EA042461B1 - COMPOUNDS, THEIR SALTS AND METHODS FOR THE TREATMENT OF DISEASES - Google Patents

Description

cross reference

This application claims priority over U.S. Provisional Application No. 62/548301, filed August 21, 2017, and Swedish Patent Application No. 1730225-8, filed August 24, 2017, the contents of which are incorporated herein in their entirety by reference. .

Technical field

Provided herein are compounds and pharmaceutically acceptable salts thereof for the treatment of diseases and conditions associated with the serotonin 5-HT receptor.

State of the art

Serotonin, or 5-hydroxytryptamine (5-HT), plays an important role in the functioning of the mammalian body. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator that is involved in such diverse behavioral patterns and body responses as sleep, eating, the ability to move, perceive pain, learn and remember, as well as sexual behavior, control of body temperature and blood pressure. pressure. In the spine, serotonin plays an important role in the control systems of afferent peripheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)). Peripheral functions of the cardiovascular and hematopoietic systems, as well as the gastrointestinal tract, are also attributed to 5-HT. 5-HT has been found to mediate various contractile, secretory, and electrophysiological effects, including contraction of vascular and other organ smooth muscle, and platelet aggregation. (Fuller, Biology of Serotonergic Transmission, 1982; Boullin, Serotonin In Mental Abnormalities 1:316 (1978); Barchas et al., Serotonin and Behavior, (1973)). The 5-HT2A subtype receptors (also referred to as a subclass) are widely but discretely expressed in the human brain, including many cortical, limbic, and forebrain regions, which are hypothesized to be involved in the modulation of higher cognitive and emotional functions. Receptors of this subtype are also expressed on the surface of mature platelets, where they partially mediate platelet aggregation, which is one of the initial steps in vascular thrombus formation. Given the wide distribution of serotonin in the body, it will be understandable that there is great interest in drugs that act on the serotonergic systems (Gershon et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena et al., J. Cardiovascular Pharmacol. 15 : Supp. 7 (1990)). Serotonin receptors belong to a large family of human genes that includes transmembrane proteins that function as transducers of intercellular communication. They exist on the surface of various cell types (including neurons and platelets), where, after activation by the endogenous serotonin ligand or externally administered drugs, they change their conformational structure and subsequently interact with downstream cell signaling mediators. Many of these receptors, including the 5-HT2A subclass, are G-protein coupled receptors (GPCRs), which signal through the activation of guanine nucleotide-binding proteins (G-proteins), resulting in the creation or inhibition of second messengers such as cyclic AMP, inositol phosphates and diacylglycerol. These second messengers then modulate the function of various intracellular enzymes, including kinases and ion channels, which ultimately affects cellular excitability and function.

At least 14 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7). Each subtype exhibits a unique distribution, preference for different ligands, and functional correlates.

Serotonin can be an important link in various pathological conditions, such as some psychiatric disorders (depression, aggressiveness, panic attacks, obsessive-compulsive syndrome, psychosis, schizophrenia, suicidal tendencies), some neurodegenerative disorders (Alzheimer's dementia, Parkinson's disease, Huntington's disease), anorexia , bulimia, alcoholism-related disorders, cerebrovascular accident and migraine (Meltzer, Neuropsychopharmacology, 21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev. , 14:35 (1990)).

Given the wide distribution of serotonin in the body and its role in numerous physiological and pathological processes, there is understandable great interest in drugs that act on the serotonergic systems (Gershon et al., The Peripheral Actions of 5Hydroxytryptamine, 246 (1989); Saxena et al., J Cardiovascular Pharmacol 15: Supp 7 (1990)).

At least 14 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7) that mediate the effects of serotonin. Each subtype exhibits a unique distribution, preference for different ligands, and functional correlates. Serotonin receptors belong to a large family of human genes that includes transmembrane proteins that function as transducers of intercellular communication. They exist on the surface of various cell types (including neurons and platelets), where, after activation by the endogenous serotonin ligand or externally administered drugs, they change their conformational structure and subsequently interact with downstream cell signaling mediators. Many of these receptors, including subclass 5

- 1 042461

HT2A are G-protein coupled receptors (GPCRs) that transmit signals through the activation of guanine nucleotide-binding proteins (G-proteins), which leads to the creation or inhibition of second messengers, such as cyclic AMP, inositol phosphates and diacylglycerol. These second messengers then modulate the function of various intracellular enzymes, including kinases and ion channels, which ultimately affects cellular excitability and function.

The 5-HT2A subtype receptors (also referred to as a subclass) are widely but discretely expressed in the human brain, including many cortical, limbic, and forebrain regions, which are hypothesized to be involved in the modulation of higher cognitive and emotional functions. Receptors of this subtype are also expressed on the surface of mature platelets, where they partially mediate platelet aggregation, which is one of the initial steps in vascular thrombus formation.

Antipsychotic drugs have been found to interact with a wide variety of neurotransmitter receptors in the central monoaminergic system, including dopaminergic, serotonergic, adrenergic, muscarinic, and histaminergic receptors. It is likely that the therapeutic effect and side effects of these drugs are mediated by individual receptor subtypes. The high degree of genetic and pharmacological homology between these receptor subtypes has hindered the development of selective receptor subtype compounds, as well as the determination of the normal physiological or pathophysiological role of any particular receptor subtype. Thus, there is a need to develop drugs that have a selective effect on certain classes and subclasses of neurotransmitter receptors of the monoaminergic system.

According to the generally accepted theory, the mechanism of action of antipsychotic drugs is the antagonism of dopamine D ₂ receptors. Unfortunately, it is likely that this dopamine D ₂ receptor antagonism also mediates extrapyramidal side effects, along with some additional adverse effects of antipsychotic drug use, such as worsening depressive symptoms, anhedonia, and cognitive impairment. 5-HT2A receptor antagonism is an additional molecular mechanism in antipsychotic drugs, possibly due to antagonism of increased signaling through the serotonergic systems. Thus, 5-HT2A antagonists are good candidates for the treatment of psychosis without the development of extrapyramidal side effects or other undesirable effects associated with blockade of dopamine D ₂ receptors.

Traditionally, GPCRs such as the 5-HT2A receptor have been assumed to exist in a quiescent state only if not activated by agonist binding (a drug that activates the receptor). It is now understood that many, if not most, monoamine GPCRs, including serotonin receptors, can exist in a partially activated state in the absence of their endogenous agonists. This increased basal activity (constitutive activity) can be inhibited by compounds called inverse agonists. Both agonists and inverse agonists have intrinsic activity at the receptor in that they alone can activate or inactivate these molecules, respectively. In contrast, classical or neutral antagonists compete against agonists and inverse agonists for receptor access, but they lack the inherent ability to inhibit increased basal or constitutive receptor responses. Therefore, there is a need for new compounds for the manufacture of antipsychotic drugs that target serotonin receptors.

The essence of the invention

This document provides compounds according to formula (I) ^R 3 I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m and n are independently integers selected from the group consisting of 0, 1, 2 and 3;

p and q are independently integers selected from the group consisting of 0, 1, 2, 3 and 4;

R2 is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, nitro, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C ₂ . ₆ alkenyl, unsubstituted or substituted C ₂ .balkenyloxy, unsubstituted or substituted alkynyl, unsubstituted or substituted C ₂ . ₆ alkynyloxy, unsubstituted or substituted M^alkoxy, unsubstituted or substituted

- 2 042461

C _3-6 cycloalkyl, unsubstituted or substituted with C ₃ . ₆ heteroalicyclyl containing one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen , oxygen and sulfur, cyclopropyloxy and cyclobutyloxy;

R _2a , R2b, R2c and R _2d are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, nitro, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _2-6 alkenyloxy, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C _2-6 alkynyloxy, unsubstituted or substituted C ₁ . ₈ alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, and also substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; or R2 and R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

where R _12a , R _12b , R _12c , R _13a , R _13b , R _14a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C ₁ . ₄ alkyl and C ₁ . ₄ alkoxy; Z1, Z2 and Z ₃ are independently selected from the group consisting of C, N, O and S; and where the dotted bond represents the optional unsaturation between the atoms forming the bond;

R ₃ is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted With ₆ . ₁₀ aryl, as well as substituted or unsubstituted C2-9heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur;

R4 _a , R _4b , R _5a and R _5b are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C ₁ . ₆ alkyl; where when m and n are 1, then R _4a , R4 _b , R _5a , R _5b are hydrogen;

R6 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted C ₁ . ₄ alkoxy; substituted or unsubstituted C ₆ . ₁₀ arila; or R6 and _R3 taken together with the piperidine ring and the carbon and nitrogen atoms to which they are attached form a heteroalicyclic ring system according to the following formulas:

where R6a is halogen and R6b is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted C ₁ . ₄ alkoxy, substituted or unsubstituted C ₆ . ₁₀ arila;

R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted alkoxy;

R ₈ is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C ₁ . ₄ alkyl, substituted or unsubstituted C ₂ . ₄ alkenyls, substituted or unsubstituted

- 3 042461 C _3-6 cycloalkyl, as well as substituted or unsubstituted alkoxy;

X is O or S;

where R1 and R _1d are fluorine and R _1a , R _1b and R _1c are hydrogen; and when said substituent is substituted, it means that one or more hydrogen atoms in said substituent may be substituted by group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl, C ₃ -C ₁₀ cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, arylalkyl, heteroarylalkyl, (heteroalicyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio , arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino; where alkoxy means -O-alkyl, acyl means hydrogen, alkyl, alkenyl, alkynyl or aryl, linked as substituents through a carbonyl group;

O-carboxy means -OC(=O)R,

C-amido means -C(=O)NR _A RB,

S-sulfonamido means -SO2NRARB,

N-amido means -N(R _A )C(=O)R,

N-sulfonamido means -N( _RA )SO ₂ R, amino means -NR2, ester means -C(=O)OR, sulfinyl means -S(=O)R, sulfonyl means -SO2R, where R, RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _8-12 cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, arylalkyl, or (heteroalicyclyl)alkyl; or R _A and RB may be combined to form heteroalicyclyl and heteroaryl; alkyl means C _1-20 alkyl; alkenyl means C _2-20 alkenyl; alkynyl means C _2-20 alkynyl; aryl means C _6-10 aryl; heteroaryl means C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; and heteroalicyclyl means 3-18-membered heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

Preferably, R2, R _2a , R _2b , R _2c , R _2d and R ₃ are independently selected from unsubstituted or substituted C _1-6 haloalkyl or unsubstituted or substituted C _1-6 hydroxyalkyl. It is also preferred that R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

where R _12a , R _12b , R _12c , R _13a , R _13b , R14a and R _14b are as defined in paragraph 1; and where the dotted bond represents the optional unsaturation between the atoms forming the bond.

Preferably, R2 is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _1-6 haloalkyl, unsubstituted or substituted C _1-6 hydroxyalkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _1-6 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; R2d is selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _1-6 haloalkyl, unsubstituted or substituted C _1-6 hydroxyalkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _1-6 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; and R2a, R2b and R2c are hydrogen.

It is also preferred that R2 is selected from the group consisting of halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _1-6 haloalkoxy , C _3-4 cycloalkyl,

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C _3-4 cycloalkyl-C _1-3 alkyl; and R _2a , R _2b , R2c and R _2d are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, O^haloalkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkyl-C _1-3 alkyl.

Preferably, the ring system formed by the substituents R2 and _R2b is of formula (III) and _R12a and _R12b are hydrogen or methyl and _R13a and _R13b are hydrogen or methyl.

Preferably, R _2a , R _2c , R _2d and R _2b , provided that R _2b does not form a ring system with R 2 , are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, methyl, -CD ₃ , methoxy , -OCD ₃ , -OCF ₃ and -CF ₃ . It is also preferred that R _2a , R _2c and R _2b are hydrogen and R _2d is hydrogen, fluorine or hydroxyl. It is also preferred that one of R _2a and R _2b is fluorine and the other is hydrogen, and R _2c and R _2d are hydrogen. It is also preferred that R2, provided that R2 does not form a ring system with R2b, is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-1yloxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methyl-butoxy, hexyloxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy, 4-methoxybutoxy, 2-hydroxyethoxy, 1,2-dihydroxyethyl, 2-hydroxy-2,3-dimethylbutoxy, -OCF ₃ and (1,3-difluoropropan-2-yl)oxy . Preferably, when R1 and R _1d are fluoro, R1a, R1b and R1c are hydrogen; R2 is selected from the group consisting of methoxy, ethoxy, npropoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, isobutoxy, mpem-butoxy, pentyloxy, 4-methyl-butoxy, hexyloxy, 4 -methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy, 4-methoxybutoxy, 2-hydroxyethoxy, 1 ,2-dihydroxyethyl, 2-hydroxy-2,3-dimethylbutoxy, -OCF3 and (1,3-difluoropropan-2-yl)oxy; and R2a, R2b, R _2c and R _2d are hydrogen; or R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following general formula:

where R _12a and R _12b are hydrogen or methyl, R _13a and R _13b are hydrogen or methyl, and R _2a , R _2c and R _2d are hydrogen. Also preferably, when R1 and R _1d are fluoro, R _1a , R _1b and R _1c are hydrogen; R2 is selected from the group consisting of ethoxy, isopropoxy, n-propoxy, allyloxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy and 2,2-difluoroethoxy, a R _2a , R _2b , R _2c and R _2d are hydrogen; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formula:

a R _2a , R _2c and R _2d are hydrogen.

Preferably, R ₂ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, t-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2difluoroethoxy; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2- dimethyl-2,3-dihydrobenzofuran-5-yl.

Preferably, the halogen is fluorine.

Preferably, R ₃ is selected from the group consisting of hydrogen, deuterium, hydroxyl, -OD, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted -(CH ₂ ) _s -C _3-6 cycloalkyl, substituted or unsubstituted -(CH ₂ ) _s -C _2-5 heteroalicyclyl containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted -(CH ₂ ) _s -C _2-5 heteroaryl containing at least one a heteroatom selected from nitrogen, oxygen and sulfur, as well as substituted or unsubstituted -(CH ₂ ) _s -C ₆ aryl, with each value of s selected from the group consisting of 0, 1, 2 and 3. Also preferably, when R ₃ selected from the group consisting of hydrogen, methyl, -CD3, ethyl, -CD2CD3, n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD3CD3, -(CR _9a R _9b ) _t C(=O)OR _9c and -( CH ₂ ) _t C(=O)NR _9a R _9b where R _9a , R _9b and R _9c independently represent hydrogen

- 5 042461 or C _1-4 alkyl, each value of t being selected from the group consisting of 0, 1, 2 and 3. It is also preferred that R3 is hydrogen or methyl.

Preferably R _4a , R _4b , R 5 _a and R 5 _b are independently hydrogen or methyl. It is also preferred that R _4a , R _4b and R 5 _a are hydrogen and R 5 _b is methyl or hydrogen. It is also preferred that R4 _a , R5 _a and R5 _b are hydrogen and R _4b is methyl or hydrogen. It is also preferred that R _4a , R _4b , R _5a and R _5b are hydrogen.

Preferably q is 0 or R6 is selected from halo and C _1-4 alkyl. It is also preferred that q is 1. It is also preferred that R6 is fluorine.

Preferably p is 0.

Preferably, R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, C _1-2 haloalkyl and C _1-2 haloalkoxy. It is also preferred that R ₈ is selected from the group consisting of hydrogen, -CF3, -CHF2, -CF2CF3 -OCF3, -OCF2CF3 and -OCHF2. It is also preferred that R ₈ is hydrogen.

Preferably X is O.

Preferably, m and n are independently selected from the group consisting of 0 and 1. It is also preferred that m is 1 and n is 0 or 1.

Preferably, R _4a , R _4b , R5 _a , R5 _b , R ₆ , R ₇ , R ₈ are each hydrogen; m and n are each 1; p and q are 0 or 1; X is O; and R3 is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, -CD2CD3, n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD3CD3, -(CR _9a R _9b ) _t C(=O)OR _9c and -(CH ₂ ) _t C(=O)NR _9a R _9b , where R _9a , R _9b and R _9c are independently hydrogen or C _1-4 lkyl, with each value of t selected from the group consisting of 0, 1, 2 and 3. It is also preferred that R _4a , R _4b , R _5a , R _5b , R ₆ , R ₇ , R ₈ are each hydrogen; m and n are each 1; p and q are 0; X is O; and R3 is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, -CD2CD3, n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD3CD3, -(CR _9a R _9b ) _t C(=O)OR _9c and -(CH ₂ ) _t C(=O)NR _9a R _9b , where R _9a , R _9b and R _9c independently represent hydrogen or C _1-4 alkyl, each value of t is selected from the group consisting of 0, 1, 2 and 3. More preferably R3 is methyl or hydrogen. More preferably, R ₂ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy and 2,2-difluoroethoxy; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2- dimethyl2,3-dihydrobenzofuran-5-yl.

Preferred compounds are compounds selected from the group consisting of

-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperide in-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl} urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperide in-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl} urea;

-[(2,4-difluorophenyl)methyl] -3 - [(2,2-d imethyl-2,3 -dihydro-1 -benzofuran-5 -yl)methyl] -1 -(1 methylpiperide in-4-yl ) urea;

-[(2,4-difluorophenyl)methyl]-3-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperide in-4-yl) urea;

-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxyphenyl)methyl]-1-(1-methylpiperide in-4yl)urea;

-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

- {[4-(tert-butoxy)phenyl] methyl } -1 - [(2,4-d ifluorophenyl)methyl] -1 - (1 -methylpiperidin-4-6 042461 yl) urea;

-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea;

-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-d-iflorphenyl)methyl]-3-[(3-methyl-1H-indol-5-yl)methyl]-1-(1-methylpiperide in-4 yl)urea;

- [(2,4-d-iflorphenyl)methyl]-3-[(2-methyl-1,3-benzoxazol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea;

- [(2,4-d ifluorophenyl)methyl] -3 -[(1 -methyl-2,3 -dihydro-1 H-indol-5 -yl)methyl] -1 - (1 methylpiperidin-4-yl)urea ;

- [(2,4-d-iflorphenyl)methyl]-3-[(3-methyl-1,2-benzoxazol-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea;

- [(2,4-d iflorphenyl)methyl] -3 - [(1,2-dimethyl-1 H-indol-5 -yl) methyl] -1 - (1 methylpiperidin-4-yl) urea;

3-[(4-cyclopropoxyphenyl)methyl]-1-[1-(2,4-difluorophenyl)ethyl]-1-(1-methylpiperide in4-yl)urea;

- [(2,4-d iflorphenyl)methyl] -3 - (1 -methylpiperidin-4-yl) -1 - [(quinolin-6yl)methyl] urea;

1-[(2,4-difluorophenyl)methyl]-3-[(3-methyl-1,2-benzoxazol-5-yl)methyl]-1-(1methylpiperidin-4-yl)urea;

-[(1,3-benzoxazol-6-yl)methyl]-1-[(2,4-d-iflorphenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(1,3-benzoxazol-5-yl)methyl]-1-[(2,4-d-iflorphenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-d-iflorphenyl)methyl]-3-[(1-methyl-1H-indol-5-yl)methyl]-1-(1-methylpiperide in-4 yl)urea;

-[(2,4-difluorophenyl)methyl]-1 -[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl] 3 -(1-methylpiperidin-4-yl ) urea;

3-[(2,4-difluorophenyl)methyl]-1-[(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran7-yl)methyl]-3-(1-methylpiperidine -4-yl)urea;

- [(2,4-d-iflorphenyl)methyl]-1-[(2,2-dimethyl-2H-chromen-7-yl)methyl]-3-(1-methylpiperidin-4-yl)urea;

- 7 042461

-[(2,4-d-iflorphenyl)methyl]-3-[(1-methyl-1H-indazol-6-yl)methyl]-1-(1-methylpiperide in 4-yl)urea;

-[(2,4-d-iflorphenyl)methyl]-3-[(2-methyl-1H-indol-5-yl)methyl]-1-(1-methylpiperide in-4yl)urea;

1-[(2,4-difluorophenyl)methyl]-3-[(1,1-dioxo-2,3-dihydro-1X ⁶ -benzothiophen-5-yl)methyl]-

-(1-methylpiperidin-4-yl)ureas;

- [(2,4-d iflorphenyl)methyl] -3 - [(2,3 -dihydro-1 H-ind en-5 -yl) methyl] -1 - (1 methylpiperidin-4-yl) urea;

- [(1,3-benzothiazol-6-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

- [(2,4-d ifluorophenyl)methyl] -3 -[(1,3 -dimethyl-2-oxo-2,3 -dihydro-1 Η-1,3 -benzodiazol-5 yl)methyl] -1 - (1-methylpiperidin-4-yl)ureas;

- [(2,4-d iflorphenyl)methyl]-3-[(2H-indazol-6-yl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-d-iflophenyl)methyl]-3-[(3-methyl-2H-indazol-5-yl)methyl]-1-(1-methylpiperide in 4-yl)urea;

- [(2,4-d ifluorophenyl)methyl] -3 -[(4- {[2-( ^2H3 )methyl(1,1,1,3,3,3 - ^2H6 )propan-2yl]oxy} phenyl)methyl]-1-(1-methylpiperidin-4-yl)urea;

-[(4-cycle opoxyphenyl)methyl]-1-[(1R)-1-(2,4-difluorophenyl)ethyl]-1-(1-methylpiperidin-4-yl)urea;

- [(3-cyano-4-methoxyphenyl)methyl] -1 - [(2,4-d iftorophenyl)methyl] -1 - (1 -methylpiperidin4-yl)urea;

- [(2,4-d-iflorphenyl)methyl]-1-[(4-fluorophenyl)methyl]-3-(1-methylpiperidin-4yl)urea;

3-[(2-chloro-4-methoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin4-yl)urea;

- [(2,4-d ifluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl] -1 (1-methylpiperidin-4-yl) urea;

- [(2,4-d iflorphenyl)methyl] -3 - {[4-methoxy-2-(trifluoromethyl)phenyl]methyl} -1 -(1-methylpiperidin-4-yl)ureas;

- [(2,4-d iflorphenyl)methyl] -1 - [(2-fluoro-4-nitrophenyl) methyl] -3 - (1 -methylpiperidin-4yl) urea;

- 8 042461

-[(2,4-d-iflorphenyl)methyl]-3-[(1-methyl-1 Η-1,3-benzodiazol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea;

- [(2,4-d-iflorphenyl)methyl]-3-[(1-methyl-1 H-indazol-5-yl)methyl]-1-(1-methylpiperidin4-yl)urea;

1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)methyl]-1(1-methylpiperidin-4-yl) urea;

1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)methyl]-1(1-methylpiperidin-4-yl) urea;

1-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1-(piperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-( ^2H3 )methoxyphenyl]methyl}-1-(1- _{methylpiperidin} -4yl)urea;

1-[(2,4-difluorophenyl)methyl]-3-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl}-1-(1methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl] -1 -{1 -[(1,1,1,3,3,3 - ² H ₆ )propan-2-yl]piperidin-4-yl} -3 - {[4(propan-2-yloxy)phenyl]methyl} urea;

-[(2,4-difluorophenyl)methyl]-1-(piper idin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl} urea;

1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea;

-[(1 Η-1,3-benzodiazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea;

l-[(7R,8aS)-oκtahydroindolizin-7-yl]-3-[(4-cyclopropopoκcφenyl)methyl]-l-[(2,4difluorophenyl)methyl]urea;

1-[(7K,8a8)-octahydroindolizin-7-yl]-1-[(2,4-difluorophenyl)methyl]-3-{[4-(propan-2yloxy)phenyl]methyl}urea;

1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea;

-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(quinoxalin-6yl)methyl]urea;

3-[(2,4-diφτopφenyl)methyl]-3-[(lR,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octaan-3-yl]-l-{[4(propane -2-yloxy)phenyl] methyl } urea;

-[(2,4-difluorophenyl)methyl]-1-[(3R,4S)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2yloxy)phenyl]methyl} urea;

-[(2,4-difluorophenyl)methyl] -1 -[(3 S,4R)-1,3-dimethylpiperidin-4-yl]-3 - {[4-(propan-2-9 042461 yloxy)phenyl] methyl } urea;

-[(2,4-difluorophenyl)methyl]-1-(1,4-dimethylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl} urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-(2-hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-({ 3-fluoro-4-[(2-hydroxyethoxy)methyl]phenyl } methyl)-1-(1-methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(1H-indazol-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-({4-[(1R)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea;

1-[(2,4-difluorophenyl)methyl]-3-({4-[(18)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(1,3-d ihydro-2-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-(3-methoxypropoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro-4-nitrophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(4-chloro-3-methoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-fluoro-2-(trifluoromethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea;

3-[(2,4-difluorophenyl)methyl]-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[2-methyl-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea;

-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]urea;

-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]urea;

-[(2,4-difluorophenyl)methyl]-3-[(3-fluoro-4-methoxyphenyl)methyl]-1-(1-methylpiperid in-4 yl)urea;

- 10 042461

-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro-4-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4 yl)urea;

-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)-1-[(4phenoxyphenyl)methyl]urea;

3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea;

-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1-(piperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-ethoxyphenyl)methyl]-3-(piperidin-4-yl)urea;

-[(2H-1,3-benzode ioxol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperide in4-yl)urea;

-[(2,4-difluorophenyl)methyl] -1 - [ 1 -( ² H ₃ )methyl piper idin-4-yl] -3 - {[4-(propan-2yloxy)phenyl] methyl } urea;

-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4propoxyphenyl)methyl]urea;

- {[4-(cyclopropylmethoxy)phenyl] methyl } -1 - [(2,4-difluorophenyl)methyl] -1 -(1 methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[3-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[2-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[3-methyl-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(4-fluoro-3-methoxyphenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-({4-[(2-ethylhexyl)oxy]phenyl}methyl)-1-(1-methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl] -1 -(1 -methylpiperide in-4-yl)-3 - {[4-(prop-2-in-1 yloxy)phenyl]methyl} urea;

- {[4-(tert-butoxy)phenyl] methyl } -1 - [(2,4-d ifluorophenyl)methyl] -1 - (piper idin-4- 11 042461 yl) urea;

1-[(2,6-difluoro-4-methoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(1methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl}-3-(1-methylpiperidin4-yl)urea;

- {[4-(1,1-d iftoroethyl)phenyl] methyl } -3 -[(2,4-difluorophenyl)methyl] -3 -(1 -methylpiperide in-4 yl)urea;

-[(2,4-difluorophenyl)methyl]-1-({4-[(1,3-difluoropropan-2-yl)oxy]phenyl} methyl)-3-(1methylpiperidin-4-yl)urea ;

- {[4-(2,2-d iflorethoxy)phenyl] methyl } -1 - [(2,4-difluorophenyl)methyl] -1 - (1 methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4yl)urea;

1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1(piperidin-4-yl)urea and

-[(2,4-difluorophenyl)methyl] -3 - {[2,3 -dihydro (2,2,3,3 - ² H ₄ )-1 -benzofuran-5-yl] methyl } -1 -(1 methylpiperidin-4-yl)urea.

More preferred compounds are those selected from the group consisting of 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea;

-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4propoxyphenyl)methyl]urea;

- {[4-(cyclopropylmethoxy)phenyl] methyl} -1 - [(2,4-difluorophenyl)methyl] -1 - (1 methylpiperidin-4-yl)urea;

1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4yl)urea;

- {[4-(2,2-d iflorethoxy)phenyl] methyl } -1 - [(2,4-difluorophenyl)methyl] -1 - (1 methylpiperidin-4-yl)urea;

- 12 042461

- {[4-(tert-butoxy)phenyl] methyl (-1 - [(2,4-d ifluorophenyl)methyl] -1 - (piperidin-4yl) urea;

-(4-(allyloxy)benzyl)-1-(2,4-d iflobenzyl)-1-(1-methylpiperidin-4-yl)urea;

-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl (-1-(1-methylpiperide in-4yl)urea;

3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperide in-4yl)urea;

-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperide in-4-yl)urea;

-[(2,4-difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl (-3-(1-methylpiperidin4-yl)urea;

- {[4-(tert-butoxy)phenyl] methyl} -1 - [(2,4-d iftorophenyl)methyl] -1 - (1 -methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl] -3 - [(2,2-d imethyl-2,3 -dihydro-1 -benzofuran-5 -yl)methyl] -1 -(1 methylpiperide in-4-yl ) urea;

-[(2,4-difluorophenyl)methyl] -1 -(piper idin-4-yl)-3 - {[4-(propan-2yloxy)phenyl]methyl ( ureas;

-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxyphenyl)methyl]-1-(1-methylpiperide in-4yl)urea;

-[(2,4-difluorophenyl)methyl] -1 -(1-methylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl (ureas and

-[(2,4-difluorophenyl)methyl] -1 -(1-methylpiperidin-4-yl)-3 -{[4-(2methyl propoxy)phenyl]methyl (ureas.

More preferred compounds are those selected from the group consisting of 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea;

-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4propoxyphenyl)methyl]urea;

- {[4-(cyclopropylmethoxy)phenyl]methyl (-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperide in-4-yl)urea;

1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4yl)urea;

-(4-(allyloxy)benzyl)-1-(2,4-d iflobenzyl)-1-(1-methylpiperidin-4-yl)urea;

-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea;

-[(2,4-difluorophenyl)methyl] -1 -(piper idin-4-yl)-3 - {[4-(propan-2yloxy)phenyl]methyl (ureas and

-[(2,4-difluorophenyl)methyl] -1 -(1-methylpiperidin-4-yl)-3 -{[4-(propan-2yloxy)phenyl]methyl (ureas.

A preferred compound is 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4yl)-3-[(4-propoxyphenyl)methyl]urea, or a pharmaceutically acceptable salt or stereoisomer thereof.

A preferred compound is 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea, or a pharmaceutically acceptable salt or stereoisomer thereof.

- 13 042461

A preferred compound is 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt or stereoisomer thereof.

A preferred compound is 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4difluorophenyl)methyl]-3-(piperidin-4-yl)urea, or a pharmaceutically acceptable salt or stereoisomer thereof.

A preferred compound is 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1(1-methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt or stereoisomer thereof.

A preferred compound is 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt or stereoisomer thereof.

A preferred compound is 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea or a pharmaceutically acceptable salt or stereoisomer thereof .

A preferred compound is 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea or a pharmaceutically an acceptable salt or stereoisomer.

The present invention provides a method of treating a serotonin 5-HT2A receptor related disease or condition in a patient, comprising administering to the patient an effective amount of any of the above compounds of the invention, or a pharmaceutically acceptable salt or stereoisomer thereof. Preferably, there is provided a method of treating a disease or condition, wherein the disease or condition is selected from the group consisting of Parkinson's disease psychosis, Parkinson's disease hallucinations, and Parkinson's disease delusions.

The present invention provides the use of any of the above compounds of the invention, or a pharmaceutically acceptable salt or stereoisomer thereof, for the treatment of a disease or condition associated with the 5-HT2A serotonin receptor. Preferably, the proposed use for the treatment of a disease or condition, where the disease or condition is selected from the group consisting of psychosis in Parkinson's disease, hallucinations associated with Parkinson's disease, and delusions associated with Parkinson's disease.

Detailed Description of the Invention

Definitions.

Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by a person skilled in the art. All patents, applications, published applications, and other publications referenced in this document are incorporated by reference in their entirety. Where there is more than one definition of a term mentioned in this document, the definition provided in this section should govern, unless otherwise noted.

In the context of this document, all R groups, including, without limitation, R1, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R7, R8 and R ₉ are substituents that can be attached to the specified atom . A non-limiting list of R groups includes, but is not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. If two R groups are covalently bonded to the same atom or to adjacent atoms, then they may be taken together or combined, as defined herein, to form a cycloalkyl, aryl, heteroaryl, or heteroalicyclyl group. For example, but without limitation, if R _a and R _b from the group NR _a R _b are indicated as taken together or combined, this means that they are covalently bonded to each other at the terminal atoms to form a ring that contains nitrogen _R ^a —nC '

R ^b .

As will be appreciated by one of skill in the art, any given unsaturated valency atom described in the text, formulas, diagrams, examples, and figures herein is intended to have a sufficient number of hydrogen atoms to saturate the valence.

In each case where a group is described as unsubstituted or substituted if it is substituted, the substituents (which may be present one or more times, such as 1, 2, 3 or 4 times) are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl , aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido . Whenever a group, such as an unsubstituted or substituted alkyl group, is described without using the terms unsubstituted or substituted, such as alkyl, this follows

- 14 042461 to be understood as unsubstituted alkyl, only if this document does not specifically indicate that such a group may carry substituents. For example, C _1-6 alkyl means unsubstituted alkyl containing from 1 to 6 carbon atoms.

When a substituent on a group is deemed to be substituted, the substituent itself is substituted by one or more of the substituents indicated. When said substituent is substituted, it means that one or more hydrogen atoms on said substituent may be substituted by group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl , heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido , Ssulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, as well as their protected derivatives. Protective groups that can form protected derivatives of the above substituents are well known to those skilled in the art and can be found in Greene and Wuts, Protective Groups in Organic Synthesis, ^3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety by reference. In the context of this document, the terms Cm to C _n , Cm-C _n or Cm- _n , where m and n are integers, denote the number of carbon atoms in the corresponding group. That is, the group may contain from m to n carbon atoms, inclusive. Thus, the term C ₁ -C ₆ -alkyl group refers to all alkyl groups having from 1 to 6 carbon atoms, ie. CH3-, CH3CH2-, CH3CH2CH2-, (CHz) 2CH-, CH3CH2CH2CH2-, CH ₃ CH 2 CH (CH ₃ )-, CH3CH ( _CH ) CH2-, CH ₃ CH (CH) ₃ CH ₂ - and (CH ₃ ) ₃ C-. If the values of m and n are not given relative to the group, then the widest ranges described in these definitions are assumed.

As used herein, the term alkyl refers to a straight chain or branched hydrocarbon group that is fully saturated (no double or triple bonds). The alkyl group may have from 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as 1-20 refers to each whole number in that range, for example, 1 to 20 carbon atoms means that an alkyl group may consist of 1 carbon, 2 carbons, 3 carbons, etc., up to 20 carbons, although the present definition also covers the occurrence of the term alkyl when no numerical range is indicated). The alkyl group may also be a medium sized alkyl having 1 to 10 carbon atoms, such as C _1-6 . The alkyl group may also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be referred to as C ₁ -C ₄ alkyl, C _1-4 alkyl, or similar designations. By way of example only, the term C ₁ -C ₄ alkyl or C _1-4 alkyl indicates that one to four carbon atoms are present in the alkyl chain, i. the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Representative alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. When substituted, the substituent group(s) is(are) one or more groups individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo , alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, as well as their protected derivatives. In the context of this document, the term optionally, for example, optionally deuterated, means that the group may be unsubstituted or substituted with one or more of the indicated substituents, for example, one or more hydrogen atoms may be replaced with one or more deuterium atoms.

As used herein, the term alkenyl refers to an alkyl group that contains one or more double bonds in a straight or branched hydrocarbon chain. If more than one double bond is present, the double bonds may be conjugated or unconjugated. The alkenyl group may have from 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as 2 to 20 refers to each whole number in that range, for example, 2 to 20 carbon atoms means, that an alkenyl group may consist of 2 carbons, 3 carbons, 4 carbons, etc., up to 20 carbons, although the present definition also covers the occurrence of the term alkenyl when no numerical range is indicated). When substituted, the substituent group(s) is(are) one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl , hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy and amino, including mono- and disubstituted amino groups, as well as their protected derivatives.

- 15 042461

In the context of this document, the term alkynyl refers to an alkyl group that contains one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl group may have from 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as 2 to 20 refers to each whole number in that range, for example, 2 to 20 carbon atoms means, that an alkynyl group may be composed of 2 carbons, 3 carbons, 4 carbons, etc., up to 20 carbons, although the present definition also covers the occurrence of the term alkynyl when no numerical range is indicated). The alkynyl group may be unsubstituted or substituted. When substituted, the substituents may be selected from the groups described above with respect to the substitution of the alkenyl group. In the context of this document, the term hetero refers to heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.

As used herein, the term heteroalkyl, when used alone or in combination with another term, refers to a straight or branched chain alkyl group containing the number of carbon atoms indicated, with one or more carbon atoms, for example, 1, 2, 3 or 4 carbon atoms, and the associated hydrogen atoms have been independently replaced by similar or different heteroatoms selected from nitrogen, oxygen and sulfur. The carbon atoms to be replaced may be in the middle or at the end of the alkyl group. Examples of heteroalkyl include, but are not limited to, -S-alkyl, -O-alkyl, -NH-alkyl, -alkylene-O-alkyl, etc. As used herein, the term aryl refers to a carbocyclic (full carbon) ring or two or more articulated rings (rings that have two adjacent atoms) that have a fully delocalized pi electron system. Examples of aryl groups include, without limitation, benzene, naphthalene, and azulene. The aryl group may be substituted. Upon substitution, hydrogen atoms are replaced by substituent group(s) which(s) are one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, as well as their protected derivatives. When substituted, substituents on an aryl group may form a non-aromatic ring fused to an aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

In the context of this document, the term heteroaryl refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized pi-electron system) in which at least one of the atoms in the ring system is a heteroatom, i.e., an element other than carbon, including, without limitation, nitrogen, oxygen, and sulfur. Examples of monocyclic heteroaryl include, without limitation, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, oxadiazole, and triazine. Examples of polycyclic heteroaryl include, without limitation, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purines, benzofuran, benzothiophene, benzopyranones (eg, coumarin, chromone, and isocoumarin). Heteroaryl may be substituted. Upon substitution, hydrogen atoms are replaced by substituent group(s) which(s) are one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, as well as their protected derivatives. When substituted, substituents on a heteroaryl group may form a non-aromatic ring fused to an aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

Aralkyl or arylalkyl is an aryl group substituted with an alkylene group. The alkylene and aryl group of the aralkyl may be substituted. Examples include, without limitation, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some instances, the alkylene group is a lower alkylene group. Heteroaralkyl or heteroarylalkyl is a heteroaryl group substituted with an alkylene group. The alkylene and heteroaryl group of heteroaralkyl may be substituted. Examples include, without limitation, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, as well as their substituted and benzo-fused analogs. In some instances, the alkylene group is a lower alkylene group. Alkylene is a straight chain attachment group that forms bonds to connect molecular fragments via their terminal carbons. Alkylene can have from 1 to 20 carbon atoms. The alkylene may also be a medium sized alkylene having 1 to 10 carbon atoms, eg C1-b. Also, the alkylene may be a lower alkylene having 1 to 4 carbon atoms. Alkylene may be designated as C1- _C4 alkylene, _C1-4 alkylene, or similar designations. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) and butylene (-(CH ₂ ) ₄ -) groups. In the case of methylene, the two linked moieties are linked to the same carbon atom. The lower alkylene group may be substituted.

In the context of this document, the term heteroalkylene, when used alone or in combination with another term, refers to an alkylene group containing the specified number of carbon atoms, where one or more carbon atoms, for example, 1, 2, 3 or 4 carbon atoms, have been independently substituted with the same or distinct heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroalkylene include, without limitation -CH2-O-, -CH2-CH2-O-, -CH2- _CH2 -CH2- _O- , -CH2- _NH- , -CH2-CH2-NH-, -CH2-CH2 -CH2-NH-, -CH2-CH2-NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, -O-CH2CH2-O-CH2-CH2- and the like.

In the context of this document, the term alkylidene refers to a divalent group, such as =CR'R, which is attached to one carbon atom of another group, forming a double bond. Alkylidene groups include, without limitation, methylidene (=CH ₂ ) and ethylidene (=CHCH ₃ ). As used herein, the term arylalkylidene refers to an alkylidene group in which R' or R'' is an aryl group. The alkylidene group may be substituted. In the context of this document, the term alkoxy refers to the group -OR, where R is alkyl, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy , tert-amox and the like. Alkoxy may be substituted.

As used herein, the term alkylthio refers to the formula -SR, where R is alkyl as defined above, e.g. etc.

The alkylthio may be substituted.

In the context of this document, the terms aryloxy and arylthio refer to RO- and RS- where R is aryl as defined above, e.g. may be substituted.

As used herein, the term alkenyloxy refers to the formula -OR where R is alkenyl as defined above, eg vinyloxy, propenyloxy, n-butenyloxy, isobutenyloxy, sec-pentenyloxy, t-pentenyloxy, and the like. Alkenyloxy may be substituted.

As used herein, the term acyl refers to hydrogen, alkyl, alkenyl, alkynyl, or aryl substituted as substituents via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acrylic.

The acyl may be substituted.

As used herein, the term cycloalkyl refers to a fully saturated (no double bonds) mono- or polycyclic hydrocarbon ring system. When two or more rings are present, the rings may be joined together in a fused, bridged, or spiro ring system. Cycloalkyl groups may contain C ₃ to C ₁₀ , for example C ₃ to C ₆ . The cycloalkyl group may be unsubstituted or substituted. Exemplary cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. In the case of substitution, the substituent(s) may be alkyl or selected from the above with respect to substitution of the alkyl group, unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

In the context of this document, the term cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring, however, if there are more than one such bonds, they cannot form a fully delocalized system of pi electrons in the ring (otherwise the group will be aryl, as defined in this document). When two or more rings are present, the rings may be linked together in a fused, bridged, or spiro ring system. Cycloalkenyl groups may contain C ₃ to C ₁₀ , for example C ₃ to C ₈ or C ₅ to C ₁₀ . For example, C ₃ - ₈ cycloalkenyl includes C ₄ - ₈ cycloalkenyl, C _5-8 cycloalkenyl, or C ₆ . ₈ cycloalkenyl. The cycloalkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be aryl or be selected(s) from the groups described above with respect to substitution of an alkyl group, unless otherwise indicated. When substituted, substituents on the cycloalkenyl group may form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

As used herein, the term cycloalkynyl refers to a cycloalkyl group that contains one or more triple bonds in the ring. When two or more rings are present, the rings can be joined together in a fused, bridged, or spiro ring system. Cycloalkynyl groups may contain from C ₈ to C ₁₂ . The cycloalkynyl group can

- 17 042461 be unsubstituted or substituted. When substituted, the substituent(s) may be aryl or be selected(s) from the groups described above with respect to substitution of an alkyl group, unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to a cycloalkynyl group, including aryl and heteroaryl.

As used herein, heteroalicyclic or heteroalicyclyl refers to a 318-membered ring which is composed of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heteroalicyclic or heteroalicyclyl groups may contain C ₂ to C ₁₀ , in some embodiments, they may contain C ₂ to C ₉ , and in other embodiments, C 2 to C ₈ . The heteroalicyclic or heteroalicyclyl groups may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be linked together to form a fused, bridged, or spiro ring system; the nitrogen, carbon and sulfur atoms in the heteroalicyclic or heteroalicyclyl group may be oxidized; nitrogen can be quaternized; rings may also contain one or more double bonds, provided they do not form a completely delocalized pi-electron system throughout the rings, examples include 2Hbenzo[b][1,4]oxazin-3(4H)-one, 3,4- dihydroquinoline-2(III)-one, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3- dihydro-1H-benzo[d]imidazole, indoline, 1,3dihydro-2H-benzo[d]imidazol-2-one and benzo[d]oxazol-2(3H)-one. Heteroalicyclyl groups may be unsubstituted or substituted. When substituted, the substituents may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy , aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, as well as their protected derivatives. Examples of such heteroalicyclic or heteroalicyclyl groups include, without limitation, azepinyl, dioxalanyl, imidazolinyl, morpholinyl, oxetanyl, furanyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. When substituted, substituents on the heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, including aryl and heteroaryl.

The term fused bicyclic ring refers to a ring system in which two rings have two adjacent atoms. The two rings share the same covalent bond. An example of a fused bicyclic ring is decalin.

The term spirobicyclic ring refers to a bicyclic ring in which two rings share one atom.

The term bridged ring system refers to a ring system in which two rings share three or more atoms. The two atoms at the head of the bridge are separated by a bridge containing at least one atom. A specific example is norbornane, also known as bicyclo[2.2.1]heptane. The structure of bicyclo[2.2.1]heptane is shown below, where the atoms in the head of the bridge are also indicated atoms in the head of the bridge

(Cycloalkyl)alkyl is a cycloalkyl group substituted with an alkylene group. Alkylene and cycloalkyl in (cycloalkyl)alkyl may be substituted. Examples include, without limitation, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some instances, the alkylene group is a lower alkylene group.

(Cycloalkenyl)alkyl is a cycloalkenyl group substituted with an alkylene group. Alkylene and cycloalkenyl in (cycloalkenyl)alkyl may be substituted. In some instances, the alkylene group is a lower alkylene group.

(Cycloalkynyl)alkyl is a cycloalkynyl group substituted with an alkylene group. Alkylene and cycloalkynyl in (cycloalkynyl)alkyl may be substituted. In some instances, the alkylene group is a lower alkylene group.

In the context of this document, the term halogen or halo refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

As used herein, the term haloalkyl refers to an alkyl group in which

- 18 042461 one or more hydrogen atoms are replaced by a halogen atom.

Such groups include, without limitation, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1chloro-2-fluoromethyl, 2-fluoroisobutyl. The haloalkyl may be substituted.

As used herein, the term haloalkoxy refers to an RO group in which R is a haloalkyl group. Such groups include, without limitation, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-1-fluoromethoxy, 2-fluoroisobutoxy. The haloalkoxy may be substituted.

The term O-carboxy group refers to an RC(=O)O- group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined in this document. O-carboxy may be substituted.

The term C-carboxy group refers to a -C(=O)OR group in which R is as defined with respect to O-carboxy. C-carboxy may be substituted.

The term trihalomethanesulfonyl group refers to an X3CSO2 group in which X is halogen.

The dotted bond, , represents the optional unsaturation between the atoms that form the bond. Such a bond may be unsaturated (eg C=C, C=N, C=O) or saturated (eg C-C, C-N, C-O). If the bond indicated by the dotted line is present in the ring system, it may be part of an aromatic ring system.

The nitro group belongs to the -NO2 group.

The cyano group refers to the -CN group.

The cyanato group belongs to the -OCN group.

The isocyanato group refers to the -NCO group.

The thiocyanato group refers to the -SCN group.

The carbonyl group refers to the -C(=O)- group.

The thiocarbonyl group refers to the -C(=S)- group.

The oxo group belongs to the =O group.

The hydroxy group or hydroxyl group refers to the -OH group.

The isothiocyanato group refers to the -NCS group.

The term sulfinyl group refers to a -S(=O)-R group in which R is as defined with respect to O-carboxy. The sulfinyl may be substituted.

The term sulfonyl group refers to the SO2R group in which R is as defined with respect to O-carboxy. The sulfonyl may be substituted.

The term S-sulfonamido group refers to the -SO2NRARB group, in which RA and RB, independently of each other, may correspond to the definition with respect to the R group as defined for Ocarboxy, or may be combined to form a ring system selected from the group consisting of substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The S-sulfonamido may be substituted.

The term N-sulfonamido group refers to the group RSO2N(RA)-, in which R and RA independently of each other can be defined with respect to the R group as defined for Ocarboxy. The N-sulfonamido may be substituted.

The term trihalomethanesulfonamido group refers to the group X ₃ CSO ₂ N(R)-, in which X is halogen and R is as defined with respect to O-carboxy. The trihalomethanesulfonamido may be substituted.

The term C-amido group refers to a -C(=O)NRARB group in which RA and RB, independently of each other, may be defined with respect to an R group as defined for O-carboxy, or may be combined to form a ring a system selected from the group consisting of substituted or unsubstituted C ₃ _ ₈ cycloalkyl, substituted or unsubstituted C ₃ _ ₈ cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. C-amido may be substituted.

The term N-amido-group refers to the group RC(=O)NRA-, in which R and RA independently of each other can meet the definition in relation to the R-group, as defined for O-carboxy. Namido may be substituted.

The term ester refers to the group -C(=O)OR, in which R is as defined with respect to O-carboxy. The ester may be substituted.

Lower alkoxyalkyl refers to an alkoxy group linked via a lower alkylene group. The lower alkoxyalkyl may be substituted.

The term amine or amino refers to RNH2 (primary amine), R2NH (secondary amine), R ₃ N (tertiary amine). The amino group may be substituted.

Aminoalkyl refers to an amino group linked via a lower alkylene group. Aminoalkyl may be substituted.

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In the context of this document, 0 (zero), for example, in relation to a subscript letter, indicates its absence. For example, -(CH ₂ ) _s -C ₂ . ₆ alkyl, where S may be 0, means that the -(CH2)- group is absent, and the remaining group is -C ₂ _ ₆ alkyl.

Any unsubstituted or monosubstituted amino group on a compound of this document may be converted to an amide, any hydroxyl group may be converted to an ester, and any carboxyl group may be converted to an amide or ester using methods well known to those skilled in the art (see ., e.g., Greene and Wuts, Protective Groups in Organic Synthesis, ^3rd Ed., John Wiley & Sons, New York, NY, 1999).

Abbreviations used herein for any protecting groups, amino acids and other compounds, unless otherwise indicated, correspond to their common use, recognized abbreviations or the requirements of the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 11:942944 (1972)).

The following terms, which are used in this document, have a generally accepted meaning in the chemical literature.

