Compounds, salts thereof, and methods for treating diseases

Abstract

To provide compounds for treatment of diseases and conditions associated with the serotonin receptor 5-HT.SOLUTION: The present disclosure provides a urea derivative compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, prodrug, stereoisomer and deuterated analogue thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] cross reference This application is a continuation of U.S. Provisional Patent Application No. 62 / 548,300, filed August 21, 2017. No. 1 and Swedish Application No. 1730225-8 filed on August 24, 2017 No. 6,313,935, filed on Dec. 13, 2003, and which claims the benefit of priority to each of the above-mentioned applications, the contents of each of which are incorporated herein by reference in their entireties. To be incorporated.

[0002] Compounds and their applications for the treatment of diseases and conditions associated with the 5-HT serotonin receptor Pharmaceutically acceptable salts are provided herein. [Background technology]

[0003] Serotonin, or 5-hydroxytryptamine (5-HT), is a hormone that regulates the functions of the mammalian body. In the central nervous system, 5-HT plays an important role in regulating sleep, feeding, and locomotion. , in various behaviors and responses such as pain perception, learning and memory, sexual behavior, and regulation of body temperature and blood pressure. It is an important neurotransmitter and neuromodulator involved in the The neurotransmitter plays an important role in the regulation of afferent peripheral nociceptors (Moulignie r, Rev. Neurol. 150:3-15, 1994)). cardiovascular system, blood system, and Peripheral functions in the gastrointestinal system have also been attributed to 5-HT. 5-HT is involved in both vascular and non-vascular Mediates a variety of contractile, secretory, and electrophysiological effects, including smooth muscle contraction and platelet aggregation. (Fuller, Biology of Seroton ergic Transmission,1982,Boullin,Serotoni n In Mental Abnormalities 1:316(1978), Ba rchas,et al.,Serotonin and Behavior,(197 3) The 5-HT2A receptor subtype (also called subclass) is associated with higher cognition and Human brain regions contain many cortical, limbic, and forebrain regions hypothesized to be involved in regulating emotional functioning. This receptor subtype is also involved in the process of vascular thrombosis. Expressed on mature platelets where it mediates, in part, one of the first steps in platelet aggregation .

[0004] Given the wide distribution of serotonin in the body, drugs that affect the serotonergic system It is understandable that there is a great interest in e Peripheral Actions of 5-Hydroxytryptam ine, 246 (1989), Saxena, et al., J. Cardiovasc. ular Pharmacol.15:Supp.7(1990)). Serotonin receptors is a large human gene for a transmembrane protein that functions as a transducer of cell-cell communication. They are members of the IL-1 family of IL-1 receptors that are expressed on the surface of various cell types, including neurons and platelets. These are present in the brain and can be stimulated by either their endogenous ligand, serotonin, or by exogenously administered drugs. Upon activation by either the IL-1 or IL-2 receptor, they undergo conformational changes and subsequently mediate downstream cell signaling pathways. Many of these receptors, including the 5-HT2A subclass, interact with neurotransmitters. Signaling by activating guanine nucleotide-binding proteins (G proteins) It is a G protein-coupled receptor (GPCR) that transmits cyclic AMP and inositol phosphate. Production or inhibition of second messenger molecules such as acid salts and diacylglycerol These second messengers then ultimately affect cell excitability and function. It affects the function of various intracellular enzymes, including kinases and ion channels.

[0005] At least 14 genetically distinct 5-HT receptor subtypes have been identified, including 7 Each subtype is assigned to one of the 5-HT1-7 families. The distribution of, selectivity for various ligands, and functional correlation(s) are shown.

[0006] Serotonin is a hormone that is involved in certain mental disorders (depression, aggression, panic attacks, obsessive-compulsive disorder, dementia, schizophrenia, suicidal tendencies), certain neurodegenerative disorders (Alzheimer's disease, neuropathy, Huntington's chorea), anorexia, bulimia, and disorders related to alcoholism It is an important component in various types of pathological conditions such as cerebrovascular accidents, cerebrovascular accidents, and migraines. Possible (Meltzer, Neuropsychopharmacology, 21: 106S-115S (1999), Barnes & Sharp, Neuropharma cology, 38:1083-1152 (1999), Glennon, Neuros. ci. Biobehavioral Rev., 14:35 (1990)).

[0007] Serotonin's widespread distribution in the body and its role in a wide range of physiological and pathological processes Given its role in the regulation of serotonergic function, there has been great interest in drugs that affect the serotonergic system. It is understood that there exists (Gershon, et al., The Periphery ral Actions of 5-Hydroxytryptamine,246(1 989), Saxena, et al., J. Cardiovascular Phar macol.15:Supp.7(1990)).

[0008] The effects of serotonin are identified and belong to one of seven families (5-HT1-7). At least 14 genetically distinct 5-HT receptor subtypes have been assigned to Each subtype has a unique distribution, preference for different ligands, and Show functional correlation(s). Serotonin receptors act as transducers of intercellular communication. They are members of a large human gene family of transmembrane proteins that function in It is present on the surface of various cell types, including neurons and platelets, and is their endogenous ligand. Upon their activation, either by serotonin or by exogenously administered drugs, These conformational changes subsequently interact with downstream mediators of cell signaling. Many of these receptors, including the 5-HT2A subclass, bind guanine nucleotides. G proteins signal by activating other G proteins It is a GPCR that binds cyclic AMP, inositol phosphate, and diacylglycerol. This then leads to the production or inhibition of second messenger molecules such as serole. These second messengers mediate kinase activity, which ultimately affect cellular excitability and function. and regulates the function of various intracellular enzymes, including ion channels.

[0009] The 5-HT2A receptor subtype (also called subclass) is involved in higher cognition and emotion in the human brain, including many cortical, limbic, and forebrain regions hypothesized to be involved in regulating function. This receptor subtype is widely and discretely expressed in the vascular Expressed on mature platelets where it mediates, in part, platelet aggregation, one of the first steps in the process will be done.

[0010] Antipsychotic drugs include dopaminergic, serotonergic, adrenergic, and muscarinergic drugs. Many central monoaminergic neurotransmitter receptors, including phosphodiesterase and histaminergic receptors The therapeutic and side effects of these drugs have been shown to vary with different receptors. The high degree of differentiation between these receptor subtypes is likely mediated by The degree of genetic and pharmacological homology allows for the development of subtype-selective compounds, as well as the development of any specific This has prevented the determination of the normal physiological or pathophysiological roles of the receptor subtypes. Among the monoaminergic neurotransmitter receptors, there are specific receptor classes and subclasses. There is a need to develop drugs that are selective for .

[0011] The prevailing theory regarding the mechanism of action of antipsychotic drugs is that they act by antagonizing dopamine D2 receptors. Unfortunately, antagonism of dopamine D2 receptors also leads to extrapyramidal side effects. , as well as some of the side effects of antipsychotic therapy, such as worsening of depressive symptoms, anhedonia, and impaired cognitive processing. Antagonism of the 5-HT2A receptor is likely to mediate additional undesirable effects. Antispermia, possibly by antagonizing augmented or excessive signaling by the serotonergic system. It is an alternative molecular mechanism for the therapeutic efficacy of 5-HT2A antagonists. Agonists have extrapyramidal side effects or dopamine D 2 Other undesirable effects associated with blocking the receptor These drugs are good candidates for treating psychiatric disorders without any side effects.

[0012] Traditionally, GPCRs such as the 5-HT2A receptor are stimulated by agonists (drugs that activate the receptor). It is considered to exist in a dormant state unless activated by the binding of a substance (a substance that binds to the receptors). Many, if not most, of the GPCR monoamine receptors, including the nin receptors, These endogenous agonists can exist in a partially activated state in the absence of It is now understood that this increased basal activity (constitutive activity) is due to the inverse agonist Both agonists and inverse agonists can be inhibited by compounds called , since only they can activate or inactivate these molecules, respectively. In contrast, classical or neutral antagonists have intrinsic activity at the receptor. Competes with agonists and inverse agonists for access to the body, but is highly They have no intrinsic ability to inhibit the basal or constitutive receptor response established.

[0013] As a result, new chemical compounds have been developed to generate antipsychotic drugs that target serotonin receptors. There is a need for a combination. Summary of the Invention

[0014] A compound of formula (I), [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, prodrug, stereoisomer thereof Monomeric and deuterated analogs are provided herein, 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 , R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, hydroxyl , -OD, halogen, cyano, amino, -SO 2 R 10 , -OC(=O)R 11 , -C( =O)OR 11 , -NR 10 C(=O)R 11 , unsubstituted or substituted C 1-6 Alkyl, Unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxyalumin Kill, no replacement or replacement C 1-6 Aminoalkyl, unsubstituted or substituted C 2-6 Arke Nyl, unsubstituted or substituted C 1-6 Alkoxy, unsubstituted or substituted C 3-6 Cycloal Kill, no replacement or replacement C 3-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 1 , R 1a , R 1b , R 1c , and R 1d At least one of the groups is not hydrogen and is R 10 and R 11 is In this case, hydrogen, amino, unsubstituted or substituted C 1-6 is selected from the group consisting of alkyl, R 2 , R 2a , R 2b , R 2c , and R 2d are independently hydrogen, deuterium, amino, hydroxyl oxyl, -OD, halogen, cyano, nitro, unsubstituted or substituted C 1-6 Alkyl, Unsubstituted or substituted C1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxyalumin Kill, no replacement or replacement C 2-6 Alkenyl, unsubstituted or substituted C 2-6 Alkenyl Oxy, unsubstituted or substituted C 2-6 Alkynyl, unsubstituted or substituted C 2-6 Alkini C 1-8 Alkoxy, unsubstituted or substituted C 3-6 Cyclo Alkyl, unsubstituted or substituted C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl R is selected from the group consisting of aryl, and substituted or unsubstituted heteroaryl; 2 is hydrogen, hydroxy or benzyloxy, or 2 and R 2b Or R 2c teeth , together with the atoms to which they are attached, form a ring system, R 3 is hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted C 1-6 Alkyl , unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxya Ru(Cl), unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 3-6 Cycloa Ru(Cl), unsubstituted or substituted C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; R 4a , R 4b , R 5a , and R 5b are independently hydrogen, deuterium, and unsubstituted or substitution C 1-6 alkyl, and when m and n are 1, R4a , R 4 b , R 5a , R 5b is hydrogen, R 6 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted or unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Alkoxy, substituted or is selected from the group consisting of unsubstituted aryl; R 7 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted or unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 From the group consisting of alkoxy Selected from R 8 is absent or represents 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 Selected from the group consisting of alkoxy Selected, X is selected from O or S. Some embodiments disclosed herein include administering to a subject an effective amount of a compound of formula (I), administering to the patient a pharma- ceutically acceptable salt, polymorph, or stereoisomer thereof. The present invention relates to a method for treating a disease in a patient with autism, the disease being abnormal hormonal activity, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's psychosis, addiction (alcohol, cocaine, Methamphetamine, nicotine, and opioids), Addison's disease, ADHD, Alzheimer's -psychosis, affective disorders, aggression, agitation, akathisia, alcohol addiction, alcohol withdrawal, Amenorrhea, amyotrophic lateral sclerosis, anhedonia, anorexia, anti-NMDAR encephalitis, anxiety, appetite disorders, Asthma, autism, behavioral disorders, behavioral disorders related to dementia, behavioral disorders related to impulse control disorders (ICD) Binge eating disorder, bipolar disorder, blindness, borderline personality disorder, bradykinesia, Bulimia, ICD-related purchases, cardiac arrhythmias, cerebrovascular accidents, Charles Bonnet syndrome, chemistry Therapy-induced vomiting, childhood autism, chronic pain, chronic insomnia, cocaine addiction, cognitive impairment, craniofacial Facial pain, Temporomandibular joint (TMJ) / Temporomandibular joint disorder (TMD), Cushing's disease, Delusions, Dementia, Lewy syndrome Dementia with Lewy bodies or dementia with Lewy bodies, Creutzfeldt-Jakob disease (CJD) Associated dementia and psychosis, Gerstmann-Sträussler-Scheinker disease (GSSD) and Fatal Familial Insomnia (FFI), depression, diabetes (non-insulin dependent), diabetic Peripheral neuropathy, drug addiction, double vision, Down's syndrome, dyskinesia, dysthymia, dystonia , ejaculation disorder, emphysema, epilepsy, extrapyramidal disorder, fibromyalgia, weakness, Friedreich's ataxia , frontotemporal dementia, ICD-related gambling, galactorrhea, generalized anxiety disorder, glaucoma, Hair loss or thinning, hallucinations, headaches, hemorrhoids, Huntington's disease, hyperprolactinemia, hypertension, ICD-related hypersexuality, hypotension, hypoglutamic acidemia, impulse control disorders, idiopathic hematologic Thrombocytopenic purpura, impotence, incontinence, elevated intraocular pressure, infertility, inflammatory pain, insomnia, ischemia , ischemic stroke, Lewy body disease (LBD), learning disabilities, sexual drive (reduced), sexual drive decline in fertility, male hypofertility, low sperm motility, lupus, Machado-Joseph disease, major depression, mania, Menopause symptoms, metabolic syndrome, methamphetamine addiction, migraine, mild cognitive impairment ( MCI), motor tics, multiple infarct dementia, multiple sclerosis, multiple developmental disorders, myocardial infarction , myoclonus, neuropathic pain, neurodegenerative disorders, neuropsychiatric disorders, nicotine addiction, dementia , depression, apathy, hallucinations, drooling (sialorrhea), constipation, pain, genitourinary disorders, and Non-motor symptoms of Parkinson's disease selected from among sleep disorders, obsessive-compulsive disorder, on-off phenomenon, Biogenic addiction, osteoporosis, pancreatitis, panic attacks, Parkinson's disease, Parkinson's dementia , Parkinson's disease psychosis, Periodic limb movements during sleep (PLMS), Peripheral vascular disease, Pituitary tumor including ulcers, postherpetic neuralgia, progressive supranuclear palsy, and Creutzfeldt-Jakob disease (CJD). Prion Disease, Gerstmann-Sträussler-Scheinker Disease (GSSD) and Fatality Familial insomnia (FFI), prolactinoma, affective dysregulation disorder (PBA), psychomotor retardation, Psychosis, psychosis secondary to neurodegenerative disorders, psychosomatic disorders, psychotic depression, post-traumatic stress Disorders (PTSD), Raynaud's disease, reflex sympathetic dystrophy, restless legs syndrome, retinal disease, schizoaffective disorder, schizophrenia, negative symptoms of schizophrenia, schizophrenia cognitive impairment associated with sepsis, serotonin syndrome, sexual dysfunction, and sexual dysfunction associated with antidepressant use Dysfunction, sleep apnea, sleep disorder, sleep maintenance disorder insomnia, social anxiety disorder, spinal cord injury, spinal cord Spinocerebellar atrophy, suicidality, thrombosis, thrombotic stroke, thrombotic thrombocytopenic purpura, tinnitus, fatigue Labor, Tourette's syndrome, Transient insomnia, Traumatic brain injury, Treatment-resistant depression, Treatment-resistant integration Ataxia, tremors, vaginal dryness, vasospastic awakenings, vascular dementia, hallucinations associated with Parkinson's disease, Parkinson's disease-related delusions, cancer, brain cancer, glioma, pancreatic cancer, hypoactive sexual desire disorder, Patients with type 2 diabetes mellitus, type 2 diabetes mellitus, or type 2 diabetes mellitus with dementia, and liver fibrosis It is selected. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] definition Unless otherwise defined, all technical and scientific terms used herein are understood to be of ordinary skill in the art. All patents, applications, and related documents referenced herein have the same meaning as commonly understood by law. Published applications and other publications are incorporated by reference in their entirety. If there are a plurality of definitions for a term in this document, the definition in this section shall prevail unless stated otherwise. Righteousness takes precedence.

[0016] As used herein, R 1 , R 2、 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Any "R" group(s) may be any group other than those shown, including, but not limited to, A non-limiting list of R groups includes hydrogen, aza, aryl ... alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl Examples of aryl include, but are not limited to, aryl, heteroaryl, and heteroalicyclyl. If two "R" groups are covalently attached to the same atom or adjacent atoms, they As defined herein, "together" or "combined" means a cycloa It may form an alkyl, aryl, heteroaryl, or heteroalicyclyl group. This is not a limitation, but NR a R b R in the group a and R b "Together" or " When a compound is indicated as being "combined," it means that they are covalently bonded to each other at their terminal atoms. Combined, nitrogen: [ka] It means forming a ring containing:

[0017] As one of ordinary skill in the art will readily appreciate, the text, formulas, schemes, examples, and figures herein Any given atom with unsatisfied valences disclosed may be used to satisfy the valences. It is assumed that there are a sufficient number of hydrogen atoms.

[0018] Whenever a group is described as "unsubstituted or substituted," if it is substituted, the substituent The substituent(s) (which may be present one or more times, such as 1, 2, 3, or 4 times) are independently selected from the group consisting of aryl, ... Kyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl , aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, ( Heteroalicyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, a Sil, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, Halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide , N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, halide haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamine and amino (including mono- and di-substituted amino groups) and their protected derivatives. Be selected.

[0019] Groups such as "unsubstituted or substituted" alkyl groups may be described without using the term "unsubstituted or substituted." When described as an alkyl group, for example when described as "alkyl", the group may have a substituent. Unless otherwise defined herein, the term "unsubstituted alkyl" is understood to mean "unsubstituted alkyl." For example, C 1-6 Alkyl means an unsubstituted alkyl containing 1 to 6 carbon atoms.

[0020] When a substituent on a group is deemed to be "substituted," the substituent itself is not limited to the indicated substituent. When a referenced substituent is substituted, it is One or more hydrogen atoms on the exemplified substituents may be replaced with deuterium, alkyl, alkenyl, alkynyl, or , cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, Heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl , hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy thio, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thio Carbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro , silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, Trihalomethanesulfonyl, trihalomethanesulfonamide, and amino (mono- and di-substituted) substituted amino groups), and protected derivatives thereof. This means that the substituents may be replaced with one or more protecting groups that may form protective derivatives of the above substituents. Protective groups are known to those skilled in the art and are described in reference Gr. eene and Wuts,Protective Groups in Organ icSynthesis,3 rd Ed., John Wiley & Sons, N ew York, NY, 1999.

[0021] As used herein, "C m ~C n ", "C m -C n " or "C m-n " ( where "m" and "n" are integers) refer to the number of carbon atoms in the relevant group, i.e. The group may contain from "m" to "n" carbon atoms (inclusive). For example, "C 1 ~C 6 "Alkyl" means any alkyl group having 1 to 6 carbon atoms, i.e. CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 C H 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )-, CH 3 CH(CH) 3 CH 2 -, CH 3 CH(CH) 3 CH 2 - and (CH 3 ) 3 Refers to C-. There are "m" and "n" If no specification is made regarding a group, the broadest range described in these definitions is intended. Let us assume that.

[0022] As used herein, "alkyl" means fully saturated (no double or triple bonds). An alkyl group refers to a straight or branched hydrocarbon chain group having 1 to 20 carbon atoms. (Whenever it appears herein, a numerical range such as "1 to 20" is intended to cover a given This refers to each integer within the range. For example, "1 to 20 carbon atoms" means that the alkyl group has one carbon atom. Atoms, 2 carbon atoms, 3 carbon atoms, etc. - up to 20 carbon atoms (including 20) However, this definition applies to the term "alkyl" without a numerical range. (This term also includes occurrences of the term "C 1-6 " etc., having 1 to 10 carbon atoms The alkyl group may be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group of the compound can be "C 1 -C 4 Alkyl, C 1-4 a It may be designated as "C 1 -C 4 Alkyl " or "C 1-4 "Alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain. i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, Typically, the butyl group is selected from the group consisting of butyl, iso-butyl, sec-butyl, and t-butyl. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Examples of aryl groups include, but are in no way limited to, butyl, tert-butyl, pentyl, hexyl, and the like. When substituted, the substituent(s) can be alkenyl, alkynyl, cycloalkyl ... chloroalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, Aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo , alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, aryl Chiral thio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide , N-Amido, S-Sulfonamide, N-Sulfonamide, Nitro, Silyl, Sulfenyl aryl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl Nyl, trihalomethanesulfonamido, and amino (including mono- and di-substituted amino groups) and protective derivatives thereof. be.

[0023] As used herein, "optionally" means, for example, "optionally deuterated." The term "optionally" refers to an alkyl group that is unsubstituted or substituted with one or more of the indicated substituents. For example, one or more hydrogen(s) can be substituted with one or more deuterium(s). may be replaced by:

[0024] As used herein, "alkenyl" refers to an alkyl group or aryl group in a straight or branched hydrocarbon chain. Refers to an alkyl group that contains one or more double bonds. If more than one double bond is present, The double bond may be conjugated or unconjugated. The group may have 2 to 20 carbon atoms (wherever it appears herein, " Numerical ranges such as "2 to 20" refer to integers within the given range, e.g., "2 to 20 carbon atoms." "Atoms" refers to alkenyl groups with 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to It means that the alkyl group may consist of 20 carbon atoms (inclusive), but this definition is not limited to the numerical range (This also includes occurrences of the term "alkenyl" where no substituent is specified). The substituent(s) may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloa alkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, alkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, aralkyl koxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloa Alkoxy, and amino (including mono- and di-substituted amino groups), and their protected derivatives is one or more group(s) individually and independently selected from the group consisting of

[0025] As used herein, "alkynyl" refers to an alkynyl group in a straight or branched hydrocarbon chain. An alkynyl group is an alkyl group that contains one or more triple bonds. (Anywhere it appears in this specification, a numerical range such as "2 to 20" may have any For example, "2 to 20 carbon atoms" means that the alkynyl group has 2 1 carbon atom, 3 carbon atoms, 4 carbon atoms, etc. up to 20 carbon atoms (including 20 However, this definition does not include the "alkyne" Alkynyl groups can be unsubstituted or substituted. If substituted, the substituent(s) may be any of those disclosed above for alkenyl group substitution. The substituents may be selected from the same groups as those shown in

[0026] As used herein, "hetero" refers to an atom selected from nitrogen, oxygen, phosphorus, and sulfur. This refers to the heteroatom that is

[0027] As used herein, "heteroalkyl" refers to any group, either alone or in combination with another term. In total, one or more carbon atoms (multiple), such as 1, 2, 3, or 4 carbon atoms (multiple). and the associated hydrogen atom(s) are the same or selected from nitrogen, oxygen, and sulfur. A straight chain of the indicated number of carbon atoms, independently replaced with different heteroatoms The substituted carbon atom(s) is / are located in the middle of the alkyl group. Examples of heteroalkyl include -S-alkyl, -O ... , -NH-alkyl, -alkylene-O-alkyl, etc. do not have.

[0028] As used herein, "aryl" refers to a carbocyclic ring having a completely delocalized pi-electron system. Refers to a ring of the formula (all carbon) or two or more fused rings (rings that share two adjacent atoms) Examples of aryl groups include benzene, naphthalene, and azulene. The aryl group may be substituted. When substituted, it is not limited to hydrogen atoms. The group can be any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyclo, Alkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroara alkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryl Oxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio , cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfur N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfur haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonyl Sulfonamide, and amino (including mono- and di-substituted amino groups), and their protection and a substituent(s) that is / are one or more group(s) independently selected from When substituted, the substituents on an aryl group are cycloalkyl, fused to an aryl group, including cycloalkenyl, cycloalkynyl, and heterocyclyl Non-aromatic rings may be formed.

[0029] As used herein, "heteroaryl" refers to any group consisting of at least one atom in a ring system. At least one of the atoms is a heteroatom, i.e., including, but not limited to, nitrogen, oxygen, and sulfur. Monocyclic or polycyclic aromatic ring systems (with fully delocalized π-electron systems) that are not carbon-based elements Examples of monocyclic "heteroaryl" include furan, thiophene, furan, Talazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole Sazol, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyridine imidines, pyrazines, tetrazoles, oxadiazoles, and triazines. Examples of polycyclic "heteroaryl" include, but are not limited to, quinoline, isoquinoline, Phosphorus, quinazoline, quinoxaline, indole, purine, benzofuran, benzothiophene and benzopyranones (e.g., coumarins, chromones, and isocoumarins). Heteroaryl may be substituted, but is not limited to, aryl. When substituted, In this case, the hydrogen atom is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl. aryl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, Heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy , aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, a Arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide , S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfi haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalonyl fluoromethanesulfonamide, and amino (including mono- and di-substituted amino groups), and and a substituent group(s) which is / are one or more group(s) independently selected from the following protective derivatives: When substituted, the substituents on the heteroaryl group are Aryl, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl The aromatic ring may form a non-aromatic ring fused to the aromatic ring.

[0030] "Aralkyl" or "arylalkyl" refers to an alkylene group that is substituted with The alkylene and aryl groups of the aralkyl are substituted or unsubstituted. Examples include benzyl, substituted benzyl, 2-phenylethyl, 3-phenyl In some cases, alkyl groups include, but are not limited to, propyl and naphthylalkyl. In this case, the alkylene group is a lower alkylene group.

[0031] A "heteroaralkyl" or "heteroarylalkyl" refers to a heteroaryl group that is an alkyl group or a heteroaryl group. Heteroaryl groups are linked via an alkylene group. Heteroaryl groups may be substituted. Examples include 2-thienylmethyl, 3-thienylmethyl, enylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, Isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, and These include, but are not limited to, substituted versions of the above, as well as benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group.

[0032] "Alkylene" refers to a group that has bonds to join molecular fragments through their terminal carbon atoms. The alkylene is a linear tethering group that forms an alkylene ring. The alkylene can have 1 to 20 carbon atoms. Len said, "C 1-6 " and other medium-sized alkylenes having 1 to 10 carbon atoms. The alkylene may also be a lower alkylene having 1 to 4 carbon atoms. Len said, "C 1 -C 4 Alkylene", "C 1-4 "Alkylene" or similar names and designations A non-limiting example is methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and butylene (-(CH 2 ) 4 -) group In the case of methylene, the two linked fragments are attached to the same carbon atom. The alkylene groups may be optionally substituted.

[0033] As used herein, "heteroalkylene" refers to any heteroalkyl group, either alone or in combination with another term. In one embodiment, one or more of the carbon atoms, such as 1, 2, 3, or 4 carbon atoms, are independently and each of the heteroatoms is replaced by the same or different heteroatoms selected from oxygen, sulfur, and nitrogen. Heteroalkylene refers to an alkylene group of the indicated number of carbon atoms. As an example, -CH 2 -O-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH2 -O- , -CH 2 -NH-, -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -NH-CH 2 -, -O-CH 2 -CH 2 -O-CH 2 -CH 2 -O- , -O-CH 2 -CH 2 -O-CH 2 -CH 2 - but are not limited to these stomach.

[0034] As used herein, "alkylidene" refers to a dialkyl group that is bonded to a carbon atom of another group. It refers to a divalent group such as =CR'R'' that forms a double bond. As an alkylidene group, methylidene N(=CH 2 ) and ethylidene (=CHCH 3 ), but are not limited to As used herein, "arylalkylidene" refers to any alkyl group in which either R' or R'' is aryl. The alkylidene group refers to an alkylidene group, one of which is an aryl group. The alkylidene group may be optionally substituted. stomach.

[0035] As used herein, "alkoxy" refers to a group in which R is an alkyl group, e.g., methoxy. , ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy ), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy , tert-amoxy, etc. Alkoxy refers to the group -OR, which may be optionally substituted. .

[0036] As used herein, "alkylthio" refers to a group in which R is alkyl, as defined above. For example, methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methyl ether Isopropyl mercapto, n-butyl mercapto, isobutyl mercapto butylmercapto, sec-butylmercapto, tert-butylmercapto, etc. Alkylthio may be optionally substituted.

[0037] As used herein, "aryloxy" and "arylthio" refer to any group in which R is Aryl as defined above, for example, phenoxy, naphthalenyloxy, azulenyloxy, RO- and RS- are anthracenyloxy, naphthalenylthio, phenylthio, etc. Both the aryloxy and arylthio groups may be optionally substituted.

