI (800 mg, 3.98 mmol), DIPEA (760 mg, 3.98 mmol) and 4-(1-(2,4-difluorophenyl)ethyl)piperidine-4-carbonitrile hydrochloride (500 mg, 1.99 mmol) were mixed in DMF (10 mL). After stirring at 20 °C for 2 h, the mixture was filtered, concentrated, and purified by preparative HPLC (column: Xtimate C18 150 * 40 mm *Purified by 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B: 25, end B: 35, gradient time (min): 8, hold time at 100% B (min): 2), and obtained racemic-4-(1-(2,4-difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (300 mg, 0.692 mmol). This was further purified by SFC (column: Chiralcel OD-3 150×4.6 mm inner diameter, 3 μm mobile phase: A: CO2 B: ethanol (0.05% DEA) gradient: hold 5% to 40% of B for 5 minutes, hold 40% for 2.5 minutes, then hold 5% of B for 2.5 minutes flow rate: 2.5 mL / min column temperature: 35°C ABPR: 1500 psi), (S)-4-(1-(2,4-difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (104.2 mg, 34%) was obtained. 1 H NMR (400 MHz, CDCl3) δ H 9.30 - 9.00 (m, 1H), 8.95 - 8.71 (m, 2H), 8.34 - 8.18 (m, 1H), 7.77 - 7.42 (m, 3H), 7.07 - 6.66 (m, 2H), 5.02 - 4.77 (m, 1H), 3.77 - 2.89 (m, 5H), 2.49 - 1.63 (m, 3H), 1.54 (s, 1H), 1.48 (d, 2H). 19 F NMR (376.5 MHz, CDCl3) δ F -110.440, -110.463, -110.575, -110.680. LCMS purity 99%, de value 100%, C 24 H 21 Calculated MS ESI value for C H F2N5O [M+H] is 434.2, measured value is 434.2.

[0336] (R)-4-(1-(2,4-difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (85.2 mg, 27%). 1 H NMR ((400 MHz, CDCl3) δ H9.31 - 9.00 (m, 1H), 8.98 - 8.70 (m, 2H), 8.26 (m, 1H), 7.74 - 7.61 (m, 1H), 7.59 - 7.39 (m, 2H), 7.05 - 6.70 (m, 2H), 5.01 - 4.71 (m, 1H), 3.68 - 2.97 (m, 4H), 2.51 - 1.96 (m, 1H), 1.94 - 1.66 (m, 2H), 1.55 (m, 2H), 1.47 (d, 2H) 19 19F NMR (376.5 MHz, CDCl3) δ F -110.440, -110.463, -110.575, -110.680. LCMS purity 97%, de value 99%, C 24 H 21 Calculated MS ESI for C19H16F2N5O [M + H]: 434.2, found 434.2.

[0337] Example 61. Synthesis of (S)-1-([2,4'-bipyridin]-3-carbonyl)-4-(1-(2,4-difluorophenyl)ethyl)piperidine-4-carbonitrile (A237) and (R)-1-([2,4'-bipyridin]-3-carbonyl)-4-(1-(2,4-difluorophenyl)ethyl)piperidine-4-carbonitrile (A238)

Chemical formula

[0338] Synthesis of Example 62.1-(2-(Pyrimidin-4-yl)nicotinoyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)piperidine-4-carbonitrile (A239)

Chemical Structure

[0339] Synthesis of A185 To a solution of tert-butyl 4-cyano-4-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)piperidine-1-carboxylate (200 mg, 0.5414 mmol) in dioxane (2 mL) was added HCl / dioxane (3 mL, 4 M, 12.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h under nitrogen. The mixture was concentrated to afford 4-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)piperidine-4-carbonitrile hydrochloride (150 mg). 1 H NMR (400 MHz, CDCl3) δ H 8.92 (s, 2H), 3.57 (d, 2H), 3.32 - 3.31 (m, 1H), 3.28 (m, 3H), 3.05 (m, 2H), 2.42 - 2.29 (m, 3H).