EtOAc - ethyl acetate;

DIEA - N,N-diisopropylethylamine;

HCl - hydrochloric acid;

DMF - N,N-dimethylformamide;

THF - tetrahydrofuran;

CDCl ₃ - chloroform-d;

DMSO-dh dimethylsulfoxide-d6;

MgSO ₄ - magnesium sulfate;

POCl ₃ - phosphorus(V) oxychloride;

KOH - potassium hydroxide;

NaOH - sodium hydroxide;

Na ₂ SO ₄ - sodium sulfate;

K2CO3 - potassium carbonate;

Na ₂ CO ₃ - sodium carbonate;

TFA - trifluoroacetic acid;

Boc tert-butoxycarbonyl;

FMOC fluorenylmethyloxycarbonyl;

FMOC-Cl - 9-fluorenylmethoxycarbonyl chloride;

TEOS - 2-(trimethylsilyl)ethoxycarbonyl;

equiv. - equivalents;

min - minutes;

cat. - catalytic;

HCl - hydrochloric acid;

HPLC - high performance liquid chromatography.

It should be understood that in any compound described herein having one or more stereocenters or chiral centers, unless the absolute stereochemistry has been clearly stated, then each center may independently have the R-configuration, S-configuration, or mixtures thereof. Thus, the compounds provided herein may be enantiomerically pure or may be stereoisomeric mixtures. In addition, the compounds provided herein may be scalemic mixtures. In addition, it should be understood that in any compound having one or more double bonds forming geometric isomers that can be defined as E or Z, each double bond can independently be E or Z, or a mixture thereof. It is also intended that all tautomeric forms be included.

In the context of this document, the terms tautomer and tautomeric refer to alternative versions of the compounds described herein, which differ in the position of the proton. Non-limiting examples include keto-enol and imine-enamine tautomers or tautomeric forms of heteroaryl groups containing a ring atom attached to both the -NH- ring moiety and the ═N- ring moiety, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

It should be understood that isotopes may be present in the compounds described herein. Any chemical element present in the structure of a compound can contain any isotope of the specified element. For example, in the compound described herein, the hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. For example, the term methyl includes -CH ₃ , -CD ₃ , -CH2D, etc.

As used herein, the term pharmaceutically acceptable salt refers to a salt of a compound that does not alter the biological activity and properties of that compound. pharmaceuticals

- 20 042461 cal salts can be obtained by reacting a compound described herein with an acid or base. Salts obtained by reaction with a base include, without limitation, the ammonium salt (NH4+); alkali metal salts, for example, without limitation sodium or potassium; alkaline earth metal salts, for example without limitation calcium or magnesium; salts of organic bases, for example, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, Nmethyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; as well as salts with an amino group of amino acids, for example, without limitation, arginine and lysine. Useful acid-forming salts include, but are not limited to, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caprate, caproate, caprylate, camsylates, citrates, decanoates, formates, fumarates, gluconates, glutarate, glycolates, hexanoates, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates such as methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates and tosylates. Pharmaceutically acceptable solvates and hydrates are complexes of the compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

As used herein, the term prodrug refers to a compound that may not be pharmaceutically active, but which is converted to an active drug when administered in vivo. A prodrug may be designed to alter the metabolic stability or transport characteristics of the drug, mask side effects or toxicity, improve the palatability of the drug, or alter other characteristics or properties of the drug. Prodrugs are often useful because they are easier to administer than the parent drug. They may, for example, be orally bioavailable as opposed to the parent drug. The prodrug may also have a higher solubility than the parent drug in pharmaceutical compositions. A non-limiting example of a prodrug is a compound described herein that is administered as an ester (prodrug) to promote absorption across the cell membrane where water solubility is detrimental to motility, but which is then metabolically hydrolyzed to a carboxylic acid (the active ingredient ) upon entry into the cell, where water solubility is beneficial. An additional example of a prodrug would be a short peptide (polyamino acid) linked to an acid group, in which the peptide is metabolized in vivo to release the active parent compound. With knowledge of pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is known, those skilled in the art will be able to develop prodrugs of that compound (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press , New York, pages 388-392). A specific example of prodrugs relates to the formation of a nitrogenous base containing a piperidyl group of formula (I), in which the nitrogenous base can be formed by metabolic cleavage of the group attached to the nitrogen in the piperidyl group forming the nitrogenous base, for example, as shown in formula A. Specific examples are acyl and tosyl groups attached to nitrogen

The term anti-drug refers to a compound or composition that acts against prohibited drugs or their use. The compounds of the present application may act as anti-drugs.

In the context of the document, the term to modulate the activity of a receptor means either to activate it, i.e. increase its cellular function from its baseline measured in the specific environment in which it is located, or deactivate it, i.e. reduce its cellular function from baseline as measured in the particular environment in which it is present and/or render it unable to perform its cellular function at all even in the presence of a natural binding partner. The natural binding partner is an endogenous molecule that acts as an agonist for this receptor. The term agonist is defined as a compound that increases the basal activity of a receptor (ie signaling mediated by that receptor).

- 21 042461

As used herein, the term partial agonist refers to a compound that has affinity for a receptor but, unlike an agonist, exhibits only a partial degree of the pharmacological response normally associated with the receptor when bound to the receptor, even though a significant number of receptors are occupied by the compound.

The term inverse agonist is defined as a compound that reduces or suppresses the basal activity of the receptor such that the compound is not technically an antagonist, but rather an agonist with negative intrinsic activity. In the context of this document, the term antagonist refers to a compound that binds to a receptor to form a complex that does not produce any responses, as if the receptor was unoccupied. The antagonist reduces the effect of the agonist on the receptor. An antagonist may bind reversibly or irreversibly, effectively abolishing receptor activity permanently, or at least before the antagonist is metabolized, dissociated, or otherwise removed by a physical or biological process. In the context of this document, the term subject refers to an animal that is being treated, observed or experimented. The term animal includes cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, crustaceans, reptiles, and in particular mammals. The term mammal includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates such as monkeys, chimpanzees, higher primates and, in particular, humans.

In the context of this document, the term patient refers to a subject who is being treated with the assistance of a medical professional, such as a physician or veterinarian, in an attempt to cure or at least alleviate the effects of a particular disease or disorder, or in an attempt to primarily prevent the occurrence of such a disease, or violations. As used herein, the term carrier refers to a compound that facilitates the introduction of the compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a widely used carrier that facilitates the entry of many organic compounds into the cells or tissues of a subject.

In the context of this document, the term diluent refers to an ingredient of a pharmaceutical composition that does not have pharmacological activity, but may be necessary or desirable from a pharmaceutical point of view. For example, a diluent may be used to bulk up an effective drug that is too small to be manufactured or administered. Also, the diluent may be a liquid for dissolving the drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is an aqueous buffer solution, such as, but not limited to, phosphate-buffered saline, which mimics the composition of human blood.

In the context of this document, the term excipient refers to an inert substance that is added to a pharmaceutical composition to impart to the composition, among other things, mass, uniformity, stability, binding ability, lubricity, disintegration ability, etc. A diluent is a kind of excipient. The term receptor is intended to include any molecule that is present within or on the surface of a cell and can affect cellular physiology if inhibited or stimulated by a ligand. Typically, the receptor contains an extracellular ligand-binding domain, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding (signaling). The receptor also includes any intracellular molecule that generates a signal in response to ligation. A receptor also includes any molecule that has a structure characteristic of the receptor, but without an identifiable ligand. In addition, the receptor includes a truncated, modified, mutated receptor, or any molecule containing part or all of the receptor sequence.

The term ligand is intended to include any substance that interacts with a receptor.

The terms selectivity or selectivity are defined as the ability of a compound to generate a desired response to a particular type, subtype, class, or subclass of receptors while substantially eliciting a response from other types of receptors. The terms selectivity or selectivity with respect to one or more specific subtypes of a compound means the ability of a compound to increase the activity of subtypes while slightly increasing the activity of other subtypes or not increasing such activity at all. The selectivity of a compound between target receptors can, for example, be determined by the ratio of the degrees of activity or affinity for those targets. For example, a compound will have 10-fold selectivity for Target 1 over Target 2 if said compound has a pKi value of 10 nM for Target 1 and 100 nM for Target 2. Thus, said compound will be 10-fold more effective at against Target 1, i.e. its selectivity for Target 1 will be 10 times higher. In the context of this document, the term IC ₅₀ refers to the amount, concentration or dose of a specific test compound,

- 22 042461 at which 50% inhibition of the maximum response is achieved. IC ₅₀ can be determined by analysis. The assay may be an R-SAT® assay as described herein, but is not limited thereto.

In the context of this document, the term EC ₅₀ refers to the amount, concentration, or dose of a particular test compound that elicits a dose-dependent response at 50% of the maximum expression level for a particular response that is induced, provoked, or stimulated by a particular test compound, in an assay that measures such response, for example, without limitation, during the R-SAT® assay as described herein. As used herein, the term pKi refers to the negative logarithm of Ki, the equilibrium dissociation constant of an antagonist-receptor complex, as measured by antagonist functional assay or radioligand assay, eg, R-SAT® assay, as described herein. As used herein, the term co-administration of pharmacologically active compounds refers to the delivery of two or more separate chemical entities in vitro or in vivo. Co-administration means the simultaneous delivery of separate agents; simultaneous delivery of a mixture of agents; and delivery of one agent followed by delivery of a second agent or additional agents. Co-administered agents are generally designed to act in combination with each other.

As used herein, the term "effective amount" means that amount of an active compound or pharmaceutical agent that elicits a biological or drug response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other professional, and which includes alleviating or alleviating symptoms of the disease being treated.

As used herein, the term prevent/prevent should not be taken to mean that the condition and/or disease will not recur after use of a compound or pharmaceutical composition according to the embodiments described herein to provide prevention. Moreover, this term should also not be taken to mean that the condition will not occur, at least to some extent, after such use in order to prevent said condition. Rather, the term prevent/avoid means that the condition to be prevented, if reoccurring despite such use, will be less severe than without such use. Compounds This document provides compounds according to formula (I) ^R 3 I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m and n are independently integers selected from the group consisting of 0, 1, 2 and 3; p and q are independently integers selected from the group consisting of 0, 1, 2, 3 and 4; R1 and R _1d are fluorine and R _1a , R _1b and R _1c are hydrogen;

R ₂ is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, nitro, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkenyloxy, unsubstituted or substituted alkynyl, unsubstituted or substituted alkynyloxy, unsubstituted or substituted C _1-8 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur, cyclopropyloxy and cyclobutyloxy; R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, nitro, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkenyloxy, unsubstituted or substituted alkynyl, unsubstituted or substituted alkynyloxy, unsubstituted or substituted C _1-8 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur, a substituted or unsubstituted C _6-10 aryl, and a substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; or R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

- 23 042461

where R _12a , R _12b , R _12c , R _13a , R _13b , R _14a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C ₁ . ₄ alkyl and C ₁ . ₄ alkoxy; Z1, Z2 and Z ₃ are independently selected from the group consisting of C, N, O and S; and where the dotted-line bond ----- represents the optional unsaturation between the atoms forming this bond;

R ₃ is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted with C ₂ . ₆ alkenyl, unsubstituted or substituted with C ₃ . ₆ cycloalkyl, unsubstituted or substituted with C ₃ . ₆ heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted With ₆ . ₁₀ aryl, as well as substituted or unsubstituted C ₂ .9heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur.

R4 _a , R _4b , R _5a and R _5b are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C ₁ . ₆ alkyl; where when m and n are 1, then R _4a , R 4 _b , R _5a , R _5b are hydrogen.

R ₆ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted C ₁ . ₄ alkoxy; substituted or unsubstituted C ₆ . ₁₀ arila; or R6 and _R3 taken together with the piperidine ring and the carbon and nitrogen atoms to which they are attached form a heteroalicyclic ring system according to the following formulas:

where R _6a is halogen and R _6b is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted C ₁ . ₄ alkoxy, substituted or unsubstituted C ₆ . ₁₀ arila;

R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted alkoxy;

R8 is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C1. ₄ alkyl, substituted or unsubstituted C ₂ . ₄ alkenyl, substituted or unsubstituted C ₃ . ₆ cycloalkyl, as well as substituted or unsubstituted alkoxy;

X is O or S; and when said substituent is substituted, it means that one or more hydrogen atoms in said substituent may be substituted by group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl, C ₃ -C ₁₀ cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, arylalkyl, heteroarylalkyl, (heteroalicyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio , arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino; where alkoxy means -O-alkyl, acyl means hydrogen, alkyl, alkenyl, alkynyl or aryl, linked as substituents through a carbonyl group;

O-carboxy means -OC(=O)R,

C-amido means -C(=O)NR _A RB,

S-sulfonamido means -SO2NRARB,

N-amido means -N(R _A )C(=O)R,

N-sulfonamido means -N(R _A )SO ₂ R, amino means -NR ₂ , ester means -C(=O)OR,

- 24 042461 sulfinyl means -S(=O)R, sulfonyl means -SO2R, where R, R _a and RB independently of each other represent hydrogen, alkyl, alkenyl, alkynyl, C ₃₁₀ cycloalkyl, C _3-10 cycloalkenyl, C ₈ . ₁₂ cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, arylalkyl, or (heteroalicyclyl)alkyl; or R _A and RB may be combined to form heteroalicyclyl and heteroaryl;

alkyl means C1. ₂₀ alkyl;

alkenyl means C ₂ . ₂₀ alkenyl;

alkynyl means C ₂ . ₂₀ alkynyl;

aryl means C ₆ . ₁₀ aryl;

heteroaryl means C ₂ .9heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; and heteroalicyclyl means 3-18-membered heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

This document also provides compounds according to formula (I):

R ₃ I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m and n are independently integers selected from the group consisting of 0, 1, 2 and 3; p and q are independently integers selected from the group consisting of 0, 1, 2, 3 and 4; R1 and R _1d are fluorine and R _1a , R _1b and R _1c are hydrogen;

R2 is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted with C ₂ . ₆ alkenyl, unsubstituted or substituted with C ₁ . ₆ alkoxy, unsubstituted or substituted C ₃ . ₆ cycloalkyl, unsubstituted or substituted with C ₃ . ₆ heteroalicyclyl, substituted or unsubstituted C ₆ . ₁₀ aryl, as well as substituted or unsubstituted C ₂ .9heteroaryl; R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted with C ₂ . ₆ alkenyl, unsubstituted or substituted with C ₁ . ₆ alkoxy, unsubstituted or substituted C ₃ . ₆ cycloalkyl, unsubstituted or substituted with C ₃ . ₆ heteroalicyclyl, substituted or unsubstituted C ₆ . ₁₀ aryl, as well as substituted or unsubstituted C ₂ .9heteroaryl; or R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

where R _12a , R _12b , R _12c , R _13a , R _13b , R _14a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C ₁ . ₄ alkyl and C ₁ . ₄ alkoxy; Z1, Z ₂ and Z ₃ are independently selected from the group consisting of C, N, O and S; and where the dotted bond represents the optional unsaturation between the atoms forming the bond;

R ₃ is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted with C ₂ . ₆ alkenyl, unsubstituted or substituted with C ₃ . ₆ cycloalkyl, unsubstituted or substituted with C ₃ . ₆ heteroalicyclyl, substituted or unsubstituted C ₆ . ₁₀ aryl, as well as substituted or unsubstituted C ₂ .9heteroaryl;

R4 _a , R _4b , R _5a and R _5b are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C ₁ . ₆ alkyl; where when m and n are 1, then R _4a , R 4 _b , R _5a , R _5b are hydrogen;

R ₆ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C ₁ . ₄ alkyl, as well as substituted or unsubstituted C ₁ . ₄ alkoxy, substitute

- 25 042461 pure or unsubstituted C _6-10 aryl;

R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted C _1-4 alkoxy;

R ₈ is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted C _1-4 alkoxy;

X is O or S.

This document also provides compounds according to formula (I)

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m and n are independently integers selected from the group consisting of 0, 1, 2 and 3; p and q are independently integers selected from the group consisting of 0, 1, 2, 3 and 4; R1 and R _1d are fluorine;

R2 is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted alkenyloxy, unsubstituted or substituted C _1-6 alkoxy, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C3-6 heteroalicyclyl, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl;

R2d is selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _1-6 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl; or R _2a , R _2c and R _2d are hydrogen and R 2 and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

where R _12a , R _12b , R _12c , R1 _3a , R _13b , R14a and R14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl and C _1-4 alkoxy; Z1, Z2 and Z ₃ are independently selected from the group consisting of C, N, O and S; and where the dotted bond represents the optional unsaturation between the atoms forming the bond;

or R _1a , R _1b , R _1c , R _2a , R _2b and R _2c are hydrogen;

R ₃ is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl, substituted or unsubstituted C _{6 -10} aryl, as well as substituted or unsubstituted C _2-9 heteroaryl;

R4 _a , R _4b , R5 _a and R5 _b are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C _1-6 alkyl; where when m and n are 1, then R _4a , R 4 _b , R 5 _a , R 5 _b are hydrogen;

R ₆ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted C _1-4 alkoxy; substituted or unsubstituted C _6-10 aryl; or R6 and _R3 taken together with the piperidine ring and the carbon and nitrogen atoms to which they are attached form a heteroalicyclic ring system according to the following formulas:

- 26 042461

where R _6a is halogen and R _6b is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted C _1-4 alkoxy , substituted or unsubstituted C _6-10 aryl;

R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted C _1-4 alkoxy;

R ₈ is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted O _1-4 alkoxy;

X is O or S.

This document also provides compounds according to formula (I)

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

m and n are independently integers selected from the group consisting of 0, 1, 2 and 3;

p and q are independently integers selected from the group consisting of 0, 1, 2, 3 and 4;

R ₁ and R _1d are fluorine;

_R2 is selected from the group consisting of deuterium, amino, -OD, halo, cyano, unsubstituted or substituted _C1-6 alkyl, unsubstituted or substituted _C1-6 haloalkyl, unsubstituted or substituted _C1-6 hydroxyalkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted alkenyloxy, unsubstituted or substituted C _1-6 alkoxy, unsubstituted or substituted

C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; where R2 is not benzyloxy;

R _2d is selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted € _1-6 alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted C _1-6 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl;

and R _1a , R _1b , R _1c , R _2a , R _2b and R _2c are hydrogen;

or R _2a , R _2c and R _2d are hydrogen and R 2 and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

where R _12a , R _12b , R _12c , R _13a , R _13b , R _14a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl and C _1-4 alkoxy; Z1, Z2 and Z3 are independently selected from the group consisting of C, N, O and S; and where the dotted bond represents the optional unsaturation between the atoms forming the bond;

R3 is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl, substituted or unsubstituted C _6-10 aryl, as well as substituted or unsubstituted C _2-9 heteroaryl;

R4 _a , R _4b , R5 _a and R5 _b are independently selected from the group consisting of hydrogen, deuterium, and

- 27 042461 substituted or substituted C _1-6 alkyl; where when m and n are 1, then R _4a , R 4 _b , R 5 _a , R 5 _b are hydrogen;

R6 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted C _6-10 aryl ;

R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted C _1-4 alkoxu;

R ₈ is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted C _1-4 alkoxy;

X is O or S.

In some embodiments, R2 is selected from the group consisting of halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkyl -C _1-3 alkyl and their deuterated analogs; R _2a , R _2b , R _2c and R2d are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkyl-C _1-3 alkyl and their deuterated analogs, or R _2a , R _2c and R 2d are hydrogen and R 2 and R _2b taken together with the phenyl ring to which they are attached, and the atoms to which they are attached form a bicyclic fused ring system having the following formulas:

^Z 3 ^-R 12b ^R 12a (VII), where R _12a , R _12b , R _12c , R _13a , R _13b , R _14a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl and C _1-4 alkoxy; Z1, Z2 and Z ₃ are independently selected from the group consisting of C, N, O and S; and where the dotted bond represents the optional unsaturation between the atoms forming the bond; for example R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, methyl, -CD ₃ , methoxy, -OCD ₃ , -OCF ₃ and -CF ₃ ; and R2 is selected from halo, amino, methyl, _-CD3 , ethyl, -CD2CD3, optionally deuterated n-propyl, optionally deuterated isopropyl, optionally deuterated n-butyl, optionally deuterated isobutyl, optionally deuterated n-pentyl, optionally deuterated 2-methyl -butyl, optionally deuterated n-hexyl, optionally deuterated 2-methyl-pentyl, optionally deuterated methoxy, optionally deuterated ethoxy, optionally deuterated n-propoxy, optionally deuterated isopropoxy, optionally deuterated allyloxy, optionally deuterated prop-2yn-1-yloxy, optionally deuterated n-butoxy, optionally deuterated isobutoxy, optionally deuterated tert-butoxy, optionally deuterated pentyloxy, optionally deuterated 4-methylbutoxy, optionally deuterated hexyloxy, optionally deuterated 4-methylpentoxy, optionally deuterated deuterated cyclopropyloxy, optionally deuterated cyclopropylmethoxy, optionally deuterated cyclopropylethoxy, optionally deuterated cyclobutyloxy, optionally deuterated cyclobutyloxy, optionally deuterated cyclobutylmethoxy, optionally deuterated cyclobutylethoxy, optionally deuterated C _1-6 haloalkoxy, -OCF ₃ , -OCF2CF3, -OCHF2, -OCDF2, -CF ₃ , -CF ₂ CF ₃ , -CH2F, -CF2CH3, -CDF2 -CH2CF3, -CD2CF3, -CF2, 1,1,2,2-tetrafluorobutyl and 1,1,1,2,2-pentafluorobutyl. In some embodiments, R2 is not a nitro group.

In some embodiments, R2 is selected from the group consisting of halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkyl -C _1-3 alkyl and their deuterated analogs; R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-4 cycloalkyl, C _3-4 cycloalkyl-C _1-3 alkyl and their deuterated analogs, or R _2a , R _2c and R _2d are hydrogen and R ₂ and R _2b taken together with the phenyl ring to which they are attached, and the atoms to which they are attached form a bicyclic fused ring system having the following general formula:

- 28 042461

Rl3b R. _o ^K 12a ₍ w _{) or}

Rl3b RlSa/R^a

GG ^R 12b

2a (iv), where R _12a , R _12b , R _13a , R _13b , Ri4a and Ri4b are independently absent or selected from the group consisting of halogen, hydroxyl, cyano, C _1-4 alkyl and C _1-4 alkoxy; for example, R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, methyl, -CD3, methoxy, -OCD ₃ , -OCF ₃ and -CF3; and R2 is selected from halo, methyl, -CD3, ethyl, -CD2CD3, optionally deuterated npropyl, optionally deuterated isopropyl, optionally deuterated n-butyl, optionally deuterated isobutyl, optionally deuterated n-pentyl, optionally deuterated 2-methyl-butyl, optionally deuterated n-hexyl, optionally deuterated 2-methyl-pentyl, optionally deuterated methoxy, optionally deuterated ethoxy, optionally deuterated n-propoxy, optionally deuterated isopropoxy, optionally deuterated allyloxy, optionally deuterated prop-2-yn-1-yloxy, optionally deuterated n- butoxy, optionally deuterated isobutoxy, optionally deuterated tert-butoxy, optionally deuterated pentyloxy, optionally deuterated 4-methylbutoxy, optionally deuterated hexyloxy, optionally deuterated 4-methylpentoxy, optionally deuterated deuterated cyclopropylmethoxy, optionally deuterated cyclopropylethoxy, optionally deuterated cyclobutyloxy, optionally deuterated cyclobutyloxy, optionally deuterated cyclobutylmethoxy, optionally deuterated cyclobutylethoxy, optionally deuterated C1-6 haloalkoxy, -OCF3, -OCF2CF3, -OCHF2, -OCDF2, -CF3, -CF2CF3 , -CH2F, -CH2CF3, -CDF2 -CH2CF3, -CD2CF3, -CF2, 1,1,2,2-tetrafluorobutyl and 1,1,1,2,2-pentafluorobutyl R2 is not a nitro group.

In some embodiments, R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system selected from the group consisting of

wherein R _12a , R _12b , R _13a , R _13b , R _14a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl and C _1-4 alkoxy. In some embodiments, the ring system formed between R2 and R _2b is a ring of formula (III), R _12a and R _12b are hydrogen or methyl, and R _13a and R _13b are hydrogen or methyl. In some embodiments, R _2a , R _2b , R _2c are hydrogen, R _2d is hydrogen, fluorine, or hydroxyl, and R 2 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentyloxy, 4-methylbutoxy, hexyloxy and 4-methylpentoxy.

In some embodiments, R2, provided that R2 does not form a ring system with R _2b , is selected from the group consisting of -OCD3, -OC(CD ₃ ) ₃ , methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2 -in-1-yloxy n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methyl-butoxy, hexyloxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-fluoroethoxy, 3fluoropropoxy, 2,2-difluoroethoxy, 4-methoxybutoxy, 2-hydroxyletoxy, 1,2-dihydroxyethyl, 2hydroxy-2,3-dimethylbutoxy, phenoxy, -OCF ₃ and (1 ,3-difluoropropan-2-yl)oxy.

In some embodiments, R ₂ , provided that R ₂ does not form a ring system with R _2b , is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-in-1yloxy n-butoxy, isobutoxy , tert-butoxy, pentyloxy, 4-methyl-butoxy, hexyloxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, -OCF ₃ and (1,3-difluoropropan-2yl)oxy.

R ₂ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2- dimethyl-2,3-dihydrobenzofuran-5-yl.

- 29 042461

In some embodiments, R2 and R2d are independently selected from the group consisting of deuterium, halogen, methyl, -CD3, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentyloxy, 4-methyl-butoxy, hexyloxy , 4-methylpentoxy, -OCD3, -OCF3, cyclopropyloxy, 2-fluoroethoxy, 3fluoropropoxy, 2,2-difluoroethoxy and -CF ₃ .

In some embodiments, R2 is C _1-6 alkoxy, eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentyloxy, 4-methyl-butoxy, hexyloxy, and 4methylpentoxy. In some embodiments, R ₂ is n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropylmethoxy, or cyclopropyloxy.

In some embodiments, R2, provided R2 does not form a ring system with _R2b , is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-1yloxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methyl-butoxy, hexyloxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy, 4-methoxybutoxy, 2-hydroxyethoxy, 1,2-dihydroxyethyl, -OCF3 and (1,3-difluoropropan-2-yl)oxy; and R _2a , R _2b , R _2c and R _2d are hydrogen; or R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following general formula:

where R _12a and R _12b are hydrogen or methyl, R _13a and R _13b are hydrogen or methyl, and R _2a , R _2c and R _2d are hydrogen.

In some embodiments, R2 is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, t-butoxy, n-butoxy, isobutoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and 2,2-difluoroethoxy, a R _2a , R _2b , R _2c and R _2d are hydrogen; or R2 and R2b, taken together with the atoms to which they are attached, form a heteroalicyclic ring system, the ring system formed, taken together with the phenyl group to which it is fused, has the following formula:

a R _2a , R _2c and R _2d are hydrogen.

In some embodiments, R2 is selected from the group consisting of n-propoxy, isopropoxy, isobutoxy, and cyclopropyloxy.

In some embodiments, R ₃ is selected from hydrogen, deuterium, hydroxyl, -OD, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkoxy, substituted or unsubstituted -(CH ₂ ) _s -C _3-6 cycloalkyl , substituted or unsubstituted -(CH ₂ ) _s -C _2-5 heteroalicyclyl, substituted or unsubstituted -(CH ₂ ) _s -C _2-5 heteroaryl, and substituted or unsubstituted -(CH ₂ ) _s -C ₆ aryl, and each value of s is selected from 0, 1,2 and 3. R ₃ , for example, can be hydrogen, methyl, -CD ₃ , ethyl, -CD ₂ CD ₃ , n-propyl, -CD ₂ CD ₂ CD ₃ , isopropyl , -CDCD ₃ CD ₃ , -(CR _9a R _9b ) _t C(=O)OR _9c and -(CH ₂ ) _t C(=O)NR _9a R _9b , where R _9a , R _9b and R _9c are independently selected hydrogen and C _1-4 alkyl, each value of t being selected from the group consisting of 0, 1, 2 and 3.

In some embodiments, R3 is hydrogen or methyl.

In some embodiments, R2 is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, t-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2-dimethyl- 2,3-dihydrobenzofuran-5-yl and R ₃ is hydrogen or methyl.

In some embodiments, R3 is taken together with R6 that is attached to a carbon atom adjacent to a nitrogen atom to form a heteroalicyclic ring system according to the following formulae:

The resulting heteroalicyclic ring system may optionally contain additional substituents R _6b and/or R ₇ as shown above. In some embodiments, R4 _a , R4 _b ,

- 30 042461

R5 _a and R5 _b are independently selected from the group consisting of hydrogen, methyl and -CF3, eg R4 _a , R4 _b and R5 _a are hydrogen and R5 _b is methyl or hydrogen; or R _4a , R 5 _a and R 5 _b are hydrogen and R 4 _b is methyl or hydrogen. In some embodiments, R4 _a , R4 _b , R5 _a and R5 _b are independently selected from the group consisting of hydrogen, methyl and -CF3, e.g. R4 _a , R4 _b and R5 _a are hydrogen and R5 _b is methyl, -CF3 or hydrogen; or R4 _a , R5 _a and R5 _b are hydrogen and R4 _b is methyl, -CF3 or hydrogen. In some embodiments, R4 _a , R4 _b , R5 _a and R5 _b are hydrogen.

In some embodiments, R ₆ is absent (for example, when unsaturation is present or q is 0) or is selected from the group consisting of hydrogen, deuterium _{, halogen, hydroxyl, -OD, substituted or unsubstituted C 1_4 alkyl} , and substituted or unsubstituted C ₁ _ ₄ alkoxy, for example deuterium, halogen, methyl and methoxy.

In some embodiments, R ₆ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, -OD, substituted or unsubstituted C ₁ _ ₄ αkyl, and substituted or unsubstituted C ₁ _ ₄ alkoxy, e.g., deuterium, halogen, methyl and methoxy.

In some embodiments, R ₆ is fluorine, aq is 1.

In some embodiments, R ₇ is absent (eg, when p is 0 or unsaturation is present) or is selected from hydrogen, deuterium, halogen, and substituted or unsubstituted C _{1_4} alkyl, such as hydrogen, _fluorine , and methyl.

Therefore, in some embodiments, p is equal to 0.

In some embodiments, R8 is selected from the group consisting of hydrogen, halo, methyl, ethyl, propyl, methoxy, ethoxy, C _{1 -2} haloalkyl, and C1-2 haloalkoxy, e.g., hydrogen, -CF ₃ , -CHF2, - CF2CF3, -OCF3, -OCF2CF3 and -OCHF2.

In some embodiments, X is O.

In some embodiments, m and n are independently selected from the group consisting of 0 and 1, for example, m is 1 and n is 0 or 1.

Some embodiments relate to compounds according to formula (IIa or IIb)

or their pharmaceutically acceptable salt or stereoisomer, where m is 1;

n is 0 or 1;

R1 and R _1d are both fluorine;

R2 is unsubstituted or substituted C ₁ _ ₆ αlkoxy such as methoxy, ethoxy, npropoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methyl-butoxy , hexyloxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, -OCF3 and (1,3-difluoropropan-2-yl)oxy;

R2d is hydrogen;

R ₃ is hydrogen, methyl or ethyl;

t is 0 or 1; and when t is 1, R _6a is a halogen such as fluorine.

In some embodiments of formula (IIa) or (IIb), R ₃ is methyl.

In some embodiments of formula (IIa) or (IIb), R ₂ is ethoxy, npropoxy, isopropoxy, allyloxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, isobutoxy, and 2-fluoroethoxy, or R ₂ is comprised of a ring and taken together with a phenyl ring , to which it is attached, and with the atoms to which it is attached, forms a bicyclic fused ring system having the following formula:

- 31 042461

In some embodiments, the compound is 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea ; 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-(4-(tert-butoxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 1-(2,4-difluorobenzyl)-3-(4-ethoxybenzyl)-1-(1-methylpiperidin-4-yl)urea; 3-(4-cyclopropoxybenzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 1-(2,4-difluorobenzyl)-3-(4-(2fluoroethoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea; 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; or 3-(benzofuran-5-ylmethyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea.

In some embodiments, the compound is 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 1-[(2,4-difluorophenyl)methyl]-1-(1methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea; 3-{[4-(2,2-difluoroethoxy)phenyl]methyl } 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-{[4-(tert-butoxy)phenyl]methyl}-1[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea; 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)1-(1-methylpiperidin-4-yl)urea; 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1methylpiperidin-4-yl)urea; 3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl}-3(1-methylpiperidin-4-yl)urea; 3-{[4-(tert-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxyphenyl)methyl]1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4(propan-2-yloxy)phenyl]methyl}urea and 1-[(2,4 -difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3{[4-(2-methylpropoxy)phenyl]methyl}urea.

In some embodiments, R4 _a , R4 _b , R _5a , R5 _b , R6, R7, R ₈ are each hydrogen; m and n are each 1, and p and q are each 0 or 1; X is O; a R ₃ is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, -CD2CD3, n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD3CD3, -(CR _9a R _9b )tC(=O)OR _9c and -(CH ₂ )tC(=O)NR _9a R _9b , where R _9a , R _9b and R _9c independently represent hydrogen or Ci-4-alkyl, and each value of t is selected from the group consisting of 0, 1, 2 and 3.

In some embodiments, R4 _a , R4 _b , R _5a , R _5b , R6, R7, R ₈ are each hydrogen; m and n are each 1, and p and q are each 0; X is O; a R ₃ is hydrogen or methyl.

In some embodiments, R _4a , R _4b , R _5a , R _5b , R6, R7, R ₈ , if present, are each hydrogen; m and n are each 1, and p and q are each 0; X is O; a R3 is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, -CD2CD3, n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD3CD3, -(CR9aR9b)tC(=O)OR9c and -(CH2)tC (=O)NR9aR9b, where R _9a , R _9b and R _9c independently represent hydrogen or C ₁ . ₄ -alkyl, and each value of t is selected from the group consisting of 0, 1, 2 and 3.

In some embodiments, R4 _a , R4 _b , R _5a , R _5b , R6, R7, R ₈ , if present, are each hydrogen; m and n are each 1, and p and q are each 0; X is O; a R ₃ is hydrogen or methyl.

In some embodiments, R _4a , R _4b , R _5a , R _5b , R6, R7, R ₈ , if present, are each hydrogen; m and n are each 1, and p and q are each 0; X is O; a R ₃ is hydrogen or methyl; a R ₂ is selected from the group consisting of ethoxy, npropoxy, isopropoxy, allyloxy, isobutoxy, t-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy and 2,2-difluoroethoxy; or R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2-dimethyl-2 ,3dihydrobenzofuran-5-yl.

In some embodiments, R4 _a , R4 _b , R _5a , R _5b , R6, R7, R ₈ , if present, are each hydrogen; m and n are each 1, and p and q are each 0; X is O; a R3 is hydrogen or methyl; a R2 is selected from the group consisting of ethoxy, npropoxy, isopropoxy, allyloxy, isobutoxy, t-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy and 2,2-difluoroethoxy; or R2 and _R2b taken together with the phenyl ring, to

- 32 042461 to which they are attached, and the atoms to which they are attached, form unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl. Some embodiments relate to compounds according to formula (Va) or (Vb)

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ₂ is selected from the group consisting of substituted or unsubstituted C _1-6 alkoxy; R ₃ is hydrogen or methyl, and R _12a and R _12b are the same and are selected from hydrogen or methyl.

In some embodiments of formula (Va), R ₂ is ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and 2,2-difluoroethoxy.

In some embodiments of formula (Va), R ₂ is n-propoxy, isopropoxy, isobutoxy, and cyclopropyloxy.

In some embodiments of formula (Vb), the bicyclic ring system is selected from the following formulas:

(Sha), (shb) and (shc).

In certain embodiments, a compound provided herein exhibits a % hERG inhibition of less than 65%. In some embodiments, the % inhibition of hERG is less than 50%. In certain embodiments, a compound provided herein exhibits a % hERG inhibition of less than 40%, such as less than 30%.

In certain embodiments, a compound provided herein exhibits a % hERG inhibition of less than 65% and a pKi value for 5-HT2A of 8.4 or greater. In some embodiments, the % inhibition of hERG is less than 50%. In certain embodiments, a compound provided herein exhibits a % hERG inhibition of less than 40%, such as less than 30%, and a pKi value for 5-HT2A of 8.4 or greater.

Compounds according to formulas (I) and (II) described herein, their pharmaceutically acceptable salts, polymorphs or stereoisomers can be used in a method of treating a disease associated with the serotonin 5-HT2 receptor in a patient, and the disease can be selected from group consisting of hormonal disorders, Alzheimer's disease, dementia in Alzheimer's disease, psychosis in Alzheimer's disease, addiction (alcohol, cocaine, methamphetamine, nicotine or opioid), Addison's disease, ADHD, psychosis in Alzheimer's disease, affective disorders, aggressiveness, anxiety agitation, akathisia, alcoholism, alcohol withdrawal, amenorrhea, amyotrophic lateral sclerosis, anhedonia, anorexia, anti-NMDA receptor encephalitis, anxiety disorder, appetite disorders, asthma, autism, behavioral disorders, behavioral disorders associated with dementia, compulsive overeating associated with impulse disorder control disorder (RIC), bipolar disorder, blindness, borderline personality disorder, borderline personality disorder, bradykinesia, bulimia, RIC-related shopping addict, cardiac arrhythmia, acute cerebrovascular accident, Charles Bonnet syndrome, chemotherapy-induced vomiting, childhood autism, chronic pain, chronic insomnia, cocaine addiction, cognitive impairment, craniofacial pain, temporomandibular joint (TMJ) dysfunction/disease, Cushing's disease, delusions, dementia, dementia with Lewy bodies, dementia and psychosis associated with Creutzfeldt-Jakob disease (CJD), Gerstmann-Streussler-Scheinker syndrome (HSS) and fatal family insomnia (FFI), depression, diabetes mellitus (non-insulin dependent), diabetic peripheral neuropathy, drug abuse, diplopia, Down's syndrome, dyskinesia, dysthymia, dystonia, ejaculation disorders , emphysema, epilepsy, extrapyramidal race tridis, fibromyalgia, frailty, Friedreich's ataxia, frontotemporal dementia, RIC-related gambling, galactorrhea, generalized anxiety disorder, glaucoma, hair loss or thinning, hallucinations, headache, hemorrhoids, Huntington's disease, hyperprolactinemia, hypertension, hypersexuality associated with RIC, hypotension, hypoglutamatergic disorders, impulse control disorder, idiopathic thrombocytopenic purpura

- 33 042461 erythema, impotence, incontinence, increased intraocular pressure, infertility, inflammatory pain, insomnia, coronary disease, ischemic stroke, Lewy body disease (BTL), learning disabilities, decreased libido, loss of libido, low male fertility, low sperm motility, lupus, Machado-Joseph disease, major depressive episode, mania, menopausal symptoms, metabolic syndrome, methamphetamine addiction, migraine, mild cognitive impairment (MCI), motor tics, multi-infarct dementia, multiple sclerosis, multiple developmental disorders, myocardial infarction , myoclonus, neuropathic pain, neurodegenerative disorder, neuropsychiatric disease, nicotine addiction, non-motor symptoms in Parkinson's disease selected from dementia, depression, apathy, hallucinations, increased salivation (sialorrhea), constipation, pain, urogenital problems and sleep disorders, obsessive comp Pulse syndrome, on-off phenomenon, opioid addiction, osteoporosis, pancreatitis, panic attacks, Parkinson's disease, dementia in Parkinson's disease, psychosis in Parkinson's disease, periodic limb movement syndrome during sleep (PLMS), peripheral vascular disease, pituitary tumor, postherpetic neuralgia , progressive supranuclear palsy, prion infection including Creutzfeldt-Jakob disease (CJD), Gerstmann-Streussler-Scheinker syndrome (HSS) and fatal familial insomnia (FFI), prolactinomas, affective lability, psychomotor retardation, psychosis, psychosis caused by neurodegenerative disorders, psychosomatic disorders, psychotic depression, post-traumatic stress disorder (PTSD), Raynaud's disease, sympathetic reflex dystrophy, restless leg syndrome, retinopathy, schizoaffective disorder, schizophrenia, negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia, sepsis CVD, serotonin syndrome, sexual dysfunction, antidepressant-related sexual dysfunction, sleep apnea, sleep disturbances, sleep maintenance insomnia, social anxiety disorder, spinal injury, spinocerebellar atrophy, suicidal tendencies, thrombosis, thrombotic stroke, thrombocytopenic thrombohaemolytic purpura, ringing in the ears, fatigue, Tourette syndrome, transient insomnia, traumatic brain injury, treatment-resistant depression, treatment-resistant schizophrenia, tremor, vaginal dryness, vasospasm, wakefulness, vascular dementia, hallucinations associated with Parkinson's disease, delusions associated with Parkinson's disease ; cancer, brain cancer, glioma, pancreatic cancer, decreased sex drive, type 2 diabetes in adulthood with Parkinson's disease or dementia and liver fibrosis. Suitable routes of administration of the compounds of formula (I) may, for example, include oral, rectal, transmucosal, topical or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransfer) patches, and the like, for prolonged and/or time-controlled, pulsed administration at a given rate.

Pharmaceutical compositions of the present invention may be prepared in a manner known per se, for example by conventional mixing, dissolving, granulating, drageeing, elutriating, emulsifying, encapsulating, entrapping or tableting processes. Pharmaceutical compositions for use in accordance with the present invention may thus be prepared by conventional methods using one or more physiologically acceptable carriers, including excipients which aid in the processing of the active compounds into formulations that can be used pharmaceutically.

A suitable dosage form depends on the chosen route of administration. Any of the well known methods, carriers and excipients may be used as appropriate and as known in the art, eg Remington's Pharmaceutical Sciences supra.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers, which are well known in the art. Such carriers make it possible to prepare the compounds of the present invention in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. for ingestion by the patient to be treated.

Examples

Unless otherwise noted, starting materials were obtained from commercial suppliers such as (but not limited to) Chemtronica, Merck (Sigma-Aldrich), Fluorochem, Fisher, Bepharm, Broadpharm, Larodan, Activate Scientific, and Enamine. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian spectrometer at 400 MHz and 25°C. Chemical shifts are reported in ppm (δ) using residual solvent as an internal standard. Peak multiplicity is expressed as: s, singlet; e, doublet; t, triplet; square, quartet; n, pentet; d, heptet; m, multiplet; shir.s, wide

- 34 042461 singlet or combinations thereof, including without limitation dd, doublet of doublets and dt, double triplet. LCMS was obtained using an Agilent 1100 HPLC system in combination with an Agilent MSD mass spectrometer operating in ESI (+) ionization mode. Column: Waters symmetry C18 2.1x30mm or Chromolith RP18 2x50mm. Solvent A: water + 0.1% TFA, solvent B: acetonitrile + 0.1% TFA. Wavelength: 254 nm.

Preparative HPLC was obtained using a Gilson system. Flow rate: 10 ml/min. Column: kromasil 100-5-C18. Wavelength: 220 nm. Solvent A: water + 0.1% TFA, solvent B: acetonitrile + 0.1% TFA. Gradient: 40 to 95% B in 15 min.

The following are examples of abbreviations used:

EtOAc - ethyl acetate;

DIEA - N,N-diisopropylethylamine;

HCl - hydrochloric acid;

DMF - N,N-dimethylformamide;

THF - tetrahydrofuran;

CDCl ₃ - chloroform-d;

DMSO-66 - dimethylsulfoxide-b6;

MgSO ₄ - magnesium sulfate;

POCl ₃ - phosphorus (U) oxychloride;

KOH - potassium hydroxide;

NaOH - sodium hydroxide;

Na ₂ SO ₄ - sodium sulfate;

K ₂ CO ₃ - potassium carbonate;

Na ₂ CO ₃ - sodium carbonate;

TFA - trifluoroacetic acid;

Boc - tert-butoxycarbonyl;

FMOC - fluorenylmethyloxycarbonyl;

FMOC-Cl - 9-fluorenylmethoxycarbonyl chloride;

TEOS - 2-(trimethylsilyl)ethoxycarbonyl;

equiv. - equivalents;

min - minutes;

cat. - catalytic;

HCl - hydrochloric acid;

HPLC - high performance liquid chromatography.

Preparation of starting materials and intermediate compounds.

Intermediate 1: 2-[4-(2-methylpropoxy)phenyl]acetyl chloride

Thionyl chloride (21.6 ml, 298 mmol) was added to 2-[4-(2-methylpropoxy)phenyl]acetic acid (6.21 g, 29.8 mmol) in dichloromethane (29.8 ml). The mixture was stirred at ambient temperature for 18 hours and then concentrated to give the title compound (6.77 g, 100%).

Intermediate 2: 2-[4-(propan-2-yloxy)phenyl]acetyl chloride

The compound was prepared by analogy with 2-[4-(2-methylpropoxy)phenyl]acetyl chloride using 2-[4(propan-2-yloxy)phenyl]acetic acid.

Intermediate 3: 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene

2-[4-(2-Methylpropoxy)phenyl]acetyl chloride (6.12 g, 27 mmol) was dissolved in acetone (8 ml) and the resulting solution was added over 10 min to sodium azide (2.46 g, 37.8 mmol ) in water (8 ml). After stirring for an additional 1 hour, the mixture was diluted with water and extracted with toluene (3x25 ml). The organic phase was dried using sodium sulfate and filtered. The filtrate was carefully concentrated to about 25 ml. The mixture was stirred at 65° C. for 20 min and then concentrated to give the title compound (5.41 g, 98%).

- 35 042461

Intermediate 4: 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene

The compound was prepared by analogy with 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene using 2-[4-(propan-2-yloxy)phenyl]acetyl chloride.

Intermediate 5: N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine

4-Fluorobenzylamine (80.8 mmol, 10.4 g) was dissolved in ethanol (80 ml) and N-methyl-4-piperidone (80.8 mmol, 9.43 g) was added. Sodium triacetoxyborohydride (161.6 mmol, 35.4 g) was added in portions and the mixture was stirred at room temperature for 4 h. Sodium hydroxide (aqueous solution, 5 M) was added until pH > 13 was reached and the resulting mixture was stirred for 1 h, and then partitioned between diethyl ether and water. The organic phase was collected and the aqueous phase was re-extracted with diethyl ether. The combined organic phases were dried and evaporated to give the desired intermediate as a yellow oil (17.48 g, 97%).

Intermediate 6: N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine

2,4-Difluorobenzylamine (4.0 g, 27.1 mmol) was dissolved in ethanol (30 ml) and N-methyl-4-piperidone (3.16 g, 27.1 mmol) was added followed by sodium triacetoxyborohydride (54.2 mmol, 11.85 g). The mixture was stirred at room temperature for 2 h, then partitioned between diethyl ether and 2 M sodium hydroxide (100 ml). The organic phase was collected and extracted with 2 M hydrochloric acid (50 ml), then the acidic aqueous phase was made basic with 5 M sodium hydroxide (30 ml) and extracted with diethyl ether. The organic extract was dried and evaporated to give the title compound as a yellow oil (5.96 g, 91% yield).

Intermediate 7: (3S,4R)-3-fluoro-N-[(4-fluorophenyl)methyl]-1-methylpiperidine-4-amine and (3R,4S)-3-fluoro-N-[(4-fluorophenyl )methyl]-1-methylpiperidine-4-amine

[Sodium triacetoxyborohydride (100 mmol, 21.2 g) was added to a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (10.86 g, 50 mmol) and 4-fluorobenzylamine (6.286 ml, 55 mmol) in ethanol ( 100 ml). After stirring for 4 hours at ambient temperature, saturated sodium bicarbonate (100 ml) was added. The mixture was extracted with dichloromethane (3x100 ml), dried using a phase separator and concentrated. The crude material was purified by column chromatography using silica gel eluting with 25-100% ethyl acetate in petroleum ether to give the title compound as a 1:1 mixture of enantiomers (8.90 g, 55%).

(3S,4R)-3-Fluoro-N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine and (3R,4S)-3-fluoro-N-[(4-fluorophenyl)methyl]- 1-methylpiperidine-4-amine

Trifluoroacetic acid (5 ml) was added to a 1:1 mixture of tert-butyl (3S,4R)-3fluoro-4-{[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate and tert-butyl (3R, 4S)-3-fluoro-4-{[(4fluorophenyl)methyl]amino}piperidine-1-carboxylate (1.73 g, 5.31 mmol) in dichloromethane (15 mL). Through

- 36 042461 min the mixture was concentrated and re-dissolved in ethanol (53 ml). Formaldehyde (37% aqueous solution, 198 μl, 2.66 mmol) and sodium triacetoxyborohydride (1.13 g, 5.31 mmol) were added. After stirring for 30 minutes at ambient temperature, additional formaldehyde (37% aqueous solution, 99 μl, 1.33 mmol) and sodium triacetoxyborohydride (565 mg, 2.66 mmol) were added. After additional stirring for 45 minutes, the mixture was concentrated. Sodium bicarbonate (saturated, 100 ml) was added and the resulting mixture was extracted with dichloromethane (3x100 ml). The organic phase was dried using a phase separator and concentrated. The crude material was purified by silica gel column chromatography eluting with 5-15% methanol in dichloromethane to give the title compounds as a 1:1 mixture of enantiomers (545 mg, 43%).

Intermediate 8: tert-butyl (3R,4R)-3-fluoro-4-{[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate and tert-butyl (3S,4S)-3-fluoro-4 -{[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate

To a mixture of (4-fluorophenyl)methanamine (1.07 ml, 9.44 mmol) and tert-butyl 3-fluoro-4-oxo-piperidine-1-carboxylate (1.87 g, 8.58 mmol) in dichloromethane (35 ml) portionwise sodium triacetoxyborohydride (2.73 g, 12.9 mmol) was added over 20 minutes and continued stirring for 1 hour at room temperature. The reaction was diluted with sodium bicarbonate (saturated aqueous solution, 100 ml) and was extracted with dichloromethane (3x50 ml). The organic phase was dried (phase separator) and concentrated. The crude material (3 g) was purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to give (2.2 g, 78%) tert-butyl (3S,4R)3-fluoro-4-{[ (4-fluorophenyl)methyl]amino}piperidine-1-carboxylate and tert-butyl (3R,4S)-3-fluoro-4-{[(4fluorophenyl)methyl]amino}piperidine-1-carboxylate as a racemic mixture and ( 0.25 g, 9%) tert-butyl (3R,4R)-3-fluoro-4-{[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate and tert-butyl (3S,4S)-3fluoro-4 -{[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate as a racemic mixture.