[0038] As used herein, "alkenyloxy" refers to an alkoxy group in which R is an alkoxy group as defined above. Nyl, for example, vinyloxy, propenyloxy, n-butenyloxy, iso-butenyl The formula -OR is oxy, sec-pentenyloxy, tert-pentenyloxy, etc. The alkenyloxy may be optionally substituted.

[0039] As used herein, "acyl" refers to an acyl group attached via a carbonyl group as a substituent. The term refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl radical that is substituted with aryl. Examples include: Acyl includes formyl, acetyl, propanoyl, benzoyl, and acryl. , which may be substituted.

[0040] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic ring. If it consists of two or more rings, these rings may be fused, The cycloalkyl groups may be linked together in a bridged or spiro-linked fashion. 3 ~C 6 etc. C 3 ~C 10 The cycloalkyl group may be unsubstituted or substituted. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl ... Substituted aryl groups include, but are in no way limited to, pentyl, cyclohexyl, and the like. When present, the substituent(s) can be alkyl or, unless otherwise stated, aliphatic. The substitution of the alkyl group may be selected from those given above. The substituents on the cycloalkyl group are fused to a cycloalkyl group, including aryl and heteroaryl. The aromatic ring may be formed by bonding the ring to the ring.

[0041] As used herein, "cycloalkenyl" refers to a group having one or more double bonds within the ring. However, if more than one is present, they form a completely depolarized ring. cannot form a localized π-electron system (otherwise the group is not capable of forming a When it consists of two or more rings, the rings may be fused, bridged, or Cycloalkenyl groups can be linked together in a C or spiro bond fashion. 3 ~C 8 or C 5 ~C 10 C etc. 3 ~C 10 For example, C 3-8 For cycloalkenyl , C 4-8 Cycloalkenyl, C 5-8 Cycloalkenyl, or C 6-8 Cycloarke Cycloalkenyl groups can be unsubstituted or substituted. Where indicated, the substituent(s) may be alkyl or may be unspecified. As long as the alkyl group is substituted, it may be selected from the groups disclosed above. The substituents on the cycloalkenyl group are cycloalkenyl, including aryl and heteroaryl. The aromatic ring may be fused to the alkyl group.

[0042] As used herein, "cycloalkynyl" refers to a group having one or more triple bonds within the ring. When it consists of two or more rings, these rings may be fused, bridged, or may be linked together in a spiro-bonded fashion. 8 ~C 12 Example The cycloalkynyl group can be unsubstituted or substituted. If present, the substituent(s) can be alkyl or, unless otherwise indicated, and may be selected from those groups disclosed above for alkyl group substitution. If substituted, Substituents on the cycloalkynyl group include aryl and heteroaryl. The aromatic ring may be formed fused to the group.

[0043] As used herein, "heteroalicyclic" or "heteroalicyclyl" refers to a heterocyclic ring system. and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A heteroalicyclic or heteroalicyclyl group refers to a 3- to 18-membered ring having 2 ~C 10 of In some embodiments, C 2 ~C 9 and in other embodiments, , C 2 ~C8 "Heteroalicyclic" or "heteroalicyclyl" refers to a fused ring system. monocyclic, bicyclic, tricyclic, or cyclic rings which may be linked together in a bonded, bridged, or spiro-linked fashion; The nitrogen atom, carbon atom, and the like in the "heteroalicyclic" or "heteroalicyclyl" may be tetracyclic ring systems. The nitrogen and sulfur atoms may be optionally oxidized and the nitrogen may be optionally quaternized. These rings may also contain one or more double bonds, provided that they are completely non-conductive throughout all rings. Provided that they do not form localized π-electron systems, examples include 2H-benzo[b][1,4]o Quinoline-3(4H)-one, 3,4-dihydroquinolin-2(1H)-one, 1,2, 3,4-Tetrahydroquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxo Sazin, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo [d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazo Heteroaryl-2-ones, and benzo[d]oxazol-2(3H)-ones. The cyclyl group may be unsubstituted or substituted. When substituted, the substituent ( (multiple possible) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, hete Aralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, a Aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, aryl Ruthio, cyano, halogen, C-amide, N-amide, S-sulfonamide, N-sulfo Amides, isocyanates, thiocyanates, isothiocyanates, nitro, silyl, halide haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamine and amino (including mono- and di-substituted amino groups) and their protected derivatives. Such "heteroalicyclic" or Examples of "heteroalicyclyl" include azepinyl, dioxolanyl, imidazolinyl, Morpholinyl, oxetanyl, furanyl, oxiranyl, piperidinyl N-oxide, piperidine Perizinyl, piperazinyl, pyrrolidinyl, pyranyl, 4-piperidonyl, pyrazolidinyl 2-oxopyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiamol thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. When substituted, the substituents on a heteroalicyclyl group include, but are not limited to, Aromatic rings fused to heteroalicyclyl groups, including aryl and heteroaryl, do.

[0044] "Fused bicyclic ring" refers to a ring system in which two rings share two adjacent atoms. The two rings share one covalent bond. An example of a fused bicyclic ring is decalin. do.

[0045] "Spirobicyclic ring" refers to a bicyclic ring in which the two rings share one atom.

[0046] A "bridged ring system" refers to a ring system in which two rings share three or more atoms. The bridgehead atoms are separated by a bridge containing at least one atom, specific examples being: Norbornane, also known as bicyclo[2.2.1]heptane. Bicyclo[2.2.1] The structure of heptane is shown below, with the bridgehead atoms shown. [ka]

[0047] "(Cycloalkyl)alkyl" refers to a group bonded via an alkylene group as a substituent. Cycloalkyl groups. (Cycloalkyl)alkyl alkylene and cycloalkyl may be substituted. Examples include cyclopropylmethyl, cyclobutylmethyl, Cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropyl Cyclopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, Examples include, but are not limited to, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower alkylene group.

[0048] "(Cycloalkenyl)alkyl" refers to a group that is bonded via an alkylene group as a substituent. The alkylene and cycloalkenyl groups of (cycloalkenyl)alkyl are Alkenyl may be optionally substituted. In some cases, the alkylene group may be a lower alkylene. It is based on

[0049] "(Cycloalkynyl)alkyl" refers to a group that is bonded as a substituent via an alkylene group. The alkylene and cycloalkynyl groups of (cycloalkynyl)alkyl are The alkylene group may be a lower alkylene. It is based on

[0050] As used herein, "halo" or "halogen" refers to any of the following: F (fluoro), Cl (chloro), Br (bromo) or I (iodine).

[0051] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms is a haloalkyl. These groups include chloromethyl, Fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl Haloalkyl groups include, but are not limited to, 2-fluoroisobutyl and 2-fluoromethyl. The alkyl group may be substituted.

[0052] As used herein, "haloalkoxy" refers to an R 2 -alkyl group in which R is a haloalkyl group. Such groups include chloromethoxy, fluoromethoxy, and difluoromethoxy. , trifluoromethoxy and 1-chloro-1-fluoromethoxy, 2-fluoroisobutyric acid Haloalkoxy is an optionally substituted alkyl group, but is not limited to alkoxy. stomach.

[0053] An "O-carboxy" group refers to an aryl group where R is hydrogen, alkyl, alkenyl, aryl, aryl or aryl, as defined herein. , alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heptyl aryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl O-carboxy refers to the group "RC(=O)O-" which may be optionally substituted. .

[0054] A "C-carboxy" group is one in which R is the same as defined for O-carboxy. The resulting "-C(=O)OR" group refers to the C-carboxy group which may be optionally substituted.

[0055] A "trihalomethanesulfonyl" group is a group consisting of "X" where X is a halogen. 3 CSO 2 - "Base" Point.

[0056] JPEG0007628578000004.jpg23170

[0057] The "nitro" group is defined as "-NO 2 " group.

[0058] A "cyano" group refers to a "-CN" group.

[0059] A "cyanato" group refers to a "-OCN" group.

[0060] An "isocyanato" group refers to a "-NCO" group.

[0061] A "thiocyanato" group refers to a "-SCN" group.

[0062] A "carbonyl" group refers to a "-C(=O)-" group.

[0063] A "thiocarbonyl" group refers to a "-C(=S)-" group.

[0064] An "oxo" group refers to a "=O" group.

[0065] A "hydroxy" or "hydroxyl" group refers to an "-OH" group.

[0066] An "isothiocyanato" group refers to a "-NCS" group.

[0067] A "sulfinyl" group may be defined as R is as defined for O-carboxy. Sulfinyl refers to the radical "-S(=O)-R" which may be optionally substituted.

[0068] A "sulfonyl" group may be the same as defined for O-carboxy. "SO 2 R" group. The sulfonyl may be optionally substituted.

[0069] An "S-sulfonamide" group is R A and R B are independently attached to the O-carboxy may be the same as or in combination with those defined for the R groups defined above. , substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkeny aryl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, which may form a ring system selected from the group consisting of "-SO 2 NR A R B " group. The S-sulfonamide may be optionally substituted.

[0070] An "N-sulfonamido" group is a group consisting of R and R A are independent of each other, for O-carboxy The RSO groups may be the same as those defined for R groups defined above. 2 N(R A )-" The N-sulfonamide may be optionally substituted.

[0071] A "trihalomethanesulfonamido" group is a group in which X is a halogen and R is an O-carbo "X" may be the same as that defined for 3 CSO 2 It refers to the "N(R)-" group. The trihalomethanesulfonamides may be optionally substituted.

[0072] A "C-amide" group is a group consisting of R A and R B are defined independently for O-carboxy. R groups may be the same as those defined for the R groups listed above, or may be combined to provide substitutions. 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 "-C(=O)NR" which may form a ring system selected from the group consisting of heteroaryl A R B " group. C-amides may be optionally substituted.

[0073] An "N-amido" group is one in which R and R A are independently defined for O-carboxy. The R groups may be the same as those defined for the R groups in the formula "RC(=O)NR A -" refers to the group The N-amide may be substituted.

[0074] "Ester" refers to an ester in which R can be the same as defined for O-carboxy. -C(=O)OR" group. Esters may be optionally substituted.

[0075] A lower alkoxyalkyl refers to an alkoxy group bonded via a lower alkylene group. A lower alkoxyalkyl may be optionally substituted.

[0076] "Amine" or "amino" means the RNH 2 " (primary amine), "R 2 NH” (No. secondary amine), "R 3 N" (tertiary amine). The amino group may be substituted .

[0077] Aminoalkyl refers to an amino group bonded through a lower alkylene group. The alkyl may be optionally substituted.

[0078] As used herein, for example, with respect to a subscript "0" (zero), it means that For example, S can be "0" -(CH 2 ) s -C 2-6 a Rukill is -(CH 2 )- is absent and the remaining groups are -C 2-6 It means that it is alkyl. Taste.

[0079] Using techniques well known to those skilled in the art (e.g., Greene and Wuts, Protective e Groups in Organic Synthesis,3 rd Ed.,Jo Wiley & Sons, New York, NY, 1999) can be used to convert any unsubstituted or monosubstituted amine group of the compounds herein to an amide. Any hydroxyl groups may be converted to esters, any carboxylic acid groups may be converted to esters, The carboxyl groups may also be converted to either amides or esters.

[0080] As used herein, any protecting groups, amino acids, and other chemical abbreviations may be used interchangeably. Unless otherwise indicated, their common usage, recognized abbreviations, or IUPAC-I abbreviations are used. UB Commission on Biochemical Nomenclature e (see Biochem. 11:942-944 (1972)).

[0081] As used herein, the following terms have their accepted meanings in the chemical literature: . JPEG0007628578000005.jpg161163

[0082] Any compound disclosed herein that contains one or more stereocenters or chiral centers may be In the above, where the absolute stereochemistry is not clearly indicated, each center may independently be in the R-configuration or It is understood that the aryl group may be in the S- or S-configuration or a mixture thereof. The compounds provided herein may be enantiomerically pure or may be stereoisomeric mixtures. Additionally, the compounds provided herein may be scalemic mixtures. In addition, one or more double bonds (multiple) that generate geometric isomers that can be defined as E or Z. In any compound having the formula (I), each double bond is independently selected from E or Z or their It is understood that the compounds may be mixtures. Likewise, all tautomeric forms are intended to be included. It is being done.

[0083] As used herein, "tautomer" and "tautomerism" refer to isomers in which the position of a proton changes refers to alternative forms of the compounds disclosed herein that are different. Non-limiting examples include enol -keto tautomers and imine-enamine tautomers, or pyrazoles, imidazoles, Ring -NH- moieties and ring =N- such as benzimidazole, triazole, and tetrazole Tautomeric forms of heteroaryl groups that contain ring atoms that are attached to both moieties are included.

[0084] It is understood that isotopes may be present in the compounds described herein. Each chemical element may include any isotope of that element. For example, the compounds described herein may In this case, hydrogen atoms include hydrogen-1 (protium) and hydrogen-2 (deuterium). The isotope may be any hydrogen isotope, but is not limited to these. Reference to encompasses all possible isotopic forms unless the context clearly dictates otherwise. For example, the term "methyl" is -CH 3 , -CD 3 , -CH 2 Including D etc.

[0085] As used herein, a "pharmaceutically acceptable salt" refers to a compound that retains its biological activity and Pharmaceutical salts refer to salts of compounds that do not abrogate the properties of the compounds disclosed herein. The salts formed with bases include aliphatic acid, aryl, phenyl ... Ammonium salts (NH 4 + ), alkali metals (including sodium or potassium salts, ), alkaline earth (including but not limited to calcium or magnesium salts), salts of organic bases (dicyclohexylamine, piperidine, piperazine, etc.); amine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine amine, tris(hydroxymethyl)methylamine, and Salts with the amino group of amino acids (including, but not limited to, arginine and lysine) ) Useful acid-based salts include, but are not limited to, acetates, azides, etc. Pinate, aspartate, ascorbate, benzoate, butyrate, caprate, Caproate, Caprylate, Camsylate, Citrate, Decanoate, Formate, Fumarate Salt, Gluconate, Glutarate, Glycolate, Hexanoate, Laurate, Lactate Salt, maleate, nitrate, oleate, oxalate, octanoate, propanoate, Palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfos Phosphonates, e.g., methanesulfonates, ethanesulfonates, p-toluenesulfonates , salicylates, tartrates, and tosylates.

[0086] Pharmaceutically acceptable solvates and hydrates are compounds that contain a compound and 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 solvents. Or it is a complex with water molecules.

[0087] As used herein, a "prodrug" refers to a compound that may not be pharma- ceutical active. A prodrug is a compound that is converted to an active drug upon in vivo administration. modifying the therapeutic stability or transport properties, masking side effects or toxicity, or may be designed to improve the flavor of the drug or to modify other characteristics or properties of the drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A prodrug may have better solubility in a pharmaceutical composition than the active parent drug. One example of a prodrug is one that is absorbed through cell membranes where water solubility is detrimental to mobility. They are administered as esters ("prodrugs") to facilitate absorption, but are subsequently Once inside the cell, it is metabolically hydrolyzed to a carboxylic acid (the active entity), which is where the Further examples of prodrugs include, but are not limited to, the compounds disclosed in Short peptides (polypeptides) linked to acid groups that are metabolized in vivo to release the active parent compound. Based on knowledge of in vivo pharmacodynamic processes and drug metabolism, Once a pharma- ceutical active compound is known, one of skill in the art can design a prodrug of the compound. (See, for example, Nogrady (1985) Medicinal Chemistry istry A Biochemical Approach,Oxford Univ. See The City Press, New York, pages 388-392. Specific examples of prodrugs include those which react with the basic nitrogen containing piperidyl group of formula (I). In this regard, the basic nitrogen may be, for example, a group attached to the nitrogen of a piperidyl group, as shown in formula A. to form basic nitrogen. Specific examples are: Attached to that nitrogen are an acyl group and a tosyl group. [ka]

[0088] "Anti-drug" means a substance that acts against or counteracts illegal drugs or their use. The compounds of the present application function as antidrugs. Possible.

[0089] As used herein, "modulating" the activity of a receptor means activating it. , i.e., the baseline level of that cell's function measured in the particular environment in which it is found. or inactivating it, i.e., increasing its cellular function beyond Either it is reduced below a reference level measured in the environment in which it is found, and and / or completely unable to carry out its cellular function even in the presence of its natural binding partner. A natural binding partner is an endogenous molecule that is an agonist for the receptor. It is.

[0090] An "agonist" is an antagonist that inhibits the basal activity of a receptor (i.e., the signal mediated by the receptor). is defined as a compound that increases neurotransmission.

[0091] As used herein, a "partial agonist" refers to an agonist that has affinity for a receptor. However, unlike agonists, when bound to a receptor, a large number of receptors are occupied by the compound. Even when they are administered, they usually only elicit a minor receptor-related pharmacological response. This refers to a compound that is

[0092] An "inverse agonist" is an inverse agonist that is not technically an antagonist, but rather has a negative intrinsic effect on the Compounds that reduce or suppress the basal activity of a receptor such that they are potent agonists. is defined.

[0093] As used herein, an "antagonist" refers to an agent that binds to a receptor and inhibits the receptor from being occupied. Refers to compounds that form a complex that does not produce any response as if the compound were not present. Antagonists reduce the action of agonists at the receptor. , reversibly or irreversibly bind to the receptor, permanently or at least partially inhibiting its activity. The antagonist is metabolized, dissociated, or otherwise physically or biologically Until it is removed by the process, it can be effectively eliminated.

[0094] As used herein, a "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" refers to cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, crustaceans, and the like. "Mammals" includes mice, rats, rabbits, hamsters, and other mammals. rats, dogs, cats, sheep, goats, cattle, horses, primates, e.g. monkeys, timberland rats Examples of animals that may be included include, but are not limited to, monkeys, monkeys, and great apes, particularly humans.

[0095] As used herein, a "patient" refers to a person who has been cured or has been treated for a particular disease or disorder. or at least attempt to ameliorate the effects of the disease or disorder from the outset. To prevent this from happening, you should have your doctor or a medical professional treat you. Refers to the subject being treated.

[0096] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. Examples, but not limitation, include dimethyl sulfoxide (DMSO). MSOs are a common method for facilitating the uptake of many organic compounds into cells or tissues of interest. It is a carrier used in

[0097] As used herein, a "diluent" is an agent that lacks pharmacological activity but is pharma- ceutical necessary. Refers to an ingredient in a pharmaceutical composition that may be present or desirable. For example, the use of a diluent This can increase the bulk of potent drugs that are too small in mass to be manufactured or administered. It is also a liquid for dissolving drugs that are administered by injection, ingestion, or inhalation. A common form of diluent in the art is phosphorus diluent, which mimics the composition of human blood. and buffered aqueous solutions such as, but not limited to, acid buffered saline.

[0098] As used herein, an "excipient" refers to an agent that adds, without limitation, bulk, consistency, Inactive substances added to pharmaceutical compositions to provide stability, binding capacity, lubrication, disintegration, etc. A "diluent" is a type of excipient.

[0099] A "receptor" can affect cell physiology when inhibited or stimulated by a ligand It is intended to include any molecule that is present within a cell or on the surface of a cell. Receptors consist of an extracellular domain that has ligand-binding properties and a membrane domain that anchors the receptor within the cell membrane. a transmembrane domain, and a domain that generates a cellular signal in response to ligand binding ("signal transduction"). A receptor is any cellular molecule that produces a signal in response to ligation. Receptors are molecules that have the characteristic structure of a receptor but do not have an identifiable ligand. In addition, receptors include truncated, modified, mutated receptors, and includes any molecule that contains part or all of the sequence of the receptor.

[0100] "Ligand" is intended to include any substance that interacts with a receptor.

[0101] "Selective" or "selectivity" refers to the ability to selectively bind to a particular receptor type, subtype, class, or subtype. generate the desired response from one receptor class while maximally suppressing responses from other receptor types Selective elimination of one or more specific subtypes of a compound is defined as the ability of the compound not to produce "Selectivity" refers to the ability to increase the activity of one subtype while suppressing the activity of other subtypes. It refers to the ability of a compound to cause little or no increase in activity between receptor targets. The selectivity of compounds is determined, for example, by the ratio of their potencies or affinities for their targets. For example, if a compound has a pKi of 10 nM for target 1 and 10 nM for target 2, If a compound has a pKi of 0 nM, it will have 10-fold higher selectivity for target 1 than for target 2. Therefore, the compound is 10 times more potent at target 1, i.e. It is 10-fold more selective for target 1.

[0102] As used herein, "IC50" refers to the specific compound that achieves 50% inhibition of the maximal response. IC50 refers to the amount, concentration, or dosage of a test compound that is The assay may be an R-SAT® assay as described herein, It is not limited to the RSAT assay.

[0103] As used herein, "EC50" refers to the R-SAT (Registered Trademark) Such assays include, but are not limited to, assays in which a particular test compound induces, induces, or in an assay that measures a particular response to be enhanced, 50% of the maximum expression of such response. Dose-dependent response refers to the amount, concentration or dosage of a particular test compound that elicits a dose-dependent response in %.

[0104] As used herein, "pKi" refers to the pKi of a functional antagonist or radioligand. In a bond binding assay, such as the R-SAT® assay described herein, It refers to the negative logarithm of the equilibrium dissociation constant, Ki, of the antagonist-receptor complex being measured.

[0105] As used herein, "co-administration" of pharmacologically active compounds refers to in vitro Co-administration refers to the delivery of two or more separate chemical entities, whether in vivo or in vivo. Simultaneous delivery of separate agents, simultaneous delivery of a mixture of agents, as well as delivery of one agent followed by a second Co-administered drugs typically have a high degree of dosing sensitivity to one another. They are intended to work together.

[0106] As used herein, the term "effective amount" refers to an amount that reduces or alleviates the symptoms of the disease being treated. Any tissue, system, or animal that is being explored by a researcher, veterinarian, physician, or other clinician, including an active compound or drug that induces a biological or medicinal response in a substance or in humans means the amount of

[0107] As used herein, "preventing / preventing" refers to preventing or preventing a condition and / or disease from , a compound or pharmaceutical composition according to the embodiments disclosed herein for achieving prophylaxis This should not be interpreted as meaning that the condition cannot occur again after use. The term is intended to be used to describe a condition that, at least to some extent, develops following such use to prevent the condition. nor should it be understood to mean the inability to obtain a if the condition being prevented occurs despite such use, or in the absence of such use is intended to mean that the condition will be less severe than

[0108] compound A compound according to formula (I), [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, prodrug, stereoisomer thereof Monomeric and deuterated analogs are provided herein, 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 , R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, hydroxyl , -OD, halogen, cyano, unsubstituted or substituted amino, -SO 2 R 10 , -OC(=O )R 11 , -C(=O)OR 11 , -NR 10 C(=O)R 11 , unsubstituted or substituted C1 -6 Alkyl, unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hide oxyalkyl, unsubstituted or substituted C 1-6 Aminoalkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 1-6 Alkoxy, unsubstituted or substituted C 3-6 Cycloa Ru(Cl), unsubstituted or substituted C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and and substituted or unsubstituted heteroaryl; R 1 , R 1a , R 1b , R 1c , and R 1d At least one of the groups is not hydrogen and is R 10 and R 11 is independent and hydrogen, amino, unsubstituted or substituted C 1-6 is selected from the group consisting of alkyl, R 2 , R 2a , R 2b , R 2c , and R 2d are independently hydrogen, deuterium, amino, hydroxyl oxyl, -OD, halogen, cyano, nitro, unsubstituted or substituted C 1-6 Alkyl, non Replacement or Substitution C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxyalkyl, Unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 2-6 Alkenyloxy, non Replacement or Substitution C 2-6 Alkynyl, unsubstituted or substituted C 2-6 Alkynyloxy, non-substituted Replacement or substitution C 1-8 Alkoxy, unsubstituted or substituted C 3-6Cycloalkyl, unsubstituted or or substitution C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl. R is selected from the group consisting of substituted heteroaryl; 2 is hydrogen, hydroxy, or benzyl Not oxy or R 2 and R 2b Or R 2 and R 2c are combined Together with the atoms present, they form a ring system or R 2 and R 2b Or R 2c teeth, Together with the atoms to which they are attached, they form a ring system or R 2a and R 2b Or R 2c and R 2d together with the atoms to which they are attached form a ring system , R 3 is hydrogen, deuterium, hydroxyl, -OD, 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 3-6 Cycloalkyl, non Replacement or Substitution C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl. is selected from unsubstituted heteroaryl; R 4a , R 4b , R 5a , and R 5b are independently hydrogen, deuterium, and unsubstituted or substituted exchange C 1-6 alkyl, and when m and n are 1, R 4a , R 4b , R5a , R 5b is hydrogen, R 6 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted or R 6 and R 3 are combined Together with the atom(s) form a ring system or R 6 and R 3 are combined Together with the atoms, they form a ring system, R 7 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Selected from the group consisting of alkoxy Selected, R 8 is absent or hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted substitution 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.

[0109] A compound according to formula (I), [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, prodrug, stereoisomer thereof Monomeric and deuterated analogs are also provided herein, 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 , R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, hydroxyl , -OD, halogen, cyano, amino, -SO 2 R 10 , -OC(=O)R 11 , -C( =O)OR 11 , unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-6 HelloA Ru(Cl), unsubstituted or substituted C 1-6 Hydroxyalkyl, unsubstituted or substituted C 1-6 Ami No alkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 1-6 Alcoki C, unsubstituted or substituted 3-6 Cycloalkyl, unsubstituted or substituted C 3-6 Heteroaris from the group consisting of aryl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Selected from R 1 , R 1a , R 1b , R 1c , and R 1d At least one of them is water. Not a single element, but R 10 and R 11 are independently hydrogen, amino, unsubstituted or substituted C 1-6 a selected from the group consisting of rutile and alkyl; R 2 , R 2a , R 2b , R 2c , and R 2d are independently hydrogen, deuterium, amino, hydroxyl oxyl, -OD, halogen, cyano, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or is a substitution C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxyalkyl, unsubstituted or or substitution 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 R is selected from the group consisting of substituted aryl, and substituted or unsubstituted heteroaryl; 2 , R 2a , R 2b , R 2c , and R 2d At least one of the groups is not selected from hydrogen. , or R 2 and R 2b Or R 2c together with the atoms to which they are attached, Forming a ring system, R 3 is hydrogen, deuterium, hydroxyl, -OD, 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 3-6 Cycloalkyl, non Replacement or Substitution C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl. is selected from unsubstituted heteroaryl; R 4a , R 4b , R 5a , and R 5b are independently hydrogen, deuterium, and unsubstituted or substituted exchange C 1-6alkyl, and when m and n are 1, R 4a , R 4b , R 5a , R 5b is hydrogen, R 6 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted substituted aryl; R 7 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Selected from the group consisting of alkoxy Selected, R 8 is absent or hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted substitution 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.