[0340] Synthesis of A239 To a solution of 2-(pyrimidin-4-yl)pyridine-3-carboxylic acid (78.9 mg, 0.3924 mmol) in DMF (2 mL) were added HATU (186 mg, 0.4905 mmol) and DIPEA (0.170 mL, 0.9810 mmol) at 25 °C, and the mixture was stirred at 25 °C for 30 min. 4-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)piperidine-4-carbonitrile hydrochloride (100 mg, 0.3270 m mol) was added to the mixture. After stirring at 25 °C for 2 h, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column Welch Xtimate C18 150 * 25 mm *Purified by 5 μm, condition: water (0.05% NH₃H₂O)-ACN, start B: 30, end B: 60, gradient time (min): 8, 100% B hold time (min): 2) to obtain the product (50 mg, 0.11 mmol), and this was further purified by preparative HPLC (column Phenomenex Gemini-NX 80*40 mm*3 μm, condition: water (0.05% NH₃H₂O + 10 mM NH₄HCO₃)-ACN, start B 40, end B 40, gradient time (min): 8, 100% B hold time (min) 2.5 Purified further by a flow rate (ml / min) of 30 and injection 4) to obtain 1-(2-(pyrimidin-4-yl)nicotinoyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)piperidine-4-carbonitrile (9.3 mg, 18.6%). 1 ¹H NMR (400 MHz, CDCl₃) δ H 9.28 - 9.10 (m, 1H), 8.99 - 8.75 (m, 4H), 8.30 (m, 1H), 7.69 (d, 1H), 7.50 (m, 1H), 5.06 - 4.79 (m, 1H), 3.75 - 3.24 (m, 2H), 3.14 - 2.88 (m, 3H), 2.23 - 1.65 (m, 4H). 19 ¹⁹F NMR (376.5 MHz, CDCl₃) δ F -70.275. LCMS purity 98%, C 22 H 18 Calculated MS ESI for C₂₀H₁₅F₄N₇O [M + H] 454.2, found 454.2.

[0341] Example 63. Synthesis of 4-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A240)

Chemical Structure

[0342] Synthesis of A188 To tert-butyl 4-cyano-4-(2-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (750 mg, 1.94 mmol), HCl / dioxane (4 M, 10 mL) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to obtain 4-(2-fluoro-4-(trifluoromethyl)benzyl)piperidine -4-carbonitrile hydrochloride (0.5 g). 1 H NMR (400 MHz, CDCl3) δ H 7.57 - 7.36 (m, 2H), 7.24 - 7.18 (m, 1H), 3.58 (d, 3H), 3.19 (d, 2H), 2.34 - 2.06 (m, 4H), 1.81 (s, 2H), 1.26 (s, 2H).

[0343] Synthesis of A240 To a solution of 2-(pyrimidin-4-yl)nicotinic acid (372 mg, 1.85 mmol) in DMF (2 mL) were added HATU (1.05 g, 2.77 mmol), DIPEA (0.968 mL, 5.55 mmol), and 4-(2-fluoro-4-(trifluoromethyl)benzyl)piperidine-4-carbonitrile hydrochloride (600 mg, 1.85 mmol). After stirring at 25 °C for 30 minutes, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 30, end B: 60, gradient time (min) 8, hold time at 100% B (min): 2) to give the product (100 mg), and further purified by SFC (column: Chiralpak AD (250 mm * 30 mm, 10 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA) gradient: hold 5% - 40% of B for 2 minutes, hold 40% for 1.2 minutes, then hold 5% of B for 0.8 minutes flow rate: 4 mL / min column temperature: 35 °C ABPR: 1500 psi) to give 4-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (56.5 mg, 56.5%). 1 1H NMR (400 MHz, CDCl3) δ H 9.28 - 9.03 (m, 1H), 8.96 - 8.86 (m, 1H), 8.78 (m, 1H), 8.27 (m, 1H), 7.74 - 7.65 (m, 1H), 7.60 - 7.53 (m, 1H), 7.51 - 7.44 (m, 2H), 7.37 (m, 1H), 4.99 - 4.74 (m, 1H), 3.72 - 3.35 (m, 2H), 3.32 - 2.99 (m, 4H), 2.14 - 1.62 (m, 4H). 19 19F NMR (376.5 MHz, CDCl3) δ F -62.858, -113.187, -113.322. LCMS purity 99%, C24 H 19 The calculated MS ESI value for F4N5O [M+H] is 470.1, and the measured value is 470.1.