Intermediate 9: 2-[3-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride

Sulfuric acid (49 μl, 882 μmol) was added to 2-(3-fluoro-4-hydroxyphenyl)acetic acid (500 mg, 2.94 mmol) in methanol (5 ml). After 1.5 h, sodium acetate trihydrate (2 mmol) was added and the mixture was concentrated. The crude material was suspended in ethyl acetate (5 ml), filtered and concentrated. Dimethylformamide (3 ml), isobutyl bromide (799 μl, 7.35 mmol), potassium carbonate (813 mg, 5.88 mmol) and tetrabutylammonium iodide (109 mg, 294 μmol) were added. The mixture was heated to 70°C and stirred for 16 h, and then cooled to ambient temperature and diluted with ethyl acetate (50 ml). The mixture was washed with water (5x30 ml), dried (phase separator) and concentrated. The crude material was purified by column chromatography using silica gel eluting with 0-10% ethyl acetate in petroleum ether to give the intermediate ester (619 mg, 88%). The material was dissolved in methanol (4 ml) and sodium hydroxide (aqueous solution, 2 M, 2.58 ml, 5.15 mmol) was added. After 1 h hydrochloric acid (aqueous solution, 2 M, 3 ml) was added and the mixture was extracted with ethyl acetate (3x10 ml). The combined organic phases were dried (phase separator), concentrated and redissolved in dichloromethane (2 ml). Thionyl chloride (1.87 ml, 25.8 mmol) was added and the mixture was stirred at ambient temperature for 16 h and then concentrated to give the desired acyl chloride (633 mg, quant.). Intermediate 10: 2-[2fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride

The compound was prepared by analogy with 2-[3-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride using 2-(2-fluoro-4-hydroxyphenyl)acetic acid. Yield: 87%.

Intermediate 11: tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1carboxylate

- 37 042461

The compound was prepared in analogy to N-[(4-fluorophenyl)methyl]-1-methylpiperidine-4-amine using (2,4-difluorophenyl)methanamine and tert-butyl 4-oxo-piperidine-1-carboxylate to give the desired intermediate ( quantitative output).

Intermediate 12: N-[(2,4-dimethoxyphenyl)methyl]-1-methylpiperidin-4-amine

The compound was prepared in analogy to N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine using 2,4-dimethoxybenzylamine and 1-methylpiperidin-4-one. Yield: 71%.

Intermediate 13: N-[(3,5-dimethoxyphenyl)methyl]-1-methylpiperidin-4-amine

The compound was prepared in analogy to N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine using (3,5-dimethoxyphenyl)methanamine and 1-methylpiperidin-4-one to give the desired intermediate (88%) .

Tetrahydrofuran was used instead of ethanol.

Intermediate 13A: N-[(3,5-difluorophenyl)methyl]-1-methylpiperidin-4-amine

The compound was prepared in analogy to N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine using (3,5-difluorophenyl)methanamine and 1-methylpiperidin-4-one to give the desired intermediate (54%) . Tetrahydrofuran was used instead of ethanol.

Intermediate 14: methyl 2-[3-hydroxy-2-(2-methylprop-2-en-1-yl)phenyl]acetate and methyl 2-[3-hydroxy-4-(2-methylprop-2-en- 1-yl)phenyl]acetate

A mixture of 3-bromo-2-methylprop-1-ene (4.15 ml, 41.2 mmol), methyl 2-(3-hydroxyphenyl)acetate (4.56 g, 27.4 mmol), tetrabutylammonium iodide (1, 01 g, 2.74 mmol) and K ₂ CO ₃ (7.58 g, 54.9 mmol) in DMF (20 ml) were heated to 60°C for 15 h. The mixture was purified by column chromatography using silica gel, eluting with 17% ethyl acetate in petroleum ether to give methyl 2-{3-[(2methylprop-2-en-1-yl)oxy]phenyl}acetate (4.7 g).

A solution of methyl 2-{3-[(2-methylprop-2-en-1-yl)oxy]phenyl}acetate (3.6 g, 16.3 mmol) in NMP (50 ml) was heated to 220°C for 8 hours Water (160 ml) was added and the mixture was extracted with diethyl ether (800 ml). The organic phase was washed with water (3x300 ml), dried using Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel eluting with 25% ethyl acetate in petroleum ether to give methyl 2-[3-hydroxy-2-(2-methylprop-2-en-1-yl)phenyl]acetate (700 mg ) and methyl 2-[3-hydroxy- 38 042461

4-(2-methylprop-2-en-1-yl)phenyl]acetate.

Intermediate 15: 4-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran

A solution of methyl 2-[3-hydroxy-2-(2-methylprop-2-en-1-yl)phenyl]acetate (700 mg) in formic acid (10 ml) was heated to 100°C for 20 min. The solvent was concentrated to give methyl 2(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)acetate (670 mg). Sodium hydroxide (1.98 ml, 5 M aq., 9.89 mmol) was added to a solution of methyl 2-(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)acetate (670 mg) in methanol (6 ml). The mixture was stirred at room temperature for 1 hour. Diethyl ether (100 ml) and HCl (3 ml, 5 M aq.) were added. The organic phase was washed with water (30 ml), dried using Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(2,2dimethyl-2,3-dihydro-1-benzofuran-4-yl)acetic acid (540 mg). Thionyl chloride (2.0 ml, 27.5 mmol) was added to 2-(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)acetic acid (540 mg, 2.62 mmol) in CH2Cl2 (3 ml). The mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was dissolved in acetone (3 ml), cooled to 0° C. and NaN ₃ (238 mg, 3.67 mmol) in water (3 ml) was added dropwise. The mixture was stirred at 0° C. for 1 h. The mixture was extracted with toluene (100 ml), the organic phase was dried using Na ₂ SO ₄ , filtered and concentrated (to 20 ml) under reduced pressure. The solution was heated to 60° C. for 1 hour then concentrated under reduced pressure to give 4-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran (492 mg) which was used without further purification.

Intermediate 16: 6-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran

6-(Isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran was obtained by analogy with 4-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran and used without further cleaning.

Intermediate 17: (4-{[2-( ^2H3 )methyl( ^2H6 )propan-2-yl]oxy}phenyl)methanamine

Sodium hydride (39.6 mg, 1.65 mmol) was added to a solution of tert-butaiol-d ₁₀ (100 mg, 1.19 mmol) in tetrahydrofuran (1 ml). After 35 minutes, gas evolution ceased and the mixture was concentrated to give white solids. The solids were taken up in tetrahydrofuran (1 ml) and a solution of 4-fluorobenzonitrile (100 mg, 0.826 mmol) in tetrahydrofuran (1 ml) was added. After 2 h the mixture was heated to 65°C. After 21 hours, NaOH (2 ml, 1 M aqueous solution) was added and the mixture was extracted with ethyl acetate (1 ml). The organic phase was separated, dried using a phase separator and concentrated. The crude material was purified by column chromatography using silica gel eluting with 1-6% ethyl acetate in petroleum ether to give methyl 4-{[2-(2H ₃ )methyl(2H ₆ )propan-2-yl]oxy}benzonitrile (63 .7 mg, 42%).

Cold borane (2 ml, 1M in tetrahydrofuran) was added to 4-{[2-( ^2H3 )methyl( ^2H6 )propan-2yl]oxy}benzonitrile (61.4 mg, 0.333 mmol) and the resulting mixture was heated to 65° WITH. After 18 hours the mixture was concentrated and methanol (2 ml) was added. The mixture was heated to 50° C. for 15 min when gas evolution ceased. The mixture was concentrated, redissolved in ethyl acetate (3 ml), washed with NaOH (1 ml, 1 M aq.), the organic phase was separated, dried using a phase separator and concentrated to give the desired intermediate as an oil (32.4 mg, 52 %).

Intermediate 18: (3,5-dihydro-2H-1,4-benzodioxepin-8-yl)methanamine

Sodium hydride (15.3 mg, 0.638 mmol) was added to a solution of 2-[5-(aminomethyl)-2-fluorophenoxy]ethan1-ol (50.6 mg, 0.254 mmol) in tetrahydrofuran (5 ml). After 20 minutes of stirring at room temperature, the mixture was heated to 50°C. After 3.5 hours, K2CO3 was added (using a spatula) and the mixture was heated to 60°C. After 2 h, the mixture was heated in a microwave reactor to 200°С for 30 min.

- 39 042461 obtaining a brown solution. Sodium hydroxide (2 ml, 1 M aqueous solution) was added and the mixture was extracted with ethyl acetate (3x3 ml), the combined organic phases were dried using a phase separator and concentrated to obtain a solution of the desired intermediate (1 ml). The material was used without further purification.

Intermediate 19: 2-(aminomethyl)-5-fluoro-N,N-dimethylaniline

Sodium hydride (88 mg, 60%, 3.67 mmol) was added to a stirred solution of 2-amino-4fluorobenzonitrile (100 mg, 0.735 mmol) in tetrahydrofuran (1 ml) followed by the addition of methyl iodide (183 μl, 2.94 mmol) . After 2 hours, additional sodium hydride (42 mg, 60%, 1.75 mmol) was added followed by methyl iodide (90 μl, 1.45 mmol). After 17 h stirring at room temperature, NaOH (2 ml, 1 M aqueous solution) was added, the aqueous phase was extracted with ethyl acetate (3x3 ml), the combined organic phases were dried using a phase separator and concentrated. The crude material was purified by silica gel column chromatography eluting with 1-15% ethyl acetate in petroleum ether to give 2(dimethylamino)-4-fluorobenzonitrile (111 mg, 92%).

Borane (2.0 ml, 1M in THF, 2.0 mmol) was added to 2-(dimethylamino)-4-fluorobenzonitrile (111 mg, 0.676 mmol). After 18 hours of stirring at room temperature, additional borane (2 ml, 1M b THF, 2 mmol) was added and the mixture was heated to 45°C. After a further 24 hours of stirring at 45° C., the mixture was diluted with ethyl acetate (5 ml) and washed with NaOH (3x4 ml, 1 M aqueous solution). The organic phase was dried using a phase separator and concentrated to give the desired intermediate (112 mg).

Intermediate 20: (4-cyclopropoxyphenyl)methanamine

4-cyanophenol (1.0 g, 7.97 mmol), cesium carbonate (16.0 mmol, 5.25 g), sodium iodide (0.8 mmol, 121 mg), cyclopropyl bromide (31.9 mmol, 2 .64 ml) and N,N-dimethylacetamide (4.0 ml) were stirred at 150°C for 20 hours in a sealed vessel with thick walls, and then partitioned between water and diethyl ether. The organic phase was washed with water several times, then dried and evaporated, the residue was purified by silica gel chromatography eluting with 25-50% ethyl acetate in petroleum ether to give 4-cyclopropyloxy-benzonitrile (832 mg, 5.22 mmol, 65% yield) . 4-cyclopropyloxy-benzonitrile (1.188 g, 7.46 mmol) was cooled in an ice bath and borane (1M in tetrahydrofuran, 30 ml, 30 mmol) was added. The mixture was stirred at room temperature for 20 h and at 60° C. for 30 min, then quenched with methanol (10 ml), evaporated and heated in methanol (20 ml) at reflux for 2 h. The mixture was evaporated and distributed between diethyl ether and sodium hydroxide (aqueous solution, 1 M). The organic phase was collected and extracted with hydrochloric acid (aqueous solution, 1 M). The aqueous phase was made basic with sodium hydroxide (aqueous solution, 5 M), then extracted with diethyl ether. The organic phase was dried and evaporated to give crude (4-cyclopropoxyphenyl)methanamine (878 mg, 72% yield).

Intermediate 21: tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1carboxylate

(2,4-Difluorophenyl)methanamine (8.0 g, 54.7 mmol) was added to tert-butyl 4-oxopiperidine-1-carboxylate (11.3 g, 54.7 mmol) in ethanol (60 ml) followed by triacetoxyborohydride sodium (23.9 g, 110 mmol). The reaction mixture was stirred for 2 hours at room temperature. Then NaOH (160 ml, 2 M aq.) was added and the mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried using MgSO ₄ , filtered and concentrated under reduced pressure to give the desired intermediate (18.3 g). Intermediate

- 40 042461 This compound was used without further purification.

Intermediate 22: 2-(trimethylsilyl)ethyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate f o

O\(2,4-Difluorophenyl)methanamine (1.68 g, 11.4 mmol) was added to 2-(trimethylsilyl)ethyl 4-oxo-piperidine-1-carboxylate (2.4 g, 9.27 mmol) in CH ₂ Cl ₂ (20 ml) followed by the addition of sodium triacetoxyborohydride (4.46 g, 20.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. Then NaOH (0.5 M, aq.) was added and the mixture was extracted with CH ₂ Cl ₂ . The organic phase was dried using MgSO ₄ , filtered and concentrated under reduced pressure. The crude intermediate was purified by silica gel column chromatography eluting with ethyl acetate to give 2-(trimethylsilyl)ethyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (3.49 g).

Solution of 2-(trimethylsilyl)ethyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (2.04 g, 5.49 mmol) and pyridine (1.8 ml, 22.0 mmol ) in CH ₂ Cl ₂ (10 ml) was added to a solution of triphosgene (1.09 g, 3.66 mmol) in CH ₂ Cl ₂ (10 ml) at 0°C. The reaction mixture was stirred for 1 hour at this temperature. The mixture was then concentrated under reduced pressure, dissolved in diethyl ether and washed with HCl (0.5 M, aq.) The organic phase was dried using MgSO ₄ , filtered and concentrated under reduced pressure. The crude intermediate was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexanes to give the desired intermediate (1.98 g).

Intermediate 23: 7-(aminomethyl)-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-ol

He

LiAlH ₄ (28.3 mg, 0.745 mmol) was added portionwise to 2,2-dimethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-7-carbonitrile (30 mg, 0.149 mmol) in THF (4 0 ml) at room temperature. The mixture was heated to 50°C overnight, then NaSO ₄ *10 H ₂ O was added in portions until gas evolution ceased, the mixture was diluted with ethyl acetate (5 ml), filtered and concentrated to obtain the desired intermediate compound (30.0 mg, 97% yield ).

Intermediate 24: (2,2-dimethyl-2H-chromen-7-yl)methanamine

LiAlH ₄ (37.7 mg, 0.993 mmol) was added portionwise to 2,2-dimethyl-2H-chromene-7-carbonitrile (46 mg, 0.248 mmol) in THF (4.0 ml) at room temperature. The mixture was heated to 50°C overnight, then NaSO ₄ *10 H ₂ O was added in portions until gas evolution ceased, the mixture was diluted with ethyl acetate (5 ml), filtered and concentrated to obtain the desired intermediate compound (46.0 mg, 97% yield ).

Intermediate 25: (3-methyl-1H-indazol-5-yl)methanamine

LiAlH ₄ (84.5 mg, 2.23 mmol) was added portionwise to 3-methyl-1H-indazole-5-carbonitrile (70 mg, 0.445 mmol) in THF (10.0 ml) at room temperature. The mixture was heated to 50°C overnight, then NaSO ₄ *10 H ₂ O was added in portions until gas evolution ceased, the mixture was diluted with ethyl acetate (15 ml), filtered and concentrated to obtain the desired intermediate compound (23.7 mg, 31% yield ).

Intermediate 26: N-{[2-(benzyloxy)-4-fluorophenyl]methyl}-1-methylpiperidin-4-amine

- 41 042461

Gasoline alcohol (0.77 g, 7.2 mmol) was added to a stirred suspension of potassium tert-butoxide (0.97 g, 8.6 mg) in dioxane (15 ml) at room temperature. After 10 minutes of stirring at room temperature, 2,4-difluorobenzonitrile (1.00 g, 7.2 mmol) was added in one portion. After an additional 90 minutes, water (10 ml) was added and the mixture was extracted with diethyl ether (3x10 ml), the combined organic phases were dried using a phase separator and concentrated to obtain solids. The crude material was purified by column chromatography using silica gel eluting with 25-50% dichloromethane in petroleum ether to give 2-(benzyloxy)-4fluorobenzonitrile as a white solid (1.33 g, 81%).

A cold solution of borane (1.4 ml, 1M in tetrahydrofuran) was added to 2-(benzyloxy)-4fluorobenzonitrile (208 mg, 915 μmol). After 15 hours of stirring at room temperature, additional borane (1.4 ml, 1M in tetrahydrofuran) was added. After a further 19 hours of stirring, additional borane (1.0 ml, 1M in tetrahydrofuran) was added. After 3 h, the mixture was added to sodium hydroxide (5 ml, 1 M, aqueous solution), extracted with ethyl acetate (3x5 ml), the combined organic phases were dried using a phase separator and concentrated to give [2-(benzyloxy)-4fluorophenyl]methanamine as oils (260 mg, quantitative yield). The material was used without further purification. N-methyl-4-piperidone (150 mg, 1.32 mmol) was added to a stirred solution of [2(benzyloxy)-4-fluorophenyl]methanamine (204 mg, 882 µmol) in ethanol (5 mL), triacetoxyborohydride was added after 5 min. sodium (372 mg, 1.76 mmol). After 6 h, the reaction mixture was concentrated, redissolved in dichloromethane (5 ml), washed with sodium hydroxide (5 ml, 1 M, aqueous solution), the aqueous phase was extracted with additional dichloromethane (2x1 ml), the combined organic phases were dried using a phase separator and concentrated to give the desired intermediate as a yellow oil (253 mg, 87%).

Intermediate 27: tert-Butyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate

Diphosgene (184 μl, 1.54 mmol) in CH ₂ Cl ₂ (2 ml) was added dropwise to a mixture of tert-butyl 4-{[(2,4difluorophenyl)methyl]amino}piperidine-1-carboxylate (1.00 g , 3.07 mmol) and DIPEA (1.07 ml, 6.15 mmol) in CH2Cl2 (8 ml) at room temperature. After 10 min stirring at room temperature, additional diphosgene (100 μl, 0.837 mmol) in CH ₂ Cl ₂ (1 ml) was added. After an additional 2 hours of stirring, NaOH (1 ml, 1 M aq.) was added. The organic phase was dried using a phase separator and concentrated. The crude material was purified by silica gel chromatography eluting with 3-12% ethyl acetate in petroleum ether to give the desired intermediate (1.34 g).

Intermediate 28: Phenyl N-[(4-cyclopropoxyphenyl)methyl]carbamate

4-cyanophenol (1 g, 7.97 mmol), cesium carbonate (16.0 mmol, 5.25 g), sodium iodide (0.8 mmol, 121 mg), cyclopropyl bromide (31.9 mmol, 2.64 ml) and dimethylacetamide (4.0 ml) were stirred at a temperature of 150°C for 20 h in a hermetically sealed vessel, and then partitioned between water and diethyl

- 42 042461 on air. The organic phase was washed with water several times, then dried and evaporated, the crude material was purified by column chromatography using silica gel, eluting with 2030% ethyl acetate in petroleum ether, to give 4-cyclopropyloxy-benzonitrile (405 mg, 2.54 mmol, 32% yield ). This procedure was repeated once to give 4-cyclopropyloxybenzonitrile (832 mg, 5.22 mmol, 65% yield). The two batches were combined to give 1.188 g (7.46 mmol) of material which was cooled in an ice bath and a solution of BH3 (30 mL, 1M in tetrahydrofuran, 30 mmol) was added. The mixture was stirred at room temperature for 20 h and at 60° C. for 30 min, then it was quenched with methanol (10 ml), evaporated and heated in methanol (20 ml) at reflux for 2 h. The mixture was evaporated and partitioned between ether and 1 M NaOH. The organic phase was collected and extracted with 1 M HCl, the aqueous phase was separated and basified with 5 M NaOH, then extracted with diethyl ether, and the organic phase was collected, dried and evaporated to give crude 4-cyclopropyloxy-benzylamine (878 mg, 5.37 mmol, 72% yield). %). This material was dissolved in dichloromethane (5 ml), pyridine (8.1 mmol, 660 μl) was added followed by phenyl chloroformate (7.0 mmol, 906 μl) dissolved in dichloromethane (4.0 ml) dropwise in an ice bath , the mixture was stirred for 30 min, then partitioned between dichloromethane and 1 M HCl, the organic phase was separated, dried and evaporated to obtain a crystalline material. This material was recrystallized from EtOAc/hexanes to give the title compound (881 mg, 3.1 mmol, 58% yield). Another portion (218 mg, 0.77 mmol) was crystallized from the mother liquor. The overall yield of phenyl N-[(4-cyclopropoxyphenyl)methyl]carbamate was 72%.

Intermediate 29: 1-butoxy-4-(isocyanatomethyl)benzene

2-(4-Butoxyphenyl)acetic acid (4.0 g, 18.81 mmol) was refluxed for 2 h in a mixture of dichloromethane (24 ml), thionyl chloride (16 ml) and DMF (160 μl). The mixture was evaporated and diethyl ether was added. The solids were removed and the ether extract was evaporated to give 2-(4-butoxyphenyl)acetyl chloride (4.35 g, 100% yield). This acid chloride (3.5 g, 14.7 mmol) was dissolved in acetone (10 ml) and added at 0°C over 10 min to a solution of sodium azide (1.35 g, 20.53 mmol) in water (10 ml). After stirring at 0° C. for 1 hour, the mixture was diluted with cold water (40 ml) and extracted with toluene (2x40 ml). The organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated to 60 ml on a rotary evaporator using a water bath at 30°C. The toluene solution was then heated to 65° C. in an oil bath until gas evolution ceased (30 min). The mixture was stirred for an additional 5 minutes and then evaporated to give an oil which was dissolved in n-heptane (40 ml). The solution was filtered to remove solids and the filtrate was evaporated to give the title compound as an oil (3.21 g, 100% yield).

Intermediate 30: 1-ethoxy-4-(isocyanatomethyl)benzene

The compound was obtained by analogy with 1-butoxy-4-(isocyanatomethyl)benzene.

Intermediate 31: Phenyl N-({4-[(tert-butyldimethylsilyl)oxy]-2-fluorophenyl}methyl)carbamate

2-Fluoro-4-hydroxy-benzaldehyde (982 mg, 7.0 mmol), imidazole (20.0 mmol, 1.375 g) and DMF (4.0 ml) were stirred and a solution of t-butyldimethylsilyl chloride (14.0 mmol, 2.175 g) dissolved in DMF (4.0 ml). The mixture was stirred at 20° C. for 20 hours and then partitioned between water and diethyl ether. The organic phase was washed with water several times, dried, evaporated and the residue was purified by column chromatography using silica gel eluting with 30% ethyl acetate in petroleum ether to give silylated benzaldehyde as an oil. The

The material was dissolved in ethanol (5 ml) and sodium borohydride (7.0 mmol, 270 mg) was added. The mixture was stirred for 1 hour, then concentrated and partitioned between water and diethyl ether. The organic phase was separated and evaporated to give the intermediate benzyl alcohol (961 mg, 3.75 mmol, 54% yield over two steps). This alcohol (961 mg, 3.75 mmol) was dissolved in dichloromethane (4 ml) and diisopropylethylamine (9.4 mmol, 1.64 ml) was added followed by ptoluenesulfonyl chloride (5.63 mmol, 1.083 g). The mixture was stirred for 72 hours and then purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to give the benzyl tosylate intermediate (866 mg, 2.11 mmol, 56% yield). This material (853 mg, 2.07 mmol), potassium phthalimide (4.0 mmol, 750 mg) and DMF (3.0 ml) were mixed and pyridine (1.0 mmol, 81 μl) was added. The mixture was stirred for 22 h, then partitioned between 0.5 M HCl and diethyl ether. The organic phase was separated, then evaporated, and the residue was purified by column chromatography using silica gel, eluting with 30% ethyl acetate in petroleum ether, to give the intermediate phthalimide derivative (735 mg, 1.9 mmol). This material was stirred in a mixture of ethanol (5 ml) and a solution of methylamine (8 M, 40 mmol, 5.0 ml) for 20 h, then concentrated, and the residue was purified by column chromatography using silica gel, eluting with methanol, to obtain intermediate benzylamine (104 mg, 0.407 mmol, 20% yield for two steps). This material (104 mg, 0.407 mmol) was dissolved in dichloromethane (2.0 ml) and pyridine (1.0 mmol, 82 μl) was added, the mixture was cooled in an ice bath and phenyl chloroformate (0.8 mmol, 104 μl) was added. The mixture was stirred for 1 h, then partitioned between water and diethyl ether, the organic phase was separated, evaporated, and the residue was purified by column chromatography using silica gel, eluting with 30% ethyl acetate in petroleum ether, to give phenyl N-({4-[ (tert-Butyldimethylsilyl)oxy]-2-fluorophenyl}methyl)carbamate (165 mg, 100% yield).

Intermediate 33: 2-[3-Fluoro-4-(propan-2-yloxy)phenyl]acetyl chloride

The compound was prepared in analogy to 2-[3-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride using 2-(3-fluoro-4-hydroxyphenyl)acetic acid and 2-iodopropane instead of isobutyl bromide. Tetrabutylammonium iodide was excluded.

Intermediate 34: 2-fluoro-4-(isocyanatomethyl)-1-(propan-2-yloxy)benzene

The compound was prepared by analogy with 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene using 2-[3-fluoro-4-(propan-2-yloxy)phenyl]acetyl chloride.

Intermediate 35: 2-[2-fluoro-4-(propan-2-yloxy)phenyl]acetyl chloride

The compound was prepared by analogy with 2-[2-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride using 2-(2-fluoro-4-hydroxyphenyl)acetic acid and 2-iodopropane.

Intermediate 36: 2-fluoro-1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene

The compound was prepared by analogy with 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene using 2-[2-fluoro-4-(propan-2-yloxy)phenyl]acetyl chloride.

Intermediate 37: 2-[3-methyl-4-(propan-2-yloxy)phenyl]acetyl chloride

The compound was prepared in analogy to 2-[2-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride using 2-(4-hydroxy-3-methylphenyl)acetic acid and 2-iodopropane instead of isobutyl bromide. Tetrabutylammonium iodide was excluded.

Intermediate 38: 4-(isocyanatomethyl)-2-methyl-1-(propan-2-yloxy)benzene

- 44 042461

The compound was prepared by analogy with 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene using 2-[3-methyl-4-(propan-2-yloxy)phenyl]acetyl chloride.

Example 1: 1-[(2,4-dimethoxyphenyl)methyl]-3-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-3-[(4-fluorophenyl)methyl]urea; trifluoroacetic acid (1а) and 1-[(2,4-dimethoxyphenyl)methyl]-3-[(3S,4R)-3fluoro-1-methylpiperidin-4-yl]-3-[(4-fluorophenyl)methyl]urea ; trifluoroacetic acid (1b)

(2,4-Dimethoxyphenyl)methanamine (104 µmol) and triethylamine (35 µl, 250 µmol) in dichloromethane were added to diphosgene (6 µl, 50 µmol) in dichloromethane (0.5 ml) using a syringe pump (0.5 ml /h). The mixture was further stirred for 1 hour at ambient temperature and then (3R,4S)-3-fluoro-N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine and (3S,4R)- 3-fluoro-N[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (1:1, 83 µmol) in dichloromethane (0.5 ml). After 24 h the mixture was washed with water (1.5 ml). The aqueous phase was extracted with dichloromethane (1.5 ml). The combined organic phase was dried (phase separator) and concentrated. The crude material was purified by HPLC eluting with 20-85% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compounds. Yield: 31.3 mg, 55%: 1H NMR (400 MHz, chloroform-d) δ 7.18 - 7.08 (m, 2H), 7.05 (d, 1H), 7.00 (t, 2H ), 6.38 (dd, W), 6.32 (d, 1H), 5.17 - 4.95 (m, 2H), 4.79 (dd, 1H), 4.51 (d, 1H) , 4.43 (d, 1H), 4.20 (qvd, 2H), 3.91-3.72 (m, 5H), 3.45 (s, 3H), 3.03 (dd, 1H), 2.94-2.75(m, 4H), 2.63-2.45(m, 1H), 1.77(d, 1H); LC-MS: 434.3 [M+H] ⁺ .

Example 2: 3-[(2,4-dimethoxyphenyl)methyl]-3-(1-methylpiperidin-4-yl)-1-{[4-(2-methylpropoxy)phenyl]methyl}urea (2)

N-[(2,4-Dimethoxyphenyl)methyl]-1-methylpiperidin-4-amine (0.34 mmol, 90 mg) in dichloromethane was added to 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene (0. 37 mmol, 77 mg) in dichloromethane. The solution was stirred for 1 h and then partitioned between dichloromethane and sodium hydroxide (aqueous solution, 0.5 M). The organic phase was separated, dried (sodium sulfate), filtered and evaporated. The crude product was purified by column chromatography using silica gel. Yield: 101 mg, 63%: ¹ H NMR (400 MHz, chloroform-d) δ 7.11 - 7.03 (m, 3H), 6.78 (d, 2H), 6.41 (dd, 1H) , 6.38 (d, 1H), 4.72 (t, 1H), 4.45 (m, 1H), 4.29 (d, 2H), 4.24 (s, 2H), 3.80 ( s, 3H), 3.73-3.65 (m, 5H), 2.86 (d, 2H), 2.26 (s, 3H), 2.14-1.99 (m, 3H), 1 .77-1.61 (m, 4H), 1.01 (d, 6H); LC-MS: 470.3 [M+H]+.

Example 3: 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (3)

1-(Isocyanatomethyl)-4-(2-methylpropoxy)benzene (61.5 mg, 300 µmol) in dichloromethane (1 ml) to

- 45 042461 was added to N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4-amine (60.0 mg, 250 μmol) in dichloromethane (1 ml). The mixture was stirred overnight and then concentrated. The crude material was purified by HPLC eluting with 38-72% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (31 mg, 22%). 1H NMR (400 MHz, chloroform-d) δ 7.13 (m, 1H), 7.04 (m, 2H), 6.79 (m, 4H), 4.78 - 4.65 (m, 2H) , 4.36 (s, 2H), 4.29 (s, 2H), 3.72 - 3.65 (m, 2H), 3.65 - 3.56 (m, 2H), 2.85 (m , 2H), 2.79 (s, 3H), 2.16 (d, 2H), 2.07 (m, 1H), 1.96-1.85 (m, 2H), 1.02 (d, 6H); LC-MS: 446.3 [M+H]+.

Example 4: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4yl)urea; trifluoroacetic acid (4)

tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate f o

I Sun

A solution of 1 - (isocyanatomethyl)-4-(2-methylpropoxy)benzene (396 mg, 1.93 mmol) in dichloromethane (0.2 ml) for 1 min. The mixture was stirred for 2.5 h, then additional 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene (198 mg, 0.96 mmol) was added in one portion. The mixture was stirred for 1.5 h, then concentrated to give the desired intermediate (811 mg).

-[(2,4-Difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea; trifluoroacetic acid.

To a stirred solution of tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate (57 mg, 0.11 mmol ) in dichloromethane (1.5 ml) was added trifluoroacetic acid (0.5 ml) at room temperature. After 1 h the reaction mixture was concentrated. The crude material was purified by HPLC eluting with 30-80% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (23 mg, 39%). ¹ H NMR (400 MHz, chloroform-d) δ 9.60 (br s, 1H), 9.08 (br s, 1H), 7.13 (q, 1H), 7.03 (d, 2H ), 6.80 (t, 4H), 4.69 - 4.53 (m, 2H), 4.36 (s, 2H), 4.28 (s, 2H), 3.68 (d, 2H) , 3.41 (d, 2H), 2.95 (d, 2H), 2.13 - 1.98 (m, 1H), 2.00 - 1.84 (m, 4H), 1.01 (d , 6H); LC-MS: 432.2 [M+H] ⁺ .

Example 5: 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (5)

1-(Isocyanatomethyl)-4-(propan-2-yloxy)benzene (23.9 mg, 125 µmol) was added to N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (20.0 mg , 83.2 µmol) in dichloromethane (500 µl). The mixture was stirred overnight and then concentrated. The crude material was purified by HPLC eluting with 3060% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (32 mg, 71%). 1H NMR (400 MHz, chloroform-d) δ 11.99 (br s, 1H), 7.12 (q, 1H), 7.02 (d, 2H), 6.87 - 6.75 (m, 4H), 4.83 - 4.66 (m, 2H), 4.51 (hept, 1H), 4.37 (s, 2H), 4.29 (s, 2H), 3.63 (d, 2H ), 2.97 - 2.84 (m, 2H), 2.81 (s, 3H), 2.29 - 2.13 (m, 2H), 1.93 (d, 2H), 1.32 ( d, 6H); LC-MS: 432.3 [M+H] ⁺ .

Example 6: 3-{[3-fluoro-4-(2-methylpropoxy)phenyl]methyl}-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (6)

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2-[3-Fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride (48.9 μl, 200 μmol) in acetone (100 μl) was added to sodium azide (18.2 mg, 280 μmol) in water (100 μl ) at 0°C. After 1 h, the mixture was diluted with water (1 ml) and extracted with toluene (3x1 ml). The organic phase was dried using sodium sulfate and filtered. The filtrate was carefully concentrated to about 1 ml. The mixture was stirred at 60°C for 15 min and then cooled to 0°C. N-[(4fluorophenyl)methyl]-1-methylpiperidin-4-amine (48.9 mg, 220 µmol) in toluene (1 mL) was added and the mixture warmed to ambient temperature. After 2 hours the mixture was concentrated and the crude material was purified by HPLC eluting with 25-45% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (69.8 mg, 62%). 1H NMR (400 MHz, chloroform-d) δ 12.41 (br s, 1H), 7.16 (dd, 2H), 7.01 (t, 2H), 6.86-6.71 (m, 3H), 4.80 (s, 1H), 4.69 (ddd, 1H), 4.35 (s, 2H), 4.22 (s, 2H), 3.73 (d, 2H), 3, 55 (d, 2H), 2.84 (t, 2H), 2.76 (s, 3H), 2.26-2.12 (m, 2H), 2.08 (d.sq., 1H), 1.88 (d, 2H), 1.01 (d, 6H); LC-MS: 446.3 [M+H]+.

Example 7: 3-{[2-fluoro-4-(2-methylpropoxy)phenyl]methyl}-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (7)

The compound was prepared in analogy to Example 6 using 2-[2-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride. Yield: 29%. 1H NMR (400 MHz, chloroform-d) δ 12.55 (br s, 1H), 7.13 (dd, 2H), 7.04 (t, 1H), 6.99 (t, 2H), 6 .58 (dd, 1H), 6.51 (dd, 1H), 4.81-4.62 (m, 2H), 4.32 (s, 2H), 4.28 (s, 2H), 3, 66 (d, 2H), 3.55 (d, 2H), 2.83 (t, 2H), 2.76 (s, 3H), 2.16 (tt, 2H), 2.05 (d.sq. ., 1H), 1.87 (d, 2H), 1.01 (d, 6H); LCMS: 446.3 [M+H]+.

Example 8: 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4 -yl) urea; trifluoroacetic acid (8)

Methyl 2-{4-[(2-methylprop-2-en-1-yl)oxy]phenyl}acetate

3-Bromo-2-methylprop-1-ene (1.41 ml, 14 mmol) was added to methyl 2-(4-hydroxyphenyl)acetate (1.66 g, 10 mmol) and potassium carbonate (3.46 g, 25 mmol) in acetone (50 ml). The mixture was heated to reflux and stirred overnight, then cooled to ambient temperature, diluted with ethyl acetate (20 ml), filtered through a pad of celite and concentrated (2.11 g, 96%).

Methyl 2-[4-hydroxy-3-(2-methylprop-2-en-1-yl)phenyl]acetate

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Methyl 2-{4-[(2-methylprop-2-en-1-yl)oxy]phenyl}acetate (1.94 g, 8.81 mmol) was dissolved in N-methyl 2-pyrrolidone (45 mL). The mixture was heated to 200°C and stirred overnight, then cooled to ambient temperature and concentrated (2.56 g, quantitative yield, contains 20% Nmethyl-2-pyrrolidone).

Methyl 2-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)acetate

Methyl 2-[4-hydroxy-3-(2-methylprop-2-en-1-yl)phenyl]acetate (2.43 g, contains 20% N-methyl-2-pyrrolidone, 8.81 mmol) was dissolved in formic acid (33.2 ml). The mixture was heated to 100° C. and stirred overnight, then cooled to ambient temperature and concentrated. The crude material was purified by column chromatography using silica gel eluting with 0-15% ethyl acetate in petroleum ether to give the desired intermediate (1.84 g, 95%).

5-(Isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran

Methyl 2-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)acetate (1.84 g, 8.35 mmol) was dissolved in methanol (15 ml) and sodium hydroxide (aqueous solution) was added , 2 M, 8.35 ml, 16.7 mmol). After 30 min hydrochloric acid (aqueous solution, 1 M, 50 ml) was added and the mixture was extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with brine (20 ml), dried (phase separator), concentrated and redissolved in dichloromethane (2 ml). Thionyl chloride (6.08 ml, 83.5 mmol) was added and the mixture was stirred at ambient temperature for 18 hours and then concentrated. The crude material was dissolved in acetone (5.52 ml) and cooled to 0°C. Sodium azide (760 mg, 11.7 mmol) in water (5.52 ml) was added. After stirring for 1 h, the mixture was diluted with water (50 ml) and extracted with toluene (3x50 ml). The organic phase was dried using magnesium sulfate and filtered. The filtrate was carefully concentrated to about 55 ml. The mixture was stirred at 60° C. for 20 minutes and then concentrated (1.77 g, quant.).

1-[(2,4-Difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl )urea; trifluoroacetic acid 5-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1benzofuran (203 mg, 1 mmol) in dichloromethane (2.5 ml) was added to N-[(2,4-difluorophenyl)methyl] -1-methylpiperidin-4-amine (288 mg, 1.2 mmol) in dichloromethane (2.5 ml). The mixture was stirred for 30 minutes and then concentrated. The crude material was purified by reverse phase chromatography eluting with 10-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (448 mg, 80%). ¹ H NMR (400 MHz, chloroform-d) δ 12.72 (br s, 1H), 7.13 (q, 1H), 6.89-6.77 (m, 4H), 6.61 (d , 1H), 4.74 (tt, 1H), 4.66 (s, 1H), 4.36 (s, 2H), 4.26 (s, 2H), 3.60 (d, 2H), 2 .94 (s, 2H), 2.90-2.73 (m, 5H), 2.18 (qvd, 2H), 1.91 (d, 2H), 1.46 (s, 6H); LC-MS: 444.3 [M+H]+.

Example 9: 1-[(2,4-difluorophenyl)methyl]-3-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4 -yl) urea; trifluoroacetic acid (9)

(3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)methanamine

3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-carboxylic acid (115 mg, 600 µmol) was dissolved in dichloromethane (2 ml) and oxalyl chloride (56.7 µl, 660 µmol) was added. The mixture was stirred at ambient temperature for 5 minutes and then N,N-dimethylformamide (2.3 μl) was added. After 40 minutes, ammonia (28% aqueous solution, 1.02 ml, 54 mmol) was added and the resulting mixture was vigorously stirred for an additional 30 minutes. The organic phase was separated. The aqueous phase was extracted with dichloromethane (2 ml). The combined organic phase was dried (phase separator) and concentrated. Borane (1M in tetrahydrofuran, 2.4 ml, 2.4 mmol) was added and the mixture was stirred at ambient temperature for 14 h and then heated to 50°C. After an additional 7 hours, borane (1M in tetrahydrofuran, 1.2 ml, 1.2 mmol) was added again and the mixture was stirred for 17 hours. The reaction was quenched with methanol and concentrated. Sodium hydroxide (aqueous solution, 1 M, 10 ml) was added and the mixture was extracted with dichloromethane (3x10 ml). The organic phase was extracted with hydrochloric acid (aqueous solution, 1 M, 10 ml). The aqueous phase was made alkaline with sodium hydroxide (aqueous solution, 5

M) and extracted with dichloromethane (3x10 ml). The organic phase was dried (phase separator) and concentrated (45 mg, 42%).

1-[(2,4-Difluorophenyl)methyl]-3-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl )urea; trifluoroacetic acid.

To a stirred solution of diphosgene (12 µl, 100 µmol) in dichloromethane (1 ml) was added (3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methanamine (35.4 mg, 200 µmol) in dichloromethane (1 ml). Diisopropylethylamine (105 μl, 600 μmol) was added. The mixture was stirred for 15 min, then N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (71 mg, 295 µmol) was added. After an additional 30 minutes, the mixture was washed with sodium hydroxide (aqueous solution, 1 M, 2 ml). The aqueous phase was extracted with dichloromethane (1 ml). The combined organic phase was dried (phase separator) and concentrated. The crude material was purified by HPLC eluting with 20-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (91 mg, 82%). ¹ H NMR (400 MHz, chloroform-d) δ 12.56 (br s, 1H), 7.14 (q, 1H), 6.89 (dd, 1H), 6.86 - 6.77 (m , 3H), 6.68 (d, 1H), 4.75 (tt, 1H), 4.67 (s, 1H), 4.37 (s, 2H), 4.30 (s, 2H), 4 .21 (s, 2H), 3.61 (d, 2H), 2.86 (t, 2H), 2.79 (s, 3H), 2.18 (qvd, 2H), 1.92 (d, 2H), 1.29 (s, 6H); LC-MS: 444.0 [M+H]+.

Example 10: 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1methylpiperidin-4-yl)urea (10)

Bis(phenyl N-[(2,3-dihydro-1-benzofuran-5-yl)methyl]carbamate)

(2,3-Dihydro-1-benzofuran-5-yl)methanamine (59 mg, 0.39 mmol) and pyridine (65 μl, 0.8 mmol) were stirred in dichloromethane (1 ml) and phenyl chloroformate (71 µl, 0.55 mmol). The mixture was stirred at room temperature for 2 h, then partitioned between dichloromethane and sodium hydroxide (aqueous solution, 0.5 M). The organic phase was separated, dried, evaporated and the residue was purified by column chromatography using silica gel eluting with 67% ethyl acetate in petroleum ether to give the desired intermediate (88 mg, 83%).

1-(2,4-Difluorobenzyl)-3-((2,3-dihydrobenzofuran-5-yl)methyl)-1-(1-methylpiperidin-4-yl)urea.

N-[(2,4-Difluorophenyl)methyl]-1-methylpiperidin-4-amine (101 mg, 0.40 mmol) and bis(phenyl N-[(2,3dihydro-1-benzofuran-5-yl)methyl ]carbamate) (88 mg, 0.326 mmol) was dissolved in toluene (2.0 ml) and diisopropylethylamine (105 μl, 6.0 mmol) was added. The mixture was stirred at 120° C. for 17 h, then partitioned between sodium hydroxide (aqueous solution, 0.5 M) and ether. The organic phase was separated and concentrated. The residue was purified by column chromatography using silica gel, eluting with 0-33% methanol in ethyl acetate. Fractions containing the desired material were combined, concentrated, suspended in diethyl ether and filtered to remove solids. The clear solution was evaporated to give the title compound as an oil (92 mg, 68%). This oil was triturated in ether/hexanes to give the title compound as a crystalline, non-hygroscopic free base (69.2 mg, 51%). 1H NMR (400 MHz, chloroform-d) δ 7.22 (q, 1H), 7.01 (s, 1H), 6.91 (d, 1H), 6.85 - 6.74 (m, 2H) , 6.68 (d, 1H), 4.55 (t, 2H), 4.52 (t, 1H), 4.40 (s, 2H), 4.30 (d, 2H), 4.29 ( m, 1H), 3.15 (t, 2H), 2.90 (d, 2H), 2.29 (s, 3H), 2.11 (m, 2H), 1.71 (m, 4H); LC-MS: 416.2 [M+H]+.

Example 11 (comparative): 1-[(3,5-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (11)

- 49 042461

The compound was prepared in analogy to Example 2 using N-[(3,5-difluorophenyl)methyl]-1-methylpiperidin-4-amine and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 62%. 1H NMR (400 MHz, chloroform-d) δ 7.02 (d, 2H), 6.83 - 6.78 (m, 2H), 6.74 (d, 2H), 6.73 - 6.67 ( m, 1H), 4.73 (m, 1H), 4.60 (s, 1H), 4.37 (s, 2H), 4.32-4.25 (m, 2H), 3.68 (d , 2H), 3.61 - 3.52 (m, 2H), 2.84 (m, 2H), 2.78 (s, 3H), 2.27 - 2.13 (m, 2H), 2, 05 (d.s., 1H), 1.96-1.85 (m, 2H), 1.01 (d, 6H); LC-MS: 446.3 [M+H]+.

Example 12 (comparative): 1-[(3,5-dimethoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (12)

The compound was prepared in analogy to Example 2 using X-[(3,5-dimethoxyphenyl)methyl]-1-methylpiperidine-4-amine and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 34%. 1H NMR (400 MHz, chloroform-d) δ 7.02 (d, 2H), 6.80 - 6.74 (m, 2H), 6.34 (m, 3H), 4.62 - 4.54 ( m, 1H), 4.46 - 4.36 (m, 1H), 4.29 (s, 2H), 4.27 (d, 2H), 3.72 (s, 6H), 3.68 (d , 2H), 2.94 - 2.85 (m, 2H), 2.27 (s, 3H), 2.15 - 2.01 (m, 3H), 1.81 1.63 (m, 4H) , 1.01 (d, 6H); LC-MS: 470.3 [M+H]+.

Example 13: 1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (13)

2-(Benzyloxy)-4-fluorobenzonitrile

To a stirred suspension of potassium tert-butoxide (2.34 g, 21 mmol) in dioxane (15 ml) at room temperature was added benzyl alcohol (2.33 g, 22 mmol) in one portion. The mixture was stirred for 10 minutes, then 2,4-difluorobenzonitrile (1.00 g, 7.2 mmol) was added in one portion. The mixture was stirred for 1.5 h, then water (10 ml) was added and the mixture was extracted with diethyl ether (3x10 ml). The combined organic phases were dried using a phase separator and concentrated to give solids. The crude material was purified by column chromatography using silica gel eluting with 25-50% dichloromethane in petroleum ether to give the desired intermediate (1.33 g, 5.8 mmol, 81%).

[2-(Benzyloxy)-4-fluorophenyl]methanamine

2-(Benzyloxy)-4-fluorobenzonitrile (208 mg, 0.92 mmol) was dissolved in a 4° C. solution of BH ₃ (1.4 ml, 1M in tetrahydrofuran). After 5 h, additional BH ₃ solution (1.4 ml) was added at room temperature, after another 19 h, additional BH ₃ solution (1 ml) was added and stirring was continued for 3 h, then NaOH (5 ml, 1 M) was added dropwise aqueous solution) and the mixture was extracted with ethyl acetate (3x5 ml). The combined organic phases were dried using a phase separator and concentrated to an oil (260 mg). N-{[2-(benzyloxy)-4-fluorophenyl]methyl}-1-methylpiperidin-4-amine

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To a stirred solution of [2-(benzyloxy)-4-fluorophenyl]methanamine (204 mg) in ethanol (5 mL) was added 1-methylpiperidin-4-one (163 μL) at room temperature, followed by sodium triacetoxyborohydride (372 mg) in one serving. The mixture was stirred for 6 h, then concentrated, diluted with NaOH (5 ml, 1 M aqueous solution) and washed with dichloromethane (3x5 ml). The combined organic phases were dried using a phase separator and concentrated to an oil (253 mg).

1-{[2-(Benzyloxy)-4-fluorophenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea (13b)

A solution of 1-(isocyanatomethyl)-4- (2methylpropoxy)benzene (112 mg) in dichloromethane (1 ml). The mixture was stirred for 3 h, then washed with NaOH (3x 1 ml, 1 M aqueous solution). The organic phase was dried using a phase separator and concentrated to an oil (229 mg).

1-[(4-Fluoro-2-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid.

To a stirred solution of 1-{[2-(benzyloxy)-4-fluorophenyl]methyl}-1-(1-methylpiperidin-4-yl)3-{[4-(2-methylpropoxy)phenyl]methyl}urea (90 mg ) in ethanol (5 ml) under nitrogen was added palladium (10% by weight) black (58 mg) in one portion at room temperature. The nitrogen atmosphere was changed to a hydrogen atmosphere and the mixture was stirred for 2.5 hours. The hydrogen atmosphere was removed, the mixture was filtered through a pad of celite with ethanol, and the filtered solvent was concentrated to a crude oil. The crude material was purified by HPLC eluting with 55-75% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (33 mg, 0.059 mmol, 41% over 4 steps). ¹ H NMR (400 MHz, chloroform-d) δ 12.13 (br s, 1H), 7.12 (d, 2H), 6.98 (t, 1H), 6.79 (d, 2H), 6.61 (d, 1H), 6.47 (t, 1H), 5.63 (s, 1H), 4.31 (s, 4H), 4.19 (s, 1H), 3.67 (d , 2H), 3.45 (d, 2H), 2.82 (s, 2H), 2.72 (s, 3H), 2.36 (q, 2H), 2.12 - 1.94 (m, 1H), 1.82 (d, 2H), 1.00 (d, 6H); LC-MS: 444.3 [M+H]+.