[0110] A compound according to formula (I), [ka] or its pharma- ceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, and isomers thereof. Also provided herein are isomers, 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 is deuterium, hydroxyl, -OD, halogen, cyano, amino, -S(=O) 2 R 10 , -OC(=O)R 11 , -C(=O)OR 11 , -NR 10 C(=O)R 11 , Unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or or substitution C 1-6 Hydroxyalkyl, unsubstituted or substituted C 1-6 Aminoalkyl, non-substituted Replacement or substitution C 1-6 Hydroxyalkyl, unsubstituted or substituted C 2-6 Alkenyl, non-substituted Replacement or substitution C 1-6 Alkoxy, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or or substitution C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl. substituted heteroaryl; R 1d is hydrogen, deuterium, hydroxyl, -OD, halogen, cyano, amino, -S( =O) 2 R 10 , -OC(=O)R 11 , -C(=O)OR 11 , unsubstituted or substituted C 1 -6 Alkyl, unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hide oxyalkyl, unsubstituted or substituted C 1-6 Aminoalkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 1-6 Alkoxy, unsubstituted or substituted C 3-6 Cycloa Ru(Cl), unsubstituted or substituted C 3-6Heteroalicyclyl, substituted or unsubstituted aryl, and and substituted or unsubstituted heteroaryl; R 10 and R 11 is independent and hydrogen, amino, unsubstituted or substituted C 1-6 is selected from the group consisting of alkyl, R 2 is deuterium, amino, -OD, halogen, cyano, unsubstituted or substituted C 1-6 Al Kill, Unsubstitute or Substitute C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxya Ru(Cl), unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 2-6 Alkenyleo oxy, 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; R 2 is not benzyloxy , R 2d is hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or replacement C 1-6 Alkyl, unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted exchange C 1-6 Hydroxyalkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted exchange 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 heteroaromatic alkyl groups. or R 2a , R2c , and R 2d is hydrogen and R 2 and R 2b or R 2c Those together with the atom to which it is attached form a heteroalicyclic or heteroaryl ring system. or R 1a , R 1b , R 1c , R 2a , R 2b , and R 2c is hydrogen and R 1d and R 2d At least one of the is not hydrogen, R 3 is hydrogen, deuterium, hydroxyl, -OD, 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 3-6 Cycloalkyl, non Replacement or Substitution C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl. is selected from unsubstituted heteroaryl; R 4a , R 4b , R 5a , and R 5b are independently hydrogen, deuterium, and unsubstituted or substituted exchange C 1-6 alkyl, and when m and n are 1, R 4a , R 4b , R 5a , R 5b is hydrogen, R 6 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C1-4 Alkoxy, substituted or unsubstituted or R 6 and R 3 are combined Together with the atoms, they form a ring system, R 7 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Selected from the group consisting of alkoxy Selected, R 8 is absent or hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted substitution 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.

[0111] A compound according to formula (I), [ka] or its pharma- ceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, and isomers thereof. Also provided herein are isomers, 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 is deuterium, hydroxyl, -OD, halogen, cyano, amino, -S(=O) 2 R 10 , -OC(=O)R 11 , -C(=O)OR 11 , unsubstituted or substituted C1-6 Al Kill, Unsubstitute or Substitute C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxya Ru(Cl), unsubstituted or substituted C 1-6 Aminoalkyl, unsubstituted or substituted C 1-6 Hydroxy Dialkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 1-6 Alcoki C, unsubstituted or substituted 3-6 Cycloalkyl, unsubstituted or substituted C 3-6 Heteroaris from the group consisting of aryl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Selected from R 1d is hydrogen, deuterium, hydroxyl, -OD, halogen, cyano, amino, -S( =O) 2 R 10 , -OC(=O)R 11 , -C(=O)OR 11 , unsubstituted or substituted C 1 -6 Alkyl, unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hide oxyalkyl, unsubstituted or substituted C 1-6 Aminoalkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 1-6 Alkoxy, unsubstituted or substituted C 3-6 Cycloa Ru(Cl), unsubstituted or substituted C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and and substituted or unsubstituted heteroaryl; R 10 and R 11 is independent and hydrogen, amino, unsubstituted or substituted C 1-6 is selected from the group consisting of alkyl, R2 is deuterium, amino, -OD, halogen, cyano, unsubstituted or substituted C 1-6 Al Kill, Unsubstitute or Substitute C 1-6 Haloalkyl, unsubstituted or substituted C 1-6 Hydroxya Ru(Cl), unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted C 2-6 Alkenyleo oxy, 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; R 2 is not benzyloxy , R 2d is hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or replacement C 1-6 Alkyl, unsubstituted or substituted C 1-6 Haloalkyl, unsubstituted or substituted exchange C 1-6 Hydroxyalkyl, unsubstituted or substituted C 2-6 Alkenyl, unsubstituted or substituted exchange 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 heteroaromatic alkyl groups. reels; R 1a , R 1b , R 1c , R 2a , R 2b , and R 2c is hydrogen and R 1d and R 2d at least one of is not hydrogen, or R 2a , R2c , and R 2d is hydrogen and R 2 and R 2b or R 2c Those together with the atom to which it is attached form a heteroalicyclic or heteroaryl ring system. , R 3 is hydrogen, deuterium, hydroxyl, -OD, 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 3-6 Cycloalkyl, non Replacement or Substitution C 3-6 Heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl. is selected from unsubstituted heteroaryl; R 4a , R 4b , R 5a , and R 5b are independently hydrogen, deuterium, and unsubstituted or substituted exchange C 1-6 alkyl, and when m and n are 1, R 4a , R 4b , R 5a , R 5b is hydrogen, R 6 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted substituted aryl; R 7 is hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4Selected from the group consisting of alkoxy Selected, R 8 is absent or hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted substitution 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.

[0112] In some embodiments, -SO 2 NH 2 , -SO 2 N(C 1-4 Alkyl) 2 , - SO 2 -C 1-4 Alkyl, -OC(=O)-C 1-4 Alkyl, -N(C 1-4 Alki L) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-4 Sik Roalkyl, C 3-4 Cycloalkyl-C 1-3 Alkyl and their deuterated analogues For example, R 1a , R 1b , R 1c , and R 1d is independent, water hydrogen, deuterium, halogen, amino, SO 2 NH 2 , -SO 2 CH 3 , -OC(=O)CH 3 , Methyl, -CD 3 , methoxy, -OCD 3 , -OCF 3 , and -CF 3 From the group consisting of Selected, R 1 is halogen, amino, SO 2 NH 2 , -SO 2 CH 3 , -OC(=O) CH 3 , Methyl, -CD 3 , Ethyl, -CD 2 CD 3 Optionally deuterated n-propane propyl, optionally deuterated iso-propyl, optionally deuterated n-butyl butyl, optionally deuterated iso-butyl, optionally deuterated n-pentyl, Optionally deuterated 2-methyl-butyl, optionally deuterated n-hexyl , optionally deuterated 2-methyl-pentyl, methoxy, -OCD 3 , deuterated optionally deuterated ethoxy, optionally deuterated n-propoxy, optionally deuterated isopropoxy, optionally deuterated n-butoxy, optionally deuterated iso-butoxy, optionally deuterated pentyl-oxy, Optionally deuterated 4-methyl-butoxy, optionally deuterated hexyl-oxy, deuterated Optionally 4-methylpentoxy, -OCF 3 , -OCF 2 CF 3 , -OCHF 2 , -OCDF 2 , -CF 3 , -CF 2 CF 3 , -CHF 2 , CDF 2 -CH 2 CF 3 , - CD 2 CF 3 , -CH 2 F, 1,1,2,2-tetrafluorobutyl, and 1,1,1, 2,2-pentafluorobutyl.

[0113] In some embodiments, R 1a , R 1b , R 1c , and R 1d are independently hydrogen, Hydrogen, hydroxyl, halogen, amino, -SO 2 NH 2 , -SO 2 CH 3 , -OC(= O)CH 3 , -NHC(=O)CH 3 , Methyl, -CD 3 , methoxy, benzyloxy, Dimethylamino, -OCD 3 , -OCF 3 , -OCHF 2 , and -CF 3 From the group consisting of In some embodiments, R 1a , R 1b , R 1c , and R 1d is independent , hydrogen, deuterium, hydroxyl, halogen, methyl, -CD 3 , methoxy, -OCD 3 , -OCF 3 , and -CF 3 In some embodiments, R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, hydroxyl, halogen, - OCF 3 , and -CF 3 In some embodiments, R 1a , R 1b , R 1c , and R 1d are independently selected from the group consisting of hydrogen, deuterium, and halogen. In some embodiments, R 1a, R 1b , R 1c , and R 1d is independent, In some embodiments, R 1a , R 1b , and R 1c is hydrogen, and R 1d is a halogen.

[0114] In some embodiments, R 1 is halogen, hydroxyl, -CD 3 , -CD 2 CD 3 , C 1-6 Alkyl, -OCD 3 , C 1-6 Alkoxy, -OCF 3 , -OCF 2 CF 3 , -OCHF 2 , -OCDF 2 , -CF 3 , -CF 2 CF 3 , -CHF 2 , -CDF 2 , -CH 2 CF 3 , -CD 2 CF 3 , and -CH 2 F. In some embodiments, R 1 is halogen, hydroxyl, -CD 3 , -CD 2 CD 3 , Meth Ru, Ethyl, -OCD 3 , methoxy, ethoxy, -OCF 3 , -OCF 2 CF 3 , -OC HF 2 , -OCDF 2 , -CF 3 , -CF 2 CF 3 , -CHF 2, -CDF 2 , -CH 2 CF 3 , -CD 2 CF 3 , and -CH 2 F. In this state, R 1 is halogen, hydroxyl, methyl, methoxy, -OCF 3 , -OCHF 2 , -CF 3 , -CHF 2 and -CH 2 F. In this state, R 1 -Halogen, -OCF 3 , -OCHF 2 , -CF 3 , -CHF 2 , and - CH 2 In some embodiments, R 1 is a halogen. In some embodiments, R 1 is F or Cl. In some embodiments, R 1 teeth It's F.

[0115] In some embodiments, R 1a , R 1b , and R 1c is hydrogen and R 1d is heavy Hydrogen, halogen, amino, SO 2 NH 2 , -SO 2 CH 3 , -OC(=O)CH 3 , Meth Le, -CD 3 , methoxy, -OCD 3 , -OCF 3 , and -CF 3 and R 1 Ha, Hello Gen, methyl, methoxy, -OCF 3 , and -CF3 , for example, fluoro, chloro, and -CF 3 is selected from.

[0116] In some embodiments, R 1a , R 1b , and R 1c is hydrogen and R 1d Water is hydrogen or fluoro, and R 1 is fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 , e.g., fluoro and -CF 3 is selected from.

[0117] In some embodiments, R 1a , R 1b , and R 1c is hydrogen and R 1d Is, F Ruoro, R 1 are fluoro, chloro, methoxy, and methyl, e.g., fluoro are selected.

[0118] In some embodiments, R 1a , R 1b , and R 1c is hydrogen and R 1d Ha, ha halogen, e.g., fluoro, R 1 is halogen, e.g. fluoro, e.g. , R 1 and R 1d Both are fluoro.

[0119] In some embodiments, R 1a , R 1b , R 1c , and R 1d Two of them are independent. Fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 Selected from the group consisting of The rest are hydrogen, and R 1 is fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 In some embodiments, R 1a and R 1 b are independently fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 From R 1c and R 1d is hydrogen and R 1 Fluoro, chloro, methyl , methoxy, -OCF 3 , and -CF 3 In some embodiments, In this state, R 1a and R 1c are independently fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 R 1b and R 1d is hydrogen and R 1 teeth, Fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 Selected from the group consisting of In some embodiments, R 1a and R 1d are independently fluoro, chloro, or methyl , methoxy, -OCF 3 , and -CF 3 R 1b and R 1c teeth , hydrogen, and R 1 is fluoro, chloro, methyl, methoxy, -OCF 3 , and -CF 3 is selected from the group consisting of:

[0120] In some embodiments, R 2 , R 2a , R 2b , R 2c , and R 2d is independent, water 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 Cycloa Rukill-C 1-3 alkyl, and their deuterated analogs; or R 2a , R 2c , and R 2d is hydrogen and R 2 and R 2b They are combined Together with the phenyl rings to which they are attached and the atoms to which they are attached, a bicyclic ring having the formula forming a fused ring system of the formula [ka] In the formula, R 12a , R 12b , R 12c , R 13a , R 13b , R 14a , and R 14b are independently absent or hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl , and C 1-4 alkoxy; Z 1 , Z 2 , and Z 3 is independent, is selected from the group consisting of C, N, O, and S, e.g., R 2a , R 2b , R 2c , and R 2dare independently hydrogen, deuterium, hydroxyl, halogen, methyl, -CD 3 , methoxy , -OCD 3 , -OCF 3 , and -CF 3 R 2 is halogen, Amino, methyl, -CD 3 , Ethyl, -CD 2 CD 3 Optionally deuterated n-propane propyl, optionally deuterated iso-propyl, optionally deuterated n-butyl butyl, optionally deuterated iso-butyl, 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, heavy water optionally deuterated isopropoxy, optionally deuterated allyloxy, deuterium optionally deuterated n-prop-2-yn-1-yloxy; butoxy, optionally deuterated iso-butoxy, optionally deuterated ter t-butoxy, optionally deuterated pentyl-oxy, optionally deuterated 4-Methyl-butoxy, optionally deuterated hexyl-oxy, Optionally deuterated 4-methylpentoxy, optionally deuterated cyclopropyloxy, deuterium oxide Optionally deuterated cyclopropylmethoxy, cyclobutyloxy, optionally deuterated cyclobutyloxy, optionally deuterated Cyclobutyloxy, optionally deuterated cyclobutylmethoxy, deuterated optionally deuterated cyclobutylethoxy, 1-6 Haloalkoxy, -OCF 3 , -OCF 2 CF 3 , -OCHF 2 , -OCDF 2 , -CF 3 , -CF 2 CF 3 , -CH 2 F, -CF 2 CH 3 , -CDF 2 -CH 2 CF 3 , -CD 2 CF 3 , -CF 2 , 1,1,2,2-tetrafluorobutyl, and 1,1,1,2,2-pentafluoro butyl.

[0121] In some embodiments, R 2 is not a nitro group.

[0122] In some embodiments, R 2 , R 2a , R 2b , R 2c , and R 2d is independent, water 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 Cycloa Rukill-C 1-3 alkyl, and their deuterated analogs; or R 2a , R 2c , and R 2d is hydrogen and R 2 and R 2b They are combined Together with the atom to which it is fused, it forms a heteroalicyclic ring system, and the ring system thus formed is Together with the phenyl group, the following general formula: [ka] wherein R 12a , R 12b , R 13a , R 13b , R 14a , and R 14b is In the absence or presence 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 hydrogen, deuterium, hydroxyl, halogen, methyl, -CD 3 , methoxy, - OCD 3 , -OCF 3 , and -CF 3 R 2 is halogen, methyl Le, -CD 3 , Ethyl, -CD 2 CD 3 , optionally deuterated n-propyl, heavy water optionally deuterated iso-propyl, optionally deuterated n-butyl, deuterated optionally deuterated iso-butyl, 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 n-butoxy; Optionally hydrogenated iso-butoxy, optionally deuterated tert-butoxy , optionally deuterated pentyl-oxy, optionally deuterated 4-methyl- butoxy, optionally deuterated hexyl-oxy, optionally deuterated 4- methylpentoxy, optionally deuterated cyclopropyloxy, optionally deuterated cyclopropylmethoxy, optionally deuterated cyclopropylethoxy, Optionally deuterated cyclobutyloxy, Optionally deuterated cyclobutyl oxy, optionally deuterated cyclobutylmethoxy, optionally deuterated cyclobutyl Cyclobutylethoxy, optionally deuterated C 1-6 Haloalkoxy, -OCF 3 , -OCF 2 CF 3 , -OCHF 2 , -OCDF 2 , -CF 3 , -CF 2 CF 3 , -CH 2 F, -CH 2 CF 3 , -CDF 2 -CH 2 CF 3 , -CD 2 CF 3 , -CF 2 , 1,1, 2,2-tetrafluorobutyl, and 1,1,1,2,2-pentafluorobutyl R 2 is not a nitro group.

[0123] In some embodiments, R 2 and R2b The phenyl rings to which they are attached and together with the atom to which they are attached, a bicyclic fused ring system selected from the group consisting of: Forming [ka] In the formula, R 12a , R 12b , R 12c , R 13a , R 13b , R 14a , and R 14b teeth Independently, absent or hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, and C 1-4 alkoxy is selected from the group consisting of

[0124] In some embodiments, R 2 and R 2b The ring system formed between and R 12a and R 12b are both hydrogen or methyl, and R 13a and R 13b are both hydrogen or methyl.

[0125] In some embodiments, R 2a , R 2b , R 2c is hydrogen and R 2d is hydrogen, fluoro, or hydroxyl, and R 2 is methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy, iso-butoxy, pentyl-oxy, 4-methyl-butoxy oxy, hexyl-oxy, and 4-methylpentoxy.

[0126] In some embodiments, R 2 is R 2 R2b under the condition of not forming a ring system together -OCD 3 , -OC(CD 3 ) 3 , methoxy, ethoxy, n-propoxy, isoprop oxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, iso-but oxy, tert-butoxy, pentyl-oxy, 4-methyl-butoxy, hexyl-oxy , 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclop ropyethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 2-fluoro ethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy, 4-methoxybutoxy , 2-hydroxylethoxy, 1,2-dihydroxyethyl, 2-hydroxy-2,3 -dimethylbutoxy, phenoxy, -OCF 3 and (1,3-difluoropropan-2- yl)oxy, and is selected from the group consisting of

[0127] In some embodiments, R 2 is such that R 2 does not form a ring system with R 2b under the condition of and is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2 -yn-1-yloxy, n-butoxy, iso-butoxy, tert-butoxy, pent yl-oxy, 4-methyl-butoxy, hexyl-oxy, 4-methylpentoxy, cycl opropyl-oxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy , cyclobutylmethoxy, cyclobutylethoxy, 2-fluoroethoxy, 3-fluoro propoxy, 4-fluorobutoxy, -OCF3 , and (1,3-difluoropropane -2-yl)oxy.

[0128] R 2 is ethoxy, n-propoxy, isopropoxy, allyloxy, iso-butoxy , tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoro ethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy or R 2 and R 2b are the phenyl rings to which they are attached and the Together with the atom, unsubstituted 2,3-dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl, Benzofuran-5-yl and unsubstituted 2,2-dimethyl-2,3-dihydrobenzofuran 5-yl formation.

[0129] In some embodiments, R 1 and R 1d are independently deuterium, halogen, methyl, - CD 3 , methoxy, -OCD 3 , -OCF 3 , and -CF 3 is selected from the group consisting of , or R 2 and R 2d are independently deuterium, halogen, methyl, -CD 3 , methoxy, Ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, pentyl -oxy, 4-methyl-butoxy, hexyl-oxy, 4-methylpentoxy, -OCD 3 , -OCF 3 , cyclopropyloxy, 2-fluoroethoxy, 3-fluoropropoxy Si, 2,2-difluoroethoxy, and -CF 3 is selected from the group consisting of:

[0130] In some embodiments, R 1 and R 1d is fluoro and R 2 is C 1-6 Al Koxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , iso-butoxy, pentyl-oxy, 4-methyl-butoxy, hexyl-oxy, and 4-methylpentoxy. In some embodiments, R 1 and R 1d is fluoro Yes, R 2 is n-propoxy, isopropoxy, n-butoxy, isobutoxy, te It is rt-butoxy, cyclopropylmethoxy, or cyclopropyloxy.

[0131] In some embodiments, R 1 and R 1d is fluoro and R 1a , R 1b , and R 1c is hydrogen and R 2 is R 2 R 2b provided that it does not form a ring system with Methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yl n-1-yloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyl- Oxy, 4-methylbutoxy, hexyloxy, 4-methylpentoxy, cyclopropoxy Pyroxy, 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, -OCF 3 , and (1,3-difluoropropan-2-yl)oxy R 2a , R 2b , R 2c , and R 2d is either hydrogen or Or R 2 and R 2b are the phenyl rings to which they are attached and the atoms to which they are attached. together with [ka] In the formula, R 12a and R 12b is hydrogen or methyl, and R 13a and R 13b Both is hydrogen or methyl, and R 2a , R 2c , and R 2d is hydrogen.

[0132] In some embodiments, R 1 and R 1d is fluoro and R 1a , R 1b , and R 1c is hydrogen and R 2 is ethoxy, n-propoxy, isopropoxy, allyloxy oxy, tert-butoxy, n-butoxy, iso-butoxy, cyclopropyloxy, Chloropropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and 2,2- difluoroethoxy; R 2a , R 2b , R 2c , and R 2d teeth, Hydrogen or R 2and R 2b together with the atoms to which they are attached It forms a heteroalicyclic ring system, which, together with the phenyl group to which it is fused, So, the following formula, [ka] R 2a , R 2c , and R 2d is hydrogen.

[0133] In some embodiments, R 1 and R 1d is fluoro and R 1a , R 1b , and R 1c is hydrogen and R 2 isopropoxy, n-propoxy, isobutoxy, and and cyclopropyloxy.

[0134] In some embodiments, R 3 is 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 Haeta Roalicyclyl, substituted or unsubstituted -(CH 2 ) s -C 2-5 Heteroaryl and substituted or unsubstituted -(CH 2 ) s -C 5-6 aryl, wherein each s is 0, 1, 2, and 3. 3 is, for example, hydrogen, methyl, -CD 3, Ethyl, -CD 2 CD 3 , n-propyl, -CD 2 CD 2 CD 3 , iso-propyl, -CDCD 3 CD 3 , and -(CR 9a R 9b ) t C(=O)OR 9c , and -(CH 2 ) t C(=O)NR 9a R 9b wherein R 9a , R 9b , and R 9c are independently hydrogen and C 1-4 -alkyl, and each t is selected from the group consisting of 0, 1, 2, and 3. .

[0135] In some embodiments, R 3 is hydrogen or methyl.

[0136] In some embodiments, R 1 and R 1d is fluoro and R 1a , R 1b , and R 1c is hydrogen and R 2 is ethoxy, n-propoxy, isopropoxy, allyloxy cyclopropyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethyloxy 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy or R 2 and R 2b are the phenyl groups to which they are attached. Together with the rings and the atoms to which they are attached, unsubstituted 2,3-dihydrobenzofuran -5-yl, unsubstituted benzofuran-5-yl, and unsubstituted 2,2-dimethyl-2,3-di Form hydrobenzofuran-5-yl, R 3 is hydrogen or methyl.

[0137] In some embodiments, R 3 is one bonded to the carbon atom adjacent to the nitrogen atom R 6 or R 7 together form a heteroalicyclic ring system according to the formula: [ka]

[0138] Optionally, the formed heteroalicyclic ring system may further include an additional R 6 And / or Or R 7 It may contain substituents.

[0139] In some embodiments, R 4a , R 4b , R 5a , and R 5b are independently hydrogen, Chill, and -CF 3 For example, R 4a , R 4b , and R 5a teeth, Hydrogen, R 5b is methyl or hydrogen, or R 4a , R 5a , and R 5b is hydrogen and R 4b is methyl or hydrogen.

[0140] In some embodiments, R 4a , R 4b , R 5a , and R 5b are independently hydrogen, Chill, and -CF 3 For example, R4a , R 4b , and R 5a teeth, Hydrogen, R 5b is methyl, -CF 3 or hydrogen, or R 4a , R 5a , and R 5b is hydrogen and R 4b is methyl, -CF 3 , or hydrogen.

[0141] In some embodiments, R 4a , R 4b , R 5a , and R 5b is hydrogen.

[0142] In some embodiments, R 6 is absent (e.g., when unsaturation is present or q is 0), or hydrogen, deuterium, halogen, hydroxyl, -OD, substituted or is unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Alkoxy, e.g., deuterium , halogen, methyl, and methoxy.

[0143] In some embodiments, R 6 is hydrogen, deuterium, halogen, hydroxyl, -OD, Substituted or unsubstituted C 1-4 Alkyl, and substituted or unsubstituted C 1-4 Alkoxy, e.g. , deuterium, halogen, methyl, and methoxy.

[0144] In some embodiments, R 6 is fluoro and q is 1.

[0145] In some embodiments, R 7 is absent (e.g., when p is 0 or when is present), or hydrogen, deuterium, halogens, and substituted or unsubstituted C 1-4 a alkyl, for example, selected from hydrogen, fluoro, and methyl. Thus, some In an embodiment, p is 0.

[0146] In some embodiments, R 8 is hydrogen, halogen, methyl, ethyl, propyl, metho oxy, ethoxy, C 1-2- Haloalkyl and C 1-2- Haloalkoxy, e.g., water Plain, -CF 3 , -CHF 2 , -CF 2 CF 3 , -OCF 3 , -OCF 2 CF 3 , and -O CHF 2 is selected from the group consisting of:

[0147] In some embodiments, X is O.

[0148] In some embodiments, m and n are independently selected from the group consisting of 0 and 1, e.g. For example, m is 1 and n is 0 or 1.

[0149] Some embodiments include a compound according to formula (IIa or IIb): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, prodrug, stereoisomer thereof For the monovalent and deuterated analogs, m is 1, n is 0 or 1, R 1 and R 1d are both halogen, e.g., fluoro; R 2is unsubstituted or substituted C 1-6 Alkoxy, for example, methoxy, ethoxy, n-propoxy, propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methylbutoxy cyclopropyloxy, cyclopropyloxy, cyclopropyl Methoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclo 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy OXY, -OCF 3 and (1,3-difluoropropan-2-yl)oxy; R 2d is hydrogen, R 3 is hydrogen, methyl, or ethyl; t is 0 or 1, and when t is 1, R 6a is a halogen, e.g., fluoro be.

[0150] Some embodiments include a compound according to formula (IIa) or (IIb), or a pharmaceutical composition thereof. with respect to commercially acceptable salts, hydrates, solvates, polymorphs, prodrugs, and stereoisomers thereof, During the ceremony, m is 1, n is 0 or 1, R 1 and R 1d are both halogen, e.g., fluoro, or R 1 Is fluoro and R 1d is hydrogen or hydroxyl, R 2 is unsubstituted or substituted C 1-6 Alkoxy, for example, methoxy, ethoxy, n-propoxy, propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy butoxy, isobutoxy, tert-butoxy, pentyloxy, 4-methylbutoxy cyclopropyloxy, cyclopropyloxy, cyclopropyl Methoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclo 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy OXY, -OCF 3 and (1,3-difluoropropan-2-yl)oxy, R 2 d is hydrogen, fluoro, or hydroxyl, and R 1d and R 2d At least one of Another is that instead of hydrogen, e.g., R 2d is hydrogen, and R 1d is a halogen, R 3 is hydrogen, methyl, or ethyl; t is 0 or 1, and when t is 1, R 6a is a halogen, e.g., fluoro be.

[0151] In some embodiments of formula (IIa) or (IIb), R 3 is methyl.

[0152] In some embodiments of formula (IIa) or (IIb), R 2 is ethoxy, n-propanol propoxy, isopropoxy, allyloxy, tert-butoxy, cyclopropyloxy , cyclopropylmethoxy, isobutoxy, and 2-fluoroethoxy; or R 2 taken together with the phenyl ring to which it is attached and the atom to which it is attached, Includes rings that form a bicyclic fused ring system having the formula: [ka]

[0153] 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-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-dihydro-1-phenyl) Zofuran-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-cyclohexyl) Chloropropoxybenzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpi 1-(2,4-difluorobenzyl)-3-(4-(2-fluorophenyl)- (fluoroethoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea, 3-(4 -(allyloxy)benzyl)-1-(2,4-difluorobenzyl)-1-(1-methyl 3-(benzofuran-5-ylmethyl)-1-( 2,4-Difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea.

[0154] 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-(1-methylpiperidin-4-yl )-3-[(4-propoxyphenyl)methyl]urea, 3-{[4-(cyclopropylmethyl) 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 phenyl)methyl]-1-(piperidin-4-yl)urea, 3-(4-(allyloxy)phenyl benzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidine-4-yl) urea, 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl) (2,4-O-phenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, 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-methyl 1-[(2,4-difluorophenyl)methyl]-3- [(2,3-dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidine) Lysin-4-yl)urea, 3-[(2,4-difluorophenyl)methyl]-1-{[4 -(3-fluoropropoxy)phenyl]methyl}-3-(1-methylpiperidine-4- 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-diphenyl 1-(1-methylpiperidin-4-yl)-1-benzofuran-5-yl)methyl ) 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) 1-[(2,4-difluorophenyl)methyl]-1-phenylmethyl}urea and 1-[(2,4-difluorophenyl)methyl]-1-phenylmethyl -(1-Methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl It is a trimethyl[methyl]urea.