[0344] Example 64. Synthesis of (S)-4-(1-(2,6-difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A243) and (R)-4-(1-(2,6-difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (A244)

Chemical Structure

[0345] Synthesis of A191 A solution of 1-(2,6-difluorophenyl)ethan-1-ol (2.4 g, 15.1 mmol) in CDCl3 (20 mL) was added dropwise with PBr3 (8.06 g, 30.6 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Ice water (40 mL) was added, and the mixture was extracted with DCM (40 mL×2). The combined organic layers were dried over Na2SO4, concentrated, and 2-(1-bromoethyl)-1,3-difluorobenzene (1.7 g, 51.0%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ H 7.52 - 7.38 (m, 1H), 7.14 (t, 2H), 5.63 (q, 1H), 2.05 (d, 3H). 19 H NMR (376.5 MHz, CDCl3) δ F -112.54.

[0346] Synthesis of A192 A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (1.13 g, 5.42 mmol) in THF (20 mL) was added dropwise with a solution of LDA (4.52 mL, 2 M in hexane, 9.04 mmol) at -70 °C. After stirring for 30 minutes, 2-(1-bromoethyl)-1,3-difluorobenzene (1 g, 4.52 mmol) was added at -70 °C. The mixture was stirred at -70 °C for 1 hour. The mixture was warmed to 25 °C and stirred for 16 hours. Saturated aqueous NH4Cl solution (50 mL) was added, and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1~5 / 1) to obtain tert-butyl 4-cyano-4-(1-(2,6-difluorophenyl)ethyl)piperidine-1-carboxylate (1.2 g). 1 H NMR (400 MHz, CDCl3) δ H 7.25 - 7.20 (m, 1H), 6.96 - 6.84 (m, 2H), 4.26 - 4.03 (m, 2H), 3.40 - 3.31 (m, 1H), 3.13 - 2.88 (m, 2H), 2.12 - 2.01 (m, 1H), 1.71 (d, 1H), 1.61 (d, 3H), 1.44 (s, 11H). 191H NMR (376.5 MHz, CDCl3) δ F -104.4, -111.3

[0347] Synthesis of A193 To tert-butyl 4-cyano-4-(1-(2,6-difluorophenyl)ethyl)piperidine-1-carboxylate (600 mg, 1.71 mmol) was added HCl / dioxane (10 mL, 4 M, 40.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h under nitrogen. The mixture was concentrated to give 4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile hydrochloride (500 mg), which was used directly in the next step.

[0348] Synthesis of A194 A mixture of 2-(pyrimidin-4-yl)nicotinic acid (239 mg, 1.19 mmol), HATU (756 mg, 1.99 mmol), DIPEA (0.87 mL, 4.99 mmol), and 4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile hydrochloride (250 mg, 0.99 mmol) in DMF (2 mL) was stirred at 15 °C for 2 h. The mixture was filtered, concentrated, and purified by preparative HPLC (Phenomenex G emini-NX 80 * 30 mm * 3 um, conditions: water (10 mM NH4HCO3)-ACN, start B: 30, end B: 60, gradient time (min): 9, hold time at 100% B (min): 2) to give racemic-4-(1-(2,6-difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (150 mg, 34.7%), LCMS purity 91%, C 24 H 22 F2N5O [M+H] + The calculated value of MS ESI for was 434 and the measured value was 433. This was further purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um), conditions 0.1% NH3H2O IPA, start B 30, end B 30), (S)-4-(1-(2,6-Difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (20.6 mg, 68.8%) was obtained. 1 H NMR (400 MHz, CDCl3) δ H 9.23 (s, 0.3H), 8.90 - 8.80 (m, 1H), 8.78 - 8.71 (m, 1H), 8.57 - 8.47 (m, 0.7H), 8.33 - 8.13 (m, 1H), 7.71 - 7.60 (m, 1H), 7.49 - 7.41 (m, 1H), 7.41 - 7.28 (m, 1H), 7.08 - 6.85 (m, 2H), 4.98 - 4.65 (m, 1H), 3.70 - 2.97 (m, 4H), 2.42 - 2.18 (m, 0.5H), 2.03 - 1.73 (m, 2.5H), 1.69 - 1.59 (m, 4H). LCMS purity 99%, C 24 H 22 F2N5O [M + H] + The calculated value of MS ESI for C