Example 14 1-[(4-fluorophenyl)methyl]-3-{[2-hydroxy-4-(2-methylpropoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (14)

2-(Benzyloxy)-4-(2-methylpropoxy)benzonitrile

To a stirred solution of 2-(benzyloxy)-4-benzonitrile (208 mg, 0.92 mmol) in dioxane (2 mL) at room temperature was added isobutanol (126 μL), followed by potassium tert-butoxide (146 mg) in one portion. The mixture was stirred for 17 h, then water (10 ml) was added and the mixture was extracted with diethyl ether (3x10 ml). The combined organic phases were dried using a phase separator and concentrated to an oil (287 mg). [2-(benzyloxy)-

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2-(Benzyloxy)-4-(2-methylpropoxy)benzonitrile (287 mg, mmol) was dissolved in a solution of BH ₃ at 4°C (1 ml, 1M in tetrahydrofuran). After 1.5 h the mixture was heated to 60°C, after 1.5 h an additional solution of BH ₃ (1 ml) was added and stirring was continued for 17 h. The mixture was cooled to room temperature, NaOH (4 ml, 1 M aqueous solution) and the mixture was extracted with diethyl ether (3x5 ml). The combined organic phases were dried using a phase separator and concentrated to an oil (393 mg). 3-{[2-(benzyloxy)-4-(2-methylpropoxy)phenyl]methyl}-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea

To a stirred solution of diphosgene (50 µl) in dichloromethane (1 ml) at 0°C was added dropwise a mixture of [2-(benzyloxy)-4-(2-methylpropoxy)phenyl]methanamine (102 mg) and pyridine (87 µl) in dichloromethane (1 ml) for 2 min. The mixture was stirred for 1 hour, then added dropwise to a stirred solution of N-[(4-fluorophenyl)methyl]-1-methylpiperidine-4-amine (71 mg) in dichloromethane (1 ml) at room temperature over 2 minutes. The mixture was stirred for 3 h, then washed with NaOH (3x1 ml, 1 M aqueous solution). The organic phase was dried using a phase separator and concentrated to an oil (168 mg).

1-[(4-Fluorophenyl)methyl]-3-{[2-hydroxy-4-(2-methylpropoxy)phenyl]methyl}-1-(1-methylpiperidin4-yl)urea; trifluoroacetic acid.

To a stirred solution of 3-{[2-(benzyloxy)-4-(2-methylpropoxy)phenyl]methyl}-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (168 mg) in ethanol (5 ml) under nitrogen atmosphere was added palladium (10 wt.%) black (70 mg) in one portion at room temperature. The nitrogen atmosphere was changed to a hydrogen atmosphere and the mixture was stirred for 2.5 hours. The hydrogen atmosphere was removed, the mixture was filtered through a pad of celite with ethanol, and the filtered solvent was concentrated with dichloromethane (3x5 ml). The combined organic phases were dried using a phase separator and concentrated to a crude oil. One third of the crude material was purified by HPLC eluting with 40-70% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (15 mg, 0.026 mmol, 33% over 4 steps). 1H NMR (400 MHz, chloroform-d) δ 12.65 (br s, 1H), 7.10 (dd, 2H), 6.99 (t, 2H), 6.81 (d, 1H), 6 .47 (d, 1H), 6.33 (dd, 1H), 5.05 (t, 1H), 4.64 (t, 1H), 4.36 (s, 2H), 4.19 (d, 2H), 3.67 (d, 2H), 3.55 (d, 2H), 2.89 - 2.74 (m, 5H), 2.23 (q, 2H), 2.05 (n, 1H ), 1.85 (d, 2H), 1.00 (d, 6H); LC-MS: 444.3 [M+H]+.

Example 15 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin4-yl)urea; trifluoroacetic acid (15)

•

4-(2-Fluoroethoxy)benzonitrile

2-Fluoroethanol (145 μl, 2.46 mmol) was added to a mixture of potassium tert-butoxide (277 mg, 2.46 mmol) in dioxane (2 ml). After 5 minutes of stirring at room temperature, 4-difluorobenzonitrile (199 mg, 1.64 mmol) in dioxane (2 ml) was added to the mixture. After 16 hours of stirring at room temperature, the mixture was added to a layer of diethyl ether (5 ml) on water (5 ml). The aqueous phase was extracted with diethyl ether (3x5 ml), the combined organic layers were dried using a phase separator and concentrated to give the desired intermediate as a white solid (261.3 mg).

(4-(2-Fluoroethoxy)phenyl)methanamine

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Borane (2 ml, 1M in tetrahydrofuran, 2 mmol) was added to 4-(2-fluoroethoxy)benzonitrile (133 mg, 0.805 mmol). After 1 hour of stirring at room temperature, the mixture was heated to 40°C. After 1 hour stirring, the mixture was concentrated. The residue was redissolved in methanol (2 ml), refluxed for 1 h and concentrated to an oil. NaOH (1 ml, 1 M aqueous solution) was added and the product was extracted with ethyl acetate (2x1 ml). The organic layer was dried using a phase separator and concentrated to give the desired intermediate as an oil (113.8 mg).

3-[(2,4-Difluorophenyl)methyl]-1-{[4-(2-fluoroethoxy)phenyl]methyl}-3-(1-methylpiperidin-4yl)urea; trifluoroacetic acid.

[4-(2-Fluoroethoxy)phenyl]methanamine (51.3 mg, 0.303 mmol) dissolved in dichloromethane (0.5 ml) was added to diphosgene (18.3 μl, 0.152 mmol) dissolved in dichloromethane (0. 5 ml), then diisopropylethylamine (106 μl, 0.606 mmol) was added dropwise. After 15 minutes of stirring at room temperature, N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (87.4 mg, 0.364 mmol) dissolved in dichloromethane (0.5 ml) was added. After additional stirring for 2 hours, the mixture was concentrated. The crude material was purified by HPLC eluting with 15-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (87.0 mg, 52%): 1H NMR (400 MHz, chloroform-d) δ 12.88(brs, 1H), 7.12(q, 1H), 7.05(d, 2H), 6.86-6.75(m, 4H), 4.84-4.76(m , 1H), 4.75-4.63 (m, 3H), 4.36 (s, 2H), 4.28 (d, 2H), 4.23-4.19 (m, 1H), 4, 17 - 4.12 (m, 1H), 3.57 (d, 2H), 2.90 - 2.73 (m, 5H), 2.17 (kvd, 2H), 1.89 (d, 2H) ; LC-MS: 436.3 [M+H] ⁺ .

Example 16 1-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxyphenyl)methyl]-1-(1-methylpiperidin-4yl)urea (16)

1-Ethoxy-4-(isocyanatomethyl)benzene

4-Ethoxyphenylacetic acid (10.0 g, 53.38 mmol) was refluxed for 2 h in a mixture of dichloromethane (60 ml), thionyl chloride (40 ml) and N,N-dimethylformamide (200 μl). The mixture was evaporated and triturated in diethyl ether. The diethyl ether extract was evaporated to give 2-(4-ethoxyphenyl)acetyl chloride (10.98 g, 100% yield). This material (7.0 g, 95% purity, 33.4 mmol) was dissolved in acetone (15 ml) and added at 0°C over 10 min to a solution of sodium azide (3.07 g, 46.8 mmol) in water (15 ml). After stirring at 0° C. for 1 hour, the mixture was diluted with cold water (40 ml) and extracted with toluene (2×40 ml). The organic extracts were combined, dried (sodium sulfate) and concentrated to 60 ml on a rotary evaporator using a water bath at 30°C. The toluene solution was heated to 65° C. in an oil bath until gas evolution ceased (30 min). The mixture was stirred for an additional 5 minutes and then evaporated to give an oil which was dissolved in heptane (40 ml). The solution was filtered to remove solids and the filtrate was evaporated to give the title compound as an oil (6.81 g, 100% yield).

3-[(2,4-Difluorophenyl)methyl]-1-[(4-ethoxyphenyl)methyl]-3-(1-methylpiperidin-4-yl)urea.

1-Ethoxy-4-(isocyanatomethyl)benzene (87% purity, 200 mg, 1.08 mmol) was dissolved in dichloromethane (2 ml) and N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4 was added -amine (200 mg, 832 μmol) dissolved in dichloromethane (1 ml). The mixture was stirred for 20 min, then partitioned between sodium hydroxide (aqueous solution, 0.5 M) and dichloromethane. The organic phase was evaporated and the residue was recrystallized successively from diethyl ether/hexanes, acetone/water and diethyl ether/hexanes to give 109 mg of the crude compound. The material was purified by silica gel chromatography eluting with 0-33% methanol in ethyl acetate to give the title compound (71 mg, 21% yield); 1H NMR (400 MHz, chloroform-d) δ 7.26 - 7.16 (m, 1H), 7.09 (d, 2H), 6.86 6.73 (m, 4H), 4.53 (t , 1H), 4.40 (s, 2H), 4.32 (d, 2H), 4.32 - 4.20 (m, 1H), 4.01 (q, 2H), 2.89 (d, 2H), 2.27 (s, 3H), 2.16-2.02 (m, 2H), 1.74-1.62 (m, 4H), 1.40 (t, 3H); 418.0 [M+H]+.

Example 17 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; hemitartrate (17)

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3-[(4-Cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; hemitartrate.

N-[(2,4-Difluorophenyl)methyl]-1-methylpiperidin-4-amine (1.89 mmol, 478 mg), phenyl N-[(4-cyclopropoxyphenyl)methyl] carbamate (97%, 585 mg, 2.0 mmol) and potassium carbonate (2.5 mmol, 350 mg) were suspended in toluene (5.0 ml). The mixture was stirred at 70° C. for 16 h, then partitioned between toluene and sodium hydroxide (aqueous solution, 0.5 M). The organic phase was separated and concentrated. The material was purified by silica gel chromatography eluting with 0-50% methanol in ethyl acetate. Fractions containing the desired product were combined and concentrated. Diethyl ether (10 ml) was added. The mixture was filtered and concentrated to give 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (725 mg, 1.688 mmol, yield 89%). This material (725 mg, 1.688 mmol) and L-(+)-tartaric acid (0.844 mmol, 127.3 mg) were dissolved in ethanol (5.0 ml) using an ultrasonic bath. The solvents were then evaporated to give the title compound as the hemitartrate salt (glassy, 906 mg). ¹ H NMR (400 MHz, chloroform-d) δ 7.16 (q, 1H), 7.05 (d, 2H), 6.94 (d, 2H), 6.84-6.73 (m, 2H ), 4.70 (bd, 1H), 4.62-4.48 (m, 1H), 4.41 (s 2H), 4.33 (s, 1H), 4.28 (d, 2H), 3.70 (m, 1H), 3.42 (t, 2H), 2.72 - 2.56 (m, 2H), 2.63 (s, 3H), 2.18 (m, 2H ), 1.81 (d, 2H), 0.76 (m, 4H); LC-MS: 430.3 [M+H] ⁺ .

Example 18 3-{[4-(t-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; trifluoroacetic acid (18)

The compound was prepared by analogy with 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea (Example 15) using 4fluorobenzonitrile and potassium tert-butoxide. 2-fluoroethanol was not added. The crude material was purified by HPLC eluting with 20-55% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (19.7 mg, 32%): 1H NMR (400 MHz, chloroform-d) δ 12.57 (br s, 1H), 7.12 (q, 1H), 7.00 (d, 2H), 6.88 (d, 2H), 6.81 (t, 2H), 4.81 - 4.65 (m, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.59 (d, 2H), 2.93 - 2.72 (m, 5H), 2.17 (q, 2H), 1.91 (d, 2H), 1.31 (s, 9H); LC-MS: 446.3 [M+H] ⁺ .

Example 19: 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (19)

Phenyl N-{[4-(prop-2-en-1-yloxy)phenyl]methyl}carbamate

4-(Hydroxy)benzaldehyde (10.0 g, 80.25 mmol), potassium carbonate (163.8 mmol, 22.6 g), tetrabutylammonium iodide (1.0 mmol, 377 mg), allyl bromide (121 mmol, 10 .6 ml) and N,N-dimethylformamide (4.0 ml)

- 54 042461 was stirred at a temperature of 20°C for 6 h, and then distributed between water and diethyl ether. The organic phase was washed with water several times, then dried and evaporated to give 4-(allyloxy)-benzaldehyde as an oil (13.3 g, 100%). This material (11.17 g, 68.8 mmol) was dissolved in ethanol (40 ml) and sodium borohydride (35 mmol, 1.351 g) was added portionwise. The mixture was stirred for 1 h, then concentrated, sodium hydroxide (aqueous solution, 5 M, 30 ml) and water (100 ml) were added and the mixture was extracted with diethyl ether. The organic phase was washed with water and brine and then evaporated to give 4-(allyloxy)benzyl alcohol (10.49 g, 63.9 mmol, 93%). This alcohol (3.0 g, 18.2 mmol) was dissolved in dichloromethane (10 ml) and thionyl chloride (37 mmol, 2.8 ml) was added. The mixture was stirred at 40°C for 10 min and then evaporated. The residue was dissolved in N,N-dimethylformamide (7 ml) and potassium phthalimide (20 mmol, 3.75 g) was added followed by pyridine (5 mmol, 410 μl). The mixture was stirred at room temperature for 20 hours and then at 50° C. for 30 minutes. Hydrochloric acid (aqueous solution, 1 M, 20 ml) was added. The crystals were isolated by filtration, washed with 33% methanol in water and dried to give 5.18 g of material which was recrystallized from 95% ethanol to give the phthalimide derivative (4.7 g, 88% yield). This material was stirred in 33% methylamine in ethanol (16 ml) and ethanol (15 ml) for 18 hours, then at 60° C. for 30 minutes. The mixture was partitioned between diethyl ether and sodium hydroxide (0.2 M). The organic phase was separated and extracted with hydrochloric acid (aqueous solution, 1 M). The aqueous phase was made basic with sodium hydroxide (5 M), then extracted with diethyl ether. The organic phase was dried and evaporated to give intermediate 4-allyloxy-benzylamine (2.247 g, 86%). This material (1.5 g, 9.1 mmol) and pyridine (11.83 mmol, 0.96 ml) were stirred in dichloromethane (10 ml) in an ice bath and phenyl chloroformate (10.01 mmol, 1.614 g, 1.3 ml) dissolved in dichloromethane (5 ml) over 20 min. The mixture was stirred at room temperature for 1 h, then partitioned between dichloromethane and hydrochloric acid (aqueous solution, 0.5 M). The organic phase was dried and evaporated to give an oil (2.3 g). Recrystallization from ethanol/water gave the desired intermediate as crystals (4.62 mmol, 1.31 g, 51%).

3-[(2,4-Difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)-1-{[4-(prop-2-en-1-yloxy)phenyl]methyl}urea; trifluoroacetic acid.

[N-[(2,4-Difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.588 mmol, 149 mg) and phenyl N-{[4(prop-2-en-1-yloxy)phenyl]methyl} carbamate (200 mg, 0.705 mmol) was dissolved in toluene (1.5 ml) and cesium carbonate (1.0 mmol, 326 mg) was added. The mixture was stirred at 80° C. for 2 h, then partitioned between diethyl ether and sodium hydroxide (aqueous solution, 0.5 M). The organic phase was concentrated and purified by silica gel chromatography eluting with 0-50% methanol in ethyl acetate. Fractions containing the desired product were combined and concentrated. Added diethyl ether. The mixture was filtered and concentrated to give the desired compound as the free base (112 mg, 0.261 mmol, 44% yield). This material was dissolved in dioxane (3 ml) and trifluoroacetic acid (0.27 mmol, 21 μl) was added, followed by freeze drying to give the title compound (0.27 mmol, 146 mg, 100% yield). ¹ H NMR (400 MHz, chloroform-d) δ 12.96 (s, 1H), 7.13 (q, 1H), 7.04 (d, 2H), 6.87-6.75 (m, 4H ), 6.04 (m, 1H), 5.40 (qvd, 1H), 5.29 (qvd, 1H), 4.78 - 4.63 (m, 2H), 4.51 (d, 2H) , 4.37 (s, 2H), 4.29 (d, 2H), 3.58 (d, 2H), 2.83 (t, 2H), 2.78 (s, 3H), 2.20 ( m, 2H), 1.90 (d, 2H); LC-MS: 430.3 [M+H]+.

Example 20: 3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; trifluoroacetic acid (20) f o

F

To a stirred solution of diphosgene (21.2 mg, 107 µmol) in dichloromethane (700 µl) was added (1-benzofuran-5-yl)methanamine (30.0 mg, 204 µmol) and triethylamine (56.8 µl, 408 mmol) in dichloromethane (700 µl). The mixture was stirred for 30 min, then N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (51.4 mg, 214 µmol) was added. After an additional 5 hours, the mixture was concentrated. The crude material was purified by HPLC eluting with 15-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (79 mg, 74%). 1H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, chloroform-d) δ 12.07 (br s, 1H), 7.62 (d, 1H), 7.40 (d, 1H) , 7.32 (s, 1H), 7.12 (q, 1H), 7.08 7.01 (m, 1H), 6.80 (t, 2H), 6.70 (d, 1H), 4 .90 (br s, 1H), 4.79-4.64 (m, 1H), 4.43 (s, 2H), 4.38 (s, 2H), 3.59 (d, 2H), 2.86 (t, 2H), 2.78 (s, 3H), 2.17 (qd, 2H), 1.91 (d, 2H); LC-MS: 414.2 [M+H] ⁺ .

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General procedures

Scheme S1: General procedure A (OP A).

Amine 1 (1.1 eq) was added to ketone 2 (1.0 eq) in CH ₂ Cl ₂ followed by sodium triacetoxyborohydride (1.5 eq). The reaction mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was diluted with NaOH (1 M, aq.) and was extracted with CH ₂ Cl ₂ . The organic phase was dried and concentrated under reduced pressure to give secondary amine 3, which was used in the next step without purification or with silica gel column chromatography. A solution of amine 4 (1.0 eq.) in CH ₂ Cl ₂ was added dropwise to a solution of diphosgene (0.5 eq.) in CH ₂ Cl ₂ at room temperature. DIPEA (3.0 eq.) was added and the resulting mixture was stirred for 5 minutes at room temperature. After that, a solution of secondary amine 3 (1.1 eq.) in CH ₂ Cl ₂ was added and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the desired urea 5 was purified by preparative HPLC eluting with acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the TFA salt of the product or purified by preparative HPLC eluting with acetonitrile in water containing 6 ppm ammonia (28 % aq.), to obtain the product in the form of a free base.

O

O

Scheme S2. General Procedure B (OP B).

Amine 1 (1.1 eq) was added to ketone 2 (1.0 eq) in CH ₂ Cl ₂ followed by sodium triacetoxyborohydride (1.5 eq). The reaction mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was diluted with NaOH (1 M, aq.) and was extracted with CH2Cl2. The organic phase was dried and concentrated under reduced pressure to give secondary amine 3, which was used in the next step without purification or with silica gel column chromatography. Isocyanate 4 (1.0 eq.) in CH ₂ Cl ₂ was added to a solution of secondary amine 3 (1.0 eq.) in CH ₂ Cl ₂ at room temperature, the reaction mixture was stirred for 3 h. The mixture was concentrated under reduced pressure and the desired urea 5 was purified by prep HPLC eluting with acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the TFA salt of the product or purified by preparative HPLC eluting with acetonitrile in water containing 6 ppm ammonia (28% aq) with obtaining the product in the form of a free base.

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Diagram S3. General Procedure C (OP C).

Amine 1 (1.1 eq) was added to ketone 2 (1.0 eq) in CH ₂ Cl ₂ followed by sodium triacetoxyborohydride (1.5 eq). The reaction mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was diluted with NaOH (1 M, aq.) and was extracted with CH ₂ Cl ₂ . The organic phase was dried and concentrated under reduced pressure to give secondary amine 3, which was used in the next step without purification or with silica gel column chromatography. A solution of amine 4 (1.0 eq.) in CH ₂ Cl ₂ was added dropwise to a solution of diphosgene (0.5 eq.) in CH ₂ Cl ₂ at room temperature. DIPEA (3.0 eq.) was added and the resulting mixture was stirred for 5 minutes at room temperature. After that, a solution of secondary amine 3 (1.1 eq.) in CH ₂ Cl ₂ was added and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the desired urea 5 was purified by preparative HPLC eluting with acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the TFA salt of the product or purified by preparative HPLC eluting with acetonitrile in water containing 6 ppm ammonia (28 % aq.), to obtain the product in the form of a free base.

Scheme S4. General procedure D (OP D).

Amine 1 (1.1 eq) was added to ketone 2 (1.0 eq) in CH ₂ Cl ₂ followed by sodium triacetoxyborohydride (1.5 eq). The reaction mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was diluted with NaOH (1 M, aq.) and was extracted with CH ₂ Cl ₂ . The organic phase was dried and concentrated under reduced pressure to give secondary amine 3, which was used in the next step without purification or with silica gel column chromatography. Isocyanate 4 (1.0 eq.) in CH ₂ Cl ₂ was added to a solution of secondary amine 3 (1.0 eq.) in CH ₂ Cl ₂ at room temperature, the reaction mixture was stirred for 3 h. The mixture was concentrated under reduced pressure and the desired urea 5 was purified by prep HPLC eluting with acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the TFA salt of the product or purified by preparative HPLC eluting with acetonitrile in water containing 6 ppm ammonia (28% aq) with obtaining the product in the form of a free base.

In schemes S1-S4 above, Ri, Rii, Riii, R _iv , R _v , R _vi , R _vii , R _viii , R _ix and R _x are independently absent or present 1, 2 or 3 times, and the R group described in the final connection in table. 1, for example, in example 21 R _v is present twice and twice is fluorine, R _v1 is absent, and R _v11 is present once and is methyl.

In Schemes S3 and S4, ring systems A and B are selected from the group consisting of 5- and 6-membered ring systems such as alicyclic, heteroalicyclic, aryl, and heteroaryl, and the corresponding ring system is shown in Table 1. 1. For example, the ring system in Example 22 is a heteroalicyclic ring, i. oxazol.

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Table 1. Compounds prepared according to OP A, OP B, OP C, and OP D

Example / connection Structure Raw Materials procedure 21 F about II 1 1 n y 1 > θ ММn II 1 FjC^^OH (2,4difluorophenyl)methane amine* 1-methyl piperi din-4on* (3-methyl1H- indol-5yl)methane amine* WITH 22 F O NN \ II J । n L 1 g-^6 I ^N d 1 F ₃ C^^OH (2,4difluorophenyl) methane amine* 1-methyl piperi din-4- He* (2-methyl1,3benzoxaz ol-5yl)methane amine* WITH 23 F O N N Y 1 1 1 > Oh N (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (1-methyl2,3dihydro1Nindol-5yl)methane amine* WITH

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24 F O HI Ϊ ⁿ II // Ά A 1 F ₃ C' ^X ^OH (2,4difluorophenyl) methane amine* 1-methyl piperi din-4- He* (3-methyl- 1,2- benzoxase ol-6yl)methane amine* WITH 25 F 0 ^{ν ν} YES 1 ^Η ϋ AL / ο Ν 1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (1,2- dimethyl- 1H- indol-5yl)methane amine* WITH 26 ,M=w II ο II 1 F ₃ C' ^X ^OH 1-(2,4difluorophenyl) ethane-1amine* 1-methyl piperi din-4- He* (4- cyclopropoxyphenyl)methane amine** A 27 F O N AAA YES 1 ⁿ U A A ' O , ^N d 1 FgC-^^OH (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (quinoline- 6yl)methane amine WITH 28 Z o \_/ O { ^o= \ \ o ZX M A gl z— _¥ z— (2,4difluorophenyl)methane amine* 1-methyl piperi din-4on* (3-methyl- 1,2- benzoxaz ol-5yl)methane amine* WITH

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29 F o Η TI ⁿ 11/) '^0 N (2,4difluorophenyl)methane amine* 1-methyl piperi din-4on* (Ubenzoxaz ol-6yl)methane amine* With thirty F О i IL H ] 1 ⁿ P λ 7 '^0 N 1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (1,3benzoxazol-5yl)methane amine* WITH 31 F ^{0 0} (2,4difluorophenyl)methane amine* 1-methyl piperi din-4on* (1-methyl1H- indol-5yl)methane amine* WITH 32 -z^ \> »- Z I 11° °4_Jz—— (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (4-methyl3,4- dihydro- 2H-1,4- benzox zin-6yl)methane amine* WITH 33 F 0 zL ___. JL______. o / ifX ^{H nZ} W Г ^- .ATI ΌςΓ LJ o OH ^N IL I FjC^^ON (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* 7-(amino methyl)2,2- dimethyl3,4dihydro- WITH

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2H-1- benzo pyran-4ol** 34 F0 I II.. o / doo j-- Ay^ 1 (2,4difluorophenyl) methane amine* 1-methyl piperi din-4on* (2,2dimethyl- 2Нchromen-7yl)methane amine** WITH 35 II ¹ JLa JL ^h 999/ 1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4on* (1-methyl1H- indazole- 6yl)methane amine* WITH 36 F 0 9%^^ NN IJ 1 ^h IXV ^F 11 1 (2,4difluorophenyl) methane amine* 1-methyl piperi din-4on* (2-methyl1H- indol-5yl)methane amine* WITH 37 F O NN 1 J 1 ⁿ IJ > /] //% IJ ⁰ ^KF 1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* 5-(aminomethyl)2,3dihydro1λ ⁶ benzothiophene-1,1dione* With

- 61 042461

38 F 0 N _N ---\ ί J 1 ⁿ 11) ' 0 Ϊ ^N Ji 1 F-jC^^OH (2,4difluorophenyl) methane amine* 1-methyl piperi din-4- He* (2,3- dihydro1H- inden-5yl)methane amine* WITH 39 F O N _N S 1 j ί ⁿ 1i> O N 1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (1,3-benzothiazol-6yl)methane amine* WITH 40 1 1 ¹ ij 1 -O Z> \ ^hT 1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* 5-(amino methyl)1,zdimethyl- 2.3- dihydro- 1H-1,3benzodiaz ol-2-one* WITH 41 F 0 _s 9\.. __NH (| ? ^N Y Ί \ ji j ϊ ⁿ 1 γ ^0 1 (2,4difluorophenyl) methane amine* 1 - mark lpiper idin-4on* (1Nindazol6-yl)methane amine* With 42 F □ NN YrYYUxs Ji J i ^H ί 1 > 1 (2,4difluorophenyl) methane amine* 1-methyl piperi din-4on* (3-methyl1H- indazol5-yl) methane amine** With

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43 F 0 DDoa ¹ F 4(amino methyl)- 3fluorobenzonitrile* 1-methyl piperi din-4- He* [4(propane- 2yloxy)phenyl]methane amine* A 44 F O L 1] I ⁿ Ml O ₂ N^\^ DD %A\/\ o ¹ ₽ A >X OH F | F (2fluoro-4nitrof enyl) methane amine* 1-methyl piperi din-4- He* [4(propane- 2yloxy)phenyl]methane amine* A 45 Λί ^: ^ ^Λ 'A ¹ - F (4cyclop propyl- 2fluorophenyl) methane amine* 1-methyl piperi din-4- He* [4(propane- 2yloxy)phenyl]methane amine* A 46 F 0 A ^D \ ^d A AA ^NN AAA dJ/ d 1 J 1 ⁿ LI \d ^F OD ° V A^ _F X ^he o b 1 F (2,4difluorophenyl)methane amine* 1-methyl piperi din-4on* (4-{[2( ^2H3 )methyl l( ^2Hv )propan-2yl]oxy}phenyl)methane amine** A

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47 f 1 ⁰ •Ά n II 1 ^f \/A Ar ^0H F | F (1R)-1(2,4difluorophenyl)e tan-1 amine* 1-methyl piperi din-4- He* (4- cyclopropoxyphenyl)methane amine** A 48 F 0 JL /4 JI CN fl ^NN II 1 JI h hi ^F όΆ ^{ζ 4} N ^Z OH i ^F 1 (2,4difluorophenyl) methane amine* 1-methyl piperi din-4- He* 5- (aminomethyl)-2- methoxy benzo nitrile A 49 F O h 1 1 hhi O ,.A N Af OH i ^f 9 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (4fluoropheni l)methane amine* A 50 F O II Ί ϊ ^H DJ O -A n St oh 1 I (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (2,4dimethox iphenyl) methane amine* A 51 F O Cl 1J 1 ^H IL L O. d A >< ^OH । ^F1 (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (2-chloro-4methoxyfenyl)metha namine A

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52 F 0 , Yes ^: XO ??- (2,4difluorophenyl) methane amine* 1-methyl piperi din-4- He* (3,5dihydro2Н-1,4benzodio xepin-8yl)methane min** WITH 53 F 0 CF _{3 NN} AjZ JI JJ h (11 0 ₽ J. i AND (2,4difluorophenyl)methane amine* 1 - mark lpiper idin-4on* [4- methoxy- 2- (trifluoromethyl)phenyl]methamine* A 54 F O JJ 1 0 J ' O ' L? ^N II i aA 4r he F 1 F (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (2,4difluoro-3methoxyfenyl)metha namine* A 55 F О Ji j 1 ^н ii> ό Η - I JL 1 he CH f ^/x f (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* (1-methyl1H-1,3benzodiaz ol-5yl)methane amine* WITH

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56 F 0 0 H - 1 A 1 he ^CH 3 M ^X F (2,4difluorophenyl) methane amine* 1-methyl piperide in-4-on* (1-methyl- 1H- indazol-5yl)methane amine* WITH 57 CF ₃ ⁰ hi । h hi ^F 0 kA^ ^N u | FjC-^OH [4- fluoro-2(trifluoromethyl)phenyl] methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** IN 58 fo .—Ις II o 1 J 1 ^H 1 J ' A | ГзС'^^on (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* 4- (isocyanate tomethyl) 2,2- dimethyl- 2.3- dihydro- 1- benzofur en** D 59 f o NN 1 J 1 ^H LLX ^F ^0 | FjC^^OH (2,4difluorophenyl)methane amine* 1-methyl piperi din-4- He* 6- (isocyanate tomethyl) 2,2- dimethyl- 2.3- dihydro- 1- D

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benzofur en** 60 ο-z ^Z ;-z ^Z ' λ- ⁷ >° o X “ b (4,5difluoro- 2- methoxy phenyl) methane min* 1-methyl piperi din-4on* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** IN 61 Cl 0 NW CH, f JI ^h ΐ 1 Ϊ /X ⁴ WcH ₃ and Η 1 ^F >Aoh ch ₃ <1 F (2-chloro4fluorophenyl)methanamine * 1-methyl piperi din-4- He* 1(isocyanate tomethyl)- 4(propane- 2yloxy)benzol** IN 62 Cl 0 ^H jXr Ί?^ ' F (2-chloro4fluorophenyl)methanamine * 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** IN 63 F0 |l Ί ϊ η M 't;4 (2,5difluorophenyl) methane amine* 1-methyl piperi din-4on* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** V

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64 \ Q o J — z ^z . y ⁷ AA o 4 (4-chloro3- methoxy phenyl) methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** IN 65 o Aan A Il J Ϊ h Hl 0 _: y _OH ^T (4-chloro- 2- methoxy phenyl) methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)- 4-(2- methylpropoxy)benzol** IN 66 ^0 0 A/TU 9:/- [2- methoxy -4- (trifluoromethyl)phenyl] methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)- 4-(2- methylpropoxy)benzol** IN 67 A AQ LL LL [2-chloro4- (trifluoromethyl)phenyl] methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)- 4-(2- methylpropoxy)benzol** V

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68 F O 1 and [2fluoro-4(trifluoromethyl)phenyl]methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** IN 69 ABOUT Η 1 । n n | o^-4 N 1 2(amino methyl)5-fluoroΝ,Νdimethyl lanyl and* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)4-(2- methylpropoxy)benzol** IN 70 F O 1 j 1 ⁿ ί A ' ^Ύ FA F (2,4,5trifluorophenyl)methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)- 4-(2- methylpropoxy)benzol** IN 71 O “Oy1 A o 7 (4-chloro2,6difluorophenyl) methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)- 4-(2- methylpropoxy)benzol** V 72 F O A R-g A A I > G ^he 1 F 1 F (2,6difluorophenyl) methane amine* 1-methyl piperi din-4- He* 1- (isocyanate tomethyl)- 4-(2- methylpropoxy)benzol** V

* Commercially available;

** resulting intermediate described in this document.

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Example/connection NMR m/z [M+N G 21 SNMR (400 MHz, DMSO-db) δ 10.62 (s, 1H), 9.21 (s, 1H), 7.30 - 7.16 (m, 4H), 7.08 - 7.01 (m , 2H), 7.00 - 6.95 (m, 1H), 4.43 (s, 2H), 4.35 (d, 2H), 4.25 (t, 1H), 3.51 - 3, 25 (m, 2H), 2.98 (q, 2H), 2.72 (d, 3H), 2.21 (s, 3H), 1.89-1.66 (m, 4H). 426.9 22 SNMR (400 MHz, DMSO-db) δ 9.19 (s, 1H), 7.56 (d, 1H), 7.48 (s, 1H), 7.30 - 7.16 (m, 4H), 7.13 - 6.95 (m, 1H), 4.42 (s, 2H), 4.35 (d, 2H), 4.28 4.16 (m, 1H), 3.53 - 3.14 (m, 2H), 2.98 (q, 2H), 2.72 (d, 3H), 2.59 (s, 3H), 1.90 - 1.69 (m, 4H). 429.3 23 Ή NMR (400 MHz, DMSO-db) δ 7.19 (q, 2H), 7.00 (t, 1H), 6.87 (d, 3H), 6.41 (dd, 1H), 4.39 (s, 2H), 4.11 (s, 2H), 4.00 - 3.85 (m, 1H), 3.23 - 3.12 (m, 2H), 2.86 - 2.76 (m, 2H), 2.71 (d, 2H), 2.65 (d, 3H), 2.09 (d, 3H), 1.88 (t, 2H), 1.59 - 1.37 (m, 4H ). 429.3 24 Ή NMR (400 MHz, Chloroform-d) δ 13.22 (s, 1H), 7.51 (d, 1H), 7.30 (s, 1H), 7.17 (q, 1H), 7.09 (d, 1H), 6.82 (q, 2H), 4.99 (t, 1H), 4.73 4.61 (m, 1H), 4.50 (d, 2H), 4.42 (s , 2H), 3.58 (d, 2H), 2.89 - 2.72 (m, 5H), 2.55 (s, 3H), 2.22 (q, 2H), 1.90 (d, 2H). 429.3 25 Ή NMR (400 MHz, DMSO-db) δ 7.31 - 7.14 (m, 4H), 7.06 - 6.90 (m, 3H), 6.13 (s, 1H), 4.41 ( s, 2H), 4.31 (d, 2H), 3.99 - 3.87 (m, 1H), 3.63 (s, 3H), 441.3

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2.76 - 2.65 (m, 2H), 2.38 (s, ZN), 2.09 (s, ZN), 1.88 (t, 2H), 1.59 - 1.40 (m, 4H). 26 'H NMR (400 MHz, Methanol-d4) δ 7.55 (q, 1H), 7.21 (d, 2H), 7.05 6.94 (m, 4H), 5.29 (q, 1H) , 4.44 - 4.20 (m, 2H), 3.72 (tg, 1H), 3.44 (d, 1H), 3.23 (d, 1H), 3.12 - 2.77 (m , 4H), 2.72 (s, 3H), 2.70 - 2.51 (m, 2H), 1.77 (d, 1H), 1.57 (d, 3H), 0.94 (d, 1H), 0.81 - 0.72 (m, 2H), 0.68 - 0.57 (m, 2H). 444.3 27 Ή NMR (400 MHz, DMSO-db) δ 9.51 (s, 1H), 8.99 (d, 1H), 8.56 (d, 1H), 8.05 (d, 1H), 7.84 (s, 1H), 7.78 (d, 1H), 7.70 (dd, 1H), 7.34 (t, 1H), 7.30 -7.19 (m, 2H), 7.07 (t, 1H), 4.48 (d, 2H), 4.45 (s, 2H), 3.40 (d, 2H), 2.99 (q, 2H), 2.72 (s , ZN), 1.92 - 1.73 (m, 4H). 425.3 28 'H NMR (400 MHz, Chloroform-E) δ 12.37 (br s, 1H), 7.46 (d, 1H), 7.40 (s, 1H), 7.34 (dd, 1H) , 7.15(q, 1H), 6.89-6.77(m, 2H), 4.97(brs, 1H), 4.76-4.63(m, 1H), 4, 51-4.45 (m, 2H), 4.42 (s, 2H), 3.633.56 (m, 2H), 2.94-2.75 (m, 5H), 2.54 (s, 3H) , 2.32 (d.s., 2H), 1.97-1.86 (m, 2H). 429.3 29 'H NMR (400 MHz, Chloroform-E) δ 8.07 (s, 1H), 7.69 (d, 1H), 7.39 (s, 1H), 7.25 - 7.15 (m, 2H ), 6.87-6.76 (m, 2H), 4.89-4.77 (m, 1H), 4.62-4.33 (m, 5H), 3.20 (br.s., 2H), 2.65-2.36(m, 5H), 2.06(brs, 2H), 1.81(d, 2H). 415.3 thirty 'H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.60 (s, 1H), 7.49 (d, 1H), 7.27-7.18 (m, 2H ), 6.87-6.74 (m, 2H), 4.82-4.73 (m, 1H), 4.51 (d, 2H), 4.47-4.32 (m, W), 3.08 (brd, 2H), 2.52-2.21 (m, 5H), 1.93 (brd, 2H), 1.78 (d, 2H). 415.3 31 'H NMR (400 MHz, Chloroform-d) δ 7.40 (s, 1H), 7.26-7.19 (m, 2H), 7.09-7.00 (m, 2H), 6.87 - 6.68 (m, 2H), 6.45 - 6.35 (m, 1H), 4.57 (t, 1H), 4.49 (d, 2H), 4.44-4.29 (m , 3H), 3.78 (s, 3H), 2.99 (d, 2H), 2.36 (s, 3H), 2.29-2.14 (m, 2H), 1.92-1, 68 (m, 4H). 427.3 32 'H NMR (400 MHz, Chloroform-d) δ 11.79 (br.s., 1H), 7.20-7.11 (m, 1H), 6.87-6.79 (m, 2H), 6.73 (d, 1H), 6.66 (d, 1H), 6.56 (dd, 1H), 4.86 (bd, 1H), 4.78-4.65 (m, 1H ), 4.40 (s, 2H), 4.34-4.30 (m, 2H), 4.27 (s, 445.3

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2H), 3.61 (d, 2H), 3.38-3.30 (m, 2H), 2.97-2.84 (m, 5H), 2.85-2.77 (m, 3H) , 2.34-2.20 (m, 2H), 1.93 (d, 2H). 33 'H NMR (400 MHz, Chloroform-d) δ 12.37 (s, 1H), 7.41 - 7.31 (m, 1H), 7.18 (q, 1H), 6.94 - 6.78 (m, 2H), 6.70 - 6.53 (m, 1H), 6.47 (s, 1H), 4.96 - 4.64 (m, 3H), 4.41 (s, 2H), 4.36-4.26(m, 2H), 3.58(d, 2H), 2.94-2.82(m, 2H), 2.79(s, 4H), 2.40-2, 24 (m, 2H), 2.17 (dd, 1H), 1.92 (d, 2H), 1.83 (dd, 1H), 1.43 (s, 3H), 1.30 (s, 3H ). 474.3 34 'H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.17 (m, 1H), 6.89 - 6.75 (m, 3H), 6.63 (d, 1H), 6.53 (s, 1H), 6.28 (d, 1H), 5.58 (d, 1H), 4.57 (t, 1H), 4.47 - 4.28 (m, 5H), 3.05 ( br.s., 2H), 2.39 (s, 3H), 2.26 (br.s., 2H), 1.94 - 1.72 (m, 4H), 1.41 (s, 6H) . 456.3 35 'H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.63 (d, 1H), 7.25 7.17 (m, 2H), 6.95 (d, 1H) , 6.83 - 6.73 (m, 2H), 4.80-4.70 (m, 1H), 4.53 (d, 2H), 4.48-4.29 (m, W), 4 .03 (s, ZN), 3.02 (br.s., 2H), 2.37 (s, ZN), 2.26 (br.s., 2H), 1.96-1.71 (m , 4H). 428.3 36 'H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.29 (s, 1H), 7.257.15 (m, 2H), 6.93 (d, 1H), 6, 86 - 6.69 (m, 2H), 6.15 (s, 1H), 4.60-4.51 (m, 1H), 4.46 (d, 2H), 4.39 (s, 2H) , 4.34 (br.s., 1H), 2.96 (br.s., 2H), 2.44 (s, 3N), 2.34 (s, 3N), 2.18 (br.s ., 2H), 1.74 (br.s., 4H). 427.3 37 'H NMR (400 MHz, Chloroform-d) δ 7.65 (d, 1H), 7.28 (s, 1H), 7.257.17 (m, 2H), 6.84 (q, 2H), 4, 80 (brd, 1H), 4.48-4.39 (m, 4H), 4.28 (brd, 1H), 3.48 (t, 2H), 3.33 (t, 2H), 2.95 (d, 2H), 2.32 (s, 3H), 2.15 (br s, 2H), 1.86-1.67 (m, 4H). 464.2 38 'H NMR (400 MHz, Chloroform-d) δ 12.82 (br.s., 1H), 7.20-7.09 (m, 2H), 6.95 (s, 1H), 6.91- 6.77 (m, 3H), 4.82-4.62 (m, 2H), 4.48-4.28 (m, 4H), 3.60 (d, 2H), 2.85 (q, 6H), 2.79 (s, 3H), 2.29-2.12 (m, 2H), 2.06 (u, 2H), 1.92 (d, 2H). 414.3 39 ^{1 H} NMR (400 MHz, DMSO pure) δ 9.33 (s, 1H), 8.01 (d, 1H), 7.91 (s, 1H), 7.41 (d, 1H), 7.30 - 7.08 (m, 3H), 7.01 (t, 1H), 4.54 - 4.31 (m, 4H), 4.033.89 (m, 1H), 2.72 (d, 2H), 2 .10 (s, 3H), 1.96-1.83 (m, 2H), 1.60-1.44 (m, 4H). 431.2

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40 'H NMR (400 MHz, Chloroform-d) δ 7.21 (q, 1H), 6.94-6.74 (m, 5H), 4.70 (br.s., 1H), 4.53- 4.35 (m, 5H), 3.40 (s, 3H), 3.38 (s, 3H), 3.18 (br.s., 2H), 2.66-2.27 (m, 5H ), 1.97 (br.s., 2H), 1.80 (d, 2H). 458.3 41 'H NMR (400 MHz, Chloroform-d) δ 8.11-7.93 (m, 2H), 7.64 (d, 1H), 7.41 (q, 1H), 7.25 (s, 1H ), 6.90 - 6.68 (m, 2H), 4.91 - 3.95 (m, 5H), 3.11 (d, 2H), 2.79 (br.s., 2H), 2 .43 (s, 3H), 2.35-2.04 (m, 4H), 1.98 (d, 2H). 414.3 42 'H NMR (400 MHz, Chloroform-d) δ 9.86 (br s, 1H), 7.45 (s, 1H), 7.34 (d, 1H), 7.25-7.18 ( m, 2H), 6.84-6.73 (m, 2H), 4.71-4.62 (m, 1H), 4.50 (d, 2H), 4.43 (s, 2H), 4 .36 (br.s., 1H), 2.96 (br.s., 2H), 2.54 (s, 3N), 2.34 (s, 3N), 2.18 (br.s., 2H), 1.90-1.69 (m, 4H). 428.3 43 Ή NMR (400 MHz, DMSO-db) δ 9.15 (s, 1H), 7.85 (d, 1H), 7.68 (d, 1H), 7.35 (t, 1H), 7.10 (d, 3H), 6.82 (d, 2H), 4.56 (π, 1H), 4.49 (s, 2H), 4.28 4.21 (m, 1H), 4.18 (d , 2H), 3.42 - 3.33 (m, 2H), 3.05 - 2.89 (m, 2H), 2.77 - 2.69 (m, ZN), 1.85 - 1.69 (m, 4H), 1.24 (d, 6H). 439.3 44 Ή NMR (400 MHz, DMSO-db) δ 9.22 (s, 1H), 8.09 (dd, 2H), 7.45 (t, 1H), 7.11 (d, 3H), 6.82 (d, 2H), 4.61 - 4.48 (m, 3H), 4.33 - 4.21 (m, 1H), 4.19 (d, 2H), 3.39 (d, 2H), 3.07 - 2.90 (m, 2H), 2.72 (s, 3H), 1.88 - 1.71 (m, 4H), 1.24 (d, 6H). 459.3 45 'H NMR (400 MHz, Chloroform-d) δ 12.81 (s, 1H), 7.05 - 6.97 (m, 3H), 6.85 - 6.75 (m, 3H), 6.75 - 6.68 (m, 1H), 4.79 - 4.69 (m, 2H), 4.51 (π, 1H), 4.34 (s, 2H), 4.28 (d, 2H), 3.59 (d, 2H), 2.92 - 2.81 (m, 2H), 2.77 (s, ZN), 2.18 (q, 2H), 1.96 - 1.91 (m, 1H), 1.91 - 1.81 (m, 2H), 1.32 (d, 6H), 1.05 - 0.95 (m, 2H), 0.72 - 0.63 (m, 2H) . 454.3 46 'H NMR (400 MHz, Chloroform-d) δ 12.79 (s, 1H), 7.13 (q, 1H), 7.00 (d, 2H), 6.87 (d, 2H), 6, 81 (t, 2H), 4.79 - 4.66 (m, 2H), 4.37 (s, 2H), 4.31 (d, 2H), 3.58 (d, 2H), 2.83 (t, 2H), 2.77 (s, 3H), 2.19 (q, 2H), 1.90 (d, 2H). 455.4 47 'H NMR (400 MHz, Methanol-d4) δ 7.66 - 7.54 (m, 1H), 7.26 (d, 2H), 7.04 (dd, 4H), 5.34 (q, 1H ), 4.49 - 4.27 (m, 2H), 3.78 (tg, 1H), 3.50 (d, 1H), 3.29 (d, 1H), 3.19 - 3.01 ( m, 2H), 2.97 - 2.82 (m, 1H), 2.78 (s, ZN), 2.74 - 2.54 (m, 2H), 1.82 (d, 1H), 1 .63 (d, 3H), 1.01 (d, 1H), 0.88 - 0.63 (m, 4H). 444.3

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48 1HNMR (400 MHz, Chloroform-d) δ 12.66 (br.s., 1H), 7.37 - 7.29 (m, 2H), 7.13 (q, 1H), 6.91 - 6, 78 (m, 3H), 5.04 (s, 1H), 4.68 - 4.56 (m, 1H), 4.40 (s, 2H), 4.28 (d, 2H), 3.90 (s, 3H), 3.57 (d, 2H), 2.84 (t, 2H), 2.78 (s, 3H), 2.24 (kvd, 2H), 1.89 (d, 2H) . 429.3 49 'H NMR (400 MHz, Chloroform-d) δ 12.94 (s, 1H), 7.17 - 7.07 (m, 3H), 6.95 (t, 2H), 6.82 (t, 2H ), 4.77 (s, 1H), 4.75-4.63 (m, 1H), 4.38 (s, 2H), 4.32 (d, 2H), 3.58 (d, 2H) , 2.88 - 2.73 (m, 5H), 2.21 (kvd, 2H), 1.90 (d, 2H). 392.2 50 'H NMR (400 MHz, Chloroform-d) δ 12.80 (br.s., 1H), 7.10 (d, 1H), 7.02 (q, 1H), 6.89 - 6.81 ( m, 1H), 6.75 (t, 1H), 6.40 (dd, 1H), 6.34 (d, 1H), 5.05 (t, 1H), 4.77 - 4.65 (m , 1H), 4.33 (s, 2H), 4.24 (d, 2H), 3.79 (s, 3H), 3.57 (d, 2H), 3.51 (s, 3H), 2 .87 - 2.73 (m, 5H), 2.14 (q. 2H), 1.87 (D, 2H). 434.3 51 'H NMR (400 MHz, Chloroform-d) δ 12.66 (br.s., 1H), 7.18 (d, 1H), 7.05 (q, 1H), 6.86 - 6.70 ( m, 4H), 4.91 (t, 1H), 4.75 - 4.63 (m, 1H), 4.38 - 4.30 (m, 4H), 3.77 (s, ZN), 3 .58 (d, 2H), 2.91-2.71 (m, 5H), 2.17 (q, 2H), 1.88 (d, 2H). 438.3 52 'H NMR (400 MHz, Chloroform-d) δ 12.94 (bd, 1H), 7.16 (q, 1H), 7.06 (d, 1H), 6.90 - 6.72 ( m, 4H), 4.79 - 4.66 (m, 2H), 4.62 (s, 2H), 4.38 (s, 2H), 4.32 (d, 2H), 4.04 (d , 2H), 3.98 (d, 2H), 3.57 (d, 2H), 2.88 - 2.73 (m, 5H), 2.20 (q, 2H), 1.90 (d, 2H). 446.3 53 'H NMR (400 MHz, Chloroform-d) δ 12.70 (br.s., 1H), 7.33 (d, 1H), 7.09 (d, 1H), 7.08 - 7.00 ( m, 1H), 6.97 (dd, 1H), 6.87 - 6.69 (m, 2H), 4.80 - 4.62 (m, 2H), 4.43 (d, 2H), 4 .33 (s, 2H), 3.82 (s, 3H), 3.59 (d, 2H), 2.95 - 2.71 (m, 5H), 2.30 - 2.11 (m, 2H ), 1.90 (d, 2H). 472.3 54 'H NMR (400 MHz, Chloroform-d) δ 12.63 (s, 1H), 7.08 (q, 1H), 6.91-6.74 (m, 4H), 4.84 (s, 1H ), 4.78 - 4.59 (m, 1H), 4.37 (s, 2H), 4.33 (d, 2H), 3.94 (s, 3H), 3.58 (d, 2H) , 2.90 - 2.72 (m, 5H), 2.28 - 2.13 (m, 2H), 1.89 (d, 2H). 440.3 55 'H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H), 7.85 (d, 1H), 7.42 (d, 1H), 7.24 (s, 1H), 6, 87 (t, 1H), 6.80 (t, 1H) 5.37 (m, 1H), 4.55 (s, 2H), 428.3