[0155] In some embodiments, R 1d is F and R 1 is methyl, Cl, or F. R 1a , R 1b , and R 1c are each hydrogen, and R 4a , R4b , R 5a , R 5b , R 6 , R 7 , R 8 are each hydrogen, m and n are each 1, p and q are each 0 or 1, X is O, and R 3 is hydrogen, methyl, -CD 3 , Ethyl, -CD 2 CD 3 , n-propyl, -CD 2 CD 2 CD 3 , 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 wherein R 9a , R 9b , and R 9c teeth independently, hydrogen or C 1-4 -alkyl, each t is 0, 1, 2, and 3. is selected from the group.

[0156] In some embodiments, R 1d is F and R 1 is methyl, Cl, or F. R 1a , R 1b , and R 1c are each hydrogen, and 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 each 0, X is O, and R 3 is hydrogen or methyl.

[0157] In some embodiments, R 1d and R 1 are F and R 1a , R 1b , and R 1c are each hydrogen, and R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 are, respectively, When present, they are hydrogen, m and n are each 1, p and q are each 0, and X is O and R 3 is hydrogen, methyl, -CD 3 , Ethyl, -CD 2 CD 3 , n-propionate Le, -CD 2 CD 2 CD 3 , isopropyl, cyclopropyl, -CDCD 3 CD 3 , - (CR 9a R 9b ) t C(=O)OR 9c , and -(CH 2 ) t C(=O)NR 9a R 9 b wherein R 9a , R 9b , and R 9c are independently hydrogen or C 1-4 -alkyl, and each t is selected from the group consisting of 0, 1, 2, and 3.

[0158] In some embodiments, R 1d and R 1 are F and R 1a , R 1b, and R 1c are each hydrogen, and R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 are, respectively, When present, they are hydrogen, m and n are each 1, p and q are each 0, and X is O and R 3 is hydrogen or methyl.

[0159] In some embodiments, R 1d and R 1 are F and R 1a , R 1b , and R 1c are each hydrogen, and R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 are, respectively, When present, they are hydrogen, m and n are each 1, p and q are each 0, and X is O and R 3 is hydrogen or methyl, and R 2 is ethoxy, n-propoxy, Isopropoxy, allyloxy, iso-butoxy, tert-butoxy, cyclopropyl Oxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and and 2,2-difluoroethoxy, or R 2 and R 2b teeth, Together with the phenyl ring to which they are attached and the atom to which they are attached, they are unsubstituted 2,3-Dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl, and unsubstituted Formation of 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl.

[0160] In some embodiments, R 1d and R 1 are F and R 1a , R 1b , and R 1c are each hydrogen, and R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 are, respectively, When present, they are hydrogen, m and n are each 1, p and q are each 0, and X is O and R 3 is hydrogen or methyl, and R 2 is ethoxy, n-propoxy, Isopropoxy, allyloxy, iso-butoxy, tert-butoxy, cyclopropyl Oxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and and 2,2-difluoroethoxy, or R 2 and R 2b teeth, Together with the phenyl ring to which they are attached and the atom to which they are attached, they are unsubstituted 2,3-Dihydrobenzofuran-5-yl, unsubstituted benzofuran-5-yl, and unsubstituted Formation of 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl.

[0161] Some embodiments have formula (Va) or (Vb): [ka] Compounds according to or its pharma- ceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, and isomers thereof. Regarding isomeric forms, 2 is a substituted or unsubstituted C 1-6 Selected from the group consisting of alkoxy Selected, R 3 is hydrogen or methyl, and R 12a and R 12b is the same as hydrogen or methyl.

[0162] In some embodiments of Formula (Va), R 2 is ethoxy, n-propoxy, isopropoxy epoxy, allyloxy, isobutoxy, tert-butoxy, cyclopropyloxy, Cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and 2,2 -difluoroethoxy.

[0163] In some embodiments of Formula (Va), R 2 is n-propoxy, isopropoxy, iso so-butoxy, and cyclopropyloxy.

[0164] In some embodiments of formula (Vb), the bicyclic ring system is selected from those having the formula: will be done. [ka]

[0165] In certain embodiments, the compounds provided herein exhibit less than 65% hERG inhibition. In some embodiments, the % hERG inhibition is less than 50%. In certain embodiments, the compounds provided herein have less than 40%, for example less than 30% It has hERG inhibition of %.

[0166] In certain embodiments, the compounds provided herein exhibit less than 65% hERG inhibition. % and a 5-HT2A pKi of 8.4 or greater. The % inhibition is less than 50%. In certain embodiments, the compounds provided herein , hERG inhibition % less than 40%, e.g., less than 30%, and 5-HT2A inhibition % greater than or equal to 8.4. It has a pKi.

[0167] Some embodiments disclosed herein include administering to the patient an effective amount of a compound of formula (I) and (II). , Pharmaceutically acceptable salts, polymorphs, or stereoisomers of the compounds of formula (I) and (II) and a method for treating a disease in a patient comprising administering to the patient Abnormal hormone activity, Alzheimer's disease, Alzheimer's dementia, Alzheimer's psychosis addiction (alcohol, cocaine, methamphetamine, nicotine, and opioids), Alzheimer's disease, ADHD, Alzheimer's disease, psychosis, affective disorders, aggression, agitation, akathisia, Alcohol addiction, alcohol withdrawal, amenorrhea, amyotrophic lateral sclerosis, anhedonia, anorexia, antidepressants NMDAR encephalitis, anxiety, appetite disorders, asthma, autism, behavioral disorders, behavioral disorders associated with dementia , Impulse Control Disorder (ICD)-related binge eating disorder, bipolar disorder, blindness, borderline personality disorder, borderline personality disorder, bradykinesia, bulimia, ICD-related purchases, cardiac arrhythmias, cerebrovascular Seizures, Charles Bonnet syndrome, chemotherapy-induced vomiting, childhood autism, chronic pain, chronic insomnia , cocaine addiction, cognitive impairment, craniofacial pain, temporomandibular joint (TMJ) / temporomandibular joint disorder (TMD), Syngeal disease, delusions, dementia, dementia with Lewy bodies or dementia with Lewy bodies, Creutzfeldt-Jakob disease Dementia and psychosis associated with CJD, Gerstmann-Strauss Geriatrics and Neuropsychiatric Disorders (GSSD) and Fatal Familial Insomnia (FFI), depression, diabetes mellitus ( Non-insulin dependent), diabetic peripheral neuropathy, drug addiction, diplopia, Down syndrome, dyslipidemia Kinesia, dysthymia, dystonia, ejaculation disorder, emphysema, epilepsy, extrapyramidal disorder, fibromyalgia , frailty, Friedreich's ataxia, frontotemporal dementia, ICD-related gambling, Galactorrhea, generalized anxiety disorder, glaucoma, hair loss or thinning, hallucinations, headaches, hemorrhoids, Huntington's disease , hyperprolactinemia, hypertension, ICD-related nymphomania, hypotension, hypoglutamate Blood disorders, impulse control disorders, idiopathic thrombocytopenic purpura, impotence, incontinence, increased intraocular pressure, Infertility, inflammatory pain, insomnia, ischemia, ischemic stroke, Lewy body disease (LBD), learning disabilities , sexual drive (decreased), decreased sexual drive, male low fertility, low sperm motility, lupus, masculinity De Joseph's disease, major depression, mania, menopausal symptoms, metabolic syndrome, methamphetamine Mind addiction, migraine, mild cognitive impairment (MCI), motor tics, multi-infarct dementia, multifocal Sclerosis, multiple developmental disorders, myocardial infarction, myoclonus, neuropathic pain, neurodegenerative disorders, Mental disorders, nicotine addiction, dementia, depression, apathy, hallucinations, drooling (sialorrhea) non-motor symptoms of Parkinson's disease selected from the group consisting of constipation, pain, genitourinary disorders, and sleep disorders symptoms, obsessive-compulsive disorder, on-off phenomenon, opioid addiction, osteoporosis, pancreatitis, panic attacks, Parkinson's disease, Parkinson's dementia, Parkinson's psychosis, periodic limb movements during sleep (PLM) LMS), peripheral vascular disease, pituitary tumors, postherpetic neuralgia, progressive supranuclear palsy, Kreutzfeldt-Jakob disease Prion diseases, including CJD, Gerstmann-Sträussler-Schaefer disease, Inker's disease (GSSD) and fatal familial insomnia (FFI), prolactinoma, affective regulation paroxysmal brain disorders (PBA), psychomotor retardation, psychosis, psychiatric disorders secondary to neurodegenerative disorders, psychosomatic disorders, Psychotic depression, post-traumatic stress disorder (PTSD), Raynaud's disease, reflex sympathetic nervous system disorders Schizophrenia, Restless Legs Syndrome, Retinal Disease, Schizoaffective Disorder, Schizophrenia, Negative symptoms of schizophrenia, schizophrenia-related cognitive impairment, sepsis, serotonin syndrome, sexuality Dysfunction, sexual dysfunction associated with antidepressant use, sleep apnea, sleep disorders, sleep maintenance disorders Somnolence, social anxiety disorder, spinal cord injury, spinocerebellar atrophy, suicidal tendencies, thrombosis, thrombotic stroke, blood Embolic thrombocytopenic purpura, tinnitus, fatigue, Tourette syndrome, transient insomnia, traumatic brain injury , treatment-resistant depression, treatment-resistant schizophrenia, tremors, vaginal dryness, vasospastic awakenings, vascular dementia , Parkinson's disease-related hallucinations, Parkinson's disease-related delusions, cancer, brain cancer, neuroglial pancreatic cancer, hypoactive sexual desire disorder, adult type 2 diabetes with Parkinson's disease or dementia, and liver fibrosis.

[0168] Suitable routes of administration of the compounds of formula (I) include, for example, oral, rectal, transmucosal, topical, or Enteral administration, parenteral delivery, e.g., intramuscular, subcutaneous, intravenous, intraspinal injection, as well as intrathecal, These may include direct intracerebroventricular, intraperitoneal, intranasal, or intraocular injection. For prolonged and / or timed pulsatile administration, sustained or controlled release dosage forms, e.g., depot It may also be administered via injection, osmotic pump, pill, or transdermal (e.g., electrotransport) patch.

[0169] The pharmaceutical compositions of the present invention can be prepared in a manner known per se, e.g. by conventional mixing, dissolving, granulating or other methods. Manufactured using dragee-making, levigation, emulsification, encapsulation, entrapment, or tabletting processes. It is possible.

[0170] Thus, the pharmaceutical compositions for use as described herein are medicaments that can be used pharma- ceutical One or more physiologically acceptable additives, including excipients and auxiliaries, that facilitate the processing of the active compound into a product. The pharmaceutical composition may be formulated in a conventional manner using suitable carriers. Appropriate formulations will depend on the selected administration route. Any of the well-known techniques, carriers, and excipients may be suitable, depending on the route taken. and in the art, see, for example, Remington's Pharmacy, supra. The methods may be used as understood in Cal Sciences.

[0171] For oral administration, the compounds may be administered by administering the active compound in a pharma- ceutically acceptable carrier, as known in the art. Such a carrier can be used to easily formulate the compound of the present invention. , tablets, pills, dragees, capsules, liquids, gels for oral ingestion by the patient to be treated This allows the formulation to be made into an aqueous solution, such as a syrup, a slurry, a suspension, or the like. EXAMPLES

[0172] Unless otherwise specified, starting materials were obtained from (but not limited to) Chemtronica, Me rck(Sigma-Aldrich), Fluorochem, Fisher, Bep harm, Broadpharm, Larodan, Activate Scienti fic, and Enamine.

[0173] Nuclear magnetic resonance (NMR) spectra were recorded on a 400 MHz Varian instrument at 25 °C. Chemical shifts are reported in ppm (δ) using residual solvent as internal standard. Peak multiplicities are as follows: s, singlet; d, doublet; t, triplet; q, q lutet;p, pentet;h, heptet;m, multiplet;bs, broads The doublets are represented as singlets or combinations thereof, such as dd, doublets of doublets, and Examples of suitable dt triplet include, but are not limited to, dt, triplet of doublets, and dt.

[0174] LC-MS was performed using an Agilent MSD mass spectrometer operated in ES(+) ionization mode. The data were obtained on an Agilent 1100 HPLC system coupled with a water column. Symmetry 2.1×30mm C18 or Chromolith RP- 18 2 x 50 mm. Solvent A water + 0.1% TFA and solvent B acetonitrile + 0.1% of TFA. Wavelength: 254 nM

[0175] Preparative HPLC was obtained on a Gilson system. Flow rate: 10 ml / min. Column Column: kromasil 100-5-C18. Wavelength: 220 nM. Solvent A water +0. 1% TFA and solvent B acetonitrile + 0.1% TFA. Gradient: 40% to 15% in 15 min. 95% B

[0176] Below are examples of abbreviations used: JPEG0007628578000021.jpg170170

[0177] Preparation of Starting Materials and Intermediate Compounds Intermediate 1: 2-[4-(2-methylpropoxy)phenyl]acetyl chloride [ka]

[0178] Thionyl chloride (21.6 ml, 298 mmol) in dichloromethane (29.8 ml) 2-[4-(2-methylpropoxy)phenyl]acetic acid (6.21 g, 29.8 mmol) The mixture was stirred at ambient temperature for 18 h and then concentrated to give the title compound (6 Yield: .77g, 100%)

[0179] Intermediate 2: 2-[4-(propan-2-yloxy)phenyl]acetyl chloride [ka]

[0180] The compound was converted to 2-[4-(propan-2-yloxy)phenyl]acetic acid using 2- Prepared similarly to [4-(2-methylpropoxy)phenyl]acetyl chloride.

[0181] Intermediate 3: 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene [ka]

[0182] 2-[4-(2-methylpropoxy)phenyl]acetyl chloride (6.12 g, 27 mm ol) was dissolved in acetone (8 ml), and the resulting solution was diluted with sodium azide in water (8 ml). Add 2.46 g (37.8 mmol) of ethanol over 10 min. and stir for an additional hour. After this, the mixture was diluted with water and extracted with toluene (3 x 25 ml). The organic phase was washed with sodium sulfate The mixture was dried over sodium and filtered. The filtrate was gently concentrated to about 25 ml. Stir at 65° C. for 20 min, then concentrate to give the title compound (5.41 g, 98%).

[0183] Intermediate 4: 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene hmm [ka]

[0184] The compound was synthesized using 2-[4-(propan-2-yloxy)phenyl]acetyl chloride. It was prepared in the same manner as 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene. Made.

[0185] Intermediate 5: N-[(4-fluorophenyl)methyl]-1-methylpiperidine-4-amine Min [ka]

[0186] 4-Fluorobenzylamine (80.8 mmol, 10.4 g) was dissolved in ethanol (80 ml) l) and add N-methyl-4-piperidone (80.8 mmol, 9.43 g). A small amount of sodium triacetoxyborohydride (161.6 mmol, 35.4 g) was added. Sodium hydroxide (aqueous, 5M) was added in portions and the mixture was stirred at room temperature for 4 hours. The mixture was stirred for 1 hour and then diluted with diethyl ether and water. The organic phase was collected and the aqueous phase was extracted once more with diethyl ether. The organic phase was dried and evaporated to give the desired intermediate as a yellow oil (17.48 g, 97%).

[0187] Intermediate 6: N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine- 4-Amine [ka]

[0188] 2,4-Difluorobenzylamine (4.0 g, 27.1 mmol) was dissolved in ethanol (3 0 ml) and N-methyl-4-piperidone (3.16 g, 27.1 mmol) was dissolved in followed by sodium triacetoxyborohydride (54.2 mmol, 11.85 g) was added. The mixture was stirred at room temperature for 2 hours and then diluted with diethyl ether and 2M hydroxide. The organic phase was collected and washed with 2M hydrochloric acid (50 ml). The acidic aqueous phase was then made basic with 5M sodium hydroxide (30 ml) and diluted with diethyl ether. The organic extracts were dried and evaporated to give the title compound as a yellow oil (5. Obtained as 96 g, 91% yield.

[0189] Intermediate 7: (3S,4R)-3-fluoro-N-[(4-fluorophenyl)methyl] -1-Methylpiperidin-4-amine and (3R,4S)-3-fluoro-N-[(4- Fluorophenyl)methyl]-1-methylpiperidin-4-amine [ka]

[0190] Sodium triacetoxyborohydride (100 mmol, 21.2 g) was dissolved in ethanol. tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate in 100 ml carboxylate (10.86 g, 50 mmol) and 4-fluorobenzylamine (6.2 After stirring at ambient temperature for 4 hours, the solution was added to a solution of saturated bicarbonate. Sodium (100 ml) was added. The mixture was extracted with dichloromethane (3 x 100 ml). The crude material was extracted, dried using a phase separator, and concentrated. Column chromatography using silica gel, eluted with 0% ethyl acetate. Further purification gave the title compound as a 1:1 mixture of enantiomers (8.90 g, 55%) Obtained as.

[0191] (3S,4R)-3-Fluoro-N-[(4-fluorophenyl)methyl]-1-methyl (3R,4S)-3-fluoro-N-[(4-fluorophenyl)piperidine-4-amine and (3R,4S)-3-fluoro-N-[(4-fluorophenyl)piperidine-4-amine (phenyl)methyl]-1-methylpiperidin-4-amine [ka] Trifluoroacetic acid (5 ml) was dissolved in tert-butyl(3 S,4R)-3-Fluoro-4-{[(4-fluorophenyl)methyl]amino}piperidin Dinyl-1-carboxylate and tert-butyl (3R,4S)-3-fluoro-4- {[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate 1 After 50 min, the mixture was concentrated and , redissolved in ethanol (53 ml). Formaldehyde (37% in water, 198 μl, 2.66 mmol) and sodium triacetoxyborohydride (1.13 g, 5 After stirring at ambient temperature for 30 minutes, more formaldehyde was added. (37% aqueous solution, 99 μl, 1.33 mmol) and sodium triacetoxyborohydride After stirring for an additional 45 minutes, the mixture was cooled to room temperature and cooled to room temperature. The mixture was concentrated. Sodium bicarbonate (saturated, 100 ml) was added and the resulting mixture was cooled to 5°C. The organic phase was dried using a phase separator and concentrated. The crude material was purified by column chromatography on silica gel eluting with 5-15% methanol in dichloromethane. The title compound was purified by column chromatography using ethyl acetate gel to obtain the enantiomers. This was obtained as a 1:1 mixture of mers (545 mg, 43%).

[0192] Intermediate 8: tert-Butyl(3R,4R)-3-fluoro-4-{[(4-fluoro phenyl)methyl]amino}piperidine-1-carboxylate and tert-butyl ( 3S,4S)-3-Fluoro-4-{[(4-fluorophenyl)methyl]amino}piperidine Lysine-1-carboxylate [ka]

[0193] (4-Fluorophenyl)methanamine (1.07 ml) in dichloromethane (35 ml) L, 9.44 mmol) and tert-butyl 3-fluoro-4-oxopiperidine-1 To a mixture of 1.87 g, 8.58 mmol of triacetoxy hydrogen Sodium borohydride (2.73 g, 12.9 mmol) was added in portions over 20 min. The reaction was stirred at room temperature for 1 h. The reaction was diluted with sodium bicarbonate (saturated, aq., 100 The organic phase was dried (phase separation) and extracted with dichloromethane (3 x 50 ml). The crude product (3 g) was eluted with 30% ethyl acetate in petroleum ether. Purification by column chromatography using silica gel to obtain tert-butyl (3S,4R)-3-fluoro-4-{[(4-fluorophenyl)methyl]amino} Piperidine-1-carboxylate and tert-butyl(3R,4S)-3-fluoro -4-{[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate tert-Butyl (3R,4R)-3-acetate (2.2 g, 78%) was used as a racemic mixture. Fluoro-4-{[(4-fluorophenyl)methyl]amino}piperidine-1-carbo xylate and tert-butyl(3S,4S)-3-fluoro-4-{[(4-fluoro (phenyl)methyl]amino}piperidine-1-carboxylate (0.25g, 9%) was obtained as a racemic mixture.

[0194] Intermediate 9: 2-[3-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride R [ka]

[0195] Sulfuric acid (49 μl, 882 μmol) was dissolved in 2-(3-fluorophenyl)-2-(2-methylphenyl)-2-(2-phenyl-1,2-dihydro-1,2-trifluorophenyl)-2-(1,2-dimethylphenyl)-2-(2,3-dimethyl ...1,2-dimethylphenyl 1.5-4-hydroxyphenyl)acetic acid (500 mg, 2.94 mmol). After 2 h, sodium acetate trihydrate (2 mmol) was added and the mixture was concentrated. The mixture was suspended in ethyl acetate (5 ml), filtered and concentrated. , isobutyl bromide (799 μl, 7.35 mmol), potassium carbonate (813 mg, 5. 88 mmol) and tetrabutylammonium iodide (109 mg, 294 μmol) The mixture was heated to 70° C. and stirred for 16 h, then cooled to ambient temperature and added ethyl acetate. The mixture was washed with water (5×30 ml), dried (phase separation) and diluted with ethyl acetate (50 ml). The crude material was eluted with 0-10% ethyl acetate in petroleum ether. The intermediate ether ( The material was dissolved in methanol (4 ml) and diluted with sodium hydroxide. After 1 hour, hydrochloric acid (aqueous Solution, 2M, 3 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic phase was 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. After stirring for 1 h and concentration, the desired acyl chloride (633 mg, quantitative) was obtained.

[0196] Intermediate 10: 2-[2-fluoro-4-(2-methylpropoxy)phenyl]acetamide Chill [ka]

[0197] The compound was reacted with 2-(2-fluoro-4-hydroxyphenyl)acetic acid to form 2-[3 -fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride was prepared similarly to the above. Yield: 87%.

[0198] Intermediate 11: tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amine piperidine-1-carboxylate [ka]

[0199] The compound was prepared by subjecting (2,4-difluorophenyl)methanamine and tert-butyl 4-phenylpropanediol to N-[(4-fluorophenyl)methyl]-1-oxopiperidine-1-carboxylate was used to Prepared similarly to [ethyl]-1-methylpiperidin-4-amine to give the desired intermediate (quantitative). Ta.

[0200] Intermediate 12: N-[(2,4-dimethoxyphenyl)methyl]-1-methylpiperidine -4-amine [ka]

[0201] The compound was prepared by mixing 2,4-dimethoxybenzylamine and 1-methylpiperidin-4-one. N-[(4-fluorophenyl)methyl]-1-methylpiperidine-4-amine was used The product was prepared in the same manner as in Example 1. Yield: 71%.

[0202] Intermediate 13: N-[(3,5-dimethoxyphenyl)methyl]-1-methylpiperidine -4-amine [ka]

[0203] The compounds were (3,5-dimethoxyphenyl)methanamine and 1-methylpiperidine- 4-one to N-[(4-fluorophenyl)methyl]-1-methylpiperidine This was prepared similarly to the 4-amine to give the desired intermediate (88%). was used instead of ethanol.

[0204] Intermediate 13A: N-[(3,5-difluorophenyl)methyl]-1-methylpiperidinyl 4-amine [ka]

[0205] The compound was prepared by subjecting (3,5-difluorophenyl)methanamine and 1-methylpiperidine- 4-one to N-[(4-fluorophenyl)methyl]-1-methylpiperidine This was prepared similarly to the 4-amine to give the desired intermediate (54%). was used instead of ethanol.

[0206] Intermediate 14: Methyl 2-[3-hydroxy-2-(2-methylprop-2-ene-1- 2-[3-hydroxy-4-(2-methylpropaneyl)phenyl]acetate and methyl 2-[3-hydroxy-4-(2-methylpropaneyl)phenyl]acetate -2-en-1-yl)phenyl]acetate [ka]

[0207] 3-Bromo-2-methylprop-1-ene (4.15 ml, 4 1.2mmol), methyl 2-(3-hydroxyphenyl)acetate (4.56g, 2 7.4mmol), tetrabutylammonium iodide (1.01g, 2.74mmol) , and K 2 CO 3 A mixture of (7.58 g, 54.9 mmol) was heated to 60° C. for 15 h. The mixture was filtered through a silica gel eluted with 17% ethyl acetate in petroleum ether. The methyl 2-{3-[(2-methylpropanediol) As a result, 4.7 g of 4-(1,3-prop-2-en-1-yl)oxy]phenyl} acetate was obtained.

[0208] Methyl 2-{3-[(2-methylprop-2-en-1-yl) A solution of 1,2-diphenyl)oxyphenylacetate (3.6 g, 16.3 mmol) was heated to 220°C. Heat for 8 hours. Water (160 ml) is added and the mixture is diluted with diethyl ether (800 ml). The organic phase was washed with water (3×300 ml) and extracted with Na 2 SO 4 Dry and filter The crude material was purified by elution with 25% ethyl acetate in petroleum ether. The product was purified by column chromatography using silica gel to obtain methyl 2-[3- Hydroxy-2-(2-methylprop-2-en-1-yl)phenyl]acetate (7 00mg) and methyl 2-[3-hydroxy-4-(2-methylprop-2-ene-1- As a result, the compound was obtained as a phenyl)acetate.

[0209] Intermediate 15: 4-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro- 1-Benzofuran [ka]

[0210] Methyl 2-[3-hydroxy-2-(2-methylprop-2-ene) A solution of 1,2-diphenyl-1-ylphenyl]acetate (700 mg) was heated to 100°C for 20 min. The solvent was concentrated to give methyl 2-(2,2-dimethyl-2,3-dihydro-1-benzoxazole. Furan-4-yl) acetate (670 mg) was obtained. Sodium hydroxide (1.98 ml) , 5M aqueous solution, 9.89 mmol) in methanol (6 ml) -Dimethyl-2,3-dihydro-1-benzofuran-4-yl) acetate (670mg The mixture was stirred at room temperature for 1 hour. Diethyl ether (100 ml) was added to the solution. and HCl (3 ml, 5M aqueous solution) were added. The organic phase was washed with water (30 ml) and Na 2 SO 4 Dry the mixture at 40° C., filter, and concentrate under reduced pressure to obtain 2-(2,2-dimethyl-2,3-di Hydro-1-benzofuran-4-yl)acetic acid (540 mg) was obtained. Thionyl chloride (2. 0 ml, 27.5 mmol) in CH 2 Cl 2 2-(2,2-dimethyl- 2,3-Dihydro-1-benzofuran-4-yl)acetic acid (540 mg, 2.62 mmol) ). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in acetone ( 3 ml), cooled to 0°C and dissolved in NaN 3 (238mg, 3.6 7 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h. The mixture was diluted with toluene (100 mM l), and the organic phase was extracted with Na 2 SO 4 Dry at 40°C, filter, and concentrate under reduced pressure (to 20 ml). The solution was heated to 60° C. for 1 h and then concentrated under reduced pressure to give 4-(isocyanate Methyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran (492 mg) was obtained. and used without further purification.

[0211] Intermediate 16: 6-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro- 1-Benzofuran [ka]

[0212] 6-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran The orchid was treated with 4-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-phenylenediamine. It was prepared similarly to benzofuran and used without further purification.

[0213] Intermediate 17: (4-{[2-( 2 H 3 ) Methyl ( 2 H 6 )propan-2-yl]oxy }phenyl)methanamine [ka]

[0214] Sodium hydride (39.6 mg, 1.65 mmol) was dissolved in tetrahydrofuran (1 m l) tert-butanol-d 10 (100mg, 1.19mmol) was added to a solution After 35 min, gas evolution ceased and the mixture was concentrated to a white solid. Resuspend in furan (1 ml) and dilute 4-fluorobenzoate in tetrahydrofuran (1 ml). A solution of nitrile (100 mg, 0.826 mmol) was added. After 2 h, the mixture was cooled to 6 The mixture was heated to 5° C. After 21 hours, NaOH (2 ml, 1 M aqueous solution) was added and the mixture was diluted with acetic acid. The organic phase was separated, dried using a phase separator, and concentrated. The crude material was purified by silica gel elution with 1-6% ethyl acetate in petroleum ether. The compound was purified by column chromatography using 4-{[2-( 2 H 3 ) Methyl ( 2 H 6 )propan-2-yl]oxy}benzonitrile (63.7 mg, 42%) was obtained. .