[0349] (R)-4-(1-(2,6-Difluorophenyl)ethyl)-1-(2-(pyrimidin-4-yl)nicotinoyl)piperidine-4-carbonitrile (20.6 mg, 68.8%). 1 H NMR (400 MHz, CDCl3) δ H 9.23 (s, 0.3H), 8.90 - 8.81 (m, 1H), 8.78 - 8.71 (m, 1H), 8.51 (d, 0.7H), 8.30 - 8.16 (m, 1H), 7.68 - 7.60 (m, 1H), 7.50 - 7.42 (m, 1H), 7.41 - 7.27 (m, 1H), 7.07 - 6.85 (m, 2H), 4.98 - 4.71 (m, 1H), 3.71 - 2.97 (m, 3H), 2.39 - 2.20 (m, 0.2H), 2.04 - 1.71 (m, 2.5H), 1.69 - 1.57 (m, 4H). LCMS purity 199%, C 24 H 22 F2N5O [M + H] + The calculated value of MS ESI for C

[0350] Example 65. Synthesis of (S)-1-([2,4'-bipyridine]-3-carbonyl)-4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile (A245) and (R)-1-([2,4'-bipyridine]-3-carbonyl)-4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile (A246)

Chemical formula

[0351] SFC purification of A195 Racemic-1-([2,4'-bipyridine]-3-carbonyl)-4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile (150 mg, 0.35 mmol) was further purified by SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm), conditions 0.1% NH3H2O IPA, starting B 50, ending B 50), (S)-1-([2,4'-Bipyridin]-3-carbonyl)-4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile (60.2 mg, 40.4%) was obtained. 1 H NMR (400 MHz, CDCl3) δ H 8.83 - 8.76 (m, 1H), 8.75 - 8.64 (m, 2H), 7.79 - 7.65 (m, 2.4H), 7.63 - 7.54 (m, 0.6H), 7.48 - 7.37 (m, 1H), 7.34 - 7.27 (m, 0.5H), 7.25 - 7.19 (m, 0.5H), 6.96 - 6.82 (m, 2H), 4.90 - 4.68 (m, 1H), 3.34 - 2.60 (m, 4H), 2.23 - 2.06 (m, 0.5H), 1.94 - 1.61 (m, 1H), 1.55 - 1.33 (m, 3H), 1.32 - 1.01 (m, 2H), 0.25 - 0.09 (m, 0.5H). LCMS purity 96%, C 25 H 23 F2N4O [M + H] + The calculated value of MS ESI for 433, the measured value is 433.

[0352] (R)-1-([2,4'-Bipyridin]-3-carbonyl)-4-(1-(2,6-difluorophenyl)ethyl)piperidine-4-carbonitrile (60.2 mg, 40.4%). 1 H NMR (400 MHz, CDCl3) δ H 8.82 - 8.76 (m, 1H), 8.75 - 8.64 (m, 2H), 7.79 - 7.64 (m, 2.4H), 7.63 - 7.54 (m, 0.6H), 7.49 - 7.38 (m, 1H), 7.35 - 7.27 (m, 0.5H), 7.25 - 7.20 (m, 0.5H), 6.97 - 6.82 (m, 2H), 4.88 - 4.61 (m, 1H), 3.36 - 2.66 (m, 4H), 2.22 - 2.09 (m, 0.5H), 1.94 - 1.64 (m, 1H), 1.49 - 1.35 (m, 3H), 1.33 - 1.03 (m, 2H), 0.22 - -0.07 (m, 0.5H). LCMS purity 100%, C 25 H 23 F2N4O [M + H] + The calculated value of MS ESI for 433, the ...

Claims

[Claim 1] The invention described in the specification.

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