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4.44 (s, 2H), 4.05 (s, 3H), 3.58 (d, 2H), 2.87 (s, 2H), 2.77 (s, 3H), 2.24 (d , 2H), 1.95 (d, 2H). 56 'H NMR (400 MHz, Chloroform-d) δ 12.49 (br s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.32 (d 1H), 7.19 (dd 1H), 7.14 (q 1H), 6.80 (t 2H), 4.73 (t 1H), 4.46 (s, 2H), 4.38 (s, 2H), 4.07 (s, 3H), 3.62 (d 2H), 2.89 (d 2H), 2.80 (s, 3H), 2.28 - 2.09 (m, 2H), 1.93 (d 2H). 428.3 57 'H NMR (400 MHz, Chloroform-d) δ 12.80 (br.s., 1H), 7.41-7.31 (m, 2H), 7.20-7.14 (m, 1H), 6.99 (d, 2H), 6.78 (d, 2H), 4.81-4.71 (m, 1H), 4.53 (s, 1H), 4.48 (s, 2H), 4 .26 (s, 2H), 3.67 (d, 2H), 3.60 (d, 2H), 2.90 2.74 (m, 5H), 2.26 - 2.10 (m, 2H) , 2.10 - 2.00 (m, 1H), 1.92 (d, 2H), 1.01 (d, 6H). 496.3 58 'H NMR (400 MHz, Chloroform-d) δ 7.20 - 7.10 (m, 1H), 7.02 (t, 1H), 6.83 (ddt, 2H), 6.62 (d, 1H ), 6.51 (d, 1H), 4.69 (ddt, 2H), 4.37 (s, 2H), 4.26 (d, 2H), 3.58 (d, 2H), 2.83 (s, 3H), 2.77 (s, 4H), 2.19 (qvd, 2H), 1.90 (d, 2H), 1.42 (s, 6H). 444.3 59 ^{1 H} NMR (400 MHz, DMSO-db) δ 9.23 (s, 1H), 7.28 - 7.18 (m, 2H), 7.10 - 7.00 (m, 3H), 6.65 (d, 1H), 6.54 (s, 1H), 4.41 (s, 2H), 4.21 (s, 1H), 4.18 (d, 2H), 3.39 (d, 2H) , 2.98 (d, 2H), 2.94 (s, 2H), 2.73 (s, 2H), 1.87-1.67 (m, 4H), 1.38 (s, 6H). 444.3 60 'H NMR (400 MHz, Chloroform-d) δ 12.35 (s, 1H), 7.04 (d, 2H), 6.97 6.88 (m, 1H), 6.81 (d, 2H) , 6.66 (dd, 1H), 4.83 - 4.72 (m, 2H), 4.29 (d, 2H), 4.24 (s, 2H), 3.73 (s, 3H), 3.69 (d, 2H), 3.59 (d, 2H), 2.91 - 2.83 (m, 2H), 2.79 (d, 3H), 2.30 - 2.16 (m, 2H), 2.07 (di, 1H), 1.92 (d, 2H), 1.02 (d, 6H). 476.3 61 'H NMR (400 MHz, Chloroform-d) δ 12.93 (br.s., 1H), 7.19 - 7.08 (m, 2H), 7.03 (d, 2H), 6.93 ( td, 1H), 6.79 (d, 2H), 4.83 - 4.71 (m, 1H), 4.60 4.53 (m, 1H), 4.56 - 4.44 (m, 1H ), 4.36 (s, 2H), 4.29 (d, 2H), 3.59 (d, 2H), 2.91 - 2.80 (m, 2H), 2.78 (s, 3H) , 2.27 - 2.08 (m, 2H), 1.91 (d, 2H), 1.32 (d, 6H). 448.0 62 1HNMR (400 MHz, Chloroform-d) δ 12.57 (br.s., 1H), 7.19 - 7.09 (m, 2H), 7.03 (d, 2H), 6.93 (td, 1H), 6.80 (dd, 2H), 4.82 - 4.71 (m, 1H), 4.61 - 4.53 (m, 1H), 4.35 (s, 2H), 4.29 (d, 2H), 3.69 (d, 2H), 3.60 (d, 2H), 2.94 462.0

- 75 042461

- 2.81 (m, 2H), 2.79 (s, 3H), 2.26 - 2.10 (m, 2H), 2.13-1.99 (m, 1H), 1.92 (d , 2H), 1.02 (d, 6H). 63 'H NMR (400 MHz, Chloroform-d) 12.35 (br.s., 1H), 7.06-6.98 (m, 3H), 6.98-6.91 (m, 1H), 6 .86 (s, 1H), 6.79 (d, 2H), 4.80 - 4.57 (m, 2H), 4.38 (s, 2H), 4.29 (s, 2H), 3, 68 (d, 2H), 3.60 (d, 2H), 2.96 - 2.82 (m, 2H), 2.79 (s, 3H), 2.27 - 2.12 (m, 2H) , 2.11 - 1.99 (m, 1H), 1.92 (d, 2H), 1.00 (d, 6H). 446.3 64 SNMR (400 MHz, DMSO-db) δ 9.23 (s, 1H), 7.36 (d, 1H), 7.12 (d, 2H), 7.01 (t, 1H), 6.93 ( s, 1H), 6.85 - 6.77 (m, ZN), 4.41 (s, 2H), 4.25 - 4.16 (m, ZN), 3.74 (s, ZN), 3 .70 (d, 2H), 3.39 (d, 2H), 3.04 - 2.90 (m, 2H), 2.71 (d, 3H), 1.99 (dt, 1H), 1, 88 - 1.67 (m, 4H), 0.97 (d, 6H). 474.3 65 ^{1 H} NMR (400 MHz, DMSO-db) δ 9.10 (s, 1H), 7.14-7.05 (m, 3H), 7.05-6.93 (m, 2H), 6.90 (t, 1H), 6.83 (d, 2H), 4.27 (s, 3H), 4.15 (d, 2H), 3.84 (s, 3H), 3.70 (d, 2H) , 3.37 (d, 2H), 3.05 - 2.92 (m, 2H), 2.71 (d, ZN), 2.06 - 1.92 (m, 1H), 1.74 (d , 4H), 0.97 (d, 6H) 474.3 66 'H NMR (400 MHz, Chloroform-d) δ 12.87 (brs, 1H), 7.17 (q, 2H), 7.04-6.98 (m, 3H), 6.78 ( d, Hz, 2H), 4.77 (t, 1H), 4.70 (s, 1H), 4.32 (s, 2H), 4.28 (d, 2H), 3.82 (s, 3H ), 3.67 (d, 2H), 3.57 (d, 2H), 2.85 - 2.81 (m, 2H), 2.77 (s, 3H), 2.15 (q, 2H) , 2.10-2.01 (m, 1H), 1.89 (d, 2H), 1.00 (d, 6H). 508.4 67 'H NMR (400 MHz, Chloroform-d) δ 12.90 (br s, 1H), 7.65 (s, 1H), 7.45 (d, 1H), 7.29 (d, 1H) , 7.01 (d, 2H), 6.78 (d, 2H), 4.77 (t, 1H), 4.49 (s, 1H), 4.44 (s, 2H), 4.28 ( d, 2H), 3.67 (d, 2H), 3.58 (d, 2H), 2.91 - 2.78 (m, 2H), 2.77 (s, 3H), 2.40 - 2 .13 (m, 2H), 2.14 - 1.98 (m, 1H), 1.91 (d, 2H), 1.01 (d, 6H). 512.3 68 'H NMR (400 MHz, Chloroform-d) δ 12.76 (br.s., 1H), 7.38 - 7.23 (m, 3H), 7.01 (d, 2H), 6.78 ( d, 2H), 4.74 (t, 1H), 4.60 (br.s., 1H), 4.46 (s, 2H), 4.29 (s, 2H), 3.67 (d, 2H), 3.59 (d, 2H), 2.84 (t, 2H), 2.78 (s, 3H), 2.20 (q, 2H), 2.13-1.98 (m, 1H ), 1.91 (d, 2H), 1.01 (d, 6H). 496.3 69 'H NMR (400 MHz, Chloroform-d) δ 12.11 (s, 1H), 7.61 (s, 1H), 7.18 7.02 (m, 3H), 6.94 (d, 1H) , 6.79 (d, 2H), 4.64 (t, 1H), 4.49 (s, 2H), 4.27 471.3

- 76 042461

(s, 2H), 3.67 (d, 2H), 3.50 (d, 2H), 3.15 (s, 2H), 2.80 (d, 3H), 2.72 (s, 6H) , 2.58 - 2.40 (m, 2H), 2.13 - 1.99 (m, 1H), 1.87 (d, 2H), 1.01 (d, 6H). 70 Ή NMR (400 MHz, Chloroform-d) δ 12.78 (br.s., 1H), 7.04 (d, 2H), 7.02-6.88 (m, 2H), 6.80 (d , 2H), 4.76 - 4.54 (m, 2H), 4.34 (s, 2H), 4.29 (s, 2H), 3.68 (d, 2H), 3.58 (d, 2H), 2.93 - 2.73 (m, 5H), 2.19 (q, 2H), 2.12 - 1.99 (m, 1H), 1.89 (d, 2H), 1.01 (d, 6H). 464.3 71 Ή NMR (400 MHz, Chloroform-d) δ 12.62 (br.s., 1H), 7.05 (d, 2H), 6.89 (d, 2H), 6.81 (d, 2H), 4.91 (s, 1H), 4.60-4.48 (m, 1H), 4.36 (s, 2H), 4.29 (s, 2H), 3.70 (d, 2H), 3 .62 (d, 2H), 2.89 - 2.71 (m, 5H), 2.32 (q, 2H), 2.15 - 2.01 (m, 1H), 1.92 (d, 2H ), 1.02 (d, 6H). 480.3 72 ΉNMR (400 MHz, Chloroform-d) δ 12.34 (br.s., 1H), 7.31-7.22 (m, 1H), 7.06 (d, 2H), 6.87 (t, 2H), 6.80 (d, 2H), 5.04 (s, 1H), 4.61-4.50 (m, 1H), 4.40 (s, 2H), 4.29 (s, 2H ), 3.69 (d, 2H), 3.62 (d, 2H), 2.87 - 2.73 (m, 5H), 2.41 - 2.22 (m, 2H), 2.14 - 2.00 (m, 1H), 1.92 (d, 2H), 1.01 (d, 6H), 446.3

Example 73: 1-[(2,4-difluorophenyl)methyl]-3-{[4-( ² H ₃ )methoxyphenyl]methyl}-1-(1-methylpiperidin-4yl)urea (73) l /2t t \ G

4-(H ₃ )methoxybenzonitrile

A mixture of 4-hydroxybenzonitrile (1.20 g, 10.1 mmol), iodine ( ² H ₃ )methane (2.19 mg, 15.1 mmol) and K ₂ CO ₃ (2.78 g, 20.1 mmol) in DMF (10.0 mmol) was heated to 37°C for 20 hours Was added water (20 ml) and the mixture was extracted with diethyl ether (200 ml).

The organic phase was washed with water (3x40 ml), dried using Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired intermediate (1.29 g) which was used without further purification. [4-( ² H ₃ )methoxyphenyl]methanamine

LiAlH ₄ (713 mg, 18.8 mmol) was added to a solution of 4-( ² H ₃ )methoxybenzonitrile (1.28 g, 9.40 mmol) in THF (30 ml). The mixture was heated to reflux for 4 h, then cooled to room temperature. Water (0.7 ml), THF (10 ml), NaOH (0.7 ml, 15% aq) and water (2.1 ml) were added. The mixture was stirred for 30 min, filtered, concentrated under reduced pressure, redissolved in acetonitrile and concentrated again to give the desired intermediate (1.1 g) which was used without further purification.

Phenyl N- {[4-( ² H ₃ ) methoxyphenyl] methyl} carbamate

Phenyl chloroformate (1.60 g, 10.2 mmol) in CH ₂ Cl ₂ (10 ml) was added dropwise to a solution of [4( ² H ₃ )methoxyphenyl]methanamine (1.10 g, 7.85 mmol) and pyridine ( 0.95 ml) in CH ₂ Cl ₂ (10 ml) at 0°C. The mixture was stirred at this temperature for 20 minutes, then concentrated under reduced pressure. The residue was partitioned between diethyl ether (250 ml) and HCl (15.7 ml, 1 M aq.). The organic phase was washed with water (50 ml), dried using Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by crystallization from ethyl

- 77 042461 acetate and n-heptane to obtain the desired intermediate compound (1.56 g).

-[(2,4-Difluorophenyl)methyl]-3-{[4-( ^2H3 )methoxyphenyl]methyl}-1-(1-methylpiperidin- ₄ -yl)urea.

A mixture of phenyl N-{[4-( ² H ₃ )methoxyphenyl]methyl}carbamate (676 mg, 2.60 mmol), N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (480 mg, 2.00 mmol) and K ₂ CO ₃ (414 mg, 3.00 mmol) in toluene (6 ml) were heated to 75°C for 12 h.

The mixture was purified by column chromatography using silica gel eluting with 10% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the title compound (760 mg, 94%). ¹ H NMR (400 MHz, DMSO^) δ 7.26 -7.10 (m, 4H), 7.01 (dt, 2H), 6.85 (d, 2H), 4.40 (s, 2H) , 4.18 (d, 2H), 3.91 (dt, 1H), 2.71 (d, 2H), 2.10 (s, 3H), 1.88 (td, 2H), 1.57 - 1.42 (m, 4H); LC-MS: 407.3 [M+H]+.

Example 74: 1-[(2,4-difluorophenyl)methyl]-3-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea ( 74)

[2-Methoxy-4-(propan-2-yloxy)phenyl]methanamine

LiAlH ₄ (445 mg, 11.7 mmol) was added to a solution of 2-methoxy-4-(propan-2-yloxy)benzonitrile (1.12 g, 5.86 mmol) in THF (25 ml). The mixture was heated to reflux for 2 hours, then cooled to room temperature. Water (0.5 ml), THF (10 ml), NaOH (0.5 ml, 15% aq) and water (1.5 ml) were added. The mixture was stirred for 30 minutes, filtered, concentrated under reduced pressure to give the desired intermediate (1.00 g) which was used without further purification.

Phenyl N-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl}carbamate

Phenyl chloroformate (1.04 g, 6.66 mmol) in CH ₂ Cl ₂ (7 ml) was added dropwise to a solution of [2-methoxy4-(propan-2-yloxy)phenyl]methanamine (1.00 g, 5.12 mmol) and pyridine (0.62 ml) in CH ₂ Cl ₂ (7 ml) at 0°C. The mixture was stirred at this temperature for 20 minutes, then concentrated under reduced pressure. The residue was partitioned between diethyl ether (250 ml) and HCl (10.2 ml, 1 M aq.). The organic phase was washed with water (50 ml), dried using Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 20% ethyl acetate in petroleum ether to give the desired intermediate (1.00 g).

-[(2,4-Difluorophenyl)methyl]-3-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea.

A mixture of phenyl N-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl}carbamate (938 mg, 2.98 mmol), N[(2,4-difluorophenyl)methyl]-1-methylpiperidine- 4-amine (550 mg, 2.29 mmol) and K ₂ CO ₃ (474 mg, 3.43 mmol) in toluene (7 ml) were heated to 75°C for 12 h. The mixture was concentrated under reduced pressure, NaOH was added (16 ml, 0.4 M aq.) and diethyl ether (200 ml). The organic phase was washed with water (250 ml), dried using Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The mixture was purified by column chromatography using silica gel eluting with 7% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the title compound (700 mg, 66%). 1H NMR (400 MHz, chloroform-d) δ 7.12 (dd, 2H), 6.83 - 6.70 (m, 2H), 6.38 (dd, 1H), 6.32 (d, 1H) , 4.92 (t, 1H), 4.50 (g, 1H), 4.35 (s, 2H), 4.30 (dd, 1H), 4.25 (d, 2H), 3.52 ( s, 3H), 2.86 (d, 2H), 2.26 (s, 3H), 2.12 - 2.01 (m, 2H), 1.69 - 1.59 (m, 4H), 1 .32 (d, 6H); LC-MS: 462.3 [M+H] ⁺ .

Example 75: 1-[(2,4-difluorophenyl)methyl]-1-{1-[(1,1,1,3,3,3-2 ^H ₆ )propan-2-yl]piperidin-4-yl } -3-{[4(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (75)

- 78 042461

Phenyl N-{[4-(propan-2-yloxy)phenyl]methyl}carbamate

Phenyl chloroformate (1.84 ml, 15.4 mmol) in CH ₂ Cl ₂ (5 ml) was added dropwise to a solution of [4(propan-2-yloxy)phenyl]methanamine (2.0 g, 11.9 mmol) and pyridine (1.2 ml, 15.4 mmol) in CH ₂ Cl ₂ (10 ml) at 0°C. The mixture was stirred at this temperature for 1 hour, then partitioned between dichloromethane and HCl (0.4 M aq.). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by crystallization from ethyl acetate and n-heptane to give the desired intermediate (2.93 g).

tert-Butyl

4-{[(2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate

Phenyl N-{[4-(propan-2-yloxy)phenyl]methyl}carbamate mixture (892 mg, 3.13 mmol), tert-butyl 4{[(2,4-difluorophenyl)methyl]amino}piperidine-1 -carboxylate (1.02 g, 3.13 mmol) and K ₂ CO ₃ (605 mg, 4.38 mmol) in toluene (10 ml) were heated to 75°C for 21 h. The mixture was concentrated under reduced pressure, added diethyl ether (200 ml) and NaOH (30 ml, 1 M aq.). The aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases were washed with water (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography eluting with 50% ethyl acetate in petroleum ether to give the title compound (1.2 g, 74%).

-[(2,4-Difluorophenyl)methyl] -1 -(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea (142)

TFA (4 ml) was added to tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate (1 .20 g, 2.32 mmol) in CH ₂ Cl ₂ (10 ml) at room temperature. After 20 min stirring at room temperature, the mixture was concentrated under reduced pressure, NaHCO ₃ (10 ml, sat. aq.) and diethyl ether (150 ml) were added. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired intermediate (0.80 g) which was used without further purification or the resulting concentrate was purified by preparative HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid), to give 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)3-{[4-(propan-2-yloxy)phenyl]methyl}urea .

-[(2,4-Difluorophenyl)methyl]-1-{1-[(1,1,1,3,3,3-2H ₆ )propan-2-yl]piperidin-4-yl}-3-{ [4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid NaBH ₃ CN (117 mg, 1.87 mmol) was added to (2H ₆ )propan-2-one (120 mg, 1.87 mmol) and 1-[(2,4-difluorophenyl)methyl]-1- (piperidin-4-yl)-3-{[4-(propan2-yloxy)-phenyl]-methyl}-urea (260 mg, 0.623 mmol) in ethanol (4 ml). The mixture was stirred at

- 79 042461 room temperature for 18 hours, then add additional ( ² H6)propan-2-one (90 mg, 1.40 mmol). The mixture was stirred for an additional 4 days, then concentrated under reduced pressure. The crude material was purified by preparative HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (10 mg, 3%): ¹ H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.22 (dt, 2H), 7.15-7.02 (m, 4H), 6.83 (d, 2H), 4.56 (dt, 1H), 4 .41 (s, 2H), 4.27 (d, 2H), 4.19 (d, 2H), 3.34 (d, 2H), 2.98 (d, 2H), 1.94 - 1, 79 (m, 2H), 1.75 (d, 2H), 1.24 (d, 6H); LC-MS: 466.4 [M+H]+.

Example 76: 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; trifluoroacetic acid (76) n f ₃ c he tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[(4-propoxyphenyl)methyl]carbamoyl})amino}piperidine-1-carboxylate

A solution of (4-propoxyphenyl)methanamine (52.0 mg, 0.315 mmol) in CH ₂ Cl ₂ (1.0 ml) was added dropwise to a solution of diphosgene (23.0 μl, 0.192 mmol) in CH ₂ Cl ₂ (0. 5 ml) at room temperature. DIPEA (132 μl, 0.758 mmol) was added and the resulting mixture was stirred for 10 minutes at room temperature. A solution of tert-butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine 1-carboxylate (133 mg, 0.407 mmol) in CH ₂ Cl ₂ (1.0 ml) was then added and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1-5% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the desired intermediate (150 mg). 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; trifluoroacetic acid TFA (0.5 ml) was added to tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[(4propoxyphenyl)methyl]carbamoyl})amino}piperidine-1-carboxylate (80.4 mg , 0.155 mmol) in CH ₂ Cl ₂ (1.5 ml) at room temperature. After 30 minutes of stirring at room temperature, toluene (1.5 ml) was added and the mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (42 mg, 51%): ¹ H NMR (400 MHz, DMSO-66) δ 8.50 (d, 1H), 8.10 (d, 1H), 7.27 - 7.16 (m, 2H), 7.13 (d, 2H), 7.08 - 7.01 (m, 2H), 6.84 (d, 2H), 4.41 (s, 2H), 4.29 4.05 (m, 3H), 3.89 (t, 2H), 3.27 (d, 2H) , 2.89 (q, 2H), 1.84-1.62 (m, 6H), 0.96 (t, 3H); LC-MS: 418.3 Hz K I TP +

[M+N] ⁺ .

Example 77: 3-[(1H-1,3-benzodiazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin4-yl)urea; trifluoroacetic acid (77)

2-(Trimethylsilyl)ethyl 4-({[(1H-1,3-benzodiazol-5-yl)methyl]carbamoyl}[(2,4-difluorophenyl)methyl]amino)piperidine-1-carboxylate

- 80 042461

2-(Trimethylsilyl)ethyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate (102 mg, 0.240 mmol) in DMF (2.0 mL) was added dropwise to a solution of ( 1H-1,3-benzodiazol-5yl)methanamine dihydrochloride (51.6 mg, 0.234 mmol) and DIPEA (143 μl, 0.821 mmol) in DMF (1.0 ml). The mixture was stirred for 4 days at room temperature, then additional 2(trimethylsilyl)ethyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate (34.4 mg, 0.081 mmol) was added . The mixture was stirred for an additional hour, then concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1-10% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the desired intermediate (111 mg).

3-[(1H-1,3-Benzodiazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea

TBAF (0.6 ml, 1 M in THF) was added to 2-(trimethylsilyl)ethyl 4-({[(1H-1,3-benzodiazol-5yl)methyl]carbamoyl}[(2,4-difluorophenyl)methyl] amino)piperidine-1-carboxylate (111 mg, 0.204 mmol) in THF (1.5 ml) at room temperature. After 3 hours the mixture was heated to 50°C and stirred at this temperature overnight, then concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1-100% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the desired intermediate (110 mg).

3-[(1H-1,3-Benzodiazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid.

Formaldehyde (30.5 µl, 37% aq., 0.303 mmol) was added dropwise to a solution of 3-[(1H-1,3-benzodiazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]- 1-(piperidin-4-yl)urea (110 mg, 0.275 mmol) in ethanol (2.0 ml) at room temperature. NaBH ₃ CN (26.0 mg, 0.414 mmol) was added portionwise and the reaction mixture was stirred for 3 h at room temperature. The mixture was concentrated under reduced pressure and partitioned between CH ₂ Cl ₂ (3.0 ml) and NaOH (3.0 ml, 1 M aq.). The aqueous phase was extracted with CH ₂ Cl ₂ (3x3 ml), the combined organic phases were dried using a phase separator and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel eluting with 5-10% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.), followed by purification by preparative HPLC eluting with 5-30% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (31 mg, 21%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (br s, 1H), 9.33 (s, 1H), 7.75 (d, 1H), 7.65 (s, 1H) , 7.41 (d, 1H), 7.32 (t, 1H), 7.26 - 7.15 (m, 2H), 7.04 (t, Hz, 1H), 4.43 (s, 4H ), 4.31 - 4.18 (m, 1H), 3.40 (d, 2H), 2.98 (t, 2H), 2.72 (s, 3H), 1.91 - 1.67 ( m, 4H); LC-MS: 414.3 [M+H]+.

Example 78 (comparative): 1-[(2,4-difluorophenyl)methyl]-1-(1-methylazepan-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid (78)

tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}azepane-1-carboxylate

- 81 042461

(2,4-Difluorophenyl)methanamine (112 mg, 0.779 mmol) was added to tert-butyl 4-oxoazepane-1-carboxylate (153 mg, 0.719 mmol) in CH ₂ Cl ₂ (2.0 mL) followed by sodium triacetoxyborohydride (248 mg, 1.17 mmol). The reaction mixture was stirred for 20 h at room temperature. Then NaOH (2 ml, 1 M, aq.) was added and the mixture was extracted with CH ₂ Cl ₂ (2x1.0 ml). The organic phase was dried using a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1-10% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the desired racemic intermediate (219 mg). tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}azepane-1-carboxylate)

A solution of [4-(propan-2-yloxy)phenyl]methanamine (100 mg, 0.294 mmol) in CH ₂ Cl ₂ (1.0 ml) was added dropwise to a solution of diphosgene (17.6 μl, 0.147 mmol) in CH ₂ Cl ₂ (0.5 ml) at room temperature. DIPEA (102 μl, 0.588 mmol) was added and the resulting mixture was stirred for 17 minutes at room temperature. After that, a solution of tert-butyl 4-{[(2,4-difluorophenyl)methyl]amino}azepane-1-carboxylate (58.0 mg, 0.351 mmol) in CH ₂ Cl ₂ (1.0 ml) was added and the reaction mixture stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel eluting with 1-10% methanol in CH2Cl2 containing 1% ammonia (28% aq) to give the desired intermediate (83.0 mg). 1-(azepan-4-yl)-1-[(2,4-difluorophenyl)methyl]-3-{[4-(propan-2-yloxy)phenyl]methyl}urea

TFA (0.3 ml) was added to tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}azepane-1-carboxylate (82.0 mg, 0.154 mmol) in CH ₂ Cl ₂ (3.0 ml) at room temperature. After 2 hours stirring at room temperature, toluene (1.0 ml) was added and the mixture was concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel eluting with 1-10% methanol in CH ₂ Cl ₂ containing 1% ammonia (28% aq.) to give the desired intermediate (13.7 mg, 21%).

1-[(2,4-Difluorophenyl)methyl]-1-(1-methylazepan-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid.

Formaldehyde (9.6 µl, 37% aq., 0.096 mmol) was added dropwise to a solution of 1-(azepan-4-yl)-1[(2,4-difluorophenyl)methyl]-3-{[4-(propane -2-yloxy)phenyl]methyl}urea (13.7 mg, 0.032 mmol) in ethanol (2.0 ml) at room temperature. NaBH ₃ CN (6.7 mg, 0.107 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (12 mg, 68%): ¹ H NMR (400 MHz, methanol-b ₄ ) δ 7.24 (q, 1H), 7.15 (d, 2H), 6.95 (dt, 2H), 6.83 (d, 2H), 4.63-4.47 (m, 3H), 4.28 (s, 2H), 4.26-4.04 (m, 1H), 3.56-3.42 (m, 2H), 3.29-3.02 (m, 2H), 2, 89 (s, 3H), 2.33-1.62 (m, 7H), 1.31 (d, 6H);

- 82 042461

LC-MS: 446.3 [M+H]+.

Example 79: 1-[(7R,8aS)-octahydroindolizin-7-yl]-3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4difluorophenyl)methyl]urea; trifluoroacetic acid (79)

A solution of (4-cyclopropoxyphenyl)methanamine (0.040 ml, 0.257 mmol) in dichloromethane (1 ml) was added dropwise to a solution of diphosgene (0.015 ml, 0.129 mmol) in dichloromethane (1 ml) at room temperature. DIPEA (0.134 ml, 0.772 mmol) was added and the resulting mixture was stirred for 5 minutes at room temperature. A solution of (7R,8aS)-N-[(2,4-difluorophenyl)methyl]octahydroindolizine-7-amine (75.4 mg, 0.283 mmol) in dichloromethane (1 mL) was then added and the reaction mixture was stirred overnight at room temperature.

The mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC eluting with acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (84 mg, 54%). 1H NMR (400 MHz, chloroform-d) δ 12.20 (br s, 1H), 7.177.08 (m, 1H), 7.06-7.00 (m, 2H), 6.98-6, 91(m, 2H), 6.87-6.78(m, 2H), 4.96-4.84(m, 1H), 4.69(brs, 1H), 4.37(s, 2H), 4.29 (s, 2H), 3.93 (br s, 1H), 3.74-3.66 (m, 1H), 3.61-3.49 (m, 1H), 3 .48-3.40 (m, 1H), 3.16-3.06 (m, 1H), 3.04-2.90 (m, 1H), 2.34-2.08 (m, 6H) , 1.98 (d, 1H), 1.86 (d, 1H), 0.82-0.70 (m, 4H). LC-MS: 456.3 [M+H]+

Example 80: 1-[(7R,8aS)-octahydroindolizin-7-yl]-1-[(2,4-difluorophenyl)methyl]-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid (80)

[A solution of [4-(propan-2-yloxy)phenyl]methanamine (0.023 ml, 0.148 mmol) in dichloromethane (1 ml) was added dropwise to a solution of diphosgene (0.009 ml, 0.074 mmol) in dichloromethane (1 ml) at room temperature . DIPEA (0.077 ml, 0.445 mmol) was added and the resulting mixture was stirred for 5 minutes at room temperature. A solution of (7R,8aS)-N-[(2,4-difluorophenyl)methyl]octahydroindolizine-7-amine (43.4 mg, 0.163 mmol) in dichloromethane (1 mL) was then added and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC eluting with acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (42 mg, 48%). 1H NMR (400 MHz, chloroform-d) δ 12.20 (s, 1H), 7.13 (q, 1H), 7.01 (d, 2H), 6.87 - 6.76 (m, 4H) , 4.97-4.83(m, 1H), 4.72-4.61(m, 1H), 4.51(sep, 1H), 4.37(s, 2H), 4.28(s , 2H), 3.96 (brs, 1H), 3.62-3.49 (m, 1H), 3.48-3.40 (m, 1H), 3.17-3.06 (m , 1H), 3.04-2.90 (m, 1H), 2.36-2.10 (m, 6H), 1.98 (d, 1H), 1.86 (d, 1H), 1, 32 (d, 6H). LC-MS: 458.3 [M+H]+

Example 81: 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea (81)

To a solution of (quinoxalin-b-yl)methanamine (24 mg, 0.150 mmol) in CH ₂ Cl ₂ (5 ml) was added DIPEA (0.1 ml, 0.600 mmol) followed by 2-(trimethylsilyl)ethyl 4-[( chlorocarbonyl)[(2,4difluorophenyl)methyl]amino]piperidine-1-carboxylate (78 mg, 0.180 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were evaporated in vacuo. Brine (5.0 ml) was added and the compound was extracted with CH ₂ Cl ₂ (4x7 ml). The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed by rotary evaporation. The crude material was purified by column chromatography using silica gel eluting with ethyl acetate in petroleum ether to give 2-(trimethylsilyl)ethyl 4-{[(2,4-difluorophenyl)methyl]({[(quinoxalin-6-yl)me

- 83 042461 tyl]carbamoyl})amino}piperidine-1-carboxylate (80 mg, 95%).

TBAF (2 ml, 1 M in THF) was added to 2-(trimethylsilyl)ethyl 4-{[(2,4-difluorophenyl)methyl]({[(quinoxalin-6-yl)methyl]carbamoyl})amino}piperidine- 1-carboxylate (80 mg, 0.144 mmol) in THF (1 ml) at room temperature. After 3 hours the mixture was heated to 50° C. and stirred at this temperature overnight. The mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC eluting with acetonitrile in water (containing 6 ppm ammonia) to give the title compound (40 mg, 65%). ¹ H-NMR (400 MHz, chloroform-d) δ 8.83 (d, 2H), 8.05 (d, 1H), 7.88 (s, 1H), 7.65 (dd, 1H), 7 .35 - 7.27 (m, 1H), 6.93 - 6.72 (m, 2H), 4.86 (d, 1H), 4.66 (d, 2H), 4.43 (d, 3H ), 3.16 (d, 2H), 2.73 (t, 2H), 2.13 (s, 1H), 1.78 (d, 2H), 1.68 -1.52 (m, 2H) . LC-MS: 412.2 [M+H]+.

Example 82 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea(82)

Formaldehyde (0.010 mg, 37% aq., 0.122 mmol) was added to a stirred solution of 1-[(2,4difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(quinoxalin-6-yl)methyl] urea (23 mg, 0.056 mmol) in ethanol (3 ml). Next, NaBH(OAc) ₃ (35.5 mg, 0.168 mmol) was added in portions and the reaction mixture was stirred for 4 hours at room temperature. The volatiles were evaporated in vacuo. CH ₂ Cl ₂ (7 ml) was added and the organic phase was washed with NaHCO ₃ (sat. aq.). The crude material was purified by preparative HPLC eluting with acetonitrile in water (containing 6 ppm ammonia) to give the title compound (15 mg, 60%): ¹ H NMR (400 MHz, chloroform-d) δ 8.83 (d , 2H), 8.05 (d, 1H), 7.88 (s, 1H), 7.65 (dd, 1H), 7.33-7.23 (m, 1H), 6.95-6, 68 (m, 2H), 4.93-4.83 (m, 1H), 4.65 (d, 2H), 4.48 (s, 2H), 4.40-4.27 (m, 1H) , 2.97 (d, 2H), 2.33 (s, 3H), 2.24-2.10 (m, 2H), 1.92-1.70 (m, 4H). LC-MS: 426.3 [M+H] ⁺

Example 83: 3-[(4,5-difluoro-2-methoxyphenyl)methyl]-3-(piperidin-4-yl)-1-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (83)

tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]amino}piperidine-1-carboxylate

(4,5-Difluoro-2-methoxyphenyl)methanamine (191 mg) and tert-butyl 4-oxo-piperidine-1-carboxylate (200 mg) were dissolved in ethanol. Sodium triacetoxyborohydride (319 mg) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was diluted with Na ₂ CO ₃ (sat. aq.) and was extracted with dichloromethane. The organic phase was dried and concentrated to give the desired intermediate (379 mg).

tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate

- 84 042461 tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]amino}piperidine-1-carboxylate (82 mg) was stirred in dichloromethane (1 ml) at room temperature. 1(Isocyanatomethyl)-4-(propan-2-yloxy)benzene (44 mg) dissolved in dichloromethane (0.5 ml) was added dropwise. Stir the reaction mixture overnight. The mixture was concentrated under reduced pressure and the desired urea was purified by silica gel column chromatography eluting with 50-70% ethyl acetate in petroleum ether to give the desired intermediate (77 mg).

3-[(4,5-Difluoro-2-methoxyphenyl)methyl]-3-(piperidin-4-yl)-1-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid.

tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate (77 mg) was dissolved in dichloromethane (1.4 ml). The solution was cooled to 0° C., trifluoroacetic acid was added and the reaction mixture was stirred for 90 minutes. The mixture was concentrated and the crude material was purified by HPLC eluting with 20-55% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (49 mg, 62%): 1H NMR (400 MHz, chloroform-d) δ 9.57 (s, 1H), 9.09 (s, 1H), 7.05 (d, 2H), 7.00 - 6.91 (m, 1H), 6.80 (d, 2H), 6.65 (dd, 1H), 4.73 (s, 1H), 4.67 (d.s., 1H), 4.51 (hept, 1H), 4.28 (s, 2H), 4. 24 (s, 2H), 3.72 (s, 3H), 3.42 (d, 2H), 3.03 - 2.79 (m, 2H), 2.03 - 1.85 (m, 4H) , 1.32 (d, 6H); LC-MS: 448.3 [M+H]+.

Example 84 (comparative): 3-[(2,4-difluorophenyl)methyl]-3-[(1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-1 -{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (84) f o

F (1R,3R,5S)-N-[(2,4-difluorophenyl)methyl]-8-methyl-8-azabicyclo[3.2.1]octane-3-amine F

(2,4-Difluorophenyl)methanamine (112 mg, 779 µmol) was added to 8-methyl-8-azabicyclo[3.2.1]octan3-one (99.6 mg, 716 µmol) in dichloromethane (2 ml). After 10 minutes of stirring at room temperature, sodium triacetoxyborohydride (224 mg, 1.06 µmol) was added. After another 21 hours of stirring, sodium hydroxide (2 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (3x1 ml), the organic phase was dried using a phase separator and concentrated to an oil. The crude material was purified by silica gel column chromatography eluting with 5-10% methanol in dichloromethane containing 1% ammonia (28% aqueous solution) to give the desired intermediate (174 mg).

3-[(2,4-Difluorophenyl)methyl]-3-[(1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-1-{[4-( propan2-yloxy)phenyl]methyl}urea; trifluoroacetic acid.

A solution of [4-(propan-2-yloxy)phenyl]methanamine (75.0 mg, 0.454 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a solution of diphosgene (16.9 μl, 0.141 mmol) in CH ₂ Cl ₂ (0.5 ml) at room temperature. DIPEA (98.1 μl, 0.563 mmol) was added and the resulting mixture was stirred for 5 minutes at room temperature. Then a solution of (1R,3R,5S)-N-[(2,4-difluorophenyl)methyl]-8-methyl-8azabicyclo[3.2.1]octane-3-amine (56.0 mg, 0.210 mmol) in CH ₂ Cl ₂ (1 ml) and the reaction mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (101 mg, 78%): 1H NMR (400 MHz, chloroform-d) δ 11 .75 (s, 1H), 7.33 - 7.24 (m, 1H), 7.15 (d, 2H), 6.90 - 6.72 (m, 4H), 4.52 (hept, 1H ), 4.32 (s, 2H), 4.30 (s, 2H), 4.06 (n, 1H), 3.74 (d, 2H), 2.69 - 2.54 (m, 5H) , 2.36 - 2.12 (m, 6H), 1.32 (d, 6H); LC-MS: 458.3 [M+H] ⁺ .

Example 85 1-[(2,4-difluorophenyl)methyl]-1-[(3R,4S)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2yloxy)phenyl]methyl }urea; trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]-1-[(3S,4R)-1,3dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl]methyl }urea; trifluoroacetic acid (85)

- 85 042461

1-[(2,4-Difluorophenyl)methyl]-1-[(3R,4S)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl]methyl} urea; trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]-1-[(3S,4R)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl ]methyl}urea; trifluoroacetic acid

(3R,4S)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (3S,4R)-N-[(2,4-difluorophenyl)methyl]-1, 3-dimethylpiperidine-4-amine

(3R,4R)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (3S,4S)-N-[(2,4-difluorophenyl)methyl]-1, 3-dimethylpiperidine-4-amine

F F

1,3-Dimethylpiperidin-4-one (91.0 mg, 715 µmol) was added to (2,4-difluorophenyl)methanamine (105 mg, 734 µmol) in dichloromethane (1 ml). After 5 minutes of stirring at room temperature, sodium triacetoxyborohydride (234 mg, 1.10 mmol) was added. After an additional 3 hours of stirring, sodium hydroxide (1 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (1 ml), the organic phase was dried using a phase separator and concentrated. The crude material was purified by column chromatography using silica gel eluting with 1-10% methanol in dichloromethane containing 1% ammonia (28% aqueous solution) to give the cis intermediates: (3R,4S)-N-[(2, 4-difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (3S,4R)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine (105 mg), as well as trans intermediates: (3R,4R)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (38.48)-X-[(2,4- difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine (14 mg).

1-[(2,4-Difluorophenyl)methyl]-1-[(3R,4S)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl]methyl} urea; trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]-1-[(3S,4R)-1,3dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl]methyl }urea; trifluoroacetic acid.

A solution of [4-(propan-2-yloxy)phenyl]methanamine (24.9 mg, 0.151 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a solution of diphosgene (9.1 μl, 0.076 mmol) in CH ₂ Cl ₂ (0.5 ml) at room temperature. DIPEA (52.0 μl, 0.298 mmol) was added and the resulting mixture was stirred for 10 minutes at room temperature. After that, a solution of cis intermediates was added: (3R,4S)-N-[(2,4difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (3S,4R)-N-[(2,4- difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine (43.4 mg, 0.171 mmol) in CH ₂ Cl ₂ (1 ml) and the reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure. The crude material was purified by HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title cis compounds (62 mg, 74%): 1H NMR (400 MHz, chloroform-d) δ 12.59 (br s, 1H), 7.13 - 7.01 (m, 1H), 6.98 (d, 2H), 6.89 - 6.71 (m, 4H), 4.71 - 4.11 (m, 7H), 3.71 (d, 1H), 3.38 (d, 1H), 3.13 - 3.01 (m, 1H), 2.85 - 2.66 (m, 5H), 2.40 (qvd, 1H), 1.63 (d, 1H), 1.36-1.19 (m, 9H); LC-MS: 446.3 [M+H]+.

1-[(2,4-Difluorophenyl)methyl]-1-[(3R,4R)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)fe

- 86 042461 nyl]methyl}urea; trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]-1-[(3S,4S)-1,3-dimethylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl ]methyl}urea; trifluoroacetic acid.

A solution of [4-(propan-2-yloxy)phenyl]methanamine (8.7 mg, 0.053 mmol) in CH ₂ Cl ₂ (0.5 ml) was added dropwise to a solution of diphosgene (3.1 μl, 0.026 mmol) in CH ₂ Cl ₂ (0.5 ml) at room temperature. DIPEA (18.0 μl, 0.103 mmol) was added and the resulting mixture was stirred for 10 minutes at room temperature. After that, a solution of trans intermediates was added: (3R,4R)-N-[(2,4difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (3S,4S)-N-[(2,4- difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine (14.1 mg, 0.055 mmol) in CH ₂ Cl ₂ (1 ml) and the reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure. The crude material was purified by HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title trans compounds (14 mg, 48%): 1H NMR (400 MHz, chloroform-d) δ 12.96 (brs, 1H), 7.13 (q, 1H), 7.05-6.91 (m, 2H), 6.85-6.72 (m, 4H), 4.84- 4.43 (m, 3H), 4.42 4.17 (m, 4H), 3.53 (dd, 2H), 2.89 - 2.70 (m, 4H), 2.54 (t, 1H ), 2.49 -2.32 (m, 1H), 2.16 - 1.95 (m, 1H), 1.86 (d, 1H), 1.31 (d, 6H), 0.93 ( e, 3H); LC-MS: 446.3 [M+H]+.

Example 86: 1-[(2,4-difluorophenyl)methyl]-1-(1,4-dimethylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (86)

tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}-4-methylpiperidine-1-carboxylate

2,4-Difluorobenzaldehyde (199 mg, 1.40 mmol) in dichloromethane (0.5 ml) was added to tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (330 mg, 1.54 mmol) in dichloromethane (0.54 mmol) 5 ml). After 10 minutes of stirring at room temperature, sodium triacetoxyborohydride (445 mg, 2.10 mmol) was added. After an additional 18 hours of stirring, sodium hydroxide (2 ml, 1 M aqueous solution) was added, the mixture was extracted with dichloromethane (2x1 ml), the combined organic phases were separated, dried using a phase separator and concentrated. The crude material was purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane containing 1% ammonia (28% aqueous solution) to give the desired intermediate (366 mg). Tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}-4-methylpiperidine-1-carboxylate

A solution of [4-(propan-2-yloxy)phenyl]methanamine (45 mg, 0.272 mmol) in dichloromethane (0.5 ml) was added to a stirred solution of diphosgene (16.3 μl, 136 μmol) in dichloromethane (0.5 ml ) at room temperature to give a suspension. After completion of the addition, diisopropylethylamine (95 μl, 0.545 mmol) was added dropwise to give a clear solution and gas evolution. After 5 minutes of stirring at room temperature, a solution of tert-butyl 4-{[(2,4-difluorophenyl)methyl]amino}-4-methylpiperidine-1-carboxylate (100 mg, 0.294 mmol) in dichloromethane (0.5 ml ). After an additional 90 minutes of stirring at room temperature, the mixture was concentrated to an oil. The crude material was purified by column chromatography using silica gel,

- 87 042461 eluting with 6-25% ethyl acetate in petroleum ether to give the desired intermediate (146 mg).

1-[(2,4-Difluorophenyl)methyl]-1-(4-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea

Trifluoroacetic acid (100 µl) was added to tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}4-methylpiperidine-1-carboxylate (62 mg, 117 µmol) in dichloromethane (0.9 ml). After 2 h stirring at room temperature, sodium hydroxide (2 ml, 1 M aqueous solution) and water (2 ml) were added. The mixture was extracted with dichloromethane (3 ml), the organic phase was dried using a phase separator and concentrated. The crude material was purified by column chromatography using silica gel eluting with 5-10% methanol in dichloromethane containing 1% NH ₃ (28% aqueous solution) to give the desired intermediate (45 mg). 1-[(2,4-difluorophenyl)methyl]-1-(1,4-dimethylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid Formaldehyde (13 µl, 37%, 129 µmol) was added to 1-[(2,4-difluorophenyl)methyl]-1-(4-methylpiperidin-4-yl)-3-{[4-(propane-2 -yloxy)phenyl]methyl}urea (45 mg, 104 µmol) in ethanol (1 ml). After 70 minutes of stirring at room temperature, sodium triacetoxyborohydride (67 mg, 316 μmol) was added. After 2 hours of stirring at room temperature, the mixture was concentrated to an oil. The crude material was purified by HPLC eluting with 20-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (28.1 mg, 48%): ¹ H NMR (400 MHz, chloroform-d) δ 12.49 (brs, 1H), 7.36-7.17 (m, 1H), 7.09-6.96 (m, 2H), 6.95-6.70 (m, 4H), 4.62 - 4.55 (m, 1H), 4.50 (p, 1H), 4.43 (s, 2H), 4.26 - 4.19 (m, 2H), 3.49 (d, 2H), 2.90 - 2.71 (m, 5H), 2.58 (d, 2H), 2.26 (t, 2H), 1.62 (s, 3H), 1.33 - 1.28 (m, 6H); LC-MS: 446.3 [M+H]+.

Example 87: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (87)

4-(2-Hydroxy-2,3-dimethylbutoxy)benzonitrile ।

He

Isopropyl magnesium bromide (1.48 ml, 1.3 M in tetrahydrofuran) was added dropwise to 4-(2oxopropoxy)benzonitrile (260 mg, 1.48 mmol) in diethyl ether (20 ml) at room temperature. After 1 day of stirring at room temperature, ammonium chloride (10 ml, sat. aq.) was added. The mixture was extracted with diethyl ether (50 ml), the organic phase was washed with brine, dried using magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether to give the desired intermediate (63 mg).

1-[4-(Aminomethyl)phenoxy]-2,3-dimethylbutan-2-ol

Borane (862 μl, 1M in tetrahydrofuran) was added to 4-(2-hydroxy-2,3-dimethylbutoxy)benzonitrile (63 mg, 287 μmol) in tetrahydrofuran (1 ml). After 2 days of stirring at room temperature, methanol (6 ml) was added, the mixture was heated to 75° C. and concentrated. After 15 h the mixture was concentrated to give the desired intermediate (69 mg).

tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2-hydroxy-2,3-dimethylbutoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate

- 88 042461

1-[4-(Aminomethyl)phenoxy]-2,3-dimethylbutan-2-ol (68.9 mg, 309 µmol) and diisopropylethylamine (131 µl, 936 µmol) were added to tert-butyl 4-[(chlorocarbonyl)[ (2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate (120 mg, 309 µmol) in dichloromethane (2 ml). After 18 h stirring at room temperature, sodium hydroxide (1 ml, 1 M aqueous solution) was added, the organic phase was dried using a phase separator and concentrated to an oil (223 mg).

1-[(2,4-Difluorophenyl)methyl]-3-{[4-(2-hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(piperidin-4yl)urea

Trifluoroacetic acid (100 µl) was added to tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2hydroxy-2,3-dimethylbutoxy)phenyl]methyl}carbamoyl)amino}piperidine-1- carboxylate (223 mg, 387 µmol) in dichloromethane (0.9 ml). After 17 hours of stirring at room temperature, additional trifluoroacetic acid (100 μl) was added. After 5 hours stirring at room temperature, additional trifluoroacetic acid (100 μl) was added. After 22 h stirring at room temperature, sodium hydroxide (1 ml, 1 M aqueous solution) was added, the organic phase was dried using a phase separator and concentrated. The crude material was purified by column chromatography using silica gel eluting with butanol, water, ethyl acetate and acetic acid in a ratio of 1:1:1:1 to give the desired intermediate (49.6 mg).

1-[(2,4-Difluorophenyl)methyl]-3-{[4-(2-hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid.

Formaldehyde (12.6 µl, 37%, 125 µmol) was added to 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1- (piperidin-4-yl)urea (49.6 mg, 104 µmol) in tetrahydrofuran (1 ml). After 50 minutes of stirring at room temperature, sodium triacetoxyborohydride (45 mg, 212 μmol) was added. After 19 hours of stirring at room temperature, the mixture was concentrated to an oil. The crude material was purified by HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (18 mg, 29%): 1H NMR (400 MHz, chloroform-d) δ 12, 78(brs, 1H), 7.12(q, 1H), 7.04(d, 2H), 6.84-6.78(m, 4H), 4.78-4.64(m, 2H ), 4.36 (s, 2H), 4.28 (d, 2H), 3.87 (d, 1H), 3.77 (d, 1H), 3.57 (d, 2H), 2.83 (t, 2H), 2.76 (s, 3H), 2.21 (q, 2H), 2.03 - 1.94 (m, 1H), 1.89 (d, 2H), 1.18 ( s, 3H), 1.00 (d, 3H), 0.92 (d, 3H); LCMS: 490.3 [M+H]+.