[0215] Cold borane (2 ml, 1 M in tetrahydrofuran) was added to 4-{[2-( 2 H 3 ) Methyl ( 2 H 6 )propan-2-yl]oxy}benzonitrile (61.4 mg, 0.333 mm ol) and the resulting mixture was heated to 65° C. After 18 h, the mixture was concentrated and Methanol (2 ml) was added. When gas evolution ceased, the mixture was heated to 50°C for 15 min. The mixture was concentrated, redissolved in ethyl acetate (3 ml) and diluted with NaOH (1 ml, 1 M aqueous solution), separated organic phase, dried using a phase separator, concentrated and the desired The intermediate was obtained as an oil (32.4 mg, 52%).

[0216] Intermediate 18: (3,5-dihydro-2H-1,4-benzodioxepin-8-yl)methyl Tanamine [ka]

[0217] Sodium hydride (15.3 mg, 0.638 mmol) was dissolved in tetrahydrofuran (5 2-[5-(aminomethyl)-2-fluorophenoxy]ethan-1-ol in ml (50.6 mg, 0.254 mmol) was added to a solution of 100 ml of 1,0 ... The mixture was heated to 50° C. After 3.5 h, 2 CO 3 (tip of spatula) and mix. The mixture was heated to 60° C. After 2 h, the mixture was heated to 200° C. for 30 min in a microwave reactor. Sodium hydroxide (2 ml, 1M aqueous solution) was added and the mixture was stirred for 1 h. Extract with ethyl acetate (3×3 ml) and dry the combined organic phases using a phase separator. Concentration gave a solution of the desired intermediate (1 mL). This material was used without further purification. Used.

[0218] Intermediate 19: 2-(aminomethyl)-5-fluoro-N,N-dimethylaniline [ka]

[0219] Sodium hydride (88 mg, 60%, 3.67 mmol) was dissolved in tetrahydrofuran ( 2-Amino-4-fluorobenzonitrile (100 mg, 0.735 mmol) in 1 ml l), followed by methyl iodide (183 μl, 2.94 mmol). After 2 h, additional sodium hydride (42 mg, 60%, 1.75 mmol) was added. ) was added, followed by the addition of methyl iodide (90 μl, 1.45 mmol). After stirring for 7 h, NaOH (2 ml, 1 M aqueous solution) was added and the aqueous phase was washed with ethyl acetate ( × 3 ml) and the combined organic phases were dried and concentrated using a phase separator. The material is eluted with 1-15% ethyl acetate in petroleum ether using silica gel. The compound was purified by column chromatography to give 2-(dimethylamino)-4-fluoro Benzonitrile (111 mg, 92%) was obtained.

[0220] Borane (2.0 ml, 1 M in THF, 2.0 mmol) was added to 2-(dimethylamino) -4-fluorobenzonitrile (111 mg, 0.676 mmol) was added at room temperature. After stirring for 18 hours, more borane (2 ml, 1 M in THF, 2 mmol) was added and The mixture was heated to 45° C. After stirring at 45° C. for an additional 24 h, the mixture was diluted with ethyl acetate ( The organic phase was diluted with 1×5 ml of NaOH (3×4 ml, 1 M aqueous solution) and washed with NaOH (3×4 ml, 1 M aqueous solution). Drying using a separatory oven and concentration gave the desired intermediate (112 mg).

[0221] Intermediate 20: (4-Cyclopropoxyphenyl)methanamine [ka]

[0222] 4-Cyanophenol (1.0 g, 7.97 mmol), cesium carbonate (16.0 mm ol, 5.25 g), sodium iodide (0.8 mmol, 121 mg), cyclopropyl Bromide (31.9 mmol, 2.64 ml) and N,N-dimethylacetamide (4 0.0 ml) was stirred at 150°C for 20 hours in a sealed thick-walled vessel, then added water and diethyl ether The organic phase was washed several times with water, then dried and evaporated, and the residue was dissolved in petroleum ether. Purification by silica gel chromatography eluting with 25-50% ethyl acetate in ether. The yield was 832 mg (5.22 mmol), and 4-cyclopropyloxy-benzonitrile was The yield was 65%). 6 mmol) was cooled in an ice bath and borane (1 M in tetrahydrofuran, 30 ml, 30 mL) was added. The mixture was stirred at room temperature for 20 hours and at 60° C. for 30 minutes, then It was quenched with methanol (10 ml), evaporated, and dissolved in methanol (20 ml) for 2 h. The mixture was evaporated and diluted with diethyl ether and sodium hydroxide (aqueous The organic phase was collected and extracted with hydrochloric acid (aqueous, 1M). The aqueous phase was diluted with The mixture was basified with sodium chloride (aq, 5M) and then extracted with diethyl ether. The phase was dried and evaporated to give crude (4-cyclopropoxyphenyl)methanamine (878m g, yield 72%).

[0223] Intermediate 21: tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amine piperidine-1-carboxylate [ka]

[0224] (2,4-Difluorophenyl)methanamine (8.0 g, 54.7 mmol) was dissolved in ethanol. tert-Butyl 4-oxopiperidine-1-carboxylate in alcohol (60 ml) (11.3 g, 54.7 mmol), followed by sodium triacetoxyborohydride. C. (23.9 g, 110 mmol) was added. The reaction was stirred at room temperature for 2 hours. Then, NaOH (160 ml, 2M, aq.) was added and the mixture was extracted with diethyl ether. The organic phase was washed with water and brine and then extracted with MgSO 4 Dry using, filter and then evaporate under reduced pressure. Concentration gave the desired intermediate (18.3 g), which was used without further purification. did.

[0225] Intermediate 22: 2-(trimethylsilyl)ethyl 4-[(chlorocarbonyl)[(2,4 -Difluorophenyl)methyl]amino]piperidine-1-carboxylate [ka]

[0226] (2,4-Difluorophenyl)methanamine (1.68 g, 11.4 mmol) was added to C H 2 Cl 2 2-(trimethylsilyl)ethyl 4-oxopiperidine-1 in (20 ml) -carboxylate (2.4 g, 9.27 mmol), followed by triacetoxy water Sodium borohydride (4.46 g, 20.4 mmol) was added. The reaction was stirred at room temperature for 1 The mixture was stirred for 1 h. NaOH (0.5 M, aq.) was then added and the mixture was diluted with CH 2 Cl 2 The organic phase was extracted with MgSO 4 The crude was dried using hexanes, filtered and concentrated under reduced pressure. The intermediate was purified by column chromatography on silica gel, eluting with ethyl acetate. The product was purified by HPLC to give 2-(trimethylsilyl)ethyl 4-{[(2,4-difluorophenyl)phenyl] As a result, 3.49 g of methyl)amino}piperidine-1-carboxylate was obtained.

[0227] CH 2 Cl 2 2-(Trimethylsilyl)ethyl 4-{[(2,4-dimethylsilyl)ethyl] fluorophenyl)methyl]amino}piperidine-1-carboxylate (2.04 g, A solution of (5.49 mmol) and pyridine (1.8 ml, 22.0 mmol) was 2 C l 2 To a solution of triphosgene (1.09 g, 3.66 mmol) in 10 ml of ethanol at 0°C The reaction was stirred at this temperature for 1 h. The mixture was then concentrated under reduced pressure and diluted with diethyl ether. It was dissolved in ether and washed with HCl (0.5 M aqueous solution). The organic phase was washed with MgSO 4 The crude intermediate was purified by elution with 25% acetic acid in hexanes, dried using a 500 sachette filter, and concentrated under reduced pressure. Purified by column chromatography on silica gel eluted with ethyl acetate This gave the desired intermediate (1.98 g).

[0228] Intermediate 23: 7-(aminomethyl)-2,2-dimethyl-3,4-dihydro-2H-1 -Benzopyran-4-ol [ka]

[0229] LiAlH 4 (28.3 mg, 0.745 mmol) in THF (4.0 ml) 2,2-Dimethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-7-carbamate The mixture was added in portions to 50 ml of boronic acid (30 mg, 0.149 mmol) at room temperature. Heat at 37 °C overnight and then add NaSO until gas evolution stops. 4 * 10H 2 Add O little by little The mixture was then diluted with ethyl acetate (5 mL), filtered, and concentrated to give the desired intermediate (30. The product was obtained as a 300 mg (97% yield).

[0230] Intermediate 24: (2,2-Dimethyl-2H-chromen-7-yl)methanamine [ka]

[0231] LiAlH 4 (37.7 mg, 0.993 mmol) in THF (4.0 ml) , 2-Dimethyl-2H-chromene-7-carbonitrile (46 mg, 0.248 mmol) The mixture was heated to 50° C. overnight and then cooled to 50° C. until gas evolution ceased. InNaSO 4 * 10H 2 O was added in portions and the mixture was diluted with ethyl acetate (5 ml). The mixture was filtered and concentrated to give the desired intermediate (46.0 mg, 97% yield).

[0232] Intermediate 25: (3-Methyl-1H-indazol-5-yl)methanamine [ka]

[0233] LiAlH 4 (84.5 mg, 2.23 mmol) in THF (10.0 mL) -Methyl-1H-indazole-5-carbonitrile (70 mg, 0.445 mmol) The mixture was heated to 50° C. overnight and then cooled to 50° C. until gas evolution ceased. NaSO4 * 10H 2 O was added in portions and the mixture was diluted with ethyl acetate (15 ml). It was filtered and concentrated to give the desired intermediate (23.7 mg, 31% yield).

[0234] Intermediate 26: N-{[2-(benzyloxy)-4-fluorophenyl]methyl}-1 -Methylpiperidin-4-amine [ka]

[0235] Benzyl alcohol (0.77 g, 7.2 mmol) was dissolved in dioxane (15 ml). To a stirred solution of potassium tert-butoxide (0.97 g, 8.6 mg) at room temperature After stirring at room temperature for 10 minutes, 2,4-difluorobenzonitrile (1.00 g, 7 After a further 90 min, water (10 ml) was added and the mixture was cooled to room temperature. Extract with diethyl ether (3 x 10 ml) and dry the combined organic phases using a phase separator. The crude material was purified by elution with 25-50% dichloromethane in petroleum ether. The compound was purified by column chromatography using silica gel to obtain 2- (Benzyloxy)-4-fluorobenzonitrile as a white solid (1.33 g, 81%) And obtained.

[0236] A cold solution of borane (1.4 ml, 1M in tetrahydrofuran) was added to 2-(benzyloxy) The mixture was added to 208 mg (915 μmol) of 4-fluorobenzonitrile at room temperature. After stirring at rt for 15 h, more borane (1.4 ml, 1M in tetrahydrofuran) was added. After stirring for an additional 19 hours, more borane (1.0 ml, 1 in tetrahydrofuran) was added. After 3 hours, the mixture was added to sodium hydroxide (5 ml, 1M aqueous solution). The mixture was extracted with ethyl acetate (3×5 ml) and the combined organic phases were dried using a phase separator. The mixture was concentrated to give [2-(benzyloxy)-4-fluorophenyl]methanamine as an oil ( This material was used without further purification.

[0237] Sodium triacetoxyborohydride (372 mg, 1.76 mmol) was added After 5 min, N-methyl-4-piperidone (150 mg, 1.32 mmol) was added to ethanol. [2-(benzyloxy)-4-fluorophenyl]methanamine (20 To a stirred solution of 1,400 ml of ethyl acetate (4 mg, 882 μmol), the reaction mixture was concentrated after 6 h. , redissolved in dichloromethane (5 ml) and dissolved in sodium hydroxide (5 ml, 1 M aqueous solution) ), the aqueous phase was further extracted with dichloromethane (2 x 1 ml), and the combined organic phases were The desired intermediate was obtained as a yellow oil (253 mg, 87% yield) after drying and concentration using a phase separator. %).

[0238] Intermediate 27: tert-Butyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl) (phenyl)methyl]amino]piperidine-1-carboxylate [ka]

[0239] CH 2 Cl 2 Diphosgene (184 μl, 1.54 mmol) in 2 ml of CH 2 Cl 2 tert-Butyl 4-{[(2,4-difluorophenyl)methyl ]amino}piperidine-1-carboxylate (1.00 g, 3.07 mmol) and D IPEA (1.07 ml, 6.15 mmol) was added dropwise to the mixture at room temperature. After stirring for 1 h, CH 2 Cl 2 (1 ml) in diphosgene (100 μl, 0.837 After stirring for an additional 2 h, NaOH (1 ml, 1 M aqueous solution) was added. The organic phase was dried and concentrated using a phase separator. The crude material was extracted with petroleum ether. Purify by silica gel chromatography eluting with 3-12% ethyl acetate in The desired intermediate (1.34 g) was obtained.

[0240] Intermediate 28: Phenyl N-[(4-cyclopropoxyphenyl)methyl]carbamate [ka]

[0241] 4-Cyanophenol (1g, 7.97mmol), Cesium carbonate (16.0mmol , 5.25 g), sodium iodide (0.8 mmol, 121 mg), cyclopropyl bromide (0.5 mmol, 121 mg), romide (31.9 mmol, 2.64 ml) and dimethylacetamide (4.0 ml) The mixture was stirred at 150° C. in a sealed vessel for 20 hours, then partitioned between water and diethyl ether. The organic phase was washed several times with water, then dried and evaporated, and the crude product was dissolved in 20-30 ml of petroleum ether. Column chromatography using silica gel eluted with 30% ethyl acetate Purification by HPLC gave 4-cyclopropyloxy-benzonitrile (405 mg, 2.54 m This procedure was repeated once more to give 4-cyclopropyloxy. -benzonitrile (832 mg, 5.22 mmol, 65% yield). Two batches The mixture was combined to give 1.188 g (7.46 mmol), which was cooled in an ice bath and dissolved in BH 3 solution (30 ml, 1M in tetrahydrofuran, 30 mmol) was added. The mixture was stirred at room temperature for 2 0 h and stirred at 60° C. for 30 min, then quenched with methanol (10 ml), The mixture was evaporated and heated to reflux in methanol (20 ml) for 2 hours. The organic phase was collected and extracted with 1M HCl, and the aqueous phase was separated. The mixture was then separated, made basic with 5M NaOH, and extracted with diethyl ether to recover the organic phase. , dried and evaporated to give crude 4-cyclopropyloxy-benzylamine (878 mg, 5. This material was dissolved in dichloromethane (5 ml) and Pyridine (8.1 mmol, 660 μl) was added, followed by dichloromethane (4.0 ml Phenyl chloroformate (7.0 mmol, 906 μl) dissolved in 1000 ml of ethyl acetate was added dropwise in an ice bath and mixed. The mixture was stirred for 30 min and then partitioned between dichloromethane and 1M HCl, and the organic phase was separated. The mixture was then separated, dried and evaporated to give a crystalline material which was recrystallized from EtOAc / hexane. The title compound was obtained from the mother liquor (881 mg, 3.1 mmol, 58% yield). The yield was crystallized (218 mg, 0.77 mmol). The combined yield of (methoxyphenyl)methyl)carbamate was 72%.

[0242] Intermediate 29: 1-Butoxy-4-(isocyanatomethyl)benzene [ka]

[0243] 2-(4-Butoxyphenyl)acetic acid (4.0 g, 18.81 mmol) was dissolved in dichloromethane In a mixture of ethanol (24 ml), thionyl chloride (16 ml) and DMF (160 μl), The mixture was refluxed for 1 hour. The mixture was evaporated and diethyl ether was added. The solid was removed and ether was added. The tert-butyl acetate extract was evaporated to give 2-(4-butoxyphenyl)acetyl chloride (4.35 g, yield The acid chloride (3.5 g, 14.7 mmol) was dissolved in acetone (10 mL). 1.35 g, 20.53 mmol) in water (10 ml) and The mixture was added to a solution of 10 ml of ethyl acetate (100 ml) at 0° C. for 10 min. After stirring at 0° C. for 1 h, the mixture was poured into cold water (40 ml). The mixture was diluted with toluene (2 x 40 ml) and extracted with toluene (2 x 40 ml). The organic extracts were combined, dried (N a 2 SO 4 ) and concentrated to 60 ml on a rotary evaporator using a 30°C water bath. 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 min and then evaporated to give an oil, which was dissolved in n-heptane ( The solution was filtered to remove any solids and the filtrate was evaporated to give The title compound was obtained as an oil (3.21 g, 100% yield).

[0244] Intermediate 30: 1-ethoxy-4-(isocyanatomethyl)benzene [ka]

[0245] The compound was prepared similarly to 1-butoxy-4-(isocyanatomethyl)benzene.

[0246] Intermediate 31: Phenyl N-({4-[(tert-butyldimethylsilyl)oxy]- 2-Fluorophenyl(methyl)carbamate [ka]

[0247] 2-Fluoro-4-hydroxy-benzaldehyde (982 mg, 7.0 mmol), Imidazole (20.0 mmol, 1.375 g) and DMF (4.0 ml) were stirred. t-Butyldimethylsilyl chloride (14.0 mm) dissolved in DMF (4.0 ml) A solution of 2.175 g of 1,2-diol was added. The mixture was stirred at 20° C. for 20 hours and then diluted with water. The organic phase was washed several times with water, dried and evaporated, and the residue was treated with Column chromatography using silica gel eluted with 30% ethyl acetate in petroleum ether. Purification by chromatography gave the silylated benzaldehyde as an oil. was dissolved in ethanol (5 ml) and sodium borohydride (7.0 mmol, 270 The mixture was stirred for 1 h, then concentrated and partitioned between water and diethyl ether. The organic phase was separated and evaporated to give the intermediate benzyl alcohol (961 mg, 3.7 5 mmol, 54% yield over two steps. The alcohol (961 m g, 3.75 mmol) was dissolved in dichloromethane (4 ml) and diisopropyl ethyl Amine (9.4 mmol, 1.64 ml), followed by p-toluenesulfonyl chloride (5 The mixture was stirred for 72 hours and then petroleum ether was added. Column chromatography using silica gel eluted with 30% ethyl acetate in ether. The intermediate benzyl tosylate (866 mg, 2.11 mmol, yield) was obtained by filtration. The yield was 56%. This material (853 mg, 2.07 mmol), potassium phthalimide (4.0 mmol, 750 mg) and DMF (3.0 ml) were stirred, and pyridine (1. The mixture was stirred for 22 hours and then 0.5 M HCl was added. The organic phase was separated and then evaporated, and the residue was dissolved in petroleum ether. Column chromatography was performed using silica gel, eluted with 30% ethyl acetate in ether. The intermediate phthalimide derivative (735 mg, 1.9 mmol) was obtained by purification using chromatography. This material was dissolved in ethanol (5 ml) and methylamine solution (8 M, 40 mmol) The mixture was stirred in a mixture of 100 ml of 1,000 ml of 100% ethanol for 20 hours, and then concentrated. The residue was dissolved in methanol. The intermediate is purified by column chromatography using silica gel. Benzylamine (104 mg, 0.407 mmol, 20% yield over two steps) %. This material (104 mg, 0.407 mmol) was dissolved in dichloromethane (2.0 mL) l), pyridine (1.0 mmol, 82 μl) was added, and the mixture was cooled in an ice bath. Then, phenyl chloroformate (0.8 mmol, 104 μl) was added. The mixture was stirred for 1 h. The mixture is stirred, then partitioned between water and diethyl ether, the organic phase is separated and evaporated to give a residue. The column was prepared using silica gel and eluted with 30% ethyl acetate in petroleum ether. The phenyl N-({4-[(tert-butyldimethyl (2-(methylsilyl)oxy]-2-fluorophenyl}methyl)carbamate (165 mg, yield The success rate was 100%.

[0248] Intermediate 33: 2-[3-fluoro-4-(propan-2-yloxy)phenyl] chloride Acetyl [ka]

[0249] The compound was synthesized by the reaction of 2-(3-fluoro-4-hydroxyphenyl)acetic acid and 2-iodopropanediol. 2-[3-fluoro-4-(2-methylpropane]-2-methylpropane was used instead of isobutyl bromide. It was prepared in the same manner as in Example 1, except that tetrabutylammonium iodide was omitted. Omitted.

[0250] Intermediate 34: 2-Fluoro-4-(isocyanatomethyl)-1-(propane-2-yl) (oxy)benzene [ka]

[0251] The compound was prepared by the procedure of 2-[3-fluoro-4-(propan-2-yloxy)phenyl] achloride. Cetyl is used to make 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzoxazole. It was prepared similarly to Zen.

[0252] Intermediate 35: 2-[2-fluoro-4-(propan-2-yloxy)phenyl] chloride Acetyl [ka]

[0253] The compound was synthesized by the reaction of 2-(2-fluoro-4-hydroxyphenyl)acetic acid and 2-iodopropanediol. Using acetone, 2-[2-fluoro-4-(2-methylpropoxy)phenyl]acetone chloride was It was prepared similarly to chill.

[0254] Intermediate 36: 2-Fluoro-1-(isocyanatomethyl)-4-(propane-2-yl) (oxy)benzene [ka]

[0255] The compound was prepared by the procedure of 2-[2-fluoro-4-(propan-2-yloxy)phenyl] achloride. Cetyl is used to make 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzoxazole. It was prepared similarly to Zen.

[0256] Intermediate 37: 2-[3-methyl-4-(propan-2-yloxy)phenyl]achloride Cetyl [ka]

[0257] The compound was synthesized by the reaction of 2-(4-hydroxy-3-methylphenyl)acetic acid and 2-iodopropane was used instead of isobutyl bromide to obtain 2-[2-fluoro-4-(2-methylpropoxy) (iii) Phenyl) Acetyl chloride was prepared in the same manner as above. Tetrabutylammonium iodide was omitted. did.

[0258] Intermediate 38: 4-(isocyanatomethyl)-2-methyl-1-(propan-2-yl) Oxy)benzene [ka]

[0259] The compound was treated with 2-[3-methyl-4-(propan-2-yloxy)phenyl]acetamide. Using ethyl acetate, 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene The mixture was prepared in the same manner as in Example 1.

[0260] Example 1: 1-[(2,4-dimethoxyphenyl)methyl]-3-[(3R,4S)- 3-Fluoro-1-methylpiperidin-4-yl]-3-[(4-fluorophenyl)methyl trifluoroacetic acid (1a) and 1-[(2,4-dimethoxyphenyl)methyl]urea -3-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(4-Fluorophenyl)methyl]urea;Trifluoroacetic acid (1b) [ka]

[0261] (2,4-Dimethoxyphenyl)methanamine (104 μmol) in dichloromethane and triethylamine (35 μl, 250 μmol) were added using a syringe pump (0.5 ml / diphosgene (6 μl, 50 μmol) in dichloromethane (0.5 ml) using The mixture was stirred at ambient temperature for a further hour and then diluted with dichloromethane (0.5 ml l) in (3R,4S)-3-fluoro-N-[(4-fluorophenyl)methyl]-1 -Methylpiperidin-4-amine and (3S,4R)-3-fluoro-N-[(4-fluoro (1:1, 83 μmol)-1-methylpiperidin-4-amine After 24 hours, the mixture was washed with water (1.5 ml). The aqueous phase was diluted with dichloromethane (1.5 ml). The combined organic phases were dried (phase separator) and concentrated. The column was eluted with 20-85% acetonitrile in water (containing 0.1% trifluoroacetic acid). The product was purified by HPLC using a 500 rpm chromatograph to give the title compound. Yield: 31.3 mg, 55%. 1 H NMR (400MHz, chloroform-d) δ 7.18-7.08 (m, 2H), 7.0 5(d,1H),7.00(t,2H),6.38(dd,1H),6.32(d,1H ),5.17-4.95(m,2H),4.79(dd,1H),4.51(d,1H) ,4.43(d,1H),4.20(qd,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] + .

[0262] Example 2: 3-[(2,4-dimethoxyphenyl)methyl]-3-(1-methylpiperidinyl) 4-(2-methylpropoxy)phenyl)methyl-1-(4-phenyl-2-methylpropoxy)phenyl)methyl-urea(2 ) [ka]

[0263] N-[(2,4-dimethoxyphenyl)methyl]-1-methylpiperidine in dichloromethane Lysine-4-amine (0.34 mmol, 90 mg) was dissolved in dichloromethane and 1-(isocyano) Anhydromethyl)-4-(2-methylpropoxy)benzene (0.37 mmol, 77 m g). The solution was stirred for 1 hour and then diluted with dichloromethane and sodium hydroxide (aqueous The organic phase was separated, dried (sodium sulfate), filtered and cooled to 37°C. The crude product was purified by column chromatography on silica gel. Purified. Yield: 101 mg, 63%: 1 H NMR (400MHz, chloroform-d )δ7.11-7.03(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,5 H),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] + .

[0264] Example 3: 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidinyl) (4-(2-methylpropoxy)phenyl)methyl)urea; Trifluoroacetic acid (3) [ka]

[0265] 1-(isocyanatomethyl)-4-(2-methylpropane) in dichloromethane (1 ml) (epoxy)benzene (61.5 mg, 300 μmol) in dichloromethane (1 ml) -[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (6 0.0 mg, 250 μmol). The mixture was stirred overnight and then concentrated. The material was dissolved in 38–72% acetonitrile in water (containing 0.1% trifluoroacetic acid). Purification by HPLC afforded the title compound (31 mg, 22%). 1 H.N.M. R(400MHz, chloroform-d) δ7.13(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:4 46.3[M+H] + .

[0266] Example 4: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylphenyl)methyl] (phenyl)methyl}-1-(piperidin-4-yl)urea;Trifluoro Acetic acid (4) [ka]

[0267] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2- Methylpropoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carbo Xylate [ka]

[0268] tert-Butyl 4-{[(2,4-difluoro phenyl)methyl]amino}piperidine-1-carboxylate (469 mg, 1.61 To a stirred solution of 1-(isocyanuric acid) (1 mmol) in dichloromethane (0.2 ml), (trimethyl)-4-(2-methylpropoxy)benzene (396 mg, 1.93 mmol) A solution of was added dropwise over 1 min. The mixture was stirred for 2.5 h and then further 1-(isopropyl) Cyanatomethyl)-4-(2-methylpropoxy)benzene (198 mg, 0.96 m mol) was added in one portion. The mixture was stirred for 1.5 h and then concentrated to give the desired intermediate. (811 mg) was obtained.

[0269] 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-methylpropoxy 1-(Piperidin-4-yl)urea;Trifluoroacetic acid

[0270] tert-Butyl 4-{[(2,4-difluorophenyl) (4-(2-methylpropoxy)phenyl)methyl)carba (57 mg, 0.11 mmol) of To the stirred solution was added trifluoroacetic acid (0.5 ml). After 1 hour, the reaction mixture The crude material was purified by distillation with 30-80% acetonitrile in water (0.1% trifluoride). The product was purified by HPLC eluting with 2,4-dichlorophenyl acetic acid (containing 1,2,3-dichlorophenyl acetic acid) to give the title compound (23 mg, 39%). Got it. 1 H NMR (400MHz, chloroform-d) δ 9.60 (bs, 1H), 9 .08(bs,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] + .

[0271] Example 5: 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidinyl) (4-(diphenyl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea ;Trifluoroacetic acid (5) [ka]

[0272] 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene (23. 9 mg, 125 μmol) in dichloromethane (500 μl) (phenyl)methyl]-1-methylpiperidin-4-amine (20.0 mg, 83.2 The mixture was stirred overnight and then concentrated. The crude material was dissolved in 30 mL of water. By HPLC eluting with ~60% acetonitrile (containing 0.1% trifluoroacetic acid), This was further purified to give the title compound (32 mg, 71%). 1 H NMR (400MHz, Chloroform-d) δ 11.99 (bs, 1H), 7.12 (q, 1H), 7.02 (d ,2H),6.87-6.75(m,4H),4.83-4.66(m,2H),4.5 1(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] + .

[0273] Example 6: 3-{[3-fluoro-4-(2-methylpropoxy)phenyl]methyl} -1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl) Urea; Trifluoroacetic acid (6) [ka]

[0274] 2-[3-fluoro-4-(2-methylpropoxy)phenyl]phenyl in acetone (100 μl) [Nyl]acetyl chloride (48.9 μl, 200 μmol) was dissolved in sodium azide in water (100 μl). Thorium (18.2 mg, 280 μmol) was added at 0° C. After 1 h, the mixture was diluted with water ( The mixture was diluted with toluene (3 x 1 ml) and extracted with toluene (3 x 1 ml). The organic phase was diluted with sodium sulfate. The mixture was dried using a vacuum oven and filtered. The filtrate was gently concentrated to about 1 ml. The mixture was heated at 60° C. for 15 min. The mixture was stirred for 1 h and then cooled to 0° C. N-[(4-fluorophenyl) (methyl)-1-methylpiperidin-4-amine (48.9 mg, 220 μmol) After addition, the mixture was heated to ambient temperature. After 2 h, the mixture was concentrated and the crude was dissolved in water. HPLC eluted with 25-45% acetonitrile (containing 0.1% trifluoroacetic acid) C to give the title compound (69.8 mg, 62%). 1 H NMR(40 0MHz, chloroform-d) δ12.41(bs,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),2.2 6-2.12(m,2H),2.08(dq,1H),1.88(d,2H),1.01 (d,6H);LC-MS:446.3[M+H] +

[0275] Example 7: 3-{[2-fluoro-4-(2-methylpropoxy)phenyl]methyl} -1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl) Urea; Trifluoroacetic acid (7) [ka]

[0276] The compound was prepared by the reaction of 2-[2-fluoro-4-(2-methylpropoxy)phenyl]acetyl chloride with The compound was prepared in the same manner as in Example 6 using the same ethyl acetate. Yield: 29%. 1 H NMR (400MHz ,Chloroform-d) δ12.55(bs,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(dq,1H),1.87(d,2H),1 .01(d,6H);LC-MS:446.3[M+H] + .

[0277] Example 8: 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl [1-methylpiperazinyl-2,3-dihydro-1-benzofuran-5-yl]methyl Lysine-4-yl)urea; Trifluoroacetic acid (8) [ka]

[0278] Methyl 2-{4-[(2-methylprop-2-en-1-yl)oxy]phenyl}a Acetate [ka]

[0279] 3-Bromo-2-methylprop-1-ene (1.41 ml, 14 mmol) was dissolved in acetone. Methyl 2-(4-hydroxyphenyl)acetate (1.66 g, 1 0 mmol) and potassium carbonate (3.46 g, 25 mmol). The mixture was heated Reflux and stir overnight, then cool to ambient temperature, dilute with ethyl acetate (20 mL) and rinse. The mixture was filtered through a plug of silica gel and concentrated (2.11 g, 96%).

[0280] Methyl 2-[4-hydroxy-3-(2-methylprop-2-en-1-yl)phenyl Acetate [ka]

[0281] Methyl 2-{4-[(2-methylprop-2-en-1-yl)oxy]phenyl}a Acetate (1.94 g, 8.81 mmol) 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, equivalent weight, containing 20% ​​N-methyl-2-pyrrolidone).

[0282] Methyl 2-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)a Acetate [ka]

[0283] Methyl 2-[4-hydroxy-3-(2-methylprop-2-en-1-yl)phenyl Acetate (2.43 g, containing 20% ​​N-methyl-2-pyrrolidone, 8.81 mm ol) was dissolved in formic acid (33.2 ml). The mixture was heated to 100° C. and stirred overnight. It was then cooled to ambient temperature and concentrated. The crude material was purified by diluting with 0-15% ethyl acetate in petroleum ether. Purification was performed by column chromatography on silica gel, eluting at 40°C. To give the desired intermediate (1.84 g, 95%).

[0284] 5-(isocyanatomethyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran run [ka]

[0285] Methyl 2-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)a Acetate (1.84 g, 8.35 mmol) was dissolved in methanol (15 ml) and hydroxylated. Sodium chloride (aqueous, 2M, 8.35 ml, 16.7 mmol) was added. After 30 min. Then, hydrochloric acid (aqueous, 1M, 50 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic phase was washed with brine (20 ml), dried (phase separator) and concentrated. Redissolved in dichloromethane (2 ml). Thionyl chloride (6.08 ml, 83.5 mm ol) was added and the mixture was stirred at ambient temperature for 18 h and then concentrated. The mixture was dissolved in ethanol (5.52 ml) and cooled to 0°C. Sodium azide in water (5.52 ml) was added. After stirring for 1 h, the mixture was diluted with water (5 The mixture was diluted with toluene (3×50 ml) and extracted with toluene (3×50 ml). The mixture was dried using hexane and filtered. The filtrate was gently concentrated to about 55 ml. The mixture was heated at 60° C. Stirred for 20 min and then concentrated (1.77 g, quantitative).

[0286] 1-[(2,4-difluorophenyl)methyl]-3-[(2,2-dimethyl-2,3 -Dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidine-4 -yl)urea;Trifluoroacetic acid

[0287] 5-(isocyanatomethyl)-2,2-dimethyl in dichloromethane (2.5 ml) -2,3-Dihydro-1-benzofuran (203 mg, 1 mmol) was dissolved in dichloromethane ( N-[(2,4-difluorophenyl)methyl]-1-methylpiperidinyl in 2.5 ml The mixture was stirred for 30 minutes and then added with 1,2-dimethyl-4-amine (288 mg, 1.2 mmol). The crude material was then purified by distillation using 10-40% acetonitrile in water (0.1% trifluoroacetate). The title compound (4 Yield: 48mg, 80%) 1 H NMR (400 MHz, chloroform-d) δ 12. 72(bs,1H),7.13(q,1H),6.89-6.77(m,4H),6.6 1(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(qd,2H),1.91(d,2H),1.46(s ,6H);LC-MS:444.3[M+H] + .

[0288] Example 9: 1-[(2,4-difluorophenyl)methyl]-3-[(3,3-dimethyl [1-methylpiperazinyl-2,3-dihydro-1-benzofuran-5-yl]methyl Lysine-4-yl)urea; Trifluoroacetic acid (9) [ka]

[0289] (3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)methanamine [ka]

[0290] 3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-carboxylic acid (115. 56 mg, 600 μmol) was dissolved in dichloromethane (2 ml) and oxalyl chloride ( The mixture was stirred at ambient temperature for 5 min and then diluted with N, N-Dimethylformamide (2.3 μl) was added. After 40 min, ammonia (28% Aqueous solution (1.02 mL, 54 mmol) was added and the resulting mixture was vigorously stirred for an additional 30 min. The organic phase was separated. The aqueous phase was extracted with dichloromethane (2 ml). The organic phase was dried (phase separator) and concentrated. Borane (1M in tetrahydrofuran, 2.4 mL) l, 2.4 mmol) was added and the mixture was stirred at ambient temperature for 14 h and then heated to 50 °C. After another 7 hours, borane (1M in tetrahydrofuran, 1.2 ml, 1.2 (mmol) was added and the mixture was stirred for 17 h. The reaction was quenched with methanol and concentrated Sodium hydroxide (aqueous, 1M, 10 ml) was added and the mixture was diluted with dichloromethane. The organic phase was extracted with hydrochloric acid (aq, 1M, 10 ml). The aqueous phase was made basic using sodium hydroxide (aq, 5M) and diluted with dichloromethane (3 × 10 ml). The organic phase was dried (phase separator) and concentrated (45 mg, 42%). .

[0291] 1-[(2,4-difluorophenyl)methyl]-3-[(3,3-dimethyl-2,3 -Dihydro-1-benzofuran-5-yl)methyl]-1-(1-methylpiperidine-4 -yl)urea;Trifluoroacetic acid

[0292] A stirred solution of diphosgene (12 μl, 100 μmol) in dichloromethane (1 ml) was The solution was diluted with 3,3-dimethyl-2,3-dihydro-1-phenylpropanediol (1 ml) in dichloromethane. Dibenzofuran-5-ylmethanamine (35.4 mg, 200 μmol) was added. Isopropylethylamine (105 μl, 600 μmol) was added. The mixture was stirred for 15 min. Stir for 10 minutes, then add N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine After an additional 30 min, the mixture was diluted with hydroxyethyl ether. The aqueous phase was washed with sodium chloride (aqueous, 1M, 2 ml). The combined organic phase was dried (phase separator) and concentrated. The crude material was extracted with 20 mL of water. by HPLC eluting with 50% acetonitrile (containing 0.1% trifluoroacetic acid). Purification afforded the title compound (91 mg, 82%). 1 H NMR (400MHz, Fluoroform-d) δ 12.56 (bs, 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),4.2 1(s,2H),3.61(d,2H),2.86(t,2H),2.79(s,3H) ,2.18(qd,2H),1.92(d,2H),1.29(s,6H);LC-MS :444.0[M+H] + .

[0293] Example 10: 1-[(2,4-difluorophenyl)methyl]-3-[(2,3-difluorophenyl)methyl] 1-(1-methylpiperidin-4-yl)-1-benzofuran-5-yl)methyl )Urea(10) [ka]

[0294] Bis(phenyl N-[(2,3-dihydro-1-benzofuran-5-yl)methyl]ca Rubamate) [ka]

[0295] (2,3-dihydro-1-benzofuran-5-yl)methanamine (59 mg, 0.3 9 mmol) and pyridine (65 μl, 0.8 mmol) in dichloromethane (1 ml) The mixture was stirred at rt and phenyl chloroformate (71 μl, 0.55 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then dissolved in dichloromethane and sodium hydroxide (aqueous, 0.5 M). The organic phase was separated, dried and evaporated, and the residue was purified by 67% acetic acid in petroleum ether. Purification was performed by column chromatography on silica gel eluted with ethyl acetate. This afforded the desired intermediate (88 mg, 83%).

[0296] 1-(2,4-Difluorobenzyl)-3-((2,3-dihydrobenzofuran-5- 1-(1-methylpiperidin-4-yl)urea N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (101 mg, 0.40 mmol) and bis(phenyl N-[(2,3-dihydro-1- Benzofuran-5-yl)methyl]carbamate) (88 mg, 0.326 mmol) , dissolved in toluene (2.0 ml) and diisopropylethylamine (105 μl, 6 The mixture was stirred at 120° C. for 17 hours, then sodium hydroxide was added. The mixture was partitioned between methanol (aq, 0.5M) and ether. The organic phase was separated and concentrated. The residue was A column made of silica gel, eluted with 0-33% methanol in ethyl acetate The fractions containing the desired material were pooled, concentrated, and purified by distillation. The clear solution was evaporated to give the title compound. The mixture was obtained as an oil (92 mg, 68%). The oil was triturated in ether / hexane to give the following product: The title compound was obtained as a crystalline, non-hygroscopic free base (69.2 mg, 51%). 1 H.N.M. R(400MHz, chloroform-d) δ7.22(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,2 H),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] + .

[0297] Example 11 (Comparative): 1-[(3,5-difluorophenyl)methyl]-1-(1-methylphenyl) ethylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl }Urea;Trifluoroacetic acid (11) [ka]

[0298] The compound was prepared as follows: N-[(3,5-difluorophenyl)methyl]-1-methylpiperidine- 4-Amine and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene Prepared as in Example 2 using the same procedure as in Example 2. Yield: 62%. 1 H NMR (400MHz, Chloroform-d) δ7.02(d,2H),6.83-6.78(m,2H),6.7 4(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(dq,1H),1.96-1.85( m,2H),1.01(d,6H);LC-MS:446.3[M+H] + .

[0299] Example 12 (Comparative): 1-[(3,5-dimethoxyphenyl)methyl]-1-(1-methylphenyl) ethylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl }Urea;Trifluoroacetic acid (12) [ka]

[0300] The compound was prepared as follows: N-[(3,5-dimethoxyphenyl)methyl]-1-methylpiperidine- 4-Amine and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene Prepared as in Example 2 using the same procedure as in Example 2. Yield: 34%. 1 H NMR (400MHz, Chloroform-d) δ7.02(d 2H), 6.80-6.74(m,2H), 6.3 4(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] + .

[0301] Example 13: 1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1- Methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl urea; trifluoroacetic acid (13) [ka]

[0302] 2-(Benzyloxy)-4-fluorobenzonitrile [ka] Potassium tert-butoxide (2.34 g, 21 To a stirred suspension of 1.2 mmol, benzyl alcohol (2.33 g, 22 mmol) was added The mixture was stirred for 10 minutes and then 2,4-difluorobenzonitrile ( The mixture was stirred for 1.5 hours and then diluted with water. (10 ml) was added and the mixture was extracted with diethyl ether (3×10 ml). The organic phase was dried using a phase separator and concentrated to a solid. The crude material was dissolved in petroleum ether and concentrated to a solid. Column chromatography using silica gel, eluted with 25-50% dichloromethane. Purification by HPLC gave the desired intermediate (1.33 g, 5.8 mmol, 81%). Got it.

[0303] [2-(benzyloxy)-4-fluorophenyl]methanamine [ka]

[0304] 2-(benzyloxy)-4-fluorobenzonitrile (208 mg, 0.92 mmol) l) BH at 4℃ 3 (1.4 ml, 1M in tetrahydrofuran). Hours later, BH 3 (1.4 ml) was added at room temperature, and after another 19 hours, BH 3 (1 ml) was added and stirring was continued for 3 h, followed by NaOH (5 ml, 1 M Aqueous solution) was added dropwise and the mixture was extracted with ethyl acetate (3×5 ml). It was dried using a phase separator and concentrated to an oil (260 mg).

[0305] N-{[2-(benzyloxy)-4-fluorophenyl]methyl}-1-methylpiperidine Lysine-4-amine [ka]

[0306] [2-(benzyloxy)-4-fluorophenyl] in ethanol (5 ml) at room temperature To a stirred solution of methanamine (204 mg) was added 1-methylpiperidin-4-one (1 63 μl), followed by sodium triacetoxyborohydride (372 mg) in one portion. The mixture was stirred for 6 h, then concentrated and diluted with NaOH (5 ml, 1 M aqueous solution). The combined organic phase was separated using a phase separator and washed with dichloromethane (3 x 5 ml). It was dried and concentrated to an oil (253 mg).

[0307] 1-{[2-(benzyloxy)-4-fluorophenyl]methyl}-1-(1-methyl piperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl} Urea (13b) [ka] N-{[2-(benzyloxy)-4-fluorophenyl] A stirred solution of 1-phenylmethyl-1-methylpiperidin-4-amine (127 mg) 1-(isocyanatomethyl)-4-(2-methylpropanediol) in dichloromethane (1 ml) A solution of (112 mg) phenyloxybenzene was added. The mixture was stirred for 3 hours and then diluted with N The organic phase was dried using a phase separator. and concentrated to an oil (229 mg).

[0308] 1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1-methylpiperidinyl) (4-(2-methylpropoxy)phenyl)methyl)urea; Trifluoroacetic acid

[0309] 1-{[2-(benzyloxy)-4-fluorophenyl] in ethanol (5 ml) methyl}-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropionyl) A solution of 2,4-dimethoxyphenylmethylurea (90 mg) was stirred under nitrogen and charcoal ( Palladium (10 wt%) on 58 mg was added in one portion at room temperature. The nitrogen atmosphere was replaced with hydrogen atmosphere. The atmosphere was replaced with hydrogen and the mixture was stirred for 2.5 h. The hydrogen atmosphere was removed and the mixture was washed with water and placed on a pad of Celite. The plug was filtered with ethanol and the filtered solvent was concentrated to a crude oil. HPLC eluted with 55-75% acetonitrile (containing 0.1% trifluoroacetic acid) C to give the title compound (33 mg, 0.059 mmol, 4 steps The result was 41%). 1 H NMR (400MHz, chloroform-d) δ 12.13 (bs,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] + .

[0310] Example 14: 1-[(4-fluorophenyl)methyl]-3-{[2-hydroxy-4 -(2-methylpropoxy)phenyl]methyl}-1-(1-methylpiperidine-4-yl Urea; Trifluoroacetic acid (14) [ka]

[0311] 2-(Benzyloxy)-4-(2-methylpropoxy)benzonitrile [ka]

[0312] 2-(benzyloxy)-4-fluorobenzonitrile in dioxane (2 ml) at room temperature To a stirred solution of 1,2-dichloropropane (208 mg, 0.92 mmol), 1,2-dichloropropane (126 μl) was added 1,2-dichloropropane (1.2 mmol), ... ), followed by potassium tert-butoxide (146 mg) was added in one portion. Stir for 7 h, then add water (10 ml) and diethyl ether (3×10 ml) The combined organic phase was dried using a phase separator and concentrated to an oil (287 mg). It shrunk.

[0313] [2-(benzyloxy)-4-(2-methylpropoxy)phenyl]methanamine [ka]

[0314] 2-(benzyloxy)-4-(2-methylpropoxy)benzonitrile (287mg (mmol) in BH at 4°C 3 (1 ml, 1M in tetrahydrofuran) After 1.5 hours, the mixture was heated to 60°C and after 1.5 hours, BH 3 Solution (1ml) The mixture was cooled to room temperature and NaOH (4 ml, 1M Aqueous solution) was added dropwise and the mixture was extracted with diethyl ether (3×5 ml). The phases were dried using a phase separator and concentrated to an oil (393 mg).

[0315] 3-{[2-(benzyloxy)-4-(2-methylpropoxy)phenyl]methyl} -1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl) urea [ka]

[0316] To a stirred solution of diphosgene (50 μl) in dichloromethane (1 ml) at 0°C, [2-(benzyloxy)-4-(2-methylpropoxy) A mixture of phenylmethanamine (102 mg) and pyridine (87 μl) was stirred for 2 min. The mixture was stirred for 1 hour and then diluted with N-[( 4-Fluorophenyl)methyl]-1-(1-methylpiperidin-4-amine (71mg The mixture was stirred for 3 hours and then added dropwise to a stirred solution of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether) at room temperature over a period of 2 minutes. The organic phase was dried using a phase separator. and concentrated to an oil (168 mg).

[0317] 1-[(4-fluorophenyl)methyl]-3-{[2-hydroxy-4-(2-methyl (1-methylpiperidin-4-yl)urea; Trifluoroacetic acid

[0318] 3-{[2-(benzyloxy)-4-(2-methylpropionyl) 1-[(4-fluorophenyl)methyl]-1-(1-methyl A solution of 168 mg of 1,2-dipiperidin-4-yl urea was stirred under a nitrogen atmosphere and charcoal was added. (70 mg) of palladium (10 wt%) was added in one portion at room temperature. The nitrogen atmosphere was replaced with hydrogen The atmosphere was exchanged and the mixture was stirred for 2.5 h. The hydrogen atmosphere was removed and the mixture was padded with Celite The mixture was filtered through a plug of ethanol and the filtered solvent was diluted with dichloromethane (3 × 5 ml). The combined organic phases were dried using a phase separator and concentrated to a crude oil. One third is 40-70% acetonitrile in water (containing 0.1% trifluoroacetic acid) The title compound (15 mg, 0.026 mmol, 4 33%) over three steps. 1 H NMR (400MHz, chloroform- d)δ12.65(bs,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),3.6 7(d,2H),3.55(d,2H),2.89-2.74(m,5H),2.23( q,2H),2.05(p,1H),1.85(d,2H),1.00(d,6H);L C-MS: 444.3 [M+H] + .

[0319] Example 15: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluorophenyl)methyl] {fluoroethoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea; Trifluoroacetic acid (15) [ka] .

[0320] 4-(2-Fluoroethoxy)benzonitrile [ka]

[0321] 2-Fluoroethanol (145 μl, 2.46 mmol) was dissolved in dioxane (2 ml). To a mixture of potassium tert-butoxide (277 mg, 2.46 mmol) in water was added After stirring at room temperature for 5 minutes, 4-fluorobenzonitrile ( After stirring at room temperature for 16 hours, the mixture was The mixture was added to a layer of diethyl ether (5 ml) on water (5 ml). The combined organic layers were dried and concentrated using a phase separator. The desired intermediate was obtained as a white solid (261.3 mg).

[0322] [4-(2-fluoroethoxy)phenyl]methanamine [ka]

[0323] Borane (2 ml, 1 M in tetrahydrofuran, 2 mmol) was added to 4-(2-fluoroethane (133 mg, 0.805 mmol) was added to the mixture at room temperature for 1 h. After stirring, the mixture was heated to 40° C. After stirring for 1 h, the mixture was concentrated. The residue was It was redissolved in methanol (2 ml) and refluxed for 1 h and concentrated to an oil. A 1M aqueous solution was added and the product was extracted with ethyl acetate (2×1 ml). Drying using a separatory separator and concentration gave the desired intermediate as an oil (113.8 mg).

[0324] 3-[(2,4-difluorophenyl)methyl]-1-{[4-(2-fluoroethoxy) phenyl]methyl}-3-(1-methylpiperidin-4-yl)urea;Trifluoro Acetic acid

[0325] [4-(2-fluoroethoxy)phenyl] dissolved in dichloromethane (0.5 ml) ] Methanamine (51.3 mg, 0.303 mmol) was dissolved in dichloromethane (0.5 ml Diphosgene (18.3 μl, 0.152 mmol) dissolved in diisopropyl ether (Diphosgene) was added to the flask, and then the mixture was cooled to 30° C. Diisopropylethylamine (106 μl, 0.606 mmol) was added dropwise. The mixture was stirred at room temperature for 15 minutes. After stirring for 1 h, N-[(2,4-difluorophenyl) phenyl)methyl]-1-methylpiperidin-4-amine (87.4 mg, 0.364 m After stirring for an additional 2 h, the mixture was concentrated. The crude material was dissolved in water and HPLC eluted with 15-50% acetonitrile (containing 0.1% trifluoroacetic acid) Purification by ethyl acetate gave the title compound (87.0 mg, 52%): 1 H NMR (400MHz , chloroform-d) δ 12.88 (bs, 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(qd,2H),1.89(d,2H);LC MS:436.3[M+H] + obtained.

[0326] Example 16: 1-[(2,4-difluorophenyl)methyl]-3-[(4-ethoxy phenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (16) [ka] .

[0327] 1-Ethoxy-4-(isocyanatomethyl)-benzene [ka]

[0328] 4-Ethoxyphenylacetic acid (10.0 g, 53.38 mmol) was dissolved in dichloromethane ( 60ml), thionyl chloride (40ml) and N,N-dimethylformamide (200ul The mixture was evaporated and triturated in diethyl ether. The diethyl ether extract was evaporated to give 2-(4-ethoxyphenyl)acetyl chloride (1 This material (7.0 g, 95% purity, 33.4 mmol) was obtained. l) in acetone (15 ml) and dissolved in sodium azide (3.0 ml) in water (15 ml). 7 g, 46.8 mmol) was added to a solution of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether) at 0° C. for 10 min. After stirring at 0° C. for 1 h, The mixture was diluted with cold water (40 ml) and extracted with toluene (2×40 ml). Combine, dry (sodium sulfate), and evaporate on a rotary evaporator using a 30 °C water bath. The solution was then concentrated to 60 ml with toluene until gas evolution ceased (30 min). The mixture was stirred for an additional 5 minutes and then evaporated to an oil. It was dissolved in heptane (40 ml). The solution was filtered to remove solids and the filtrate was evaporated. This afforded the title compound as an oil (6.81 grams, 100% yield).

[0329] 3-[(2,4-difluorophenyl)methyl]-1-[(4-ethoxyphenyl)methyl] ethyl]-3-(1-methylpiperidin-4-yl)urea

[0330] 1-Ethoxy-4-(isocyanatomethyl)benzene (purity 87%, 200 mg, 1 ,08mmol) was dissolved in dichloromethane (2ml) and N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4 dissolved in -amine (200 mg, 832 μmol) was added. The mixture was stirred for 20 min and then Partitioned between sodium hydroxide (aqueous, 0.5M) and dichloromethane. The organic phase was evaporated. The residue was dissolved in diethyl ether / hexane, acetone / water, and diethyl ether / hexane. Successive recrystallizations from the solvent gave 109 mg of impure compound. The material was dissolved in ethyl acetate and The product was purified by silica gel chromatography eluting with 0-33% methanol. The title compound (71 mg, 21% yield); 1 H NMR (400MHz, chloroform-d )δ7.26-7.16(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] + obtained.

[0331] Example 17: 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-diphenyl Fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea;Hemitartrate Acid salts (17) [ka]

[0332] 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl) nyl)methyl]-1-(1-methylpiperidin-4-yl)urea;Hemitartrate

[0333] N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (1.89mmol, 478mg), Phenyl N-[(4-cyclopropoxyphenyl) methyl]carbamate (97%, 585 mg, 2.0 mmol) and potassium carbonate (2. The mixture was heated at 70° C. Stirred for 16 h then partitioned between toluene and sodium hydroxide (aqueous, 0.5M). The organic phase was separated and concentrated. The material was eluted with 0-50% methanol in ethyl acetate. The product was purified by silica gel chromatography using a 100% aqueous hexanes solvent. The fractions containing the desired product were pooled. 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 m This material (725 mg, 1.688 mmol) and L-( +)-Tartaric acid (0.844 mmol, 127.3 mg) was dissolved in ethanol using an ultrasonic bath. The mixture was dissolved in ethanol (5.0 ml). The solvent was then evaporated to give the title compound as the hemi-tartrate salt ( Glassy foam, 906 mg). 1 H NMR (400MHz, chloroform Mu-d)δ7.16(q,1H),7.05(d,2H),6.94(d,2H),6. 84-6.73(m,2H),4.70(bt,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] + .

[0334] Example 18: 3-{[4-(tert-butoxy)phenyl]methyl}-1-[(2, 4-Difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; Trifluoroacetic acid (18). [ka]

[0335] The compound was synthesized using 4-fluorobenzonitrile and potassium tert-butoxide. , 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy {phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea (Example 15) No 2-fluoroethanol was added. The crude material was diluted with 20 By HPLC eluting with ~55% acetonitrile (containing 0.1% trifluoroacetic acid), and purified to give the title compound (19.7 mg, 32%): 1 H NMR 1 H NMR(4 00MHz, chloroform-d) δ12.57(bs,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);LCMS:446.3[M+H] + obtained.

[0336] Example 19: 3-(4-(allyloxy)benzyl)-1-(2,4-difluorobenzyl) diethyl)-1-(1-methylpiperidin-4-yl)urea; trifluoroacetic acid (19). [ka]

[0337] PhenylN-{[4-(prop-2-en-1-yloxy)phenyl]methyl}carbamate Bamet [ka]

[0338] 4-(hydroxy)-benzaldehyde (10.0 g, 80.25 mmol), calcium carbonate ammonium iodide (163.8 mmol, 22.6 g), tetrabutylammonium iodide (1.0 mmol, 377 mg), allyl bromide (121 mmol, 10.6 ml) and N,N-di Methylformamide (4.0 ml) was stirred at 20°C for 6 hours, then water and diethyl ether were added. The organic phase was washed several times with water, then dried and evaporated to give 4-(allyloxy) C)-benzaldehyde was obtained as an oil (13.3 g, 100%). 7 g, 68.8 mmol) was dissolved in ethanol (40 ml) and sodium borohydride was added. The mixture was stirred for 1 hour and then Concentrate and add sodium hydroxide (aqueous, 5M, 30 ml) and water (100 mL). The mixture was extracted with diethyl ether, the organic phase was washed with water and brine, and then evaporated. 4-(allyloxy)-benzyl alcohol (10.49 g, 63.9 mmol, 9 The alcohol (3.0 g, 18.2 mmol) was dissolved in dichloromethane (10 The mixture was dissolved in 100 ml of thionyl chloride (37 mmol, 2.8 ml) and thionyl chloride (37 mmol, 2.8 ml) was added. The mixture was stirred at 0° C. for 10 min and then evaporated. The residue was dissolved in N,N-dimethylformamide (7 ml l), potassium phthalimide (20 mmol, 3.75 g), followed by pyridine (5 mmol, 410 μl) was added. The mixture was incubated at room temperature for 20 h and then at 50° C. for 30 h. The mixture was stirred for 1 min. Hydrochloric acid (aq, 1M, 20 ml) was added. The crystals were isolated by filtration. After washing with 33% methanol in water and drying, 5.18 g of material was obtained, which was then diluted with 95% ethanol. The phthalimide derivative was obtained by recrystallization from ethanol (4.7 g, yield 88%). The sample was diluted with 33% methylamine in ethanol (16 ml) and 15% The mixture was stirred for 18 hours and then at 60° C. for 30 minutes. The mixture was diluted with diethyl ether and hydroxyl The organic phase was separated and extracted with hydrochloric acid (aq, 1M). The aqueous phase was made basic with sodium hydroxide (5M) and then extracted with diethyl ether. The organic phase was dried and evaporated to give the intermediate 4-allyloxy-benzylamine (2.24 This material (1.5 g, 9.1 mmol) and pyridine (11.8 3mmol, 0.96mL) in dichloromethane (10ml) was stirred in an ice bath and dichloromethane was added. Phenyl chloroformate (10.01 mmol, 1.614 g) dissolved in methane (5 ml) The mixture was stirred at room temperature for 1 hour, and then dichloromethane was added dropwise. The mixture was partitioned between ethanol and hydrochloric acid (aqueous, 0.5 M). The organic phase was dried and evaporated to an oil (2.3 g). The desired intermediate was obtained as crystals (4.62 mmol, 1.3 Obtained as 1g, 51%).