Example 88: 1-[(2,4-difluorophenyl)methyl]-3-({3-fluoro-4-[(2-hydroxyethoxy)methyl]phenyl}methyl)-1-(1methylpiperidin-4-yl)urea; trifluoroacetic acid (88)

[4-({2-[(tert-Butyldiphenylsilyl)oxy]ethoxy}methyl)-3-fluorophenyl]methanamine

tert-Butyl(chloro)diphenylsilane (97.7 μl, 0.376 mmol) and 4-dimethylaminopyridine (3.06 mg, 0.025

- 89 042461 mmol) was added to a solution of 2-{[4-(aminomethyl)-2-fluorophenyl]methoxy}ethan-1-ol (49.9 mg, 0.250 mmol) and triethylamine (105 μl, 0.751 mmol) in dichloromethane ( 1 ml). After 2 h stirring at room temperature, NaOH (1 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (3x2 ml), the combined organic phases were dried using a phase separator and concentrated to give the desired intermediate as an oil (110 mg).

3-{[4-({2-[(tert-Butyldiphenylsilyl)oxy]ethoxy}methyl)-3-fluorophenyl]methyl}-1-[(2,4difluorophenyl)methyl]-1-(1-methylpiperidine-4- silt) urea

A solution of [4-({2-[(tert-butyldiphenylsilyl)oxy]ethoxy}methyl)-3-fluorophenyl]methanamine (110 mg, 0.251 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a solution of diphosgene (15 .5 μl, 0.128 mmol) in CH ₂ Cl ₂ (0.5 ml) at room temperature. DIPEA (131 μl, 0.753 mmol) was added and the resulting mixture was stirred for 10 minutes at room temperature. After that, a solution of N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (103 mg, 0.427 mmol) in CH2Cl2 (1 ml) was added and the reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and used without further purification.

-[(2,4-Difluorophenyl)methyl]-3-({3-fluoro-4-[(2-hydroxyethoxy)methyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid.

Tetrabutylammonium fluoride (0.5 ml, 1M in tetrahydrofuran) was added to a solution of 3-{[4-({2-[(tert-butyldiphenylsilyl)oxy]ethoxy}methyl)-3-fluorophenyl]methyl}-1-[(2.4 -difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (117 mg, 0.166 mmol) in tetrahydrofuran (0.5 ml). After 1.5 hours stirring at room temperature, the mixture was concentrated. The crude material was purified by HPLC eluting with 2050% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (26.5 mg, 18% over 3 steps): 1H NMR (400 MHz, chloroform-d) δ 13.01 (br s, 1H), 7.30 (t, 1H), 7.15 (q, 1H), 6.90 (d, 1H), 6.87 - 6.78 (m, 3H ), 4.88 (t, 1H), 4.72-4.61 (m, 1H), 4.57 (s, 2H), 4.40 (s, 2H), 4.33 (d, 2H) , 3.78 - 3.71 (m, 2H), 3.63 - 3.50 (m, 4H), 2.90 - 2.73 (m, 5H), 2.23 (q, 2H), 1 .89 (d, 2H); LC-MS: 466.3 [M+H]+.

Example 89: N(5-fluoro-2-{[1-(1-methylpiperidin-4-yl)({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino]methyl}phenyl)acetamide; trifluoroacetic acid (89)

N-(5-fluoro-2-formylphenyl)acetamide

Acetic anhydride (143 μl, 1.29 mmol) was added to a solution of 2-amino-4-fluorobenzaldehyde (119 mg, 0.858 mmol) in tetrahydrofuran (1 ml). After 5 hours of stirring at room temperature, acetic anhydride (143 μl, 1.29 mmol) was added. After 16 hours of stirring at room temperature, the mixture was concentrated. The crude material was purified by silica gel column chromatography eluting with 3-25% ethyl acetate in petroleum ether to give the desired intermediate as an oil (115 mg).

K-(5-Fluoro-2-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl)acetamide

- 90 042461

1-Methylpiperidin-4-amine (42.0 μl, 0.335 mmol) was added to a solution of N(5-fluoro-2-formylphenyl)acetamide (66.6 mg, 0.368 mmol) in dichloromethane (1 ml), sodium triacetoxyborohydride ( 118 mg, 0.555 mmol) per serving. After 3 hours of stirring at room temperature, dichloromethane (1 ml) was added and the mixture was heated to 40°C. After 3 h, the mixture was cooled to room temperature and stirred for 4 days, then NaOH (2 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (1 ml), the combined organic phases were dried using a phase separator and concentrated to give the desired intermediate as an oil (126 mg). N-(5-fluoro-2-{[1-(1-methylpiperidin-4-yl)({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino]methyl}phenyl)acetamide; trifluoroacetic acid 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene (150 mg, 0.668 mmol). Was added to a solution of N-(5-fluoro-2-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl)acetamide (126 mg, 0.450 mmol) in dichloromethane (1 ml). After 17 hours of stirring at room temperature, the mixture was concentrated. The crude material was purified by HPLC eluting with 30-60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (12.1 mg, 5%): 1H NMR (400 MHz, chloroform-d) δ 12.45 (br s, 1H), 9.22 (s, 1H), 7.37 (d, 1H), 7.12 (d, 2H), 7.06 (dd, 1H), 6.85 - 6.74 (m, 3H), 5.28 (s, 1H), 4.73 - 4.40 (m, 4H), 4.30 (d, 2H), 3.43 (d, 2H), 2.79 (d, 5H), 2.46 (q, 2H), 2.20 (s, 3H), 1.78 (d, 2H), 1.31 (d, 6H); LC-MS: 471.3 [M+H]+.

Example 90: 1-{[2-Hydroxy-4-(trifluoromethyl)phenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (90)

2-[(tert-Butyldiphenylsilyl)oxy]-4-(trifluoromethyl)benzaldehyde

tert-Butyl(chloro)diphenylsilane (210 µl, 0.808 mmol) was added to a solution of 2-hydroxy-4(trifluoromethyl)benzaldehyde (102 mg, 0.536 mmol), 4-dimethylaminopyridine (12.6 mg, 0.103 mmol) and triethylamine (220 μl, 1.58 mmol) in dichloromethane (2 ml). After 17 hours of stirring at room temperature, HCl (2 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (3 x 2 ml), the combined organic phases were dried using a phase separator and concentrated. The crude material was purified by silica gel column chromatography eluting with 3-25% ethyl acetate in petroleum ether to give the desired intermediate as an oil (248 mg).

N-({2-[(tert-butyldiphenylsilyl)oxy]-4-(trifluoromethyl)phenyl}methyl)-1-methylpiperidin-4-amine

- 91 042461

1-Methylpiperidin-4-amine (72.6 µl, 0.579 mmol) was added to a solution of 2-[(tert-butyldiphenylsilyl)oxy]-4-(trifluoromethyl)benzaldehyde (248 mg, 0.579 mmol) in dichloromethane (3 ml), sodium triacetoxyborohydride (193 mg, 0.911 mmol) was added in one portion. After 18 hours of stirring at room temperature, NaOH (2 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (3x2 ml), the combined organic phases were dried using a phase separator and concentrated to give the desired intermediate as an oil (219 mg).

-({2-[(tert-Butyldiphenylsilyl)oxy]-4-(trifluoromethyl)phenyl}methyl)-1-(1-methylpiperidin-4-yl)3-{[4-(2-methylpropoxy)phenyl]methyl} urea

A solution of 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene (48 mg, 0.187 mmol) in dichloromethane (0.5 ml) was added to a solution of N-({2-[(tert-butyldiphenylsilyl)oxy]-4- (trifluoromethyl)phenyl}methyl)-1methylpiperidin-4-amine (54 mg, 0.103 mmol) in dichloromethane (1.5 ml). After 3 hours of stirring at room temperature, NaOH (2 ml, 1 M aqueous solution) was added. The mixture was extracted with dichloromethane (3x2 ml), the combined organic phases were dried using a phase separator and concentrated to give the desired intermediate (114 mg).

1-{[2-Hidroxy-4-(trifluoromethyl)phenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid.

Tetrabutylammonium fluoride (0.5 ml, 1M in tetrahydrofuran) was added to a solution of 1-({2-[(tert-butyldiphenylsilyl)oxy]-4-(trifluoromethyl)phenyl}methyl)-1-(1-methylpiperidin-4-yl)- 3-{[4-(2-methylpropoxy)phenyl]methyl}urea (114 mg, 0.156 mmol) in tetrahydrofuran (0.5 ml). After 2 hours of stirring at room temperature, the mixture was concentrated. The crude material was purified by HPLC eluting with 30-70% acetonitrile in water (containing 0.1% trifluoroacetic acid), followed by purification by column chromatography using silica gel eluting with 10% methanol in dichloromethane, followed by HPLC purification eluting 30-60 % acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (4.4 mg, 5%): ¹ H NMR (400 MHz, chloroform-d) δ 12.10 (s, 1H) , 7.17 - 7.08 (m, 4H), 7.01 (d, 1H), 6.79 (d, 2H), 5.43 (s, 1H), 4.42 (s, 2H), 4.35 - 4.20 (m, 3H), 3.67 (d, 2H), 3.50 (d, 2H), 2.91 - 2.80 (m, 2H), 2.77 (s, 3H), 2.44 (q, 2H), 2.11-1.96 (m, 1H), 1.84 (d, 2H), 1.00 (d, 6H); LC-MS: 494.3 [M+H]+.

Example 91: 1-[(4-fluoro-2-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (90) o

Trimethylsilyldiazomethane (49.8 µl, 0.099 mmol) was added to 1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy) phenyl]methyl}urea (36.8 mg, 0.083 mmol) in a mixture of methanol (0.5 ml) and ethyl acetate (1.5 ml) at 0°C. After 4 hours of stirring at room temperature, HCl (2 ml, 1 M aqueous solution) was added followed by NaOH (5 ml, 1 M aqueous solution). The aqueous phase was extracted with ethyl acetate (3x3 ml) and the combined organic phases were dried using a phase separator and concentrated. The crude material was purified by preparative HPLC eluting with 30-60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (8.7 mg, 18%): 1 H NMR (400 MHz, chloroform-d) δ 12.67 (br s, 1H), 7.02 (d, 3H), 6.79 (d, 2H), 6.61-6.52 (m, 2H), 4.86 (s, 1H ), 4.81 - 4.69 (m, 1H), 4.27 (d, 2H), 4.23 (s, 2H), 3.72 (s, 3H), 3.68 (d, 2H) , 3.57 (d, 2H), 2.94 - 2.80 (m, 2H), 2.76 (s, 3H), 2.15 (q, 2H), 2.09 - 1.97 (m , 1H), 1.89 (d, 2H), 1.01 (d, 6H); LC-MS: 458.3 [M+H]+.

Example 92 5-fluoro-2-{[1-(1-methylpiperidin-4-yl)({[4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino]methyl}phenylacetate; trifluoroacetic acid (92)

- 92 042461

-Fluoro-2-{[1-(1-methylpiperidin-4-yl)({[4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino]methyl}phenylacetate; trifluoroacetic acid.

Acetic anhydride (15 mg, 147 µmol) was added to 1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl }urea (42.4 mg, 95.6 µmol) in dichloromethane (1 ml). After 20 hours of stirring at room temperature, NaOH (2 ml, 1 M aqueous solution) was added and the mixture was extracted with dichloromethane (3x2 ml). The combined organic phases were dried using a phase separator and concentrated. The crude material was purified by preparative HPLC eluting with 30-60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (7 mg, 15%): 1H NMR (400 MHz, chloroform-d) δ 12 .55 (br s, 1H), 7.14 (dd, 1H), 6.98 (d, 2H), 6.86 (ddd, 2H), 6.76 (d, 2H), 5.04 ( t, 1H), 4.83 - 4.70 (m, 1H), 4.24 (d, 2H), 4.18 (s, 2H), 3.67 (d, 2H), 3.56 (d , 2H), 2.91-2.80 (m, 2H), 2.77 (s, 3H), 2.35 (s, 3H), 2.30-2.15 (m, 2H), 2.131, 98 (m, 1H), 1.91 (d, 2H), 1.01 (d, 6H); LC-MS: 486.4 [M+H]+.

Example 93: 1-[(2,4-difluorophenyl)methyl]-3-[(1H-indazol-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; trifluoroacetic acid (93)

To tert-butyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate (50 mg, 129 µmol) and diisopropylethylamine (33.6 µl, 193 µmol) in dichloromethane (1 ml ) was added (1Hindazol-5-yl)methanamine. The mixture was sonicated for 2 hours and then the crude product was collected by filtration. TFA (500 μl) in 1 ml THF was added to the crude material and the reaction mixture was heated to 60° C. for 1.5 h. The mixture was concentrated and then suspended in methanol, filtered and concentrated. This material, formaldehyde (11.5 µl, 155 µmol) and sodium triacetoxyborohydride (54.7 mg, 258 µmol) were stirred in tetrahydrofuran (1.0 ml) for 2 h, additional formaldehyde (17.3 µl, 233 µmol) was added ) and sodium triacetoxyborohydride (109 mg, 516 μmol) and the reaction mixture was stirred for 1 h. Ammonia (27% aqueous solution, 1 ml) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated and the crude material was purified by HPLC, eluting with 10-40% acetonitrile in water (containing 0.1% trifluoroacetic acid). Yield: 9% from carbamoyl chloride. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.97 (s, 1H), 7.60 (s, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 7 .22 (q, 1H), 6.99 - 6.90 (m, 1H), 6.87 (t, 1H), 4.53 (s, 2H), 4.46 (s, 2H), 4, 40 - 4.26 (m, 1H), 3.50 (d, 2H), 3.15 - 3.00 (m, 2H), 2.82 (s, 3H), 2.09 - 1.85 ( m, 4H); LC-MS: 414.3 [M+H]+. Example 94: 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1R)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4yl)urea; trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1S)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea ; trifluoroacetic acid (94)

1-[(2,4-Difluorophenyl)methyl]-3-[(4-ethenylphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea

- 93 042461

Compounds were prepared in analogy to OP A using (4-ethenylphenyl)methanamine and N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (1:1.2). 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1 R)-1,2dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid and 1-[(2,4difluorophenyl)methyl]-3-({4-[( 1 S)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4yl)urea; trifluoroacetic acid.

-[(2,4-Difluorophenyl)methyl]-3-[(4-ethenylphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (39.9 mg, 100 µmol) in acetone (4 ml) was added to potassium osmate(VI) dihydrate (1.8 mg, 5 µmol) and N-methylmorpholine N-oxide (50% aqueous solution, 51.8 µl, 250 µl) in water (2 ml). After 21 hours stirring at ambient temperature, the reaction was quenched with sodium thiosulfate (aqueous solution) and filtered through a pad of celite. Acetone was removed under reduced pressure and the resulting mixture was diluted with sodium hydroxide (aqueous solution, 1 M, 1 ml). The product was extracted with dichloromethane (3x1 ml), dried (phase separator) and concentrated. The crude material was purified by HPLC eluting with 10-40% acetonitrile in water (containing 0.1% trifluoroacetic acid). Compounds were isolated as a racemic mixture. Yield: 43.1 mg, 79%. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.30 (d, 2H), 7.27-7.18 (m, 3H), 7.01-6.87 (m, 2H), 4, 66 (dd, 1H), 4.52 (s, 2H), 4.39-4.24 (m, 3H), 3.63-3.54 (m, 2H), 3.51 (d, 2H) , 3.14 - 3.02 (m, 2H), 2.83 (s, 3H), 2.09 - 1.83 (m, 4H); LC-MS: 434.3 [M+H]+.

Example 95: 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-dihydro-2-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (95)

(1,3-Dihydro-2-benzofuran-5-yl)methanamine

Oxalyl chloride (56.7 µl, 660 µmol) and dimethylformamide (2.3 µl, 30 µmol) were added to 1,3dihydro-2-benzofuran-5-carboxylic acid (98.5 mg, 600 µmol) in dichloromethane (2 ml) . After 40 minutes of stirring at ambient temperature, ammonia (27% aqueous solution, 1.02 ml, 54 mmol) was added and the resulting biphasic system was stirred vigorously for 30 minutes, after which it was filtered through a pad of celite. The phases were separated and the aqueous phase was extracted with dichloromethane (2 ml). The combined organic phase was dried (phase separator) and concentrated. Borane (1M in tetrahydrofuran, 2.4 ml, 2.4 mmol) was added and the mixture was stirred for 14 h at ambient temperature and then heated to 50°C. After 7 hours, borane (1M in tetrahydrofuran, 1.2 ml, 1.2 mmol) was added again and the reaction mixture was stirred for an additional 17 hours, after which the reaction was quenched with methanol and concentrated. Sodium hydroxide (aqueous solution, 1 M, 10 ml) was added. The product was extracted with dichloromethane (3x10 ml), dried (phase separator) and concentrated. The crude material was dissolved in dichloromethane (10 ml) and extracted with hydrochloric acid (1 M, aqueous solution, 10 ml). The aqueous phase was made basic with sodium hydroxide (5 M) and extracted with dichloromethane (3x10 ml). The organic phase was dried (phase separator) and concentrated to give the desired benzylamine (27.4 mg, 31%). 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-dihydro-2benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid was obtained by analogy with OP C using (1,3-dihydro-2-benzofuran-5-yl)methanamine and N-[(2,4-difluorophenyl)methyl]-1methylpiperidin-4-amine (1:1, 5). Yield: 69%. 1H NMR (400 MHz, chloroform-d) δ 12.64 (br s, 1H), 7.21 7.07 (m, 2H), 7.02 (d, 1H), 6.99 (s, 1H ), 6.83 (t, 2H), 5.05 (d, 4H), 4.84 (s, 1H), 4.71 (tt, 1H), 4.44 - 4.32 (m, 4H) , 3.60 (d, 2H), 2.94-2.70 (m, 5H), 2.20 (qvd, 2H), 1.91 (d, 2H); LC-MS: 415.9 [M+H] ⁺ .

Example 96: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(3-methoxypropoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (96)

- 94 042461

The compound was obtained by analogy

with Example 15 (1-[(2,4-difluorophenyl)methyl]-3-{[4-(2fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea) using 3-methoxypropane -1 -ol. Yield: 35%. 1H NMR (400 MHz, chloroform-d) δ 12.62 (br s, 1H), 7.12 (q, 1H), 7.03 (d, 2H), 6.86 - 6 .77 (m, 4H), 4.79 -4.62 (m, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 4.03 (t, 2H), 3, 60 (d, 2H), 3.55 (t, 2H), 3.36 (s, 3H), 2.94-2.80 (m, 2H), 2.79 (s, 3H), 2.28 - 2.10 (m, 2H), 2.04 (p, 2H), 1.91 (d, 2H); LC-MS: 462.3 [M+H] ⁺ .

Example 97: 1-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro-4-nitrophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; trifluoroacetic acid (97)

Compounds were prepared in analogy to OP A using (2-fluoro-4-nitrophenyl)methanamine hydrochloride and N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (1:1). Yield: 75%. ¹ H NMR (400 MHz, chloroform-d) δ 12.36 (br s, 1H), 7.98 (dd, 1H), 7.88 (dd, 1H), 7.46 - 7.37 (m , 1H), 7.18 - 7.08 (m, 1H), 6.92 6.82 (m, 2H), 5.14 - 5.08 (m, 1H), 4.63 (ddd, 1H) , 4.47 (d, 2H), 4.42 (s, 2H), 3.61 (d, 2H), 2.94 - 2.75 (m, 5H), 2.36 - 2.15 (m , 2H), 1.90 (d, 2H); LC-MS: 437.3 [M+H] ⁺ .

Example 98: 3-[(4-chloro-3-methoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin4-yl)urea; trifluoroacetic acid (98)

Compounds were prepared by analogy with OP A using (4-chloro-3-methoxyphenyl)methanamine and N[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (1:1) Yield: 69%. ¹ H NMR (400 MHz, Chloroformd) δ 12.22 (s, 1H), 7.29-7.22 (m, 1H), 7.22-7.11 (m, 1H), 6.93-6 .79 (m, 2H), 6.73 (s, 1H), 6.64 (d, 1H), 4.88 (s, 1H), 4.79-4.64 (m, 1H), 4. 44 (s, 2H), 4.33 (d, 2H), 3.85 (s, 3H), 3.58 (d, 2H), 2.93-2.87 (m, 2H), 2.80 (d, 3H), 2.43 (q, 2H), 1.92 (d, 2H); LC-MS: 438.3 [M+H] ⁺ .

Example 99: 1-[(2,4-difluorophenyl)methyl]-3-{[4-fluoro-2-(trifluoromethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (99)

The compound was prepared by analogy with OP A using N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4-amine and [4-fluoro-2-(trifluoromethoxy)phenyl]methanamine (1:1). Yield: 70%. 1H NMR (400 MHz, chloroform-d) δ 12.19 (br s, 1H), 7.32-7.23 (m, 1H), 7.16-7.05 (m, 1H), 7.00 - 6.91 (m, 2H), 6.90 - 6.79 (m, 2H), 4.85 (s, 1H), 4.78 - 4.67 (m, 1H), 4.40 (s, 2H), 4.36 (d, 2H), 3.59 (d, 2H), 2.96-2.82 (m, 2H), 2.80 (s, 3H), 2 .47 - 2.30 (m, 2H), 1.92 (d, 2H); LC-MS: 476.2 [M+H]+.

Example 100: 3-[(2,4-difluorophenyl)methyl]-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (100)

- 95 042461

Compounds were prepared in analogy with OP A using (2,4-difluorophenyl)methanamine and N[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (1:1). Yield: 57%. 1H NMR (400 MHz, Chloroform-d) δ 12.50 (br s, 1H), 7.21 - 7.10 (m, 3H), 7.02 (t, 2H), 6.79 (td, 1H), 6.73 (ddd, 1H), 4.79 (t, 1H), 4.73 (ddd, 1H), 4.37 (s, 2H), 4.32 (d, 2H), 3, 58 (d, 2H), 2.93-2.73 (m, 5H), 2.36-2.18 (m, 2H), 1.90 (d, 2H); LC-MS: 392.3 [M+H] ⁺ .

Example 101: 1-{[2-(difluoromethoxy)-4-fluorophenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (101)

tert-Butyl 4-{[(4-fluoro-2-hydroxyphenyl)methyl]({[4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate

The compound was obtained by analogy with example 13 (1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea) using tert-butyl 4oxpiperidine-1-carboxylate.

1-{[2-(Difluoromethoxy)-4-fluorophenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid.

Sodium chlorodifluoroacetate (76.2 mg, 500 µmol), tert-butyl 4-{[(4-fluoro-2-hydroxyphenyl)methyl]({[4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino}piperidine- 1-carboxylate (106 mg, 200 µmol) and cesium carbonate (130 mg, 400 µmol) were suspended in water (200 µl) and dimethylformamide (2 ml). The mixture was heated to 80°C for 5 h, after which it was cooled to ambient temperature, diluted with ethyl acetate (20 ml), washed with water (5x20 ml), dried (phase separator) and concentrated. The crude material was dissolved in dichloromethane (1 ml) and 1-(isocyanatomethyl)-4-(2methylpropoxy)benzene (41 mg, 200 µmol) was added. After 1 hour the mixture was concentrated and the crude material was purified by silica gel chromatography eluting with 25-100% ethyl acetate in petroleum ether. Fractions containing the product were combined and concentrated. The material was dissolved in dichloromethane (1.5 ml) and trifluoroacetic acid (0.5 ml) was added. After 15 minutes the mixture was concentrated and redissolved in tetrahydrofuran (2 ml). Formaldehyde (37% aqueous solution, 29.8 μl, 400 μmol) and sodium triacetoxyborohydride (84.8 mg, 400 μmol) were added. After 1 h, the mixture was diluted with sodium hydroxide (aqueous solution, 1 M, 1 ml) and was extracted with dichloromethane (3x1 ml). The organic phase was dried (phase separator) and concentrated. The crude material was purified by HPLC eluting with 30-70% acetonitrile in water (containing 0.1% trifluoroacetic acid). Yield: 32 mg, 26%. ¹ H NMR (400 MHz, chloroformd) δ 12.50 (br s, 1H), 7.15 (t, 1H), 7.03 (d, 2H), 6.96-6.83 (m, 2H ), 6.80 (d, 2H), 6.59 (t, 1H), 4.77 (t, 1H), 4.67 (s, 1H), 4.37 (s, 2H), 4.29 (s, 2H), 3.69 (d, 2H), 3.58 (d, 2H), 2.93 - 2.80 (m, 2H), 2.78 (s, 3H), 2.21 ( q, 2H), 2.07 (dt, 1H), 1.90 (d, 2H), 1.02 (d, 6H); LC-MS: 494.3 [M+H]+.

Example 102: 1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (102)

- 96 042461

Compounds were prepared by analogy with OP B using N-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1methylpiperidin-4-amine (prepared by analogy with Intermediate 6 (X-[(2,4-difluoro phenyl)methyl]-1-methylpiperidin-4-amine) using [4-chloro-2-(trifluoromethyl)phenyl]methanamine) and 1(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 91%. ¹ H NMR (400 MHz, chloroform-d) δ 13.09 (br s, 1H), 7.66 (s, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.00 (d, 2H), 6.79 (d, 2H), 4.74 (t, 1H), 4.58 - 4.43 (m, 3H), 4.27 (d, 2H), 3 .69 (d, 2H), 3.59 (d, 2H), 2.83 (t, 2H), 2.77 (s, 3H), 2.16 (q, 2H), 2.13 -1, 99 (m, 1H), 1.91 (d, 2H), 1.02 (d, 6H); LC-MS: 512.3 [M+H]+.

Example 103: 1-{[4-fluoro-2-(trifluoromethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (103)

Compounds were prepared in analogy to OP B using N-{[4-fluoro-2-(trifluoromethoxy)phenyl]methyl}-1-methylpiperidin-4-amine (prepared in analogy to Intermediate 6 using [4-fluoro-2 -(trifluoromethoxy)phenyl]methanamine) and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 85%. 1H NMR (400 MHz, chloroform-d) δ 13.09 (br s, 1H), 7.25 - 7.16 (m, 1H), 7.07 6.99 (m, 3H), 6.96 (t, 1H), 6.79 (d, 2H), 4.74 (t, 1H), 4.55 (s, 1H), 4.36 (s, 2H), 4.28 (d, 2H) , 3.69 (d, 2H), 3.59 (d, 2H), 2.83 (t, 2H), 2.77 (s, 3H), 2.17 (q, 2H), 2.12 - 1.99 (m, 1H), 1.91 (d, 2H), 1.02 (d, 6H); LC-MS: 512.3 [M+H] ⁺ .

Example 104: 1-[(4-fluoro-2-methylphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (104)

F

Compounds were prepared in analogy to OP B using N-[(4-fluoro-2-methylphenyl)methyl]-1-methylpiperidin-4-amine (prepared in analogy to Intermediate 6 using (4-fluoro2-methylphenyl)methanamine) and 1 -(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 76%?H NMR (400

MHz, chloroform-d) δ 12.59 (br s, 1H), 7.10 - 7.00 (m, 3H), 6.90 (d, 1H), 6.87 - 6.76 (m, 3H), 4.78 (t, 1H), 4.60 (s, 1H), 4.28 (d, 2H), 4.25 (s, 2H), 3.68 (d, 2H), 3, 55 (d, 2H), 2.92-2.81 (m, 2H), 2.78 (s, 3H), 2.28 (s, 3H), 2.18 (q, 2H), 2.12 - 1.98 (m, 1H), 1.91 (d, 2H), 1.01 (d, 6H); LC-MS: 442.3 [M+H] ⁺ .

Example 105: 1-[(2-chloro-4-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (105) ci o

F

Compounds were prepared in analogy to OP B using X-[(2-chloro-4-methoxyphenyl)methyl]-1methylpiperidin-4-amine (prepared by analogy with Intermediate 6 using (2-chloro4-methoxyphenyl)methanamine) and 1 -(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 78%?H NMR

- 97 042461 (400 MHz, chloroform-d) δ 13.05 (br s, 1H), 7.09 - 7.00 (m, 3H), 6.92 (s, 1H), 6.79 (d , 2H), 6.74 (d, 1H), 4.74 (t, 1H), 4.69 - 4.57 (m, 1H), 4.33 (s, 2H), 4.28 (d, 2H), 3.79 (s, 3H), 3.68 (d, 2H), 3.58 (d, 2H), 2.88 - 2.80 (m, 2H), 2.77 (s, 3H ), 2.23 - 2.10 (m, 2H), 2.12 - 1.99 (m, 1H), 1.91 (d, 2H), 1.01 (d, 6H); LC-MS: 474.3 [M+H]+.

Example 106: 1-[(2,4-dichlorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid (106)

Compounds were prepared in analogy to OP B using N-[(2,4-dichlorophenyl)methyl]-1methylpiperidin-4-amine (prepared by analogy with Intermediate 6 using (2,4dichlorophenyl)methanamine) and 1-(isocyanatomethyl) -4-(propan-2-yloxy)benzene. Yield: 78%. ¹ H NMR (400 MHz, chloroform-d) δ 12.28 (br s, 1H), 7.41 (d, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 7.02 (d, 2H), 6.79 (d, 2H), 4.77 (ddd, 1H), 4.64-4.55 (m, 1H), 4.57-4.44 (m, 1H), 4.36 (s, 2H), 4.29 (d, 2H), 3.61 (d, 2H), 2.95-2.82 (m, 2H), 2.80 (s, 3H ), 2.25-2.08 (m, 2H), 1.92 (d, 2H), 1.32 (d, 6H); LC-MS: 463.9 [M+H] ⁺ .

Example 107: 1-[(2,4-dichlorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea (107)

Compounds were prepared by analogy with OP B using N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidin-4-amine (prepared by analogy with Intermediate 6 using (2,4dichlorophenyl)methanamine) and 1-( isocyanatomethyl)-4-(2-methylpropoxy)benzene. Yield: 68%. 1H NMR (400 MHz, Chloroform-d) δ 7.36 (s, 1H), 7.18 (s, 2H), 7.09 (d, 2H), 6.84-6.77 (m, 2H), 4.49 - 4.41 (m, w), 4.41 4.33 (m, 3H), 4.31 (d, 2H), 3.69 (d, 2H), 2 .91 (d, 2H), 2.30 (s, 3H), 2.23 - 1.96 (m, 3H), 1.78 - 1.61 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H); LC-MS: 478.0 [M+H] ⁺ . Example 108: 1-[(2,4-dichlorophenyl)methyl]-1-(piperidin-4-yl)3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (108)

Compounds were prepared in analogy to Example 4 (1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea) using N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidin-4-amine (prepared by analogy with intermediate 6 using (2,4dichlorophenyl)methanamine) and 1-(isocyanatomethyl)-4-(propane-2 -yloxy)benzene. Yield: 61%. 1H NMR (400 MHz, chloroform-d) δ 9.48 (br s, 1H), 9.03 (br s, 1H), 7.40 (d, 1H), 7.20 (dd, 1H) , 7.13 (d, 1H), 7.03 (d, 2H), 6.79 (d, 2H), 4.75-4.60 (m, 1H), 4.52 (d.sq., 2H), 4.36 (s, 2H), 4.28 (s, 2H), 3.41 (d, 2H), 3.06 - 2.87 (m, 2H), 2.04 - 1.87 (m, 4H), 1.32 (d, 6H); LC-MS: 450.2 [M+H] ⁺ .

Example 109: 1-[(2-chloro-4-fluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin4-yl)urea; trifluoroacetic acid (109)

- 98 042461

Compounds were prepared in analogy to Example 4 (1-[(2,4-difluorophenyl)methyl]-3-{[4-(2methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea) using N- [(2-chloro-4-fluorophenyl)methyl]1-methylpiperidin-4-amine (prepared by analogy with intermediate 6 using (2chloro-4-fluorophenyl)methanamine). Yield: 45%. 'll NMR (400 MHz, chloroform-d) δ 9.44 (br s, 1H), 9.08 (br s, 1H), 7.21-7.11 (m, 2H), 7.04 (d, 2H), 6.94 (td, 1H), 6.84 - 6.76 (m, 2H), 4.80 - 4.63 (m, 1H), 4.60 - 4.45 (m , 1H), 4.36 (s, 2H), 4.29 (s, 2H), 3.69 (d, 2H), 3.54-3.38 (m, 2H), 3.10-2, 92 (m, 2H), 2.07 (dt, 1H), 2.04 1.73 (m, 4H), 1.02 (d, 6H); LC-MS: 448.3 [M+H] ⁺ .

Example 110: 1-[(2-chloro-4-fluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (110)

Compounds were prepared in analogy to Example 4 (1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea) using N-[(2-chloro-4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (prepared by analogy with intermediate 6 using (2-chloro4-fluorophenyl)methanamine) and 1-(isocyanatomethyl)-4-(propane -2-yloxy)benzene. Yield: 60%.

1H NMR (400 MHz, Chloroform-d) δ 9.57 (br s, 1H), 9.10 (br s, 1H), 7.22-7.10 (m, 2H), 7.03 ( d, 2H), 6.94 (td, 1H), 6.79 (d, 2H), 4.76 - 4.61 (m, 1H), 4.59 - 4.44 (m, 2H), 4 .36 (s, 2H), 4.28 (s, 2H), 3.42 (d, 2H), 3.02 - 2.85 (m, 2H), 2.07 - 1.84 (m, 4H ), 1.32 (d, 6H); LC-MS: 434.3 [M+H] ⁺ .

Example 111: 1-[(2,4-dichlorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4yl)urea; trifluoroacetic acid (111)

Compounds were prepared in analogy to Example 4 (1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea) using N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidin-4-amine (prepared in analogy to Intermediate 6 using (2,4dichlorophenyl)methanamine). Yield: 40%. 1H NMR (400 MHz, chloroform-d) δ 9.51 (br s, 1H), 9.11 (br s, 1H), 7.40 (d, 1H), 7.20 (dd, 1H) , 7.13 (d, 1H), 7.09 - 7.00 (m, 2H), 6.84 - 6.77 (m, 2H), 4.75 - 4.62 (m, 1H), 4 .57 4.44 (m, 1H), 4.36 (s, 2H), 4.28 (s, 2H), 3.69 (d, 2H), 3.54 - 3.35 (m, 2H) , 3.10 - 2.90 (m, 2H), 2.07 (dt, 1H), 2.00 - 1.73 (m, 4H), 1.02 (d, 6H); LC-MS: 464.2 [M+H]+.

Example 112 (comparative): 1-[(2,6-difluoro-3-methylphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3{[4-(propan-2-yloxy)phenyl]methyl }urea; trifluoroacetic acid (112)

Compounds were prepared in analogy to OP B using N-[(2,6-difluoro-3-methylphenyl)methyl]-1-methylpiperidin-4-amine (prepared in analogy to Intermediate 6 (N-[(2,4difluorophenyl)methyl ]-1-methylpiperidin-4-amine) using (2,6-difluoro-3-methylphenyl)methanamine) and 1(isocyanatomethyl)-4-(propan-2-yloxy)benzene. Yield: 57%. 1H NMR (400 MHz, chloroform-d) δ 12.45 (br s, 1H), 7.19 - 7.06 (m, 1H), 7.04 (d, 2H), 6.88 - 6, 71 (m, 3H), 5.06 (s, 1H), 4.62-4.46 (m, 2H), 4.38 (s, 2H), 4.28 (s, 2H), 3.62 (d, 2H), 2.90 - 2.70 (m, 5H), 2.31 (qvd, 2H), 2.16 (s, 3H), 1.94 (d, 2H), 1.32 ( d, 6H); LCMS: 446.3 [M+H] ⁺ .

Example 113 (comparative): 1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}-1[(2,3,6-trifluorophenyl)methyl]urea ; trifluoroacetic acid (113)

- 99 042461

Compounds were obtained by analogy

with OP

B using 1-methyl-X-[(2,3,6-trifluorophenyl)methyl]piperidine-4-amine (prepared by analogy with Intermediate 6 (X-[(2,4-difluorophenyl)methyl]-1 -methylpiperidin-4-amine) using (2,3,6-trifluorophenyl)methanamine) and 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene. Yield: 58%. ¹ H NMR (400 MHz, chloroform-d) δ 12.69 (br s, 1H), 7.23-7.09 (m, 1H), 7.06 (d, 2H), 6.89-6 .76 (m, 3H), 4.91 (s, 1H), 4.65-4.48 (m, 2H), 4.45 (s, 2H), 4.30 (s, 2H), 3, 62 (d, 2H), 2.90 - 2.75 (m, 5H), 2.47 - 2.27 (m, 2H), 1.96 (d, 2H), 1.33 (d, 6H) ; LC-MS: 450.3 [M+H] ⁺ .

Example 114: 1-[(2,4-difluoro-3-methylphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid (114)

Compounds were prepared in analogy to OP B using P-[(2,4-difluoro-3-methylphenyl)methyl]-1methylpiperidin-4-amine (prepared in analogy to Intermediate 6 using (2,4difluoro-3-methylphenyl) methanamine) and 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene. Yield: 55%. ¹ H NMR (400 MHz, Chloroform-d) δ 12.39 (br s, 1H), 7.01 (d, 2H), 6.93 (q, 1H), 6.84 - 6.74 (m , 3H), 4.83 4.69 (m, 1H), 4.70 - 4.62 (m, 1H), 4.51 (hept, 1H), 4.35 (s, 2H), 4.28 (d, 2H), 3.61 (d, 2H), 2.95-2.75 (m, 5H), 2.28-2.11 (m, 5H), 1.92 (d, 2H), 1.32 (d, 6H); LC-MS: 446.3 [M+H]+.

Example 115: 1-[(2-fluoro-4-methylphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (115)

Compounds were prepared in analogy to OP B using X-[(2-fluoro-4-methylphenyl)methyl]-1methylpiperidin-4-amine (prepared in analogy to Intermediate 6 using (2-fluoro4-methylphenyl)methanamine) and 1 -(isocyanatomethyl)-4-(propan-2-yloxy)benzene. Yield: 59%. ¹ H NMR (400 MHz, Chloroform-d) δ 12.15 (br s, 1H), 7.06-6.97 (m, 3H), 6.92-6.83 (m, 2H), 6 .82 - 6.74 (m, 2H), 4.85 4.70 (m, 2H), 4.53 - 4.47 (m, 1H), 4.36 (s, 2H), 4.28 ( s, 2H), 3.62 (d, 2H), 2.95-2.76 (m, 5H), 2.33 (s, 3H), 2.27-2.10 (m, 2H), 1, 94 (d, 2H), 1.32 (d, 6H); LC-MS: 428.3 [M+H] ⁺ .

Example 116: 1-[(2,4-difluorophenyl)methyl]-3-{[2-methyl-4-(propan-2-yloxy)phenyl]methyl}-1-(1methylpiperidin-4-yl)urea; hemitartrate (116)

4-Hydroxy-2-methylbenzonitrile (1011 mg, 7.2 mmol), potassium carbonate (18.0 mmol, 2.49 g), tetrabutylammonium iodide (0.5 mmol, 190 mg), 2-iodopropane (18 mmol, 1.82 ml) and DMF (5.0 ml) were stirred at 70° C. for 3 hours and then partitioned between 0.5 M NaOH and diethyl ether. The organic phase was washed with water several times, then dried and evaporated to give the intermediate nitrile (1.34 g). This was reduced with lithium aluminum hydride (14.4 mmol, 552 mg) in refluxing tetrahydrofuran (6 mL) for 1 h, worked up to give the intermediate benzylamine (1.29 g, 7.2 mmol, 100% yield). This material was dissolved in dichloromethane (10 mL), pyridine (14.4 mmol, 1.20 mL) was added followed by phenyl chloroformate (9.4 mmol, 1.22 mL) dissolved in di

- 100 042461 chloromethane (4.0 ml), dropwise in an ice bath, the mixture was stirred for 30 min, then partitioned between dichloromethane and 1 M HCl, the organic phase was separated, dried and evaporated to obtain phenyl N-{[2-methyl -4-(propan-2-yloxy)phenyl]methyl}carbamate (2.39 g, 100% yield) as an oil which crystallizes slowly.

N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (2.24 mmol, 539 mg), phenyl N-{[2-methyl-4(propan-2-yloxy)phenyl]methyl }carbamate (750 mg, 2.51 mmol) and potassium carbonate (4.5 mmol, 625 mg) were suspended in toluene (5.0 ml). The mixture was stirred at 70° C. for 20 h, then partitioned between toluene and 0.5 M NaOH, the organic phase was separated, concentrated and the crude material was purified by column chromatography using silica gel, eluting with 5-50% methanol in ethyl acetate, with obtaining pure fractions. These fractions were collected and evaporated and the residue was stirred for 20 min in diethyl ether (10.0 ml) to precipitate silica, the suspension was filtered and a clear filtrate was evaporated to give the title compound as free base (703 mg, 1.57 mmol, 70% yield. This material (667 mg, 1.497 mmol) and L-(+)-tartaric acid (0.7485 mmol, 113 mg) were dissolved in methanol (4 ml), the solvents were removed by evaporation, and the residue was stirred in 2-propanol (4 ml) and processed in an ultrasonic bath. The solvent was removed and the residue was treated in vacuo (0.5-1.0 mbar) for 20 h to give the title compound (840 mg, 100% yield): 1H NMR (400 MHz, Chloroform-d) δ 7, 05 (m, 2H), 6.77 (m, 1H), 6.71 (m, 1H), 6.66 (d, 1H), 6.57 (s, 1H), 5.02 (t, 1H ), 4.58 (m, 1H), 4.44-4.33 (m, 3H), 4.31 (s, 1H), 4.28 (d, 2H), 3.40 (t, 2H) , 2.69-2.57 (m, 5H), 2.30 (s, 3H), 2.11 (m, 2H), 1.76 (d, 2H), 1.10 (d, 6H); LC-MS: 446.3 [M+H] ⁺ .

Example 117: 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-[(3S,4R)-3-fluoro-1methylpiperidin-4-yl]urea and 1- [(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]urea (117) f o

F O

tert-Butyl 3-fluoro-4-oxo-piperidine-1-carboxylate (3.0 g, 13.12 mmol), dichloromethane (15 ml), 2,4-difluorobenzylamine (13.8 mmol, 2.04 g) and acetic acid ( 300 µl) was stirred for 10 min and sodium triacetoxyborohydride (22.3 mmol, 4.87 g) was added. The mixture was stirred for 1 h, then partitioned between 0.5 M NaOH and dichloromethane. The organic phase was separated, dried and the solvents were removed. The crude material was purified by silica gel column chromatography eluting with 30-50% ethyl acetate in petroleum ether to give pure fractions of the desired compound. These fractions were collected, evaporated, and the residue was recrystallized from EtOAc/petroleum ether to give tert-butyl 4-{[(2,4-difluorophenyl)methyl]amino}-3-fluoropiperidine-1-carboxylate (racemic cis compound, 2.394 g, yield 53%). This cis compound (183 mg, 0.53 mmol), phenyl N-[(4-cyclopropoxyphenyl)methyl] carbamate (150 mg, 0.53 mmol) and potassium carbonate (1.0 mmol, 138 mg) were suspended in toluene (1.0 ml). The mixture was stirred at 70° C. for 14 h, then partitioned between toluene and 0.5 M NaOH, the organic phase was separated, washed with water, dried and then concentrated. The crude material was purified by column chromatography using silica gel eluting with 30-50% ethyl acetate in petroleum ether to give the desired protected urea intermediate. The solvents were removed, the residue was stirred in dichloromethane (2.0 ml) and trifluoroacetic acid (2.0 ml) for 30 min, then it was evaporated and given the properties of the free base by distribution between dichloromethane and 1 M NaOH. The residue after evaporation of the organic phase was purified by column chromatography using silica gel eluting with 10-100% methanol in ethyl acetate to give intermediate (156 mg, 0.36 mmol, 68% yield). This material (149 mg, 0.34 mmol), formaldehyde (1.08 mmol, 81 μl) and sodium triacetoxyborohydride (1.1 mmol, 241 mg) were stirred in tetrahydrofuran (3.0 ml) for 2 h, then partitioned between ether and 1 M NaOH. The organic phase was separated, dried, evaporated and the residue was purified by column chromatography using silica gel eluting with 10-50% methanol in ethyl acetate to give the title compound (110 mg, 0.246 mmol, 72%): 1H NMR (400 MHz , chloroform-d) δ 7.19 (q, 1H), 7.04 (d, 2H), 6.94

- 101 042461 (d, 2H), 6.86 - 6.74 (m, 2H), 4.93 (d, 1H), 4.73 - 4.44 (m, 4H), 4.30 (d, 2H), 3.70 (m, 1H), 3.24 (t, 1H), 3.05 (d, 1H), 2.59 - 2.14 (m, 3H), 2.40 (s, 3H ), 1.63 (d, 1H), 0.81-0.69 (m, 4H); LC-MS: 448.3 [M+H]+.

Example 118: 1-[(2,4-difluorophenyl)methyl]-3-[(3-fluoro-4-methoxyphenyl)methyl]-1-(1-methylpiperidin4-yl)urea (118)

F O

3-Fluoro-4-methoxybenzoic acid (975 mg, 5.73 mmol), dichloromethane (5.0 ml), DMF (20 μl) and oxalyl chloride (17 mmol, 1.45 ml) were refluxed for 1 h , the volatiles were removed and the residue was stirred in ammonium hydroxide (28% solution, 4 ml) and ethanol (4 ml) until the solids had dissolved. The solution was concentrated and the solid precipitated, the solid was collected by filtration to give the intermediate carboxamide (713 mg, 4.21 mmol, 74% yield). This material (705 mg, 4.16 mmol) was reduced with lithium aluminum hydride (2 eq, 8.3 mmol, 323 mg) in refluxing tetrahydrofuran (5 ml) for 1 h, then the reaction was quenched with 2 M NaOH and extracted with diethyl ether, the organic phase was collected and extracted with 1 M HCl, the aqueous phase was separated and basified with 5 M NaOH, then extracted with diethyl ether, and the organic phase was collected, dried and evaporated to give 3-fluoro-4-methoxy-benzylamine (495 mg, 3.19 mmol , 77% yield. This material was dissolved in dichloromethane (2 ml), pyridine (4.5 mmol, 360 μl) was added followed by phenyl chloroformate (3.5 mmol, 455 μl) dissolved in dichloromethane (2.0 ml) dropwise in an ice bath , the mixture was stirred for 30 min, then partitioned between dichloromethane and 0.5 M HCl, the organic phase was separated, dried and evaporated, and the residue was crystallized from a mixture of ethanol/water to obtain phenyl N-[(3-fluoro-4-methoxyphenyl) methyl]carbamate (357 mg, 1.3 mmol, 41% yield).

N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.5 mmol, 95%, 127 mg), phenyl N-[(3fluoro-4-methoxyphenyl)methyl] carbamate (152 mg, 0.55 mmol) and potassium carbonate (1.0 mmol, 139 mg) were suspended in toluene (2.0 ml). The mixture was stirred at 70° C. for 16 h, then partitioned between toluene and 0.5 M NaOH, the organic phase was separated, concentrated and the product was purified by column chromatography using silica gel, eluting with 5-100% methanol in ethyl acetate in petroleum ether , to give fractions which were collected, evaporated and the residue was stirred for 20 min in ether (5.0 ml) to precipitate silica, the suspension was filtered, a clear filtrate was evaporated to give the title compound (123 mg, 0.292 mmol, yield 58%): ¹ H NMR (400 MHz, chloroform-d) δ 7.21 (q, 1H), 6.94 - 6.74 (m, 5H), 4.61 (t, 1H), 4.41 (s, 2H), 4.34 - 4.22 (m, 1H), 4.31 (d, 2H), 3.86 (s, 3H), 2.91 (d, 2H), 2.29 ( s, 3H), 2.24-1.86 (m, 2H), 1.80-1.65 (m, 4H); LC-MS: 422.2 [M+H] ⁺ .

Example 119: 1-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro-4-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (119)

F o F

N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.42 mmol, 108 mg), phenyl N-({4-[(tert-butyldimethylsilyl)oxy]-2-fluorophenyl}methyl) carbamate (0.42 mmol, 160 mg) and potassium carbonate (0.7 mmol, 100 mg) were stirred in toluene (1.5 ml) at 60°C for 20 h, then partitioned between toluene and water, organic phase was separated, concentrated and the residue was purified by column chromatography using silica gel, eluting with 5-100% methanol in ethyl acetate, obtaining fractions, which were collected and evaporated, and the residue was stirred for 20 min in ether to precipitate silica, the suspension was filtered, clear the filtrate was evaporated to give the silylated intermediate (91 mg, 0.174 mmol, 41% yield). This material was dissolved in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1.0 mmol, 1.0 ml) was added, the mixture was stirred for 4 h, and then concentrated and partitioned between saturated potassium carbonate, water and diethyl ether at pH 10-11. The organic phase was collected, dried and evaporated to give a crude product which was purified by column chromatography using silica gel eluting with 5-100% methanol in ethyl acetate to give fractions which were evaporated and the residue was stirred for 20 minutes in a mixture of

- 102 042461 diethyl ether/EtOAc to precipitate silica, suspension filtered, clear filtrate evaporated to give the title compound (40 mg, 0.098 mmol, 56% yield): 1H

NMR (400 MHz, chloroform-d) δ 7.13 (q, 1H), 7.02 (t, 1H), 6.84 - 6.73 (m, 2H), 6.46 - 6.37 (m , 2H), 4.74 (t, 1H), 4.36 (s, 2H), 4.30 (d, 2H), 4.29 - 4.18 (m, 1H) 2.92 (d, 2H ), 2.30 (s, 3H), 2.14 (m, 2H), 1.81-1.63 (m, 4H); LC-MS: 408.2 [M+H]+.