[0339] 3-[(2,4-difluorophenyl)methyl]-3-(1-methylpiperidine-4- yl)-1-{[4-(prop-2-en-1-yloxy)phenyl]methyl}urea; Trifluoroacetic acid

[0340] N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.588mmol, 149mg) and phenyl N-{[4-(prop-2-ene-1 -(2-yloxy)phenyl]methyl}carbamate (200 mg, 0.705 mmol) Dissolve in toluene (1.5 ml) and add cesium carbonate (1.0 mmol, 326 mg). The mixture was stirred at 80°C for 2 hours, then diluted with diethyl ether and sodium hydroxide ( The organic phase was concentrated and partitioned between 0% to 50% methanol in ethyl acetate. The product was purified by silica gel chromatography eluting with hexanes. The fractions were pooled and concentrated. Diethyl ether was added. The mixture was filtered and concentrated to give The desired compound was obtained as the free base (112 mg, 0.261 mmol, 44% yield). The material was dissolved in dioxane (3 ml) and trifluoroacetic acid (0.27 mmol, 2 1 ul) was added, followed by lyophilization to give the title compound (0.27 mmol, 146 mg, A 100% yield was obtained. 1 H NMR (400MHz, 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(qd,1H),5.29(qd,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] + .

[0341] Example 20: 3-[(1-benzofuran-5-yl)methyl]-1-[(2,4-difluorophenyl) [fluorophenyl]methyl-1-(1-methylpiperidin-4-yl)urea; Acetic acid (20) [ka]

[0342] Stirring diphosgene (21.2 mg, 107 μmol) in dichloromethane (700 μl) To the stirred solution was added (1-benzofuran-5-yl)methylphenyl ether (700 μl) in dichloromethane. Tanamine (30.0 mg, 204 μmol) and triethylamine (56.8 μl, 4 08 mmol) was added. The mixture was stirred for 30 min and then N-[(2,4-difluoro phenyl)methyl]-1-methylpiperidin-4-amine (51.4 mg, 214 μmol l) was added. After an additional 5 h, the mixture was concentrated. The crude material was diluted with 15-50% The product was purified by HPLC eluting with acetonitrile (containing 0.1% trifluoroacetic acid). This afforded the title compound (79 mg, 74%). 1 H NMR (400MHz, chloroform rum-d)δ 1 H NMR (400MHz, chloroform-d) δ 12.07 (bs, 1 H),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(bs,1H),4.79-4.64(m,1H),4.43(s, 2H),4.38(s,2H),3.59(d,2H),2.86(t,2H),2.7 8(s,3H),2.17(qd,2H),1.91(d,2H);LC-MS:414 .2[M+H] + .

[0343] General Procedure

[0344] [ka] Scheme S1: General procedure A (GP A).

[0345] Amine 1 (1.1 equiv.) was dissolved in CH 2 Cl 2 followed by addition of ketone 2 (1.0 equiv.) in Sodium triacetoxyborohydride (1.5 eq.) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was stirred for 3 h and then concentrated under reduced pressure. The residue was diluted with NaOH (1M, aq.) and H 2 Cl 2 The organic phase was dried and concentrated under reduced pressure to give the secondary amine 3, which was obtained without further purification or by silica gel chromatography to give the following: Used in step CH 2 Cl 2 A solution of amine 4 (1.0 equiv.) in CH 2 Cl 2 The solution was added dropwise to a solution of diphosgene (0.5 equiv.) in 100 ml of water at room temperature. DIPEA (3.0 equiv.) was added. The resulting mixture was stirred at room temperature for 5 min. 2 Cl 2 Secondary amines in A solution of 3 (1.1 equiv.) was added and the reaction mixture was stirred at room temperature overnight. The mixture was cooled under reduced pressure. The concentrated urea 5 was obtained by distillation with acetonitrile in water (containing 0.1% trifluoroacetic acid). Purification by preparative HPLC eluting with 6 ppm of acetonitrile gave the TFA salt of the product. Preparative HPLC eluted with acetonitrile in water containing ammonia (28% in water) Further purification gave the product as the free base.

[0346] [ka] Scheme S2: General procedure B (GP B). Amine 1 (1.1 equiv.) was dissolved in CH 2 Cl 2 followed by addition of ketone 2 (1.0 equiv.) in Sodium triacetoxyborohydride (1.5 eq.) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was stirred for 3 h and then concentrated under reduced pressure. The residue was diluted with NaOH (1M, aq.) and H 2 Cl 2 The organic phase was dried and concentrated under reduced pressure to give the secondary amine 3, which was obtained without further purification or by silica gel chromatography to give the following: Used in step CH 2 Cl 2 Isocyanate 4 (1.0 equiv.) in CH 2 Cl 2 To a solution of secondary amine 3 (1.0 equiv.) in 1000 mL of 1000 mM NaOH at room temperature, the reaction mixture was stirred for 3 h. The mixture was concentrated under reduced pressure and the desired urea 5 was obtained by distillation with acetonitrile in water (0.1% trichloroethylene). Purification by preparative HPLC eluting with 2-fluoroacetic acid affords the TFA salt of the product. or acetonitrile in water containing 6 ppm ammonia (28% aqueous solution). Purification by preparative HPLC afforded the product as the free base.

[0347] [ka] Scheme S3: General procedure C (GP C).

[0348] Amine 1 (1.1 equiv.) was dissolved in CH 2 Cl 2 followed by addition of ketone 2 (1.0 equiv.) in Sodium triacetoxyborohydride (1.5 eq.) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was stirred for 3 h and then concentrated under reduced pressure. The residue was diluted with NaOH (1M, aq.) and H 2 Cl 2 The organic phase was dried and concentrated under reduced pressure to give the secondary amine 3, which was obtained without further purification or by silica gel chromatography to give the following: Used in step CH 2 Cl 2 A solution of amine 4 (1.0 equiv.) in CH 2 Cl 2 The solution was added dropwise to a solution of diphosgene (0.5 equiv.) in 100 ml of water at room temperature. DIPEA (3.0 equiv.) was added. The resulting mixture was stirred at room temperature for 5 min. 2 Cl 2 Secondary amines in A solution of 3 (1.1 equiv.) was added and the reaction mixture was stirred at room temperature overnight. The mixture was cooled under reduced pressure. The concentrated urea 5 was obtained by distillation with acetonitrile in water (containing 0.1% trifluoroacetic acid). Purification by preparative HPLC eluting with 6 ppm of acetonitrile gave the TFA salt of the product. Preparative HPLC eluted with acetonitrile in water containing ammonia (28% in water) Further purification gave the product as the free base.

[0349] [ka] Scheme S4: General procedure D (GP D).

[0350] Amine 1 (1.1 equiv.) was dissolved in CH 2 Cl 2 followed by addition of ketone 2 (1.0 equiv.) in Sodium triacetoxyborohydride (1.5 eq.) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was stirred for 3 h and then concentrated under reduced pressure. The residue was diluted with NaOH (1M, aq.) and H 2 Cl 2 The organic phase was dried and concentrated under reduced pressure to give the secondary amine 3, which was obtained without further purification or by silica gel chromatography to give the following: Used in step CH 2 Cl 2 Isocyanate 4 (1.0 equiv.) in CH 2 Cl 2 To a solution of secondary amine 3 (1.0 equiv.) in 1000 mL of 1000 mM NaOH at room temperature, the reaction mixture was stirred for 3 h. The mixture was concentrated under reduced pressure and the desired urea 5 was obtained by distillation with acetonitrile in water (0.1% trichloroethylene). Purification by preparative HPLC eluting with 2-fluoroacetic acid affords the TFA salt of the product. or acetonitrile in water containing 6 ppm ammonia (28% aqueous solution). Purification by preparative HPLC afforded the product as the free base.

[0351] In the above schemes S1 to S4, R i , R ii , R iii , R iv , R v , R vi , R vii , R viii , R ix , and R x are absent or 1, 2, or 3, respectively. R is present once and the R group is as disclosed in the final compound of Table 1, i.e., Example 21; v occurs twice In both cases, R vi is absent, and R vii exists once and It is methyl.

[0352] In Schemes S3 and S4, ring systems A and B are alicyclic, heteroalicyclic, aryl, and Heteroaryl and 5- and 6-membered ring systems, each of which is selected from the group consisting of: For example, ring system A in Example 22 is a heteroalicyclic ring, i.e., It's Sasol. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0353] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21]

[0354] Example 73: 1-[(2,4-difluorophenyl)methyl]-3-{[4-( 2 H 3 )Methoxyphenyl]methyl}-1-(1-methylpiperidin-4-yl)urea (73) [ka]

[0355] 4-( 2 H 3 )Methoxybenzonitrile [ka]

[0356] 4-Hydroxybenzonitrile (1.20 g, 10. 1mmol), iodine ( 2 H 3 ) methane (2.19 mg, 15.1 mmol) and K 2 C O 3 (2.78 g, 20.1 mmol) was heated to 37° C. for 20 hours. 0 ml) was added and the mixture was extracted with diethyl ether (200 ml). 3 × 40 ml) and rinse with Na 2 SO 4 Dry at 40° C., filter, and concentrate under reduced pressure to obtain the desired product. The intermediate (1.29 g) was obtained and used without further purification.

[0357] [4-( 2 H 3 )Methoxyphenyl]methanamine [ka]

[0358] LiAlH 4 (713 mg, 18.8 mmol) in THF (30 ml) 2 H 3 ) was added to a solution of methoxybenzonitrile (1.28 g, 9.40 mmol). The mixture was heated to reflux for 4 hours and then cooled to room temperature. Water (0.7 ml), THF (10 ml) , NaOH (0.7 ml, 15% aqueous solution), and water (2.1 ml) were added. Stir for 30 min, filter, concentrate under reduced pressure, redissolve in acetonitrile and concentrate again. This gave the desired intermediate (1.1 g) which was used without further purification.

[0359] Phenyl N-{[4-(2 H 3 )Methoxyphenyl]methyl}carbamate [ka]

[0360] CH 2 Cl 2 Phenyl chloroformate (1.60 g, 10.2 mmol) in (10 ml) ,CH 2 Cl 2 (10 ml) 2 H 3 )Methoxyphenyl]methanamine( 1.10 g, 7.85 mmol) and pyridine (0.95 ml) at 0° C. The mixture was stirred at this temperature for 20 min and then concentrated under reduced pressure. The residue was diluted with diethyl ether The organic phase was partitioned between ethanol (250 ml) and HCl (15.7 ml, 1M aqueous solution). 50ml) and rinse with Na 2 SO 4 The crude material was dried at 40° C., filtered and concentrated under reduced pressure. , which was purified by crystallization from ethyl acetate and n-heptane to give the desired intermediate (1.56 g ) was obtained.

[0361] 1-[(2,4-difluorophenyl)methyl]-3-{[4-( 2 H 3 )Methoxyf phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea

[0362] 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 2CO 3 A mixture of (414 mg, 3.00 mmol) was heated to 75° C. for 12 h. The mixture was diluted with CH 2 Cl 2 10% of the Purified by column chromatography on silica gel eluted with ethanol. This gave the title compound (760 mg, 94%). 1 H NMR (400MHz, DM SO-d6)δ7.26-7.10(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);LCMS:407.3[M+H] + .

[0363] Example 74: 1-[(2,4-difluorophenyl)methyl]-3-{[2-methoxyphenyl -4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidine -4-yl)urea (74) [ka]

[0364] [2-Methoxy-4-(propan-2-yloxy)phenyl]methanamine [ka]

[0365] LiAlH 4 (445 mg, 11.7 mmol) in THF (25 ml) Di-4-(propan-2-yloxy)benzonitrile (1.12 g, 5.86 mmol) ) was added to a solution of 100 ml of water (0.5 ml). The mixture was heated to reflux for 2 hours and then cooled to room temperature. l), THF (10 ml), NaOH (0.5 ml, 15% aqueous solution), and water (1.5 The mixture was stirred for 30 min, filtered and concentrated under reduced pressure to give the desired intermediate. (1.00 g) was obtained and used without further purification.

[0366] Phenyl N-{[2-methoxy-4-(propan-2-yloxy)phenyl]methyl }Carbamate [ka]

[0367] CH 2 Cl 2 Phenyl chloroformate (1.04 g, 6.66 mmol) in (7 ml) , C.H. 2 Cl 2 [2-Methoxy-4-(propan-2-yloxy)phenyl] in (7 ml) of 1.00 g, 5.12 mmol) and pyridine (0.62 ml) The solution was added dropwise at 0° C. The mixture was stirred at this temperature for 20 min and then concentrated under reduced pressure. The residue was partitioned between diethyl ether (250 ml) and HCl (10.2 ml, 1M aqueous solution). The organic phase was washed with water (50 ml) and 2 SO 4 Dry at 40°C, filter and extract under reduced pressure. Concentrate. The crude material is purified by elution with 20% ethyl acetate in petroleum ether, silica gel Purification by gel column chromatography gave the desired intermediate (1.00 g). obtained.

[0368] 1-[(2,4-difluorophenyl)methyl]-3-{[2-methoxy-4-(propionyl) 1-(1-methylpiperidin-4-yl) urea

[0369] Phenyl N-{[2-methoxy-4-(propan-2-yl)phenyl] N-[(2-methoxy)phenyl]methyl}carbamate (938 mg, 2.98 mmol), ,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (550 mg , 2.29 mmol) and K 2 CO 3 A mixture of (474 ​​mg, 3.43 mmol) was added to 7 The mixture was heated to 5° C. for 12 h. The mixture was concentrated under reduced pressure and diluted with NaOH (16 ml, 0.4 M The organic phase was washed with water (250 ml) and diethyl ether (200 ml). Wash and add Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure. CH containing NiA (28% aqueous solution) 2 Cl 2 Elute with 7% methanol in 100 ml of diacid The product was purified by column chromatography using silica gel to give the title compound (70 The yield was 0.0 mg, 66%). 1 H NMR (400MHz, 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(h,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),1.69-1.5 9(m,4H),1.32(d,6H);LCMS:462.3[M+H] + .

[0370] 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) [ka]

[0371] Phenyl N-{[4-(propan-2-yloxy)phenyl]methyl}carbamate [ka]

[0372] CH 2 Cl 2 Phenyl chloroformate (1.84 ml, 15.4 mmol) in (5 ml) ,CH 2 Cl 2 [4-(propan-2-yloxy)phenyl]meth amine (2.0 g, 11.9 mmol) and pyridine (1.2 ml, 15.4 mmol) The mixture was stirred at this temperature for 1 h and then diluted with dichloromethane. HCl (0.4 M in water). The organic phase was partitioned with Na 2 SO 4 Dry and filter with Concentration under reduced pressure. The crude material was purified by crystallization from ethyl acetate and n-heptane. The desired intermediate (2.93 g) was obtained.

[0373] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4-( 1-phenyl-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate Ruboxylate [ka]

[0374] Phenyl N-{[4-(propan-2-yloxy)phenyl tert-Butyl 4-{ [(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate (1.02 g, 3.13 mmol) and K 2 CO 3 (605mg, 4.38mmol) The mixture was heated to 75° C. for 21 h. The mixture was concentrated under reduced pressure to diethyl ether ( The aqueous phase was diluted with diethyl ether and then soaked in water for 1 h. The combined organic phase was washed with water (100 ml) and extracted again with N a 2 SO 4 The crude material was purified by elution with 50% ethyl acetate in petroleum ether. Purification was performed by column chromatography on silica gel, eluting at 40°C. To give the title compound (1.2 g, 74%).

[0375] 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3 -{[4-(propan-2-yloxy)phenyl]methyl}urea (142) [ka]

[0376] TFA (4 ml) was added to CH 2 Cl 2 tert-Butyl 4-{[(2, 4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl] Methyl}carbamoyl)amino}piperidine-1-carboxylate (1.20 g, 2. After stirring at room temperature for 20 minutes, the mixture was concentrated under reduced pressure. NaHCO 3 (10 ml, saturated aqueous solution) and diethyl ether (150 ml) were added. The organic phase was 2 SO 4 Dry at 40° C., filter, and concentrate under reduced pressure to give the desired intermediate (0. 80 g) is obtained, which can be used without further purification or the resulting concentrate can be diluted with water The fraction is eluted with 20-40% acetonitrile (containing 0.1% trifluoroacetic acid) in Purification by HPLC gave 1-[(2,4-difluorophenyl)methyl]-1-(piperidinediamine) Lysin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urine I got the ingredients.

[0377] 1-[(2,4-difluorophenyl)methyl]-1-{1-[(1,1,1,3,3 ,3- 2 H 6 )propan-2-yl]piperidin-4-yl}-3-{[4-(propane -2-yloxy)phenyl]methyl}urea;Trifluoroacetic acid

[0378] NaBH 3 CN (117 mg, 1.87 mmol) was dissolved in ethanol (4 ml) 2 H 6 ) propan-2-one (120 mg, 1.87 mmol) and 1-[(2,4-difluorophenyl) 4-(Propane- 2-yloxy)phenyl]methyl}urea (260 mg, 0.623 mmol) The mixture was stirred at room temperature for 18 hours and then further 2 H6 ) Propan-2-one (90 The mixture was stirred for an additional 4 days and then concentrated under reduced pressure. The crude material was concentrated in a 20-40% solution of acetonitrile (0.1% trifluoroacetic acid) in water. Purification by preparative HPLC eluting with 500 cc (containing acid) gave the title compound (10 mg, 3%): 1 H NMR(400MHz,DMSO-d6)δ8.91(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),3.3 4(d,2H),2.98(d,2H),1.94-1.79(m,2H),1.75( d,2H),1.24(d,6H);LCMS:466.4[M+H] + obtained.

[0379] Example 76: 1-[(2,4-difluorophenyl)methyl]-1-(piperidine-4 -yl)-3-[(4-propoxyphenyl)methyl]urea;Trifluoroacetic acid (76) [ka]

[0380] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[(4-pro (phenyl)methyl]carbamoyl})amino}piperidine-1-carboxylate [ka]

[0381] CH 2 Cl 2 (4-Propoxyphenyl)methanamine (52.0 ml) in mg, 0.315 mmol) was dissolved in CH 2 Cl 2 (0.5 ml) in diphosgene (2 3.0 μl, 0.192 mmol) was added dropwise at room temperature to a solution of DIPEA (132 μl, 0.758 mmol) was added and the resulting mixture was stirred at room temperature for 10 min. H 2 Cl 2 tert-Butyl 4-{[(2,4-difluorophenyl) )Methyl]amino}piperidine-1-carboxylate (133 mg, 0.407 mmol) A solution of l) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The product was diluted with CH 2 Cl 2 1 to 5% of the Purification was performed by column chromatography using silica gel eluted with methanol. This gave the desired intermediate (150 mg).

[0382] 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3 -[(4-Propoxyphenyl)methyl]urea;Trifluoroacetic acid TFA (0.5 ml) was added to CH 2 Cl 2 (1.5 ml) of tert-butyl 4-{[ (2,4-difluorophenyl)methyl]({[(4-propoxyphenyl)methyl]ca rubamoyl}amino}piperidine-1-carboxylate (80.4 mg, 0.155 After stirring at room temperature for 30 minutes, toluene (1.5 ml) was added. The crude material was purified by distillation with 20-40% acetonitrile in water ( The title compound was obtained by preparative HPLC eluting with 0.1% trifluoroacetic acid. (42 mg, 51%): 1 H NMR (400MHz, DMSO-d6) 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[M+H] + obtained.

[0383] Example 77: 3-[(1H-1,3-benzodiazol-5-yl)methyl]-1-[ (2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urine Trifluoroacetic acid (77) [ka]

[0384] 2-(Trimethylsilyl)ethyl 4-({[(1H-1,3-benzodiazole-5- 2,4-Difluorophenyl)methyl]amino)piperidine Lysine-1-carboxylate [ka]

[0385] 2-(Trimethylsilyl)ethyl 4-[(chlorocarbonyl) )[(2,4-difluorophenyl)methyl]amino)piperidine-1-carboxylate (102 mg, 0.240 mmol) in DMF (1.0 mL) Benzodiazol-5-yl)methanamine dihydrochloride (51.6 mg, 0.23 The mixture was added dropwise to a solution of 1000 mM NaOH (1.4 mmol) and DIPEA (143 μl, 0.821 mmol). The mixture was stirred at room temperature for 4 days and then further treated with 2-(trimethylsilyl)ethyl 4-[(chloro) (2,4-difluorophenyl)methylamino)piperidine-1-carboxylate Carboxylate (34.4 mg, 0.081 mmol) was added, and the mixture was stirred for an additional hour. The crude material was stirred for 1 h and then concentrated under reduced pressure. CH containing 2 Cl 2 A silica gel was used, which is eluted with 1-10% methanol in 100% water. Purification by column chromatography using HPLC afforded the desired intermediate (111 mg).

[0386] 3-[(1H-1,3-benzodiazol-5-yl)methyl]-1-[(2,4-di Fluorophenyl)methyl]-1-(piperidin-4-yl)urea [ka]

[0387] TBAF (0.6 ml, 1M in THF) was dissolved in 2-(trimethylsilyl) 4-({[(1H-1,3-benzodiazol-5-yl)methyl]phenylsilyl)ethyl {(2,4-difluorophenyl)methyl}amino)piperidine-1-carboxamide The mixture was added with 111 mg (0.204 mmol) of carboxylate at room temperature. After 3 h, the mixture The mixture was heated to 50° C. and stirred at this temperature overnight, then concentrated under reduced pressure. % ammonia (28% in water) 2 Cl 2 1 to 100% of the methanol in The compound was purified by column chromatography on silica gel, eluting with hexane. The desired intermediate (110 mg) was obtained.

[0388] 3-[(1H-1,3-benzodiazol-5-yl)methyl]-1-[(2,4-di Fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; Oroacetic acid Formaldehyde (30.5 μl, 37% in water, 0.303 mmol) was added to ethanol. 3-[(1H-1,3-benzodiazol-5-yl)methyl] -1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)urea (110 mg, 0.275 mmol) was added dropwise to a solution of NaBH 3 CN(26. 0 mg, 0.414 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and 2 Cl 2 (3.0ml) and NaOH (3.0ml, 1M The aqueous phase was separated into CH 2 Cl 2 (3 × 3 ml) and the combined organic phase The crude material was extracted with 1% ammonia (28 % aqueous solution) 2 Cl 2 Eluted with 5-10% methanol in water. The mixture was purified by column chromatography using silica gel, followed by elution in 5-30% water. The product was purified by preparative HPLC eluting with acetonitrile (containing 0.1% trifluoroacetic acid). The title compound (31 mg, 21%) was prepared: 1 H NMR (400MHz, DMSO- d6)δ9.60(bs,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),4.31-4.1 8(m,1H),3.40(d,2H),2.98(t,2H),2.72(s,3H) ,1.91-1.67(m,4H);LCMS:414.3[M+H] + obtained.

[0389] Example 78 (Comparative): 1-[(2,4-difluorophenyl)methyl]-1-(1-methylphenyl) Thiazepan-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl {Urea};Trifluoroacetic acid (78) [ka]

[0390] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}azepane -1-carboxylate [ka]

[0391] (2,4-difluorophenyl)methanamine (112 mg, 0.779 mmol) CH 2 Cl 2 tert-Butyl 4-oxoazepane-1-carboxylate in (2.0 ml) The mixture was added to 100 ml of ethyl acetate (153 mg, 0.719 mmol) followed by triacetoxyborohydride. Sodium chloride (248 mg, 1.17 mmol) was added and the reaction was stirred at room temperature for 20 hours. NaOH (2 ml, 1 M aqueous solution) was then added and the mixture was diluted with CH 2 Cl 2 ( The organic phase was dried using a phase separator and concentrated under reduced pressure. The crude material was purified by centrifugation in CH4 containing 1% ammonia (28% in water). 2 Cl 2 1~1 of Column chromatography using silica gel, eluted with 0% methanol Further purification gave the desired racemic intermediate (219 mg).

[0392] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4-( azepan-1-yloxy)phenyl]methyl}carbamoyl)amino}azepan-1-yloxy Boxylate) [ka]

[0393] CH 2 Cl 2 [4-(propan-2-yloxy)phenyl]meth A solution of dimethylamine (100 mg, 0.294 mmol) was dissolved in CH 2 Cl 2 (0.5ml) medium was added dropwise to a solution of diphosgene (17.6 μl, 0.147 mmol) at room temperature. A (102 μl, 0.588 mmol) was added and the resulting mixture was stirred at room temperature for 17 min. After that, CH 2 Cl 2 tert-Butyl 4-{[(2,4-diphenyl fluorophenyl)methyl]amino}azepane-1-carboxylate (58.0 mg, A solution of 0.351 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The crude material was concentrated under reduced pressure. 2 C l 2Column chromatography using silica gel, eluted with 1-10% methanol in water. Purification by chromatography gave the desired intermediate (83.0 mg).

[0394] 1-(azepan-4-yl)-1-[(2,4-difluorophenyl)methyl]-3- {[4-(propan-2-yloxy)phenyl]methyl}urea [ka]

[0395] TFA (0.3 ml) was added to CH 2 Cl 2 (3.0 ml) (2,4-difluorophenyl)methyl]({[4-(propan-2-yloxy)phenyl nyl]methyl}carbamoyl)amino}azepane-1-carboxylate (82.0 mg After stirring at room temperature for 2 hours, toluene (1.0 ml) was added and the mixture was concentrated under reduced pressure. The crude material was purified by 1% ammonia (28% (aqueous solution) 2 Cl 2 Eluted with 1-10% methanol in Purification by column chromatography on gel afforded the desired intermediate (13.7 mg , 21%).

[0396] 1-[(2,4-difluorophenyl)methyl]-1-(1-methylazepane-4-yl) (4-(propan-2-yloxy)phenyl)methyl}urea; Acetic Acid

[0397] Formaldehyde (9.6 μl, 37% aqueous solution, 0.096 mmol) was dissolved in ethanol. 1-(azepan-4-yl)-1-[(2,4-difluorophenyl) 1-[4-(propan-2-yloxy)phenyl]methyl]-3-{[4-(propan-2-yloxy)phenyl]methyl}urea 3.7 mg, 0.032 mmol) at room temperature. 3 CN(6.7m g, 0.107 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude material was concentrated under reduced pressure. The product was purified by preparative HPLC eluting with 2,4-dichlorophenyl ether (containing fluoroacetic acid) to give the title compound (12 mg, 68%): 1 H NMR (400MHz, methanol-d4) 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),3.5 6-3.42(m,2H),3.29-3.02(m,2H),2.89(s,3H), 2.33-1.62(m,7H),1.31(d,6H);LCMS:446.3[M+ H] + obtained.