Example 120 3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)-1-[(4-phenoxyphenyl)methyl]urea (120)

p-(Phenoxy)benzylamine (2.88 mmol, 575 mg) and pyridine (8.3 mmol, 670 μl) were dissolved in dichloromethane (5 ml) and added dropwise to an ice-cold solution of triphosgene (1.152 mmol, 342 mg) in dichloromethane (3 ml). The mixture was stirred for 1 h, then partitioned between dichloromethane and 1 M sulfuric acid, the organic phase was separated, dried and evaporated to give crude 1(isocyanatomethyl)-4-phenoxybenzene (0.5 g) which was used in the next step. N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.66 mmol, 167 mg) was dissolved in dichloromethane (2 ml) and 1-(isocyanatomethyl)-4-phenoxybenzene (300 mg, 1 .3 mmol). The mixture was stirred for 18 hours, then purified by silica gel column chromatography eluting with 0-30% methanol in ethyl acetate to give a residue. Diethyl ether was added to the residue and the solution was filtered to remove solids. The clear solution was evaporated to give 182 mg. This material was triturated in hexanes to give the title compound (152 mg, 49% yield): 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, 2H), 7.22 (q, 1H), 7 .16 - 7.07 (m, 3H), 6.98 (d, 2H), 6.92 (d, 2H), 6.86 - 6.76 (m, 2H), 4.64 (t, 1H ), 4.46 - 4.31 (m, 5H), 3.03 (d, 2H), 2.37 (s, 3H), 2.33 - 2.17 (m, 2H), 1.87 ( d, 2H), 1.75 (m, 2H), LC-MS: 466.3 [M+H]+.

Example 121: 3-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-3 -(1-methylpiperidin-4-yl)-1-{[4-(2methylpropoxy)phenyl]methyl}urea (121)

X-methyl-4-piperidone (5.0 mmol, 583 mg) was dissolved in ethanol (5.0 ml) and [4-methoxy-2(trifluoromethyl)phenyl]methanamine (5.0 mmol, 1026 mg) was added, followed by adding sodium triacetoxyborohydride (2.0 eq., 10.0 mmol, 2.2 g). The mixture was stirred at 20°C for 3 h, then concentrated and partitioned between diethyl ether and aqueous 0.5 M NaOH, the organic phase was collected and extracted with aqueous 2 M HCl, the aqueous phase was separated and basified with 5 M NaOH, then extracted diethyl ether. The organic phase was collected and concentrated to give N-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-methylpiperidin-4-amine (1.466 g, 96% yield). This material (150 mg, 0.496 mmol) was dissolved in dichloromethane (2 ml) and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene (0.595 mmol, 123 mg) was added. The mixture was stirred for 1 h, then concentrated, and the residue was purified by column chromatography using silica gel, eluting with 0-30% methanol in ethyl acetate in petroleum ether, to give the title compound (164 mg, 65% yield): 1H NMR (400 MHz, chloroform-d) δ 7.36 (d, 1H), 7.16 (s, 1H), 7.04 (d, 2H), 6.97 (d, 1H), 6.78 (d , 2H), 4.48 (s, 2H), 4.47 - 4.33 (m, 2H), 4.29 (d, 2H), 3.83 (s, 3H), 3.68 (d, 2H), 2.89 (d, 2H), 2.28 (s, 3H), 2.16 - 1.94 (m, 3H), 1.79 - 1.59 (m, 4H), 1.01 (d, 6H); LC-MS: 508.4 [M+H]+.

Example 122: 1-[(2-fluoro-4-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (122)

- 103 042461 (2-Fluoro-4-methoxyphenyl)methanamine hydrochloride (1.0 g, 5.2 mmol) was partitioned between diethyl ether and 0.5 M NaOH. The organic phase was separated, dried and evaporated to give (2-fluoro4-methoxyphenyl)methanamine as the free base (699 mg, 4.50 mmol). To this material were added N-methyl-4-piperidone (5.0 mmol, 583 mg), ethanol (5.0 ml) and sodium triacetoxyborohydride (9.0 mmol, 1.97 g) and the mixture was stirred at 20°C. for 18 h, then partitioned between diethyl ether and an aqueous solution of 0.5 M NaOH, the organic phase was separated and extracted with an aqueous solution of 2 M HCl, the aqueous phase was separated and basified with 5 M NaOH, and then was extracted with diethyl ether. The organic phase was separated and concentrated to give Ν-[(2-Φτορ-4methoxyphenyl)methyl]-1-methylpiperidin-4-amine (1.059 g, 93% yield). This compound (132 mg, 0.497 mmol) was dissolved in dichloromethane (2 ml) and 1-(isocyanatomethyl)-4-(propan-2yloxy)benzene (0.596 mmol, 114 mg) was added. The mixture was stirred for 1 hour, then purified by silica gel column chromatography, eluting with 0-30% methanol in ethyl acetate, to give fractions. These fractions were combined and evaporated. Diethyl ether was added to the residue and the solution was filtered to remove solids. The clear solution was evaporated to give the desired compound as the free base (135.7 mg, 61% yield). This material (41 mg, 0.0924 mmol) was dissolved in dioxane (1.0 ml), trifluoroacetic acid (1 M solution in dioxane, 1.1 eq., 0.102 mmol, 102 μl) was added and the mixture was lyophilized to give the indicated in title compound (49 mg): ¹ H NMR (400 MHz, DMSO^) δ 9.19 (s, 1H), 7.12 (d, 2H), 7.08 (t, 1H), 7.01 (t , 1H), 6.85 - 6.77 (m, 3H), 6.74 (dd, 1H), 4.56 (m, 1H), 4.37 (s, 2H), 4.25 - 4, 13 (m, 3H), 3.75 (s, 3H), 3.38 (m, 2H), 2.97 (d, 2H), 2.71 (d, 3H), 1.82 (m, 2H ), 1.71 (d, 2H), 1.24 (d, 6H); LC-MS: 444.3 [M+H]+.

Example 123: 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea; hemitartrate (123) f o _g

n tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (1.00 g, 3.06 mmol) was dissolved in dichloromethane (10 mL) and 1-butoxy-4- (isocyanatomethyl)benzene (735 mg, 3.4 mmol) dissolved in dichloromethane (2 ml). The mixture was stirred for 18 hours, then evaporated, and the residue was purified by column chromatography using silica gel, eluting with 30-50% ethyl acetate in petroleum ether, to give intermediate (1.63 g). This material was stirred in dichloromethane (6 ml) and trifluoroacetic acid (4 ml) for 20 min, then evaporated and partitioned between EtOAc and 0.5 M NaOH. The organic phase was collected, evaporated and the residue was crystallized from hexanes/EtOAc, the solids were isolated and triturated in ether to give 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1- (piperidin-4-yl)urea (765 mg, 58% yield). This material (71.8 mg, 0.166 mmol) was dissolved in 2-propanol (1 ml) and L-(+) tartaric acid (2 M solution in ethanol, 1.1 eq., 0.0915 mmol, 229 µl) was added. . A precipitate formed after 1 minute, the suspension was stirred for 20 minutes and then filtered and dried to give the title compound (62.9 mg, 0.124 mmol, 75% yield): 1H NMR (400 MHz, methanol-d ₄ ) δ 7.21 (q, 1H), 7.14 (d, 2H), 6.98-6.85 (m, 2H), 6.82 (d, 2H), 4.53 (s, 2H), 4 .31 (s, 1H), 4.36-4.21 (m, 1H), 4.28 (s, 2H), 3.95 (t, 2H), 3.39 (d, 2H), 2, 99 (m, 2H), 1.97-1.79 (m, 4H), 1.74 (n, 2H), 1.50 (sext, 2H), 0.98 (t, 3H); LC-MS: 432.3 [M+H]+.

Example 124: 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea(124) f o

3-[(4-Butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea (200 mg, 0.463 mmol) was dissolved in tetrahydrofuran (3.0 ml) and formaldehyde (1.16 mmol, 87 μl) was added followed by sodium triacetoxyborohydride (1.16 mmol, 254 mg). The mixture was stirred for 2 hours, partitioned between diethyl ether and 0.5 M NaOH, the organic phase was evaporated and the residue was suspended in diethyl ether. Filtration gave 166 mg of material which was crystallized from ethanol/water to give the title compound (108 mg, 52% yield). 1H NMR (400 MHz, chloroform-d) δ 7.21 (q, 1H), 7.09 (d, 2H), 6.85-6.73 (m, 4H), 4.53 (t, 1H) , 4.40 (s, 2H), 4.32 (d, 2H), 4.32-4.20 (m, 1H), 3.93 (t, 2H), 2.88 (d, 2H), 2.27 (s, 3H), 2.08 (m, 2H), 1.80-1.60 (m, 6H), 1.48 (g, 2H), 0.97 (t, 3H); LC-MS: 446.3 [M+H]+.

- 104 042461

Example 125 3-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4yl)urea (125)

A solution of 1-methoxy-4-(isocyanatomethyl)benzene (172 mg, 1.03 mmol) in dichloromethane (1 ml) was added to X-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (intermediate compound 2, 200 mg, 0.79 mmol) in dichloromethane (2 ml). The mixture was stirred for 1 h, then evaporated and the residue was purified by column chromatography using silica gel eluting with 0-25% methanol in ethyl acetate to give the title compound (192 mg, 60% yield): 1H NMR (400 MHz , Chloroform-d) δ 7.25 - 7.16 (m, 1H), 7.11 (d, 2H), 6.85 - 6.73 (m, 4H), 4.55 (t, 1H), 4.40 (s, 2H), 4.32 (d, 2H), 4.32-4.21 (m, 1H), 3.78 (s, 3H), 2.89 (d, 2H), 2 .27 (s, 3H), 2.13-2.03 (m, 2H), 1.74-1.61 (m, 4H); LC-MS: 403.9 [M+H] ⁺ .

Example 126: 1-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1-(piperidin-4-yl)urea; hemitartrate (126)

tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (300 mg, 0.873 mmol) was dissolved in dichloromethane (2 mL) and 1-methoxy-4-(isocyanatomethyl)benzene ( 190 mg, 1.14 mmol) dissolved in dichloromethane (1 ml). The mixture was evaporated and purified by silica gel column chromatography eluting with 50% ethyl acetate in petroleum ether to give intermediate (387 mg). This material was stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) for 1 h, then evaporated and partitioned between diethyl ether/EtOAc and 0.5 M NaOH. The organic phase was collected, evaporated and the residue was crystallized from diethyl ether/hexanes to give the title compound as the free base (195 mg, 0.46 mmol, 53% yield). This material (163 mg, 0.418 mmol) was dissolved in 2-propanol (3 ml) and L-(+)-tartaric acid (0.4 M solution in ethanol, 1.1 eq., 0.23 mmol, 575 µl) was added dropwise ), leading to crystallization. Crystals were isolated by filtration and then recrystallized from MeOH/ethanol to give the title compound (130 mg, 67% yield from free base): 1H NMR (400 MHz, methanol-d ₄ ) δ 7.21 (q, 1H) , 7.15 (d, 2H), 6.98-6.86 (m, 2H), 6.83 (d, 2H), 4.53 (s, 2H), 4.32 (s, 1H), 4.34-4.23(m, 1H), 4.29(s, 2H), 3.76(s, 3H), 3.38(d, 2H), 2.98(m, 2H), 1 .95-1.81 (m, 4H); LC-MS: 390.2 [M+H] ⁺ .

Example 127 Hemitartrate (127)

3-[(2,4-difluorophenyl)methyl]-1-[(4-ethoxyphenyl)methyl]-3-(piperidin-4-yl)urea;

tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (intermediate 1, 331 mg, 1.01 mmol) was dissolved in dichloromethane (2 ml) and 1-ethoxy-4 was added -(isocyanatomethyl)benzene (265 mg, 1.30 mmol) dissolved in dichloromethane (1 ml). The mixture was stirred for 20 minutes, then partitioned between 0.5 M NaOH and dichloromethane. The organic phase was evaporated and the residue was purified by column chromatography using silica gel eluting with 30-50% ethyl acetate in petroleum ether to give intermediate (365 mg, 0.90 mmol, 89% yield). This material was stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) for 20 min, the solvents were evaporated and the residue was partitioned between ether and 0.5 M NaOH. The organic phase was collected, dried and evaporated and the residue was crystallized from EtOAc/hexanes and then from MeOH/water to give 107 mg of material (0.26 mmol, 29% yield). This material was dissolved in 2-propanol (1.0 ml) and a solution of L-(+)-tartaric acid in ethanol (0.4 M, 1.1 eq., 0.146 mmol, 365 μl) was added. Crystals were isolated by filtration, dried to give the title compound (119 mg, 0.248 mmol, 96% yield, overall yield from starting material

- 105 042461 is 25%): Ή NMR (400 MHz, methanol^) δ 7.21 (q, 1H), 7.14 (d, 2H), 6.98-6.86 (m, 2H), 6 .82 (d, 2H), 4.53 (s, 2H), 4.32 (s, 1H), 4.34-4.23 (m, 1H), 4.28 (s, 2H), 4. 00 (q, 2H), 3.38 (d, 2H), 2.98 (m, 2H), 1.951.81 (m, 4H), 1.37 (t, 3H); LC-MS: 404.2 [M+H]+.

Example 128: 3-[(2H-1,3-Benzodioxol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (128)

2H-1,3-benzodioxole-5-carbonitrile (1.73 g, 11.75 mmol) in diethyl ether (15 ml) was added portionwise to a mixture of lithium aluminum hydride (55.2 mmol hydride, 13.8 mmol, 525 mg) in diethyl ether (15 ml). The mixture was refluxed for 2 h, then cooled and worked up (H ₂ O, 15% NaOH, 3x H ₂ O) to give crude benzylamine (1.77 g, quant.). This amine (1.0 g, 6.6 mmol) and pyridine (1.1 eq., 17.6 mmol, 1.43 ml) were dissolved in dichloromethane (5.0 ml) and added dropwise to an ice-cold solution of triphosgene (2.7 mmol, 801 mg) in dichloromethane (5.0 ml). The mixture was stirred for 1 h, then partitioned between cold 0.5 M sulfuric acid and dichloromethane. The organic phase was separated, dried and evaporated to give crude 5-(isocyanatomethyl)-2H-1,3benzodioxole (1.08 g, 92% yield).

N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (250 mg, 1.01 mmol) was dissolved in dichloromethane (1 ml) and 5-(isocyanatomethyl)-2H-1 was added in one portion ,3-benzodioxole (215 mg, 1.21 mmol) in dichloromethane (1 ml). The mixture was stirred at room temperature for 1 hour and then purified by silica gel column chromatography eluting with methanol to give the title compound (275 mg, 66% yield): 1H NMR (400 MHz, chloroform-d) δ 7.21 (q, 1H), 6.87 - 6.73 (m, 2H), 6.73 - 6.59 (m, 3H), 5.92 (s, 2H), 4.57 (t, 1H), 4.40 (s, 2H), 4.29 (d, 2H), 4.26 (m, 1H), 2.88 (d, 2H), 2.27 (s, 3H), 2, 07 (m, 2H), 1.75-1.60 (m, 4H); LC-MS: 418.2 [M+H] ⁺ .

Example 129 (comparative): 1-[(2,3-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (129)

The compound was prepared by analogy with OP B using N-[(2,3-difluorophenyl)methyl]-1-methylpiperidin-4-amine (prepared by analogy with Intermediate 6 using (2,3difluorophenyl)methanamine and 1-(isocyanatomethyl )-4-(2-methylpropoxy)benzene Yield: 87% ¹ H NMR (400 MHz, chloroform-d) δ 7.10-6.97 (m, 4H), 6.91 (t, 1H), 6.76 (d, 2H), 5.02 (s, 1H), 4.61 (dt, 1H), 4.43 (s, 2H), 4.23 (s, 2H), 3.66 (d , 2H), 3.49 (d, 2H), 2.92 - 2.77 (m, 2H), 2.72 (s, 3H), 2.20 - 1.96 (m, 3H), 1, 87 (d, 2H), 0.99 (d, 6H), LC-MS: 446.3 [M+H] ⁺ .

Example 130: 1-[(3,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (130) o

The compound was prepared by analogy with OP B using N-[(3,4-difluorophenyl)methyl]-1-methylpiperidine-4-amine (prepared by analogy with Intermediate 6 using (3,4difluorophenyl)methanamine and 1-(isocyanatomethyl)- 4-(propan-2-yloxy)benzene Yield: 82% ¹ H NMR (400 MHz, Chloroform-d) δ 7.15-7.05 (m, 1H), 7.05-6.97 (m , 3H), 6.95 - 6.89 (m, 1H), 6.81 - 6.75 (m, 2H), 4.72 (ddt, 2H), 4.50 (n, 1H), 4, 34 (s, 2H), 4.27 (s, 2H), 3.56 (d, 2H), 2.86 (t, 2H), 2.77 (s, 3H), 2.18 (qvd, 2H ), 1.89 (d, 2H), 1.31 (d, 6H), LC-MS: 432.3 [M+H] ⁺ .

- 106 042461

Example 131 1-[(2,4-difluorophenyl)methyl]-1-[1 -( ² H ₃ )methylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl]methyl} urea; trifluoroacetic acid (131) f o

1-[(2,4-Difluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea (50 mg, 0.12 mmol) dissolved in acetone (1 ml). Potassium carbonate (33 mg, 240 µmol) was added. A solution of iodine( ² H ₃ )methane (15.6 mg, 108 µmol) in acetone (170 µl) was added. After 60 minutes of stirring at room temperature, the mixture was filtered, concentrated and redissolved in dichloromethane (1.5 ml). Di-tert-butyl dicarbonate (31 mg, 144 µmol) was added. The reaction mixture was stirred at room temperature overnight. Dichloromethane (2 ml) was added to the reaction mixture. The mixture was washed with sodium hydroxide (7x2 ml, 0.1 M). The organic phase was concentrated. The crude material was purified by HPLC eluting with 25-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (11 mg, 17%): ¹ H NMR (400 MHz, chloroform-d) δ 11 .83 (s, 1H), 7.12 (q, 1H), 7.01 (d, 2H), 6.87-6.75 (m, 4H), 4.75 (t, 2H), 4. 51 (hept, 1H), 4.37 (s, 2H), 4.28 (s, 2H), 3.62 (d, 2H), 2.88 (t, 2H), 2.26-2.11 (m, 2H), 1.92 (d, 2H), 1.32 (d, 6H); LC-MS: 435.3 [M+H]+

Example 132: 1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}-1-[(2,3,4-trifluorophenyl)methyl]urea; trifluoroacetic acid (132)

tert-Butyl 4-{[(2,3,4-trifluorophenyl)methyl]amino}piperidine-1-carboxylate F

tert-Butyl 4-oxo-piperidine-1-carboxylate (200 mg, 1.0 mmol) and (2,3,4-trifluorophenyl)methanamine (178 mg, 1.1 mmol) were dissolved in ethanol (2.5 ml). The reaction mixture was stirred for 20 minutes. Sodium triacetoxyborohydride (319 mg, 1.51 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was dissolved in dichloromethane and sodium hydroxide (0.5 M in water) was added. The phases were separated. The aqueous phase was extracted with dichloromethane two more times. The combined organic phases were dried over sodium sulfate. The organic phase was concentrated and the crude material was used without further purification in the next step.

tert-Butyl 4-[({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)[(2,3,4-trifluorophenyl)methyl]amino]piperidine-1-carboxylate.

A solution of 1-(isocyanatomethyl)-4-(propan-2yloxy)benzene (44.0 mg, 0.23 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred at room temperature overnight. The organic phase was concentrated and the crude material was purified by HPLC eluting with 40-90% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the desired intermediate (84 mg).

1-(Piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}-1-[(2,3,4-trifluorophenyl)methyl]urea; trifluoroacetic acid.

tert-Butyl 4-[({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)[(2,3,4-trifluorophenyl)methyl]amino]piperidine-1-carboxylate (82 mg, 0.15 mmol) dissolved in dichloromethane (1.5 ml) was cooled to 0° C. in an ice bath. Trifluoroacetic acid (0.76 ml) was added dropwise with stirring. The cooling bath was removed and the reaction mixture was stirred at room temperature for one hour. The mixture was concentrated. The crude material was purified by HPLC eluting with 20-60%

- 107 042461 acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (31 mg, 37%): ¹ H NMR (400 MHz, chloroform-d) δ 9.50 (s, 1H) , 9.03 (s, 1H), 7.04 (d, 2H), 6.94-6.87 (m, 2H), 6.79 (d, 2H), 4.71 (s, 1H), 4.60 - 4.45 (m, 2H), 4.40 (s, 2H), 4.28 (s, 2H), 3.40 (d, 2H), 3.01 2.85 (m, 2H ), 1.98 (q, 2H), 1.92-1.82 (m, 2H), 1.32 (d, 6H); LC-MS: 436.3 [M+H]+.

Example 133: 3-[(4-chloro-2-fluorophenyl)methyl]-3-(piperidin-4-yl)-1-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (133)

The compound was prepared in analogy to Example 132 using (4-chloro-2-fluorophenyl)methanamine. The crude material was purified by HPLC eluting with 20-55% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (53 mg, 42%): 1H NMR (400 MHz, chloroform-d) δ 9, 56 (s, 1H), 9.07 (s, 1H), 7.16-7.06 (m, 3H), 7.03 (d, 2H), 6.79 (d, 2H), 4.73 - 4.56 (m, 2H), 4.51 (hept, 1H), 4.37 (s, 2H), 4.28 (s, 2H), 3.40 (d, 2H), 3.02 - 2.85 (m, 2H), 2.04-1.94 (m, 2H), 1.92-1.82 (m, 2H), 1.32 (d, 6H); LC-MS: 434.3 [M+H] ⁺ .

Example 134: 3-[(4-Chloro-2-fluorophenyl)methyl]-1-{[4-(2-methylpropoxy)phenyl]methyl}-3-(piperidin4-yl)urea; trifluoroacetic acid (134)

The compound was prepared in analogy to Example 132 using (4-chloro-2-fluorophenyl)methanamine and 1(isocyanatomethyl)-4-(2-methylpropoxy)benzene. The crude material was purified by HPLC eluting with 20-60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (71 mg, 68%): 1H NMR (400 MHz, chloroform-d) δ 9, 57 (s, 1H), 9.09 (s, 1H), 7.15-7.06 (m, 3H), 7.04 (d, 2H), 6.80 (d, 2H), 4.67 - 4.57 (m, 2H), 4.37 (s, 2H), 4.28 (s, 2H), 3.69 (d, 2H), 3.41 (d, 2H), 3.04 - 2.88 (m, 2H), 2.07 (tt, 1H), 2.01-1.85 (m, 4H), 1.02 (d, 6H); LC-MS: 448.3 [M+H] ⁺ .

Example 135: 1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}-1-[(2,3,4-trifluorophenyl)methyl]urea; trifluoroacetic acid (135)

mg, 1.86 mmol)

-Methylpiperidin-4-one (211 and (2,3,4-trifluorophenyl)methanamine (300 mg, 1.86 mmol) was dissolved in ethanol (7.5 ml). The reaction mixture was stirred for 20 min. Sodium triacetoxyborohydride ( 592 mg, 2.79 mmol) The reaction mixture was stirred at room temperature overnight The mixture was concentrated The residue was dissolved in dichloromethane and sodium hydroxide (0.5 M in water) The phases were separated The aqueous phase was extracted with dichloromethane two more times Combined the organic phases were dried over sodium sulfate The organic phase was concentrated and the crude material was used without further purification in the next step.

1-(1-Methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}-1-[(2,3,4-trifluorophenyl)methyl]urea; trifluoroacetic acid.

To a solution of 1-methyl-N-[(2,3,4-trifluorophenyl)methyl]piperidine-4-amine (40.0 mg, 0.15 mmol) in di

- 108 042461 chloromethane (0.65 ml) was added dropwise a solution of 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene (52.3 mg, 0.23 mmol) in dichloromethane (0.65 ml). The reaction mixture was stirred at room temperature overnight. The organic phase was concentrated and the crude material was purified by HPLC eluting with 40-70% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (61 mg, 70%): 1H NMR (400 MHz, chloroform-d ) δ 12.93 (s, 1H), 7.04 (d, 2H), 6.94-6.86 (m, 2H), 6.79 (d, 2H), 4.71 (ddd, 1H) , 4.63 (s, 1H), 4.50 (d.s., 1H), 4.41 (s, 2H), 4.29 (d, 2H), 3.58 (d, 2H), 2 .93 - 2.81 (m, 2H), 2.78 (s, 3H), 2.34 - 2.20 (m, 2H), 1.91 (d, 2H), 1.32 (d, 6H ); LC-MS: 450.3 [M+H] ⁺ .

Example 136: 1-[(2,6-difluoro-4-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid (136)

The compound was obtained by analogy with example 135 (1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}-1-[(2,3,4-trifluorophenyl)methyl] urea) using (2,6-difluoro-4-methoxyphenyl)methanamine. The crude material was purified by HPLC eluting with 30-60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (39 mg, 44%): 1 H NMR (400 MHz, chloroform-d) δ 12, 00 (s, 1H), 7.06 (d, 2H), 6.80 (d, 2H), 6.41 (d, 2H), 5.06 (s, 1H), 4.62 (t, 1H ), 4.52 (p, 1H), 4.32 (s, 2H), 4.30 (s, 2H), 3.78 (s, 3H), 3.64 (d, 2H), 2.92 - 2.81 (m, 2H), 2.80 (s, 3H), 2.46 - 2.30 (m, 2H), 1.94 (d, 2H), 1.33 (d, 6H); LC-MS: 462.3 [M+H] ⁺ .

Example 137: 1-[(4-chloro-2-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; trifluoroacetic acid (137)

The compound was prepared in analogy to Example 135 using (4-chloro-2-fluorophenyl)methanamine. The crude material was purified by HPLC eluting with 35-65% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (61 mg, 60%): 1H NMR (400 MHz, chloroform-d) δ 12, 64 (s, 1H), 7.10 (d, 3H), 7.02 (d, 2H), 6.82-6.76 (m, 2H), 4.75 (t, 1H), 4.65 (s, 1H), 4.51 (dt, 1H), 4.38 (s, 2H), 4.29 (d, 2H), 3.59 (d, 2H), 2.94 - 2.81 ( m, 2H), 2.79 (s, 3H), 2.34-2.19 (m, 2H), 1.91 (d, 2H), 1.33 (d, 6H); LC-MS: 448.3 [M+H] ⁺ .

Example 138: 1-[(4,5-difluoro-2-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2yloxy)phenyl]methyl}urea; trifluoroacetic acid (138)

The compound was prepared in analogy to Example 135 using (4,5-difluoro-2-methoxyphenyl)methanamine. The crude material was purified by HPLC eluting with 35-65% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (53 mg, 59%): 1H NMR (400 MHz, chloroform-d) δ 12, 63 (s, 1H), 7.04 (d, 2H), 6.98-6.88 (m, 1H), 6.80 (d, 2H), 6.66 (dd, 1H), 4.82 - 4.72 (m, 2H), 4.51 (d.s., 1H), 4.29 (d, 2H), 4.25 (s, 2H), 3.73 (s, 3H), 3 .58 (d, 2H), 2.87 (t, 2H), 2.79 (s, 3H), 2.29 2.15 (m, 2H), 1.91 (d, 2H), 1.36 - 1.29 (m, 6H); LC-MS: 462.3 [M+H] ⁺ .

Example 139: 1-[(4-chloro-2-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; trifluoroacetic acid (139)

- 109 042461

The compound was prepared in analogy to Example 135 using (4-chloro-2-fluorophenyl)methanamine and 1(isocyanatomethyl)-4-(2-methylpropoxy)benzene. The crude material was purified by HPLC eluting with 20-60% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (79 mg, 68%): 1H NMR (400 MHz, chloroform-d) δ 12, 28 (s, 1H), 7.13-7.06 (m, 3H), 7.02 (d, 2H), 6.80 (d, 2H), 4.81-4.71 (m, 1H) , 4.67 (s, 1H), 4.38 (s, 2H), 4.28 (s, 2H), 3.70 (d, 2H), 3.60 (d, 2H), 2.94 2 .83 (m, 2H), 2.80 (s, 3H), 2.33-2.19 (m, 2H), 2.07 (hept, 1H), 1.92 (d, 2H), 1, 02 (d, 6H); LC-MS: 462.3 [M+H]+.

Example 140 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea

4-propoxybenzonitrile

4-Hydroxybenzonitrile (6.00 g, 50.4 mmol), potassium carbonate (17.4 g, 126 mmol) and n-propyl iodide (21.4 g, 126 mmol) were heated in DMF (70 ml) to 70° C for 12 hours. After cooling, water (150 ml) was added and the reaction mixture was extracted with diethyl ether (2x250 ml). The combined organic phase was washed with water (200 ml), dried (sodium sulfate) and evaporated to give the desired intermediate (8.00 g, 98%). 1-(4-propoxyphenyl)methanamine

4-Propoxybenzonitrile (8.00 g, 49.6 mmol) was dissolved in tetrahydrofuran (50 ml). Lithium aluminum hydride (2.82 g, 74.4 mmol) was added and the suspension was refluxed for 3 h. After cooling, the reaction mixture was quenched with water (3 ml), aqueous sodium hydroxide solution (15%, 3 ml) and water ( 9 ml). The precipitate was filtered, the filtrate was dried (sodium sulfate) and evaporated to give the desired intermediate (7.00 g, 85%).

Phenyl N-[(4-propoxyphenyl)methyl]carbamate

1-(4-Propoxyphenyl)methanamine (1.66 g, 10.0 mmol) was dissolved in dichloromethane (10 ml). Pyridine (1.22 ml, 15.1 mmol) was added and the solution was cooled to 0°C. Phenyl chloroformate (2.04 g, 13.1 mmol) dissolved in dichloromethane (10 ml) was added dropwise. After the addition, HCl (2 M, 20 ml) was added. The organic phase was washed with water (20 ml), dried (phase separator) and evaporated. The crude product was crystallized from ethyl acetate/heptane to give the desired intermediate (1.8 g, 63%).

1-[(2,4-Difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea N[(2,4-difluorophenyl)methyl]-1- methylpiperidin-4-amine (480 mg, 2.0 mmol), phenyl N-[(4-pronoxyphenyl)methyl]carbamate (741 mg, 2.6 mmol) and potassium carbonate (414 mg, 3.0 mmol) were heated in toluene (6 ml) to 75°C for 12 hours The solvent was evaporated and the residue was treated with sodium hydroxide solution (1 M, 5 ml) and diethyl ether (70 ml). The organic phase was separated, washed with water (10 ml), dried (sodium sulfate) and evaporated. The crude product was purified by gel chromatography

- 110 042461 silica eluting with 10% methanol in dichloromethane with 1% ammonia to give the title compound (390 mg, 45%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.24-7.14 (m, 2H), 7.12 (d, 2H), 7.05-6.95 (m, 2H), 6, 84 (d, 2H), 4.39 (s, 2H), 4.18 (d, 2H), 3.97-3.91 (m, 1H), 3.88 (d, 2H), 2.70 (t, 2H), 2.09 (s, 3H), 1.88 (t, 2H), 1.70 (g, 2H), 1.56-1.41 (m, 4H), 0.96 ( t, 3H); LC-MS: 432.3 [M+H]+.

Example 141 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea

4-(cyclopropylmethoxy)benzonitrile

4-Hydroxybenzonitrile (1.02 g, 9.9 mmol), (chloromethyl)cyclopropane (2.35 g, 25.9 mmol), tetrabutylammonium iodide (369 mg, 1.0 mmol) and potassium carbonate (4.14 g , 30 mmol) was heated in DMF (20 ml) at 50° C. for 1 day. After cooling to room temperature, water (50 ml) was added and the aqueous layer was extracted with diethyl ether (2x200 ml). The combined organic phase was washed with water (4x100 ml), dried (sodium sulfate) and evaporated to give the desired intermediate as a yellow oil (1.68 g, 98%).

1-[4-(Cyclopropylmethoxy)phenyl]methanamine

4-(Cyclopropylmethoxy)benzonitrile (1.68 g, 9.7 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise to a suspension of lithium aluminum hydride (626 mg, 16.5 mmol) in tetrahydrofuran (6 ml). The reaction mixture was refluxed for 3 hours and then quenched with water (0.62 ml), NaOH (aqueous solution, 15%, 0.62 ml) and water (1.86 ml). The suspension was filtered, dried (sodium sulfate) and evaporated to give the desired intermediate (1.32 g, 77%).

Phenyl N-{[4-(cyclopropylmethoxy)phenyl]methyl}carbamate

1-[4-(Cyclopropylmethoxy)phenyl]methanamine (1.32 g, 7.4 mmol) was dissolved in dichloromethane (10 ml). The solution was cooled to 0° C. and pyridine (0.9 ml) was added. Phenyl chloroformate (1.2 ml, 9.7 mmol) dissolved in dichloromethane (10 ml) was added dropwise. The reaction mixture was stirred for 5 min and then hydrochloric acid (1 M, 20 ml) was added, the organic phase was separated and washed with water (30 ml), dried (sodium sulfate) and evaporated. The crude material was purified by silica gel chromatography eluting with 20% ethyl acetate in petroleum ether to give the desired intermediate (2.2 g, 89%).

3-{[4-(Cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea.

N-[(2,4-Difluorophenyl)methyl]-1-methylpiperidin-4-amine (685 mg, 2.85 mmol), phenyl N-{[4(cyclopropylmethoxy)phenyl]methyl}carbamate (975 mg, 3, 28 mmol) and potassium carbonate (563 mg, 4.08 mmol) were mixed in toluene (10 ml) and heated to 75°C for 12 hours. The solvent was evaporated and the residue was partitioned between diethyl ether (200 ml) and aqueous hydroxide solution sodium (1 M, 20 ml). The organic phase was washed with water (50 ml), dried (sodium sulfate) and evaporated. The crude material was purified by silica gel column chromatography eluting with 10% methanol in dichloromethane with 1% ammonia to give the title compound (525 mg, 42%). 1H NMR (400 MHz, DMSO-0 ₆ ) δ 7.24-7.14 (m, 2H), 7.11 (d, 2H), 7.05-6.96 (m, 2H), 6.83 (d, 2H), 4.39 (s, 2H), 4.17 (d, 2H), 3.94 (s, 1H), 3.77 (d, 2H), 2.78 (s, 2H) , 2.17 (s, 3H), 2.00 (d, 2H), 1.61-1.45 (m, 4H), 1.27-1.14 (m, 1H), 0.58-0 .51 (m, 2H), 0.32-0.26 (m, 2H); LC-MS: 444.3 [M+H] ⁺ .

Example 142: 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea (142)

- 111 042461

F O

Η

TFA (4 ml) was added to tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate (1 .20 g, 2.32 mmol, obtained in example 75) in CH ₂ Cl ₂ (10 ml) at room temperature. After 20 min stirring at room temperature, the mixture was concentrated under reduced pressure, NaHCO ₃ (10 ml, sat. aq.) and diethyl ether (150 ml) were added. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired intermediate (0.80 g) which was used without further purification or the resulting concentrate was purified by preparative HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid), to give 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl} urea.

Example 143: 1-[(2,4-difluorophenyl)methyl]-3-{[3-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1methylpiperidin-4-yl)urea; trifluoroacetic acid f o

The compound was obtained by analogy with 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4(2-methylpropoxy)phenyl]methyl}urea using X-[ (2,4-difluorophenyl)methyl]-1-methylpiperidine4-amine and 2-fluoro-4-(isocyanatomethyl)-1-(propan-2-yloxy)benzene (1.2:1). Yield: 60%. 1H NMR (400 MHz, chloroform-d) δ 12.71 (br s, 1H), 7.19 - 7.09 (m, 1H), 6.90 - 6.76 (m, 5H), 4, 85 - 4.64 (m, 2H), 4.58 - 4.44 (m, 1H), 4.38 (s, 2H), 4.28 (d, 2H), 3.60 (d, 2H) , 2.93-2.70(m, 5H), 2.28-2.10(m, 2H), 1.91(d, 2H), 1.34(d, 6H); LC-MS: 450.3 [M+H]+.

Example 144: 1-[(2,4-difluorophenyl)methyl]-3-{[2-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1methylpiperidin-4-yl)urea; trifluoroacetic acid

F o F

F

The compound was obtained by analogy with 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4(2-methylpropoxy)phenyl]methyl}urea using X-[ (2,4-difluorophenyl)methyl]-1-methylpiperidine4-amine and 2-fluoro-1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene (1.2:1). Yield: 58%. 1H NMR (400 MHz, chloroform-d) δ 12.89 (br s, 1H), 7.13-7.02 (m, 2H), 6.88-6.73 (m, 2H), 6, 58 (dd, 1H), 6.51 (dd, 1H), 4.80 4.63 (m, 2H), 4.48 (hept, 1H), 4.35 (s, 2H), 4.30 ( d, 2H), 3.59 (d, 2H), 2.88 - 2.72 (m, 5H), 2.17 (kvd, 2H), 1.88 (d, 2H), 1.32 (d , 6H); LC-MS: 450.3 [M+H] ⁺ .

Example 145: 1-[(2,4-difluorophenyl)methyl]-3-{[3-methyl-4-(propan-2-yloxy)phenyl]methyl}-1-(1methylpiperidin-4-yl)urea; trifluoroacetic acid f o

F

The compound was prepared by analogy with 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4(2-methylpropoxy)phenyl]methyl}urea using N-[ (2,4-difluorophenyl)methyl]-1-methylpiperidine4-amine and 4-(isocyanatomethyl)-2-methyl-1-(propan-2-yloxy)benzene (1.2:1). Yield: 74%. 1H NMR (400

- 112 042461

MHz, chloroform-d) δ 11.76 (br s, 1H), 7.15 (q, 1H), 6.88 - 6.77 (m, 4H), 6.71 (d, 1H), 4 .91 - 4.67 (m, 2H), 4.53 - 4.35 (m, 3H), 4.24 (s, 2H), 3.56 (d, 2H), 2.93 (q, 2H ), 2.79 (d, 3H), 2.42 (q, 2H), 2.13 (s, 3H), 1.92 (d, 2H), 1.32 (d, 6H); LC-MS: 446.3 [M+H] ⁺ .

Example 146: 1-[(2,4-difluorophenyl)methyl]-3-[(4-fluoro-3-methoxyphenyl)methyl]-1-(1-methylpiperidin4-yl)urea; trifluoroacetic acid

The compound was prepared by analogy with 3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1(1-methylpiperidin-4-yl)urea using N-[( 2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine and (4-fluoro-3-methoxyphenyl)methanamine (1:1). Diisopropylethylamine was used instead of triethylamine. Yield: 62%. ¹ H NMR (400 MHz, Chloroform-d) δ 12.41 (br s, 1H), 7.16 (q, 1H), 6.97 (dd, 1H), 6.84 (t, 2H), 6.76 (dd, 1H), 6.68 - 6.59 (m, 1H), 4.82 (s, 1H), 4.78 - 4.64 (m, 1H), 4.42 (s, 2H), 4.31 (d, 2H), 3.83 (s, 3H), 3.60 (d, 2H), 2.95-2.83 (m, 2H), 2.80 (s, 3H ), 2.42-2.25 (m, 2H), 1.92 (d, 2H); LC-MS: 422.3 [M+H]+.

Example 147: 1-[(2,4-difluorophenyl)methyl]-3-({4-[(2-ethylhexyl)oxy]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid

The compound was obtained by analogy with 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea using 2 -ethylhexan-1-ol. Sodium hydride in dimethylformamide was used instead of potassium tert-butoxide in tetrahydrofuran. Yield: 53%. 1H NMR (400 MHz, chloroform-d) δ 12.44 (br s, 1H), 7.12 (q, 1H), 7.03 (d, 2H), 6.86-6.79 (m, 4H), 4.80 - 4.63 (m, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 3.81 (dd, 2H), 3.61 (d, 2H ), 2.94 - 2.81 (m, 2H), 2.79 (s, 3H), 2.17 (qvd, 2H), 1.91 (d, 2H), 1.70 (g, 1H) , 1.57-1.28 (m, 8H), 0.97-0.88 (m, 6H); LC-MS: 502.4 [M+H] ⁺ .

Example 148 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(prop-2-yn-1-yloxy)phenyl]methyl}urea ; trifluoroacetic acid

analogy with

The compound was obtained according to

1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea using prop-2-yn- 1-ol. Sodium hydride in dimethylformamide was used instead of potassium tert-butoxide in tetrahydrofuran, and the intermediate nitrile was reduced with lithium aluminum hydride instead of borane. Yield: 26%. 1H NMR (400 MHz, chloroform-d) δ 13.10 (br s, 1H), 7.17-7.10 (m, 1H), 7.07 (d, 2H), 6.92-6, 86 (m, 2H), 6.82 (t, 2H), 4.78-4.62 (m, 4H), 4.37 (s, 2H), 4.30 (d, 2H), 3.59 (d, 2H), 2.85-2.75 (m, 5H), 2.52 (t, 1H), 2.26-2.10 (m, 2H), 1.90 (d, 2H); LC-MS: 428.3 [M+H] ⁺ .

Example 149: 3-{[4-(t-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4yl)urea; trifluoroacetic acid

- 113 042461

[4-(tert-Butoxy)phenyl]methanamine (27.7 mg,

154 µmol) and diisopropylethylamine (53.8 µl, 309 µmol) in dichloromethane (1 ml) were added to tert-butyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate (40 mg, 103 µmol). After 5 hours of stirring at room temperature, the mixture was washed with hydrochloric acid (aqueous solution, 1 M, 1 ml) and dried using a phase separator. Trifluoroacetic acid (100 μl) was added and the mixture was stirred for 30 minutes after which it was concentrated. The crude material was purified by HPLC eluting with 2050% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (4.7 mg, 8%): % NMR 9.36 (br s, 1H), 9.02 (br s, 1H), 7.23 - 7.09 (m, 1H), 7.01 (d, 2H), 6.89 (d, 2H), 6.87 - 6.74 ( m, 2H), 4.81 - 4.53 (m, 2H), 4.39 (s, 2H), 4.32 (s, 2H), 3.43 (d, 2H), 3.05 -2 .80 (m, 2H), 2.12-1.96 (m, 2H), 1.91 (d, 2H), 1.33 (s, 9H); LC-MS: 432.3 [M+H]+.

Example 150: 1-[(2,6-difluoro-4-methoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid

Pyridine (137 mg, 1.73 mmol) was added to triphosgene (174 mg, 586 µmol) in dichloromethane (2 ml) at room temperature followed by the addition of (2,6-difluoro-4-methoxyphenyl)methanamine (111 mg, 640 µmol ). After 20 minutes of stirring at room temperature, HCl (1 ml, 1 M aqueous solution) was added to the mixture. The organic phase was separated and dried using a phase separator. X-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (118 mg, 492 µmol) was added to this solution. After 19 hours stirring at room temperature, the mixture was concentrated and the crude material was purified by HPLC eluting with 30-70% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (137.7 mg, 51%): Ή NMR (400 MHz, chloroform-d) δ 12.34 (br s, 1H), 7.05 (q, 1H), 6.90-6.68 (m, 2H), 6.38 (d, 2H ), 4.87 - 4.62 (m, 2H), 4.41 - 4.25 (m, 4H), 3.76 (s, 3H), 3.58 (d, 2H), 2.90 - 2.66 (m, 5H), 2.31-2.06 (m, 2H), 1.88 (d, 2H); LC-MS: 440.2 [M+H] ⁺ .

Example 151 3-[(2,4-difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl}-3-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid

4-(3-Fluoropropoxy)benzonitrile

Potassium carbonate (670 mg, 4.85 mmol) was added to a solution of 1-bromo-3-fluoropropane (275 mg, 1.95 mmol) and 4-hydroxybenzonitrile (202 mg, 1.70 mmol) in N,N-dimethylformamide ( 2 ml). After 18 hours of stirring at room temperature, the mixture was added to ethyl acetate (10 ml) and washed with NaOH (3x10 ml, 1 M aqueous solution). The organic phase was dried using a phase separator and concentrated to an oil (303 mg).

[4-(3-Fluoropropoxy)phenyl]methanamine

A solution of borane (5 ml, 1M in tetrahydrofuran) at 4°C was added to 4-(3-fluoropro

- 114 042461 poxy)benzonitrile (303 mg, 1.69 mmol). After 3 hours of stirring at room temperature, an additional solution of borane (2 ml, 1M in tetrahydrofuran) was added. After 18 hours of stirring at 50° C., methanol was added dropwise and the mixture was heated to reflux for 30 minutes. The solution was concentrated, redissolved in dichloromethane (5 ml) and washed with NaOH (5 ml, 1 M aqueous solution). The organic phase was dried using a phase separator and concentrated to give solids (540 mg).

3-[(2,4-Difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl}-3-(1-methylpiperidin-4yl)urea; trifluoroacetic acid.

[4-(3-Fluoropropoxy)phenyl]methanamine (36.8 mg, 201 µmol) in dichloromethane (0.5 ml) was added to diphosgene (26.7 µl, 221 µmol) in dichloromethane (0.5 ml), followed by by adding pyridine (65 µl, 803 µmol). After 20 minutes of stirring at room temperature, N-[(2,4difluorophenyl)methyl]-1-methylpiperidine-4-amine (72.0 mg, 300 µmol) in dichloromethane (0.5 ml) was added. After 100 min stirring at room temperature, the mixture was washed with sodium hydroxide (2 ml, 1 M aqueous solution), the aqueous phase was extracted with dichloromethane (1 ml), the combined organic phases were dried using a phase separator and concentrated. The crude material was purified by HPLC eluting with 20-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (33 mg, 50% over 3 steps): ¹ H NMR (400 MHz, chloroform-d ) δ 12.89 (br s, 1H), 7.12 (q 1H), 7.04 (d, 2H), 6.89 - 6.76 (m, 4H), 4.78 - 4.64 (m, 3H), 4.58 (t, 1H), 4.36 (s, 2H), 4.28 (d, 2H), 4.06 (t, 2H), 3.58 (d, 2H) , 2.88-2.74 (m, 5H), 2.28-2.06 (m, 4H), 1.90 (d, 2H); LC-MS: 450.3 [M+H]+.

Example 152: 1-{[4-(1,1-difluoroethyl)phenyl]methyl}-3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid

Diethylaminosulfur trifluoride (2 ml, 15.1 mmol) was added to 4-acetylbenzonitrile (300 mg, 2.07 mmol) in dichloromethane (4 ml) at room temperature. The mixture was gradually heated to 50° C. over 2 hours. After 18 hours of stirring at this temperature, the mixture was added dropwise to ice over 10 minutes, water was added and the mixture was extracted with dichloromethane (3x3 ml). The combined organic phases were dried using a phase separator and concentrated to an oil. The crude material was purified by silica gel column chromatography eluting with 350% ethyl acetate in petroleum ether to give the title compound as an oil (355 mg, quant.).

[4-(1,1-Difluoroethyl)phenyl]methanamine

F F

A solution of 4-(1,1-difluoroethyl)benzonitrile (149 mg, 891 µmol) in diethyl ether (1 ml) was added dropwise over 2 min to a suspension of LiAlH ₄ (67.7 mg, 1.78 mmol) in diethyl ether (1 ml) at 0°C. After 10 minutes of stirring at 0° C., the mixture was brought to room temperature. After 1 hour at this temperature, the mixture was heated to reflux. After an additional 30 min, Na ₂ SO ₄ (decahydrate) was added in portions until gas evolution ceased. The resulting suspension was filtered using diethyl ether through a pad of celite. The solution was concentrated to give the desired intermediate as a clear oil (119 mg, 78%).

1-{[4-(1,1-Difluoroethyl)phenyl]methyl}-3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4yl)urea; trifluoroacetic acid.

[4-(1,1-Difluoroethyl)phenyl]methanamine (54.6 mg, 319 µmol) in dichloromethane (0.5 ml) was added to diphosgene (19.5 µl, 162 µmol) in dichloromethane (0.5 ml) followed by the addition of pyridine (51.6 µl, 638 µmol). After 10 min stirring at room temperature, N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (93.4 mg, 389 µmol) in dichloromethane (0.5 ml) was added. After 170 min stirring at room temperature, the mixture was washed with sodium hydroxide (2 ml, 1 M aq.

- 115 042461 solution), the aqueous phase was extracted with dichloromethane (3x0.5 ml), the combined organic phases were dried using a phase separator and concentrated to an oil (173 mg). The crude material was purified by HPLC eluting with 20-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (78 mg, 44%): ¹ H NMR (400 MHz, chloroformd) δ 12.73 (brs, 1H), 7.41 (d, 2H), 7.21-7.09 (m, 3H), 6.82 (t, 2H), 4.88 (s, 1H), 4, 74 - 4.59 (m, 1H), 4.44 4.35 (m, 4H), 3.58 (d, 2H), 2.88 - 2.71 (m, 5H), 2.29 - 2 .11 (m, 2H), 1.96-1.83 (m, 5H); LC-MS: 438.3 [M+H]+.

Example 153: 3-[(2,4-difluorophenyl)methyl]-1-({4-[(1,3-difluoropropan-2-yl)oxy]phenyl}methyl)-3-(1methylpiperidin-4-yl) urea; trifluoroacetic acid

4-[(1,3-Difluoropropan-2-yl)oxy]benzonitrile

1,3-Difluoropropan-2-ol (192 μl, 2.48 mmol) was added to potassium tert-butoxide (280 mg, 2.5 mmol) in dioxane (2 ml). After 7 minutes of stirring at room temperature, a solution of 4-fluorobenzonitrile (209 mg, 1.73 mmol) in dioxane (2 ml) was added. After 17 hours of stirring at room temperature, the reaction mixture was added to a layer of diethyl ether (5 ml) on water (5 ml). The aqueous phase was extracted with diethyl ether (3x5 ml) and the combined organic phases were dried using a phase separator and concentrated to give white solids (190 mg, 56%).

{4-[(1,3-Difluoropropan-2-yl)oxy]phenyl}methanamine

A solution of borane (2 ml, 1M in tetrahydrofuran) was added at 4°C to 4-[(1,3difluoropropan-2-yl)oxy]benzonitrile (89.2 mg, 452 µmol). After 1 hour stirring at room temperature, the solution was heated to 40°C for 1 hour. The solution was concentrated, redissolved in methanol (2 ml), heated to reflux for 1 hour and concentrated. NaOH (1 ml, 1 M aqueous solution) was added and the aqueous solution was extracted with ethyl acetate (2x1 ml). The combined organic phases were dried using a phase separator and concentrated to an oil (81.5 mg, 90%). 3-[(2,4-difluorophenyl)methyl]-1-({4-[(1,3-difluoropropan-2-yl)oxy]phenyl}methyl)-3-(1-methylpiperidin-4-yl)urea ; trifluoroacetic acid {4-[(1,3-difluoropropan-2yl)oxy]phenyl}methanamine (40.7 mg, 202 µmol) in dichloromethane (0.5 ml) was added to diphosgene (12.2 µl, 101 µmol) in dichloromethane (0.5 ml) followed by the addition of diisopropylethylamine (70.5 μl, 405 μmol). After 15 min stirring at room temperature, N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (58.3 mg, 243 µmol) in dichloromethane (0.5 ml) was added. After 2 hours of stirring at room temperature, the mixture was concentrated to an oil. The crude material was purified by HPLC eluting with 15-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (21 mg, 18%). ¹ H NMR (400 MHz, chloroform-d) δ 13.09 (br s, 1H), 7.12 (q, 1H), 7.06 (d, 2H), 6.88 (d, 2H), 6.81 (t, 2H), 4.80 - 4.53 (m, 7H), 4.37 (s, 2H), 4.29 (d, 2H), 3.57 (d, 2H), 2 .89 - 2.72 (m, 5H), 2.19 (q, 2H), 1.89 (d, 2H); LC-MS: 468.3 [M+H] ⁺ .

Example 154 3-{[4-(2,2-difluoroethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid

4-(2,2-Difluoroethoxy)benzonitrile

- 116 042461

2,2-Difluoroethan-1-ol (125 μl, 1.98 mmol) was added to potassium tert-butoxide (202 mg, 1.8 mmol) in tetrahydrofuran (1.5 ml). After 5 minutes of stirring at room temperature, a solution of 4-fluorobenzonitrile (200 mg, 1.65 mmol) in tetrahydrofuran (1.5 ml) was added. After 45 min stirring at room temperature, the reaction mixture was added to a layer of ethyl acetate (5 ml) on NaOH (3 ml, 1 M aqueous solution). The organic phase was washed with NaOH (3x3 ml, 1 M aqueous solution), the organic phase was separated, dried using a phase separator and concentrated to give white solids (256 mg, 85%).

[4-(2,2-Difluoroethoxy)phenyl]methanamine

C f o

F

A solution of borane (4 ml, 1M in tetrahydrofuran) was added at 4°C to 4-(2,2difluoroethoxy)benzonitrile (200 mg, 1.09 mmol). After 17 hours of stirring at room temperature, the solution was concentrated, redissolved in methanol (2 ml), heated to reflux for 1 hour and concentrated. The residues were dissolved in dichloromethane (5 ml) and washed with NaOH (5 ml, 1 M aqueous solution), the organic phase was separated, dried using a phase separator and concentrated to an oil (219 mg, quant.).

3-{[4-(2,2-Difluoroethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid.

Diphosgene (33 µl, 275 µmol) in dichloromethane (0.5 ml) was added to [4-(2,2-difluoroethoxy)phenyl]methanamine (103 mg, 550 µmol) in dichloromethane (0.5 ml) followed by the addition of diisopropylethylamine (192 µl, 1.10 mmol). After 20 minutes of stirring at room temperature, N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4-amine (145 mg, 605 µmol) in dichloromethane (1 ml) was added. After 30 min stirring at room temperature, NaOH (2 ml, 1 M aqueous solution) was added, the organic phase was separated, dried (phase separator) and concentrated to an oil (303 mg). The crude material was purified by HPLC eluting with 20-50% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (102 mg, 33%). 1H NMR (400 MHz, chloroform-d) δ 12.60 (br s, 1H), 7.12 (q, 1H), 7.06 (d, 2H), 6.87 - 6.76 (m, 4H), 6.06 (tt, 1H), 4.82 - 4.62 (m, 2H), 4.37 (s, 2H), 4.29 (s, 2H), 4.14 (td, 2H ), 3.58 (d, 2H), 2.84 (t, 2H), 2.77 (s, 3H), 2.30 2.11 (m, 2H), 1.89 (d, 2H); LC-MS: 454.2 [M+H]+.

Example 155: 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid

(2,2-Dimethyl-2H-chromen-6-yl)methanamine

A solution of 2,2-dimethyl-2H-chromene-6-carbonitrile (300 mg, 1.62 mmol) in diethyl ether (2 ml) was added dropwise to a suspension of lithium aluminum hydride (135 mg, 3.56 mmol) in diethyl ether ( 3 ml) at 0°C. After 30 minutes of stirring at 0° C., the mixture was brought to room temperature. After 1 hour of stirring at room temperature, sodium sulfate decahydrate was added in small portions until the evolution of gas ceased. The mixture was filtered and the organic solution was concentrated to an oil (269 mg, 88%). 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2Hchromen-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (2,2-dimethyl-2H-chromen-6-yl)methanamine (68.7 mg, 363 µmol) in dichloromethane (0.5 ml) was added to diphosgene (22 µl, 183 µmol) in dichloromethane (0.5 ml ) followed by the addition of diisopropylethylamine (190 μl, 1.09 mmol). After 10 minutes of stirring at room temperature, N-[(2,4difluorophenyl)methyl]-1-methylpiperidin-4-amine (110 mg, 456 µmol) in dichloromethane (0.5 ml) was added. After 2 hours of stirring at room temperature, the solution was concentrated to an oil. The crude material was purified by HPLC eluting with 20-40% acetonitrile in water (containing 0.1% trifluoroacetic acid).

- 117 042461 slot) to give the title compound (164 mg, 79%). 1H NMR (400 MHz, chloroform-d) δ 12.62 (br s, 1H), 7.12 (q, 1H), 6.86-6.78 (m, 3H), 6.71-6, 61 (m, 2H), 6.21 (d, 1H), 5.60 (d, 1H), 4.78 4.63 (m, 2H), 4.36 (s, 2H), 4.23 ( s, 2H), 3.58 (d, 2H), 2.84 (t, 2H), 2.77 (s, 3H), 2.18 (kvd, 2H), 1.90 (d, 2H), 1.40 (s, 6H); LC-MS: 456.3 [M+H] ⁺ .

Example 156 3-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4yl)urea

A solution of 1-methoxy-4-(isocyanatomethyl)benzene (172 mg, 1.03 mmol) in dichloromethane (1 ml) was added to N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4-amine (200 mg , 0.79 mmol) in dichloromethane (2 ml). The mixture was stirred for 1 h, then evaporated, and the residue was purified by column chromatography using silica gel, eluting with 0-25% methanol in ethyl acetate, to give the title compound (192 mg, 60%): ¹ H NMR (400 MHz , chloroform-d) δ 7.25 - 7.16 (m, 1H), 7.11 (d, 2H), 6.85 - 6.73 (m, 4H), 4.55 (t, 1H), 4.40 (s, 2H), 4.32 (d, 2H), 4.32-4.21 (m, 1H), 3.78 (s, 3H), 2.89 (d, 2H), 2 .27 (s, 3H), 2.13-2.03 (m, 2H), 1.74-1.61 (m, 4H); LC-MS: 403.9 [M+H]+.

Example 157: 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea; trifluoroacetic acid

tert-Butyl 4-({[(4-cyclopropoxyphenyl)methyl]carbamoyl}[(2,4-difluorophenyl)methyl]amino)piperidine-1-carboxylate

tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (0.45 mmol, 147 mg), phenyl N-[(4-cyclopropoxyphenyl)methyl]carbamate (130 mg, 0 .45 mmol) and Cs ₂ CO ₃ (0.8 mmol, 261 mg) were suspended in toluene (2.0 ml). The mixture was stirred at 70° C. for 2 h, then partitioned between diethyl ether and NaOH (0.1 M, aqueous solution), the solid was removed by filtration, the organic phase was separated, concentrated and the residue was purified by column chromatography using silica gel, eluting with 20-100% ethyl acetate in hexanes to give the desired intermediate (115 mg, 50%).

1-[(4-Cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea; trifluoroacetic acid.

tert-Butyl 4-({[(4-cyclopropoxyphenyl)methyl]carbamoyl}[(2,4-difluorophenyl)methyl]amino)piperidine-1-carboxylate (115 mg, 0.223 mmol) was dissolved in dichloromethane (1 ml) on ice bath and trifluoroacetic acid (1 ml) was added. The mixture was stirred for 30 minutes at 0° C., then concentrated twice from isopropyl acetate. The residue was dissolved in water and lyophilized to give the title compound (107.4 mg, 91%): 1H NMR (400 MHz, chloroform-d) δ 9.46 (br.s, 1H), 9.00 (br. s, 1H), 7.15(q, 1H), 7.05(d, 2H), 6.95(d, 2H), 6.87-6.77(m, 2H), 4.70(br .s, 1H), 4.60 (m, 1H), 4.37 (s, 2H), 4.29 (s, 2H), 3.70 (m, 1H), 3.42 (d, 2H) , 2.96 (m, 2H), 2.09-1.80 (m, 4H), 0.75 (m, 4H); LC-MS: 416.3 [M+H] ⁺ .

Example 158 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1(piperidin-4-yl )urea; trifluoroacetic acid

- 118 042461

tert-Butyl 4- {[(2,4-difluorophenyl)methyl]({ [(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]carbamoyl} )amino}piperidine-1 -carboxylate

(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)methanamine; hydrochloride (25 mg, 0.141 mmol) and triethylamine (39.3 μl, 0.28 mmol) were dissolved in dichloromethane (0.5 ml) and slowly added to a solution of diphosgene (14.6 mg, 74 μmol) in dichloromethane (0. 5 ml). The reaction mixture was stirred at room temperature for 30 minutes. tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (48 mg, 0.15 mmol) was dissolved in dichloromethane (0.5 ml), the solution was added to the reaction and stirred for night. The mixture was concentrated and purified by silica gel column chromatography eluting with 30-70% ethyl acetate in petroleum ether to give the desired intermediate (57 mg, 76%).

1-[(2,4-Difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(piperidin4-yl)urea; trifluoroacetic acid tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[(2,2-dimethyl-2,3dihydro-1-benzofuran-5-yl)methyl]carbamoyl})amino}piperidine-1 -carboxylate (57 mg, 0.11 mmol) was dissolved in dichloromethane (1.1 ml). The solution was cooled to 0°C, trifluoroacetic acid (0.16 ml) was added and stirred at 0°C for 30 minutes. The solution was concentrated. The crude material was purified by HPLC eluting with 20-55% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound (23 mg, 39%): ¹ H NMR (400 MHz, Chloroform-d) δ 9 .36 (s, 1H), 8.93 (s, 1H), 7.19 - 7.10 (m, 1H), 6.91 - 6.76 (m, 4H), 6.61 (d, 1H ), 4.69 (s, 1H), 4.60 (t, 1H), 4.37 (s, 2H), 4.26 (s, 2H), 3.43 (d, 2H), 3.05 - 2.88 (m, 4H), 2.10 - 1.83 (m, 4H), 1.46 (s, 6H); LC-MS: 430.3 [M+H]+.

Example 159: 1-[(2,4-difluorophenyl)methyl]-3-{[2,3-dihydro( ^2,2,3,3-2H ₄ )-1-benzofuran-5-yl]methyl}- 1(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (160)

4-(2-Methoxy-2-oxoethyl)phenyl2-chloroacetate

Chloroacetyl chloride (877 μl, 11 mmol) was added to methyl 2-(4-hydroxyphenyl)acetate (1.66 g, 10 mmol) and triethylamine (2.09 ml, 15 mmol) in dichloromethane (10 ml). After 1 hour stirring at room temperature, the mixture was concentrated. The crude material was purified by column chromatography using silica gel eluting with 10-25% ethyl acetate in petroleum ether to give the desired intermediate (2.23 g, 92%).

Methyl 2-(3-oxo-2,3-dihydro-1-benzofuran-5-yl)acetate

Aluminum trichloride (3.85 g, 28.8 mmol) was added to 4-(2-methoxy-2-oxoethyl)-phenyl 2-chloroacetate (1.75 mg, 7.21 mmol) and the mixture was heated to 180°C. After 30 minutes, the solid raw material was cooled to ambient temperature and added to hydrochloric acid (aqueous solution, 1 M, 100 ml). The resulting mixture was stirred for 1 h, after which it was extracted with ethyl acetate (3x100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated. Sy

The swarm material was purified by column chromatography using silica gel eluting with 25-100% ethyl acetate in petroleum ether to give the desired intermediate (486 mg, 35%). Methyl 2-[2,3-dihydro( ^2,2,3,3-2 H ₄ )-1-benzofuran-5-yl]acetate

Methyl 2-(3-oxo-2,3-dihydro-1-benzofuran-5-yl)acetate (380 mg, 1.84 mmol) was dissolved in acetic acid-d1 (3.8 ml) and the mixture was heated to 100° WITH. After 30 minutes, the mixture was concentrated, redissolved in acetic acid-d1 (3.8 ml) and stirred for an additional 30 minutes at 100°C, after which it was cooled to ambient temperature and concentrated. The crude material was dissolved in acetic acid-d1 (3.8 ml) and zinc (361 mg, 5.53 mmol) was added. The mixture was heated to 100°C and stirred for 30 min, then cooled to ambient temperature, filtered and concentrated. The crude material was purified by column chromatography using silica gel eluting with 5-20% ethyl acetate in petroleum ether to give the desired intermediate (76 mg, 21%).

-[(2,4-Difluorophenyl)methyl] -3-{[2,3-dihydro(2,2,3,3 - ² H ₄ )-1-benzofuran-5 -yl]methyl}-1-(1 -methylpiperidin-4-yl)urea; trifluoroacetic acid.

The compound was obtained by analogy with example 8 1-methylpiperidin-4-yl)urea; trifluoroacetic acid) using N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine and methyl 2-[2,3-dihydro(2,2, 3,3-2H ₄ )-1benzofuran-5-yl]acetate. Yield: 34%?H NMR (400 MHz, chloroform-d) δ 12.31 (br s, 1H), 7.18 - 7.11 (m, 1H), 6.91 (s, 1H), 6 .87 - 6.78 (m, 3H), 6.67 (d, 1H), 4.77 (t, 1H), 4.69 (s, 1H), 4.40 (s, 2H), 4, 26 (s, 2H), 3.58 (d, 2H), 2.84-2.76 (m, 5H), 2.38 (q, 2H), 1.92 (d, 2H); LC-MS: 420.0 [M+H]+.

The above examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of the subject matter disclosed herein. Modifications obvious to those skilled in the art are intended to be covered by the scope of the following claims. All publications, patents, and patent applications referred to in this specification are incorporated herein by reference to the same extent as if each such publication, patent, or patent application were specifically and separately indicated to be incorporated by reference.

Analyzes

Determination of in vitro activity of receptors.

Receptor Selection and Amplification Technology (R-SAT) analysis. Receptor Functionality Assay, Receptor Selection and Amplification Technology (R-SAT®) (with minor modifications to the procedure previously described (Brann MR US Patent 5707798, 1998; Chem. Abstr. 1998, 128, 111548) was used to screen compounds for 5-HT2A receptor activity Briefly, NIH3T3 cells were grown in 96-well tissue culture plates to 70-80% confluence Cells were transfected for 12-16 h with plasmid DNA using superfect reagent (Qiagen Inc.) R-SAT assays were typically performed with 50 ng/well receptor and 20 ng/well β-galactosidase plasmid DNA All receptor constructs used were in a pSI mammalian expression vector (Promega Inc) as described Previously, the 5-HT2A receptor gene was amplified by nested PCR (polymerase chain reaction) from brain cDNA using op-based oligodeoxynucleotides. published sequences (Saltzman et al, Biochem. Biophys. Res. Comm. 1991,181, 1469). To perform large scale transfections, cells were transfected for 12-16 h and then trypsinized and frozen in DMSO. The frozen cells were subsequently thawed, seeded at 10,000-40,000 cells per well of a 96-well plate containing a compound according to formula (I). For functional testing of antagonists, cells and compounds were further combined with a fixed concentration (approximately 3x previously determined EC50) of an agonist (typically 5-CT) for 5-HT2A or other suitable agonists for other receptors. In both methods, cells were grown in a humidified atmosphere at 5% environmental CO ₂ for five days. The medium was then removed from the plates and marker gene activity was measured by adding the β-galactosidase substrate o-nitrophenyl-bD-galactopyranoside (ONPG, in PBS with 5% NP-40). The resulting colorimetric response was measured with a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the XLFit computer program (IDBSm). Efficacy is the percentage of maximum repression compared to that of the control compound (ritanserin in the case of 5-HT2A). IC ₅₀ is the calculated concentration in moles at which half-maximal repression is achieved. IC ₅₀ determined in the RSAT analysis was converted to a Ki value,

- 120 042461 using the Cheng-Prusov method, Biochem Pharmacol., 1973 Dec 1;22(23):3099-108. pKi is the negative value of log(Ki). hERG analysis: Drugs belonging to different classes have been shown to be associated with QT interval prolongation and, in some cases, severe ventricular arrhythmias. The most common mechanism for these adverse events is inhibition of one or more cardiac potassium channels, in particular hERG. This type of current plays an important role in the repolarization of cardiomyocytes and is the most common target for drugs that prolong the QT interval. Thus, the prototypes in the present study were characterized to determine their ability to inhibit the hERG channel. Ion channel activity was measured at AVIVA Biosciences Corporation (San Diego, CA) using stably transfected Chinese Hamster Ovary (CHO) cell lines expressing hERG mRNA. The pharmacology of such a cloned channel expressed in a CHO cell line is very similar to that observed in native tissue.

Cells. The study used the CHO AVIVA cell line, which stably expresses hERG channels. Cells were cultured in DMEM/F12 medium containing 10% FBS, 1% penicillin/streptomycin and 500 μg/ml G418. Prior to testing, cells were harvested using Accumax (Innovative Cell Technologies).

Solutions. The following solutions were used for electrophysiological recordings. External solution: 2 mm CaCl ₂ ; 2 mM MgCl ₂ ; 4 mM KCl; 150 mM NaCl; 10 mM glucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5 M NaOH); internal solution: 140 mM KCl; 10 mM MgCl ₂ ; 6 mM EGTA; 5 mM HEPES-Na; 5 mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with 1 M KOH). Electrophysiology. Whole cell recordings were performed using a PX 7000A (Axon Instruments) with SealChip™ AVIVA technology. Cell voltage fixation was performed at an initial potential of -80 mV. The hERG current was then activated by increasing the depolarization to -50 mV for 300 ms. This first rise to -50 mV was used as a baseline for measuring the peak amplitude of the trace current. Next, the voltage was increased to +20 mV for 5 s in order to activate the channels. Finally, by lowering to -50 mV for 5 seconds, the activation was removed and the inactivating trace current was recorded.

Handling of prototypes and breeding. All test samples were prepared from 10 mM DMSO stock solutions provided by the sponsor. The solutions were mixed by sonication for 20 min followed by vigorous shaking. Prior to testing, compounds were diluted to test concentrations in glass vials using an external solution. Dilutions were obtained no later than 20 minutes before use.

electrophysiological procedures. After reaching the whole cell configuration, cells were observed for 90 s to assess stability and then washed with external solution for 66 s. The voltage protocol described previously (Figure 1) was then applied to the cells every 12 s throughout the procedure. Only stable cells with recording parameters above the thresholds (see Quality Control section) were allowed to participate in the drug addition procedure. An external solution containing 0.1% DMSO (stock solution) was applied to the cells to determine baseline. After stabilization of the current for 3 to 10 minutes, prototypes were used. Sample solutions were added to cells in 4 separate additions. The cells were kept in the test solution until the effect of the test sample reached equilibrium, up to a maximum of 12 minutes. Then 1 μM cisapride (positive control) was added. Finally, washing with an external solution was performed until the recovery current reached an equilibrium state.

Data analysis. Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments), and Origin (OriginLab Corporation) software.

Quality control. Reported data consisted of experiments that met all of the following criteria: Recording parameters:

membrane resistance (Rm): > 200 MΩ; access resistance (Ra): < 10 MΩ;

trace current amplitude: > 150 pA; pharmacological parameters: 1 μM cisapride: > 95% inhibition.

Beta arrestin recruitment assay.

GPCR signaling detection using Tango technology.

GPCR signaling via beta arrestin was detected using Tango technology at Thermofisher. This technology is based on the interaction of intracellular beta-arrestin proteins with the target receptor. Upon binding of the ligand to the target receptor, protease-labeled arrestin is stimulated and recruited to the engineered protease site at the C-terminus of the GPCR, which initiates the release of the bound transcription factor. The free transcription factor then enters the nucleus and stimulates beta-lactamase (bla) activity.

Test compounds are prepared at a concentration of 1000X (or more) of the desired initial concentration in 100% DMSO. The 1000X test compounds are serially diluted (10 dilutions in ¹ / ₂ -log steps) in 100% DMSO.

Substrate loading solution.

- 121 042461

The substrate loading solution contains three reagents: solution A (1 mM LiveBLAzer™FRET B/G substrate); solution B and solution C.

Agonist analysis protocol.

The type of plate used and the addition of cells (step 1) or compound (step 2) to the plate first is determined by each cell line and is described under cell line specific assay conditions.

Corning Barcode Microplates, 384-well, black, polystyrene, clear flat bottom, tissue cultured (Corning P/N 3712); Corning barcode microplates, 384-well, black, polystyrene, clear flat bottom, coated with poly-D-lysine (Corning P/N 3664).

1. 32 µl of cells diluted in assay medium to the appropriate cell density are added to the assay plate. If necessary, the cells are incubated at 37°C/5% CO ₂ for 6 or 16-24 h (depending on the specifics of the cell line), after which the compound is added.

2. 40 nl of compound 1000X or known activator titration plus 4 µl of assay medium is added to the cells on the assay plate.

3. 4 µl of assay medium is added to all wells to bring the final assay volume to 40 µl.

4. The assay plate is incubated for 5 or 16 hours (depending on the specific cell line) at 37°C/5% CO2 in a humidified incubator.

5. 8 µl of substrate loading solution is added to the assay plate.

6. The assay plate is incubated for 2 hours at room temperature in the dark.

7. The assay plate is read on a fluorescent plate reader (Tecan Safire2) and the data is analyzed.

Antagonist analysis protocol.

Agonist assay screening (see above) is performed to obtain the EC80 concentration of the known activator that is added in step 3.

1. 32 µl of cells diluted in assay medium to the appropriate cell density are added to the assay plate. If necessary, the cells are incubated at 37°C/5% CO ₂ for 6 or 16-24 h (depending on the specifics of the cell line), after which the compound is added.

2. 40 nl of 1000X compound or known antagonist titration plus 4 µl of assay medium are added to the cells on the assay plate and incubated for 30 min at 37°C/5% CO ₂ in a humidified incubator.

3. 4 µl of a concentration of 10X EC80 agonist as determined in the agonist assay is added to all wells containing test compound and a known inhibitor to bring the final assay volume to 40 µl.

4. Add 4 µl of assay medium to the remaining control wells to bring the volume to 40 µl.

5. The assay plate is incubated for 5 or 16 hours (depending on the specific cell line) at 37° C./5% CO ₂ in a humidified incubator.

6. 8 µl of substrate loading solution is added to the assay plate.

7. The assay plate is incubated for 2 hours at room temperature in the dark.

8. The assay plate is read on a fluorescent plate reader (Tecan Safire2) and the data is analyzed.

For each individual cell line, the following controls are analyzed in each plate.

Full agonist control.

The full agonist control contains 0.1% DMSO, cells and the maximum concentration of a known agonist (stim). In agonist mode, the full agonist control is used to determine the upper limit of the assay, or 100% activation. In antagonist mode, the full agonist control is used to determine the actual EC80 used in the assay when the EC80 concentration is selected from previous agonist experiments.

Control with no agonist.

The no agonist control contains 0.1% DMSO, cells and assay medium in place of the agonist (stim). In agonist mode, it is used to define the lower limit of the assay, or 0% activation. In antagonist mode, it is used to determine maximum inhibition or 100% inhibition.

cell-free control.

The cell-free control contains 0.1% DMSO and assay medium. It is used to determine the background fluorescence for the wavelength of both coumarin and fluorescein. This value is used to subtract the background.

EC80 control (only in antagonist mode).

The EC80 control is the concentration of a known agonist in the assay medium, which

- 122 042461 Ryu was determined during the experiment with agonists. In antagonist mode, the EC80 control is used to determine the actual baseline activation or 0% inhibition.

Titration of a known agonist (agonist mode) or antagonist (antagonist mode).

Titration of a known agonist or antagonist is performed on each plate for each cell line to ensure that the cell line is activated or inhibited within the expected EC ₅₀ /IC ₅₀ range as defined above.

Graphing software.

Cell profiling GPCR SelectScreen Service uses XLfit from IDBS. The dose-response curve is a curve that fits the 205 model (sigmoidal dose-response model). Custom logic has been built into the data analysis tool to take into account the various characteristics of compounds that can be observed in functional analyses. Using this logic, a relative EC50/IC50 value can be provided for each given compound.

The following equations were used for each set of data points.

The equation:

Fluorescence with background subtracted (F1 - fluorescence intensity):

Sample F1 - Cell-free control F1.

Emission ratio (using values corrected for background fluorescence):

Coumarin emission (460 nm)/fluorescein emission (530 nm).

Response rate:

Compound Response Rate/No Agonist Control Response Rate % Activation - Agonist Assays:

{(Compound Response Rate - No Agonist Control Response Rate)/Full Agonist Control Response Rate - No Agonist Control Response Rate}*100% Inhibition - Antagonist assays:

{1 - (Compound Response Rate - No Agonist Control Response Rate/EC80 Control Response Rate - No Agonist Control Response Rate)}*100 pIC ₅₀ : negative logarithm of the concentration that causes 50% inhibition.

Compounds as presented herein were analyzed as described above. The data below indicate that the compounds as presented herein may be useful as pharmaceutical agents.

The data in table one can, for example, be interpreted using the following guidelines.

High affinity pKi > 8.4.

Moderate affinity pKi > 7.7.

- 123 042461

Table 2. pKi values for exemplary compounds

Compound 5-HT2a (pKi) (R-SAT) 5HT2A (p!C50) Beta-arrestin hERG (% inhibition (1pM)) 1a/1b 7.6 2 5.5 3 8.9 33 4 8.6 AND 5 9.0 29 6 8.7 70 7 8.7 87 8 9.1 22 9 8.1 63 10 9.0 10 AND 1.0 12 1.0 13 Yu,1 34 13b 7.2 14 8.8 77 15 8.5 19 16 8.7 29 17 9.4 32 18 9.5 17 19 8.8 33 20 8.8 thirty

- 124 042461

21 6.7 22 ι, ο 10 23 7.8 13 24 6.9 10 25 7.0 26 ι, ο 27 7.1 28 8.4 32 29 8.0 thirty 7.2 31 8.2 32 8.1 33 ι, ο 34 6.5 35 6.7 36 7.6 29 37 6.2 8 38 8.4 39 7.8 21 40 ι, ο 9 41 ι, ο 23 42 6.6 43 6.9 42 44 6.8 70 46 9.1 47 6.9 48 7.0 49 8.2 50 7.0 51 7.6 52 7.4 8

- 125 042461

53 7.6 54 8.1 55 1.0 10 56 1.0 57 ι, ο 58 6.8 59 7.8 60 ι, ο 61 7.8 23 62 7.1 32 63 7.1 64 ι, ο 65 ι, ο 66 ι, ο 67 7.1 68 7.7 69 6.2 70 7.3 71 7.9 72 7.8 73 8.2 74 7.4 75 8.4 76 8.4 12 77 7.1 78 8.2 80 8.6 81 ι, ο 82 ι, ο 83 6.8 84 7.3

- 126 042461

85 8.4 85 8.8 86 ι, ο 87 8.0 88 7.2 89 ι, ο 90 7.9 91 7.8 92 9.5 45 93 7.4 94 7.0 95 7.3 8 96 8.0 97 7.4 98 8.5 62 99 7.1 100 7.7 101 7.1 102 ι, ο 103 6.6 104 7.4 105 7.0 106 7.3 107 6.9 43 108 7.1 109 7.6 110 7.6 111 7.1 112 7.4 FROM 6.9 114 8.2

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115 9.5 49 116 7.2 117 9.4 118 8.0 119 7.2 120 8.1 121 6.9 122 8.1 123 7.8 124 8.0 125 8.4 17 126 8.1 15 127 8.2 9 128 8.1 129 7.3 130 7.1 131 9.2 132 7.1 133 8.3 134 8.4 135 7.8 136 8.1 137 8.4 37 138 2.8 13 139 8.4 35 140 8.5 141 9.2 42 142 9.0 8 143 9.3 41 144 9.0 37 145 8.8 39 146 8.3 147 8.5 148 8.7 33 149 9.0 40 150 8.3 151 8.7 16 152 8.6 38 153 8.8 29 154 8.9 23 155 9.8 47 156 8.4 17 157 9.2 20 158 9.1 8 159 8.1

- 128 -

Claims (50)

CLAIM 1. Compound according to formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m and n are independently integers selected from the group consisting of 0, 1, 2 and 3; p and q are independently integers selected from the group consisting of 0, 1, 2, 3 and 4; R ₂ is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, nitro, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _2-6 alkenyloxy, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C _2-6 alkynyloxy, unsubstituted or substituted O _1-8 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms, selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur, cyclopropyloxy and cyclobutyloxy; R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, nitro, unsubstituted or substituted O _1-6 alkyl, unsubstituted or substituted C _{2- 6} alkenyl, unsubstituted or substituted C _2-6 alkenyloxy, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C _2-6 alkynyloxy, unsubstituted or substituted O _1-8 alkoxy, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; or R ₂ and R ₂ b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas: where R _12a , R _12b , R _12c , R _13a , R _13b , R1 _4a and R _14b are independently absent or selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, O _1-4 alkyl and O _1-4 alkoxy; Z1, Z ₂ and Z ₃ are independently selected from the group consisting of C, N, O and S; and where the dotted bond represents the optional unsaturation between the atoms forming the bond; R ₃ is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted _O1-6 alkyl, unsubstituted or substituted C _2-6 alkenyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _3-6 heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; R4 _a , R4 _b , R5 _a and R _5b are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted O _1-6 alkyl; where when m and n are 1, then R _4a , R 4 _b , R _5a , R _5b are hydrogen; R6 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted O _1-4 alkoxy; substituted or unsubstituted C _6-10 aryl; or R6 and _R3 taken together with the piperidine ring and the carbon and nitrogen atoms to which they are attached form a heteroalicyclic ring system in - 129 042461 according to the following formulas: where R _6a is halogen and R _6b is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted C _1-4 alkoxy, substituted or unsubstituted C _6-10 aryl; R ₇ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C _1-4 alkyl, and substituted or unsubstituted alkoxy; R ₈ is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted alkoxy; X is O or S; where R1 and R _1d are fluorine and R _1a , R _1b and R _1c are hydrogen; and when said substituent is substituted, this means that one or more hydrogen atoms in said substituent may be substituted by group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₃ -C ₁₀ cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, arylalkyl, heteroarylalkyl, (heteroalicyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio , cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, where alkoxy means -O-alkyl, acyl means hydrogen, alkyl, alkenyl, alkynyl or aryl, linked as substituents through a carbonyl group; O-carboxy means -OC(=O)R, C-amido means -C(=O)NRARB, S-sulfonamido means -SO2NRARB, N-amido means -N(RA)C(=O)R, N-sulfonamido means -N(RA)SO2R, amino means -NR2, ester means -C(=O)OR, sulfinyl means -S(=O)R, sulfonyl means -SO2R, where R, RA and RB are independently from each other are hydrogen, alkyl, alkenyl, alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _8-12 cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, arylalkyl or (heteroalicyclyl)alkyl; or RA and RB may be combined to form heteroalicyclyl and heteroaryl; alkyl means C _1-20 alkyl; alkenyl means C _2-20 alkenyl; alkynyl means C _2-20 alkynyl; aryl means C _6-10 aryl; heteroaryl means C _2-9 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; and heteroalicyclyl means 3-18-membered heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. 2. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R2, _R2a , _R2b , _R2c , _R2d and _R3 are independently selected from unsubstituted or substituted Cl _-6 haloalkyl or unsubstituted or substituted _C1-6 hydroxyalkyl. 3. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formulas: where R _12a , R _12b , R _12c , R _13a , R _13b , R _14a and R _14b are as defined in paragraph 1; and where depicted - 130 042461 a dotted line bond represents an optional unsaturation between the atoms forming this bond. 4. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein R2 is selected from the group consisting of deuterium, amino, -OD, halogen, cyano, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted with C ₁ . ₆ haloalkyl, unsubstituted or substituted with C ₁ . ₆ hydroxyalkyl, unsubstituted or substituted with C ₂ . ₆ alkenyl, unsubstituted or substituted with C ₁ . ₆ alkoxy, unsubstituted or substituted C ₃ . ₆ cycloalkyl, unsubstituted or substituted C ₃ - ₆ heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C ₆ . ₁₀ aryl, as well as substituted or unsubstituted C ₂ .9heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; R2d is selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted C ₁ . ₆ alkyl, unsubstituted or substituted with C ₁ . ₆ haloalkyl, unsubstituted or substituted C ₁ . ₆ hydroxyalkyl, unsubstituted or substituted with C ₂ . ₆ alkenyl, unsubstituted or substituted with C ₁ . ₆ alkoxy, unsubstituted or substituted C ₃ . ₆ cycloalkyl, unsubstituted or substituted C ₃ - ₆ heteroalicyclyl containing from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted C ₆ . ₁₀ aryl, as well as substituted or unsubstituted C ₂ .9heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur; R _2a , R2b and R _2c are hydrogen. 5. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 or 4, wherein R2 is selected from the group consisting of halogen, cyano, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ alkoxy, C ₂ . ₆ alkenyloxy, C ₂ . ₆ alkynyloxy, C ₁ . ₆ haloalkoxy, C ₃ - ₄ cycloalkyl, C ₃ . ₄ cycloalkyl-C1. ₃ alkyl; and R _2a , R _2b , R _2c and R _2d are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ alkoxy, C ₂ . ₆ alkenyloxy, C ₂ . ₆ alkynyloxy, C ₁ . ₆ haloalkoxy, C ₃ - ₄ cycloalkyl, C ₃ _ ₄ cycloalkyl-C1_ ₃ alkyl. 6. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the ring system formed by the substituents R2 and R2b is of formula (III), and R _12a and R _12b are hydrogen or methyl, and R _13a and R _13b are hydrogen or methyl. 7. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 46, wherein R _2a , R _2c , R _2d and R _2b , provided that R _2b does not form a ring system with R ₂ , are independently selected from the group, consisting of hydrogen, deuterium, halogen, hydroxyl, methyl, -CD ₃ , methoxy, -OCD ₃ , -OCF ₃ and -CF3. 8. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 47, wherein R _2a , R _2c and R _2b are hydrogen and R _2d is hydrogen, fluoro or hydroxyl. 9. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1, 4 and 5, wherein one of R _2a and R _2b is fluoro and the other is hydrogen and R _2c and R _2d are hydrogen. 10. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 4-9, wherein R ₂ , provided that R ₂ does not form a ring system with R _2b , is selected from the group consisting of methoxy, ethoxy, n- propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methylbutoxy, hexyloxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2- fluoroethoxy, 3fluoropropoxy, 4-fluorobutoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy, 4-methoxybutoxy, 2hydroxyethoxy, 1,2-dihydroxyethyl, 2-hydroxy-2,3-dimethylbutoxy, -OCF ₃ and (1 ,3-difluoropropan-2yl)oxy. 11. The compound or its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs. 1 and 4-10, where R1 and R _1d are fluorine, R _1a , R _1b and R _1c are hydrogen; R2 is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, nbutoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methylbutoxy, hexyloxy, 4-methylpentoxy, cyclopropyloxy , cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2difluoroethoxy, 4-methoxybutoxy, 2-hydroxyethoxy, 1,2-dihydroxyethyl, 2 -hydroxy-2,3dimethylbutoxy, -OCF3 and (1,3-difluoropropan-2-yl)oxy; and R2a, R2b, R2c and R2d are hydrogen; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following general formula: where R _12a and R _12b are hydrogen or methyl, R _13a and R _13b are hydrogen or - 131 042461 methyl, and R _2a , R2c and R2d are hydrogen. 12. The compound or its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs.1 and 4-11, where R ₁ and R _1d represent fluorine, R _1a , R _1b and R _1c represent hydrogen; R2 is selected from the group consisting of ethoxy, isopropoxy, n-propoxy, allyloxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy and 2,2-difluoroethoxy, a R _2a , R _2b , R _2c and R _2d are hydrogen; or R2 and _R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form a bicyclic fused ring system having the following formula: O (n _a ) ₅ a R _2a , R _2c and R _2d are hydrogen. 13. The compound or its pharmaceutically acceptable salt or stereoisomer according to any one of paragraphs. 1 and 4-11, where R ₂ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy; or R2 and R2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2-dimethyl-2, 3-dihydrobenzofuran-5-yl. 14. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-13, wherein the halogen is fluorine. 15. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 3-14, wherein R ₃ is selected from the group consisting of hydrogen, deuterium, hydroxyl, -OD, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted -(CH ₂ ) _s -C _3-6 cycloalkyl, substituted or unsubstituted -(CH ₂ ) _s -C _2-5 heteroalicyclyl containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted -(CH ₂ ) _s -C _2-5 heteroaryl containing at least one heteroatom selected from nitrogen, oxygen and sulfur, as well as substituted or unsubstituted -(CH ₂ ) _s -C ₆ aryl, with each value of s selected from the group consisting of 0, 1, 2 and 3. 16. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 3-15, wherein R ₃ is selected from the group consisting of hydrogen, methyl, -CD ₃ , ethyl, -CD ₂ CD ₃ , n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD ₃ CD ₃ , -(CR _9a R _9b ) _t C(=O)OR _9c and -(CH ₂ ) _t C(=O)NR _9a R _9b , where R _9a , R _9b and R _9c independently represent hydrogen or C _1-4 -alkyl, and each value of t is selected from the group consisting of 0, 1, 2 and 3. 17. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 3-16, wherein R ₃ is hydrogen or methyl. 18. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 17, wherein R4 _a , R4 _b , R _5a and R _5b are independently hydrogen or methyl. 19. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 17, wherein R4 _a , R4 _b and R _5a are hydrogen and R _5b is methyl or hydrogen. 20. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 17, wherein R4 _a , R _5a and R _5b are hydrogen and R4 _b is methyl or hydrogen. 21. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-20, wherein R4 _a , R4 _b , R _5a and R _5b are hydrogen. 22. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-21, wherein q is 0 or R6 is selected from halo and C _1-4 alkyl. 23. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-22, wherein q is 1. 24. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 23, wherein R6 is fluoro. 25. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-24, wherein p is 0. 26. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-25, wherein R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, C _1-2 haloalkyl and C _1-2 haloalkoxy . 27. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-26, wherein R ₈ is selected from the group consisting of hydrogen, -CF ₃ , -CHF2, -CF ₂ CF ₃ -OCF ₃ , -OCF2CF3 and - OCHF2. 28. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-27, wherein R8 is hydrogen. 29. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-28, wherein X is O. 30. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-29, - 132 042461 where m and n are independently selected from the group consisting of 0 and 1. 31. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-30, wherein m is 1 and n is 0 or 1. 32. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 4-13, where R _4a , R4 _b , R _5a , R ₅ b, R ₆ , R ₇ , R8 are each hydrogen; m and n are each 1; p and q are 0 or 1; X is O; And R ₃ is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, -CD ₂ CD ₃ , n-propyl, -CD ₂ CD ₂ CD ₃ , isopropyl, cyclopropyl, -CDCD3CD3, -(CR _9a R _9b )tC (=O)OR _9c and -(CH ₂ )tC(=O)NR _9a R _9b , where R _9a , R _9b and R _9c independently represent hydrogen or C1_ ₄ alkyl, with each value of t selected from the group consisting of 0, 1, 2 and 3. 33. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 and 4-13, where R4 _a , R _4b , R _5a , R _5b , R ₆ , R ₇ , R ₈ are each hydrogen; m and n are each 1; p and q are 0; X is O; And R ₃ is selected from the group consisting of hydrogen, methyl, -CD ₃ , ethyl, -CD ₂ CD ₃ , n-propyl, -CD2CD2CD3, isopropyl, cyclopropyl, -CDCD3CD3, -(CR9aR9b)tC(=O)OR9c and - (CH2)tC(=O)NR9aR9b, where R _9a , R _9b and R _9c are independently hydrogen or _{C1_4} alkyl, each t being selected from the group consisting of 0, 1, 2 and 3. 34. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 32 or 33, wherein R ₃ is methyl or hydrogen. 35. A compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 3234, wherein R ₂ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy and 2,2-difluoroethoxy; or R ₂ and R _2b taken together with the phenyl ring to which they are attached and the atoms to which they are attached form unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl and unsubstituted 2,2- dimethyl-2,3-dihydrobenzofuran-5-yl. 36. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, selected from the group consisting of 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-3-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-{[4-(tert-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(3-methyl-1H-indol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2-methyl-1,3-benzoxazol-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1-methyl-2,3-dihydro-1H-indol-5-yl)methyl]-1-(1-methylpiperidin4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(3-methyl-1,2-benzoxazol-6-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1,2-dimethyl-1H-indol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)mo - 133 042461 chevins; 3-[(4-cyclopropoxyphenyl)methyl]-1-[1-(2,4-difluorophenyl)ethyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)-1-[(quinolin-6-yl)methyl]urea; 1-[(2,4-difluorophenyl)methyl]-3-[(3-methyl-1,2-benzoxazol-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 3-[(1,3-benzoxazol-6-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(1,3-benzoxazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1-methyl-1H-indol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]-3-(1-methylpiperidin-4 -yl) urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-7-yl)methyl]3-(1 - methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(2,2-dimethyl-2H-chromen-7-yl)methyl]-3-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1-methyl-1H-indazol-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2-methyl-1H-indol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1,1-dioxo-2,3-dihydro-1λ ⁶ -benzothiophen-5-yl)methyl]-1-(1-methylpiperidin-4- silt) urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1H-inden-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(1,3-benzothiazol-6-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-dimethyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)methyl]-1( 1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2H-indazol-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(3-methyl-2H-indazol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-{[2-( ^2H3 )methyl( ^{1,1,1,3,3,3-2H6} )propan-2-yl] hydroxy}phenyl)methyl]-1(1-methylpiperidin-4-yl)urea; 3-[(4-cyclopropoxyphenyl)methyl]-1-[(1R)-1-(2,4-difluorophenyl)ethyl]-1-(1-methylpiperidin-4yl)urea; 3-[(3-cyano-4-methoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-fluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; 3-[(2-chloro-4-methoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-(1-methylpiperidin-4yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(2-fluoro-4-nitrophenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1-methyl-1H-1,3-benzodiazol-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1-methyl-1H-indazol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1-(piperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2H ₃ )methoxyphenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; 1 -[(2,4-difluorophenyl)methyl] -1-{1-[(1,1,1,3,3,3-2H ₆ )propan-2-yl]piperidin-4-yl} -3 - {[4-(propan-2yloxy)phenyl]methyl}ureas; 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 3-[(1H-1,3-benzodiazol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urine - 134 042461 fault; 1-[(7R,8aS)-octahydroindolizin-7-yl]-3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]urea; 1-[(7R,8aS)-octahydroindolizin-7-yl]-1-[(2,4-difluorophenyl)methyl]-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea; 3-[(2,4-difluorophenyl)methyl]-3-[(1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-1-{[4-( propan-2yloxy)phenyl]methyl}urea; 1 -[(2,4-difluorophenyl)methyl] -1 -[(3R,4S)-1,3-dimethylpiperidin-4-yl] -3 - {[4-(propan-2-yloxy)phenyl]methyl} urea; 1 -[(2,4-difluorophenyl)methyl] -1-[(3 S,4R)-1,3-dimethylpiperidin-4-yl] -3 - {[4-(propan-2-yloxy)phenyl]methyl }urea; 1-[(2,4-difluorophenyl)methyl]-1-(1,4-dimethylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}ureas; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-({3-fluoro-4-[(2-hydroxyethoxy)methyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1 H-indazol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1R)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1S)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-dihydro-2-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(3-methoxypropoxy)phenyl]methyl}-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro-4-nitrophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(4-chloro-3-methoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-fluoro-2-(trifluoromethoxy)phenyl]methyl}-1-(1-methylpiperidin-4yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[2-methyl-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin4-yl)urea; 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]urea; 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]urea; 1-[(2,4-difluorophenyl)methyl]-3-[(3-fluoro-4-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro-4-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)-1-[(4-phenoxyphenyl)methyl]urea; 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea; 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1-(piperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-ethoxyphenyl)methyl]-3-(piperidin-4-yl)urea; 3-[(2H-1,3-benzodioxol-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-1-[1-(2H ₃ )methylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[3-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[2-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4yl)urea; 1 -[(2,4-difluorophenyl)methyl]-3- {[3-methyl-4-(propan-2-yloxy)phenyl]methyl} -1-(1-methylpiperidin- 135 042461 4-yl) urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-fluoro-3-methoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-({4-[(2-ethylhexyl)oxy]phenyl}methyl)-1-(1-methylpiperidin-4yl)urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(prop-2-yn-1-yloxy)phenyl]methyl}urea; 3-{[4-(tert-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea; 1-[(2,6-difluoro-4-methoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl}-3-(1-methylpiperidin-4-yl)urea; 1-{[4-(1,1-difluoroethyl)phenyl]methyl}-3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-({4-[(1,3-difluoropropan-2-yl)oxy]phenyl}methyl)-3-(1-methylpiperidin-4-yl)urea ; 3-{[4-(2,2-difluoroethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4-yl)urea; 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(piperidin4-yl)urea and 1-[(2,4-difluorophenyl)methyl]-3-{[2,3-dihydro( ^2,2,3,3-2 H ₄ )-1-benzofuran-5-yl]methyl}-1-( 1-methylpiperidin-4-yl)urea. 37. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, selected from the group consisting of 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea; 3-{[4-(2,2-difluoroethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 3-{[4-(tert-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea; 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; 3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4yl)urea; 3-[(2,4-difluorophenyl)methyl]-1-{[4-(3-fluoropropoxy)phenyl]methyl}-3-(1-methylpiperidin-4-yl)urea; 3-{[4-(tert-butoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl ) urea; 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea and 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea. 38. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, selected from the group consisting of 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[(4-propoxyphenyl)methyl]urea; 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)urea; - 136 042461 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea; 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; 1 -[(2,4-difluorophenyl)methyl] -1 -(piperide in-4-yl)-3 - {[4-(propan-2-yloxy)phenyl]methyl} urea and 1-[(2,4 -difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea. 39. The compound according to claim 1, which is 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3[(4-propoxyphenyl)methyl]urea, or a pharmaceutically acceptable salt thereof, or stereoisomer. 40. The compound according to claim 1, which is 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)-3-[(4-propoxyphenyl)methyl]urea, or a pharmaceutically acceptable salt thereof or a stereoisomer. 41. The compound according to claim 1, which is 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, or its a pharmaceutically acceptable salt or stereoisomer. 42. The compound according to claim 1, which is 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea, or a pharmaceutically acceptable salt thereof or a stereoisomer. 43. The compound according to claim 1, which is 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1methylpiperidin-4-yl)urea, or a pharmaceutically acceptable salt or stereoisomer thereof. 44. The compound according to claim 1, which is 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, or its pharmaceutical acceptable salt or stereoisomer. 45. The compound according to claim 1, which is 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3{[4-(propan-2-yloxy)phenyl]methyl}urea , or a pharmaceutically acceptable salt or stereoisomer thereof. 46. The compound according to claim 1, which is 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4yl)-3-{[4-(propan-2-yloxy)phenyl]methyl} urea, or a pharmaceutically acceptable salt or stereoisomer thereof. 47. A method of treating a disease or condition associated with the serotonin 5-HT2A receptor in a patient, comprising administering to the patient an effective amount of a compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-46. 48. The method of claim 47 wherein the disease or condition is selected from the group consisting of Parkinson's disease psychosis, Parkinson's disease hallucinations, and Parkinson's disease delusions. 49. The use of a compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 46 for the treatment of a disease or condition associated with the 5HT2A serotonin receptor. 50. The use of claim 49 wherein the disease or condition is selected from the group consisting of Parkinson's disease psychosis, Parkinson's disease hallucinations, and Parkinson's disease delusions. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 137 -