[0398] Example 79: 1-[(7R,8aS)-octahydroindolizin-7-yl]-3- [(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl) Methyl]urea;Trifluoroacetic acid (79) [ka]

[0399] (4-Cyclopropoxyphenyl)methanamine (0. A solution of 0.040 ml, 0.257 mmol) in diphosgene (1 ml) in dichloromethane (0.015 ml, 0.129 mmol) was added dropwise to a solution of DIPEA (0.1 34 ml, 0.772 mmol) was added and the resulting mixture was stirred at room temperature for 5 minutes. Then, (7R,8aS)-N-[(2,4-difluorophenyl) phenyl)methyl]-octahydroindolizine-7-amine (75.4 mg, 0.283 A solution of 100 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The crude material was eluted with acetonitrile in water (containing 0.1% trifluoroacetic acid). Purification by preparative HPLC afforded the title compound (84 mg, 54%). 1 H NMR( 400MHz, chloroform-d) δ12.20(br.s,1H),7.17-7.0 8(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(br. s,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). LCMS:456.3[M+H] +

[0400] Example 80: 1-[(7R,8aS)-octahydroindolizin-7-yl]-1- [(2,4-difluorophenyl)methyl]-3-{[4-(propan-2-yloxy) )phenyl]methyl}urea;Trifluoroacetic acid (80) [ka]

[0401] [4-(propan-2-yloxy)phenyl]methane in dichloromethane (1 ml) A solution of the amine (0.023 ml, 0.148 mmol) in dichloromethane (1 ml) was added dropwise to a solution of diphosgene (0.009 ml, 0.074 mmol) at room temperature. EA (0.077 ml, 0.445 mmol) was added and the resulting mixture was stirred at room temperature for 5 min. The mixture was stirred for 1 ml. Then, (7R,8aS)-N-[(2,4- Difluorophenyl)methyl]-octahydroindolizine-7-amine (43.4mg A solution of 1,2-dichlorophenyl ether (0.163 mmol) was added and the reaction mixture was stirred at room temperature overnight. The crude material was concentrated under reduced pressure and purified by elution with acetonitrile (containing 0.1% trifluoroacetic acid) in water. Purification by preparative HPLC eluting with ethyl acetate afforded the title compound (42 mg, 48%). 1 H NMR (400MHz, 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(br.s,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). LCMS:458.3[M+ H] +

[0402] Example 81: 1-[(2,4-difluorophenyl)methyl]-1-(piperidine-4 -yl)-3-[(quinoxalin-6-yl)methyl]urea (81) [ka]

[0403] CH 2 Cl 2 (Quinoxalin-6-yl)methanamine (24 mg, 0 0.150mmol), followed by DIPEA (0.1ml, 0.600mmol), 2-(Trimethylsilyl)ethyl 4-[(chlorocarbonyl)[(2,4-difluorophenyl) phenylmethylaminopiperidine-1-carboxylate (78 mg, 0.180 m mol) was added. The reaction was stirred at room temperature overnight. The volatiles were evaporated in vacuo. Brine (5.0 ml) was added and the compound was dissolved in CH 2 Cl 2 (4 × 7 ml). Machine phase Na 2 SO 4 The crude material was dried over petroleum ether and the solvent was removed by rotary evaporation. The column was chromatographed on silica gel, eluting with ethyl acetate in ethanol. This was further purified to give 2-(trimethylsilyl)ethyl 4-{[(2,4-difluorophenyl )methyl]({[(quinoxalin-6-yl)methyl]carbamoyl})amino}piperidin The zinzyl-1-carboxylate (80 mg, 95%) was obtained.

[0404] TBAF (2 ml, 1M in THF) was dissolved in 2-(trimethylsilyl) )ethyl 4-{[(2,4-difluorophenyl)methyl]({[(quinoxaline-6- yl)methyl]carbamoyl})amino}piperidine-1-carboxylate (80mg After 3 hours, the mixture was heated to 50° C. The mixture was concentrated under reduced pressure and the crude material was purified by distillation with acetonitrile (6p The title compound (40mM) was obtained by preparative HPLC eluting with 5000 ppm ammonia. g, 65%). 1 H-NMR (400MHz, 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). LCMS: 412.2 [M+H] +

[0405] Example 82: 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidine) Lysin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea (82) [ka]

[0406] Formaldehyde (0.010 ml, 37% aqueous solution, 0.122 mmol) was dissolved in ethanol. 1-[(2,4-difluorophenyl)methyl]-1-(piperidinyl) (quinoxalin-4-yl)-3-[(quinoxalin-6-yl)methyl]urea (23 mg, 0.05 6 mmol) was added to a stirred solution of NaBH(OAc) 3 (35.5m g, 0.168 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 4 hours. The material was evaporated in vacuum. 2 Cl 2 (7 ml) was added and the organic phase was cooled to 100°C. 3 (Fatigue The crude material was washed with acetonitrile in water (containing 6 ppm ammonia). ) to afford the title compound (15 mg, 60%). 1 H NMR (400MHz, 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),4.6 5(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). LCMS:426.3[M+H] +

[0407] Example 83: 3-[(4,5-difluoro-2-methoxyphenyl)methyl]-3-( Piperidin-4-yl)-1-{[4-(propan-2-yloxy)phenyl]methyl }Urea;Trifluoroacetic acid (83) [ka]

[0408] tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]a Amino}piperidine-1-carboxylate [ka]

[0409] (4,5-difluoro-2-methoxyphenyl)methanamine (191 mg) and te rt-Butyl 4-oxopiperidine-1-carboxylate (200 mg) in ethanol The reaction was dissolved in sodium triacetoxyborohydride (319 mg). The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was diluted with Na 2 CO 3 (saturated aqueous solution) The organic phase was dried and concentrated to give the desired intermediate (379 mg). obtained.

[0410] tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]( {[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine Lysine-1-carboxylate [ka]

[0411] tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]a Amino}piperidine-1-carboxylate (82 mg) was dissolved in dichloromethane (1 mL) at room temperature. The mixture was stirred in dichloromethane (0.5 ml). (44 mg) of propane-2-yloxy)benzene was added dropwise. Stir overnight. Concentrate the mixture under reduced pressure and obtain the desired urea with 50-70% aqueous petroleum ether. By column chromatography on silica gel eluted with ethyl acetate Purification gave the desired intermediate (77 mg).

[0412] 3-[(4,5-difluoro-2-methoxyphenyl)methyl]-3-(piperidine- 4-yl)-1-{[4-(propan-2-yloxy)phenyl]methyl}urea;Tri Fluoroacetic acid

[0413] tert-Butyl 4-{[(4,5-difluoro-2-methoxyphenyl)methyl]( {[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino}piperidine Lysine-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 was stirred for 90 minutes. The mixture was concentrated and the crude material was purified by distillation using 20-55% acetonitrile in water (0.1% trifluoroacetate). Purification by HPLC eluting with 2,4-dichlorophenyl ether (containing oroacetic acid) gave the title compound (49 mg, 62%). : 1 H NMR (400MHz, 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(dq,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);LCMS:448.3[M+H] + Got .

[0414] 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) [ka]

[0415] (1R,3R,5S)-N-[(2,4-difluorophenyl)methyl]-8-methyl -8-Azabicyclo[3.2.1]octan-3-amine [ka]

[0416] (2,4-Difluorophenyl)methanamine (112 mg, 779 μmol) was added to 8-Methyl-8-azabicyclo[3.2.1]octane-3 in chloromethane (2 ml) After stirring at room temperature for 10 minutes, trimethylsilyl 2-one (99.6 mg, 716 μmol) was added. Sodium acetoxyborohydride (224 mg, 1.06 μmol) was added. After stirring for 21 hours, sodium hydroxide (2 ml, 1M aqueous solution) was added. The extract was extracted with dichloromethane (3 x 1 ml) and the organic phase was dried using a phase separator and reduced to an oil. The crude material was purified by elution with dichloromethane containing 1% ammonia (28% aqueous solution). Column chromatography using silica gel, eluted with 5-10% methanol in water. Purification by filtration gave the desired intermediate (174 mg).

[0417] 3-[(2,4-difluorophenyl)methyl]-3-[(1R,3R,5S)-8- Methyl-8-azabicyclo[3.2.1]octan-3-yl]-1-{[4-(propanediol) 2-(2-phenyloxy)phenyl]methyl}urea;Trifluoroacetic acid

[0418] CH 2 Cl 2 [4-(propan-2-yloxy)phenyl]methanamine in (1 ml) A solution of amine (75.0 mg, 0.454 mmol) was dissolved in CH 2 Cl 2 (0.5ml) The solution was added dropwise to a solution of diphosgene (16.9 μ, 0.141 mmol) at room temperature. 98.1 μl, 0.563 mmol) was added and the resulting mixture was stirred at room temperature for 5 minutes. Then, C.H. 2 Cl 2 (1R,3R,5S)-N-[(2,4-difluorophenyl) (O-phenyl)methyl]-8-methyl-8-azabicyclo[3.2.1]octane-3- A solution of the amine (56.0 mg, 0.210 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude material was extracted with 20-40% acetonite in water. The product was purified by preparative HPLC eluting with ethyl acetate (containing 0.1% trifluoroacetic acid) to give the title compound. Compound (101 mg, 78%): 1 H NMR (400MHz, 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(p,1H),3.74(d,2H),2.69-2. 54(m,5H),2.36-2.12(m,6H),1.32(d,6H);LCMS :458.3[M+H] + obtained.

[0419] Example 85: 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 (85 ) [ka]

[0420] 1-[(2,4-difluorophenyl)methyl]-1-[(3R,4S)-1,3-di Methylpiperidin-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-(Pro phenyl]methyl}urea;Trifluoroacetic acid [ka]

[0421] (3R,4S)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethyl Piperidin-4-amine and (3S,4R)-N-[(2,4-difluorophenyl)methyl] 1,3-Dimethylpiperidin-4-amine [ka]

[0422] (3R,4R)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethyl Piperidin-4-amine and (3S,4S)-N-[(2,4-difluorophenyl)methyl] 1,3-Dimethylpiperidin-4-amine [ka]

[0423] 1,3-Dimethylpiperidin-4-one (91.0 mg, 715 μmol) was dissolved in dichloromethane (2,4-Difluorophenyl)methanamine (105 mg, 73 After stirring at room temperature for 5 minutes, sodium triacetoxyborohydride was added to the mixture. After stirring for an additional 3 hours, sodium hydroxide was added. Sodium thorium (1 ml, 1M aqueous solution) was added. The mixture was extracted with dichloromethane (1 ml). The organic phase was dried and concentrated using a phase separator. The crude material was diluted with 1% ammonia. Elute with 1-10% methanol in dichloromethane containing (28% aqueous solution), Purification by column chromatography using silica gel gave the cis intermediate: 3R,4S)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidine Lysine-4-amine and (3S,4R)-N-[(2,4-difluorophenyl)methyl ]-1,3-Dimethylpiperidin-4-amine (105 mg) and the trans intermediate: (3 R,4R)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidin Din-4-amine and (3S,4S)-N-[(2,4-difluorophenyl)methyl] To the obtained mixture was obtained 1,3-dimethylpiperidin-4-amine (14 mg).

[0424] 1-[(2,4-difluorophenyl)methyl]-1-[(3R,4S)-1,3-di Methylpiperidin-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-(Pro phenyl]methyl}urea;Trifluoroacetic acid

[0425] CH 2 Cl 2 [4-(propan-2-yloxy)phenyl]methanamine in (1 ml) A solution of amine (24.9 mg, 0.151 mmol) was dissolved in CH 2 Cl 2 (0.5ml) A solution of diphosgene (9.1 μl, 0.076 mmol) was added dropwise at room temperature. 52.0 μl, 0.298 mmol) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, the solution of the cis intermediate: 2 Cl 2 (3R,4S)-N-[( 2,4-Difluorophenyl)methyl]-1,3-dimethylpiperidin-4-amine and (3S,4R)-N-[(2,4-difluorophenyl)methyl]-1,3-dimethylpyridin Peridine-4-amine (43.4 mg, 0.171 mmol) was added and the reaction mixture was heated to room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude material was dissolved in 20-40% ethanol in water. Purification by HPLC eluting with acetonitrile (containing 0.1% trifluoroacetic acid) Title cis compound (62 mg, 74%): 1 H NMR (400MHz, chloroform- d)δ12.59(bs,1H),7.13-7.01(m,1H),6.98(d,2 H),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(qd,1H),1.63(d,1H),1.36-1.1 9(m,9H);LCMS:446.3[M+H] + obtained.

[0426] 1-[(2,4-difluorophenyl)methyl]-1-[(3R,4R)-1,3-di Methylpiperidin-4-yl]-3-{[4-(propan-2-yloxy)phenyl] Methyl}urea; Trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]- 1-[(3S,4S)-1,3-Dimethylpiperidin-4-yl]-3-{[4-(Propylene glycol) phenyl]methyl}urea;Trifluoroacetic acid

[0427] CH 2 Cl 2 (0.5 ml) in [4-(propan-2-yloxy)phenyl]meth A solution of phenylamine (8.7 mg, 0.053 mmol) was dissolved in CH 2 Cl 2 (0.5ml) medium was added dropwise to a solution of diphosgene (3.1 μl, 0.026 mmol) at room temperature. (18.0 μl, 0.103 mmol) was added, and the resulting mixture was stirred at room temperature for 10 min. Then, the solution of the trans intermediate: CH 2 Cl 2 (3R,4R)-N in (1 ml) -[(2,4-difluorophenyl)methyl]-1,3-dimethylpiperidine-4-amine and (3S,4S)-N-[(2,4-difluorophenyl)methyl]-1,3-difluorophenyl Tylpiperidin-4-amine (14.1 mg, 0.055 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The crude material was dissolved in 20-40 ml of water. Purified by HPLC eluting with 0.5% acetonitrile (containing 0.1% trifluoroacetic acid) The title trans compound (14 mg, 48%): 1 H NMR (400MHz, chromium Roform-d) δ 12.96 (bs, 1H), 7.13 (q, 1H), 7.05-6.9 1(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(d,3H); LCMS: 446.3 [M+H] + obtained.

[0428] Example 86: 1-[(2,4-difluorophenyl)methyl]-1-(1,4-dimethyl 4-(4-(propan-2-yloxy)phenyl)-3-{[4-(piperidin-4-yl)phenyl]methyl {Urea};Trifluoroacetic acid (86) [ka]

[0429] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}-4-methyl Tyl piperidine-1-carboxylate [ka]

[0430] 2,4-Difluorobenzaldehyde (199 mg) in dichloromethane (0.5 ml) , 1.40 mmol) in dichloromethane (0.5 ml) No-4-methylpiperidine-1-carboxylate (330 mg, 1.54 mmol) After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (445 mg, 2.10 mmol) was added. After stirring for an additional 18 hours, sodium hydroxide ( 2 ml, 1 M aqueous solution) was added and the mixture was extracted with dichloromethane (2×1 ml) The combined organic phase was separated, dried and concentrated using a phase separator. Dissolved in 0-10% methanol in dichloromethane containing ammonia (28% aqueous solution). The desired product is obtained by purification by column chromatography using silica gel. The intermediate (366 mg) was obtained.

[0431] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4-( phenyl)methyl}carbamoyl)amino}-4-methylpiperidinyl Din-1-carboxylate [ka]

[0432] [4-(propan-2-yloxy)phenyl]methyl in dichloromethane (0.5 ml) A solution of tannin (45 mg, 0.272 mmol) in dichloromethane (0.5 ml) was was added to a stirred solution of diphosgene (16.3 μl, 136 μmol) in water at room temperature and suspended in A cloudy solution was obtained. After the addition was complete, diisopropylethylamine (95 μl, 0.545 ml) was added. mol) was added dropwise, giving a clear solution and gas evolution. After stirring at room temperature for 5 minutes, dichloromethane was added. tert-Butyl 4-{[(2,4-difluorophenyl)methanate in methane (0.5 ml) ethyl]amino}-4-methylpiperidine-1-carboxylate (100 mg, 0.29 A solution of 4 mmol) was added rapidly. After stirring at room temperature for an additional 90 min, the mixture became an oil. The crude material was purified by column chromatography on silica gel, eluting with 6-25% ethyl acetate in petroleum ether. The desired intermediate (146mM) was obtained by purification using column chromatography on silica gel. g).

[0433] 1-[(2,4-difluorophenyl)methyl]-1-(4-methylpiperidine-4- 3-{[4-(propan-2-yloxy)phenyl]methyl}urea [ka]

[0434] Trifluoroacetic acid (100 μl) was dissolved in dichloromethane (0.9 ml) to give tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(propane-2-yl)phenyl 4-Methylpiperidine-1-carbamoylamino After stirring at room temperature for 2 hours, the hydroxide Sodium (2 ml, 1M aqueous solution) and water (2 ml) were added. The mixture was diluted with dichloromethane. The crude material was extracted with ethanol (3 ml) and the organic phase was dried and concentrated using a phase separator. , 1% NH 3 (28% aqueous solution) in dichloromethane containing 5-10% methanol The compound was purified by column chromatography on silica gel, eluting with hexane. The desired intermediate (45 mg) was obtained.

[0435] 1-[(2,4-difluorophenyl)methyl]-1-(1,4-dimethylpiperidine -4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; Trifluoroacetic acid

[0436] Formaldehyde (13 μl, 37%, 129 μmol) in ethanol (1 ml) 1-[(2,4-difluorophenyl)methyl]-1-(4-methylpiperidin-4-yl) (45 mg, After stirring at room temperature for 70 minutes, triacetoxyborohydride was added to the mixture. Sodium (67 mg, 316 μmol) was added. After stirring at room temperature for 2 hours, the mixture The crude material was concentrated to an oil. The product was purified by HPLC eluting with 2,4-dichlorophenyl ether (containing fluoroacetic acid) to give the title compound (28.1 mg, 4 8%): 1 H NMR (400MHz, chloroform-d) δ 12.49 (bs, 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,3 H),1.33-1.28(m,6H);LCMS:446.3[M+H] + obtained.

[0437] Example 87: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-phenyl) hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(1-methylpiperidinyl (4-phenyl)urea;Trifluoroacetic acid (87) [ka]

[0438] 4-(2-hydroxy-2,3-dimethylbutoxy)benzonitrile [ka]

[0439] Isopropylmagnesium bromide (1.48 ml, 1.3 M in tetrahydrofuran) of 4-(2-oxopropoxy)benzonitrile ( After stirring at room temperature for one day, ammonium chloride was added dropwise to the Sodium (10 ml, saturated aqueous solution) was added. The mixture was diluted with diethyl ether (50 ml). Extract, wash the organic phase with brine, dry over magnesium sulfate, filter and concentrate. The crude material was purified using silica gel eluted with ethyl acetate in petroleum ether. Purification by column chromatography gave the desired intermediate (63 mg).

[0440] 1-[4-(aminomethyl)phenoxy]-2,3-dimethylbutan-2-ol JPEG0007628578000163.jpg30170

[0441] Borane (862 μl, 1M in tetrahydrofuran) was dissolved in tetrahydrofuran (1 ml). 4-(2-hydroxy-2,3-dimethylbutoxy)benzonitrile (63 mg, 2 After stirring at room temperature for 2 days, methanol (6 ml) was added and the mixture was cooled to 30° C. The mixture was heated to 75° C. and concentrated. After 15 h, the mixture was concentrated to give the desired intermediate (6 9 mg) was obtained.

[0442] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2- Hydroxy-2,3-dimethylbutoxy)phenyl]methyl}carbamoyl)amino}pyridine Peridine-1-carboxylate [ka]

[0443] 1-[4-(aminomethyl)phenoxy]-2,3-dimethylbutan-2-ol (6 8.9 mg, 309 μmol) and diisopropylethylamine (131 μl, 936 μ mol) in dichloromethane (2 ml) )[(2,4-difluorophenyl)methyl]amino]piperidine-1-carboxylate After stirring at room temperature for 18 hours, sodium hydroxide was added to the mixture. Sodium (1 ml, 1M aqueous solution) was added and the organic phase was dried using a phase separator and the oil ( The mixture was concentrated to a volume of 223 mg.

[0444] 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-hydroxy-2 ,3-Dimethylbutoxy)phenyl]methyl}-1-(piperidin-4-yl)urea [ka]

[0445] Trifluoroacetic acid (100 μl) was dissolved in dichloromethane (0.9 ml) to give tert-butyl 4-{[(2,4-difluorophenyl)methyl]({[4-(2-hydroxy-2, 3-Dimethylbutoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate After stirring at room temperature for 17 hours, Then, trifluoroacetic acid (100 μl) was added. After stirring at room temperature for 5 hours, Trifluoroacetic acid (100 μl) was added to the mixture. After stirring at room temperature for 22 hours, sodium hydroxide was added. Sodium (1 ml, 1M aqueous solution) was added and the organic phase was dried using a phase separator and concentrated. The crude material was eluted with butanol, water, ethyl acetate, and acetic acid in a 1:1:1:1 ratio. The desired intermediate was obtained by purification using silica gel column chromatography. The compound (49.6 mg) was obtained.

[0446] 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-hydroxy-2 ,3-dimethylbutoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl ) Urea; Trifluoroacetic acid

[0447] Formaldehyde (12.6 μl, 37%, 125 μmol) was dissolved in tetrahydrofuran. 1-[(2,4-difluorophenyl)methyl]-3-{[4-(2-phenyl) hydroxy-2,3-dimethylbutoxy)phenyl]methyl}-1-(piperidine-4-yl The mixture was stirred at room temperature for 50 minutes and then added to urea (49.6 mg, 104 μmol). Sodium triacetoxyborohydride (45 mg, 212 μmol) was added. After stirring for 19 hours, the mixture was concentrated to an oil. The crude material was purified by distillation with 20-40% acetone in water. Purification by HPLC eluting with nitrile (containing 0.1% trifluoroacetic acid) gave the title compound Compound (18 mg, 29%): 1 H NMR (400MHz, chloroform-d) δ1 2.78(bs,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),4.2 8(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,3 H), 0.92(d,3H);LCMS: 490.3[M+H] + obtained.

[0448] Example 88: 1-[(2,4-difluorophenyl)methyl]-3-({3-fluoro -4-[(2-hydroxyethoxy)methyl]phenyl}methyl)-1-(1-methylpi Peridine-4-yl)urea; Trifluoroacetic acid (88) [ka]

[0449] [4-({2-[(tert-butyldiphenylsilyl)oxy]ethoxy}methyl) -3-fluorophenyl]methanamine [ka]

[0450] tert-Butyl(chloro)diphenylsilane (97.7 μl, 0.376 mmol) and 4-dimethylaminopyridine (3.06 mg, 0.025 mmol) in dichloromethane 2-{[4-(aminomethyl)-2-fluorophenyl]methoxy} Ethan-1-ol (49.9 mg, 0.250 mmol) and triethylamine (10 5 μl, 0.751 mmol) solution. After stirring at room temperature for 2 hours, NaOH ( The mixture was extracted with dichloromethane (3×2 ml) and The combined organic phases were dried using a phase separator and concentrated to give the desired intermediate as an oil (110 ml). g).

[0451] 3-{[4-({2-[(tert-butyldiphenylsilyl)oxy]ethoxy}methyl methyl)-3-fluorophenyl]methyl}-1-[(2,4-difluorophenyl)methyl 1-(1-methylpiperidin-4-yl)urea [ka]

[0452] CH 2 Cl 2 (1 ml) of [4-({2-[(tert-butyldiphenylsilyl) oxy]ethoxy}methyl)-3-fluorophenyl]methanamine (110 mg, 0. 251 mmol) solution in CH 2 Cl 2 (0.5 ml) in diphosgene (15.5 μl DIPEA (131 μl, 0.753 mmol) was added dropwise to a solution of DIPEA (131 μl, 0.753 mmol) at room temperature. (mmol) was added and the resulting mixture was stirred at room temperature for 10 min. Then, CH 2 Cl 2 N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine in (1 ml) A solution of -4-amine (103 mg, 0.427 mmol) was added and the reaction mixture was stirred at room temperature. Stirred for 2 h. The mixture was concentrated under reduced pressure and used without further purification.

[0453] 1-[(2,4-difluorophenyl)methyl]-3-({3-fluoro-4-[(2 -hydroxyethoxy)methyl]phenyl}methyl)-1-(1-methylpiperidine-4 -yl)urea;Trifluoroacetic acid

[0454] Tetrabutylammonium fluoride (0.5 ml, 1M in tetrahydrofuran) was added to the tetrahydrofuran. 3-{[4-({2-[(tert-butyldiphenyl (2-phenyl)oxy]ethoxy}methyl)-3-fluorophenyl]methyl}-1-[(2-phenyl)oxy]ethoxy}methyl ,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea ( The mixture was stirred at room temperature for 1.5 hours and then cooled to room temperature. The mixture was concentrated. The crude material was purified by elution with 20-50% acetonitrile in water (0.1% trifluoroacetate). The product was purified by HPLC eluting with 50 mL of ethyl acetate (containing fluoroacetic acid) to give the title compound (26.5 mg, 3 18%) over three steps: 1 H NMR (400MHz, chloroform-d) δ 13.01(bs,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);LCMS:466 .3[M+H] + obtained.

[0455] Example 89: N-(5-fluoro-2-{[1-(1-methylpiperidin-4-yl) ({[4-(propan-2-yloxy)phenyl]methyl}carbamoyl)amino]methyl (ethyl)phenyl)acetamide;Trifluoroacetic acid (89) [ka]

[0456] N-(5-fluoro-2-formylphenyl)acetamide [ka]

[0457] Acetic anhydride (143 μl, 1.29 mmol) was dissolved in 2 -Amino-4-fluorobenzaldehyde (119 mg, 0.858 mmol) in solution After stirring at room temperature for 5 hours, acetic anhydride (143 μl, 1.29 mmol) was added. After stirring at room temperature for 16 h, the mixture was concentrated. The crude material was extracted with 3 mL of petroleum ether. Column chromatography using silica gel eluted with ~25% ethyl acetate Purification by HPLC afforded the desired intermediate as an oil (115 mg).

[0458] N-(5-fluoro-2-{[(1-methylpiperidin-4-yl)amino]methyl} Phenyl)acetamide [ka]

[0459] 1-Methylpiperidin-4-amine (42.0 μl, 0.335 mmol) was dissolved in dichloromethane N-(5-fluoro-2-formylphenyl)acetamide (66 0.6 mg, 0.368 mmol) and sodium triacetoxyborohydride was added to the solution. After stirring at room temperature for 3 hours, Chloromethane (1 ml) was added and the mixture was heated to 40° C. After 3 hours, the mixture was cooled to room temperature The mixture was cooled to rt and stirred for 4 days, then NaOH (2 ml, 1 M aqueous solution) was added. The residue was extracted with dichloromethane (1 ml) and the combined organic phase was dried using a phase separator. and concentrated to give the desired intermediate as an oil (126 mg).

[0460] N-(5-fluoro-2-{[1-(1-methylpiperidin-4-yl)({[4-( Propan-2-yloxy)phenyl]methyl}carbamoyl)amino]methyl}phenyl Acetamide; Trifluoroacetic acid

[0461] 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene(150 mg, 0.668 mmol) in dichloromethane (1 ml) -{[(1-methylpiperidin-4-yl)amino]methyl}phenyl)acetamide ( After stirring at room temperature for 17 hours, the mixture was The crude material was purified by distillation with 30-60% acetonitrile in water (0.1% trifluoroacetate). The compound was purified by HPLC eluting with 2,4-dichlorophenyl ether (containing oroacetic acid) to give the title compound (12.1 mg, 5% ): 1 H NMR (400MHz, chloroform-d) δ 12.45 (bs, 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);LCMS:471.3[M+H] + obtained.

[0462] Example 90: 1-{[2-hydroxy-4-(trifluoromethyl)phenyl]methyl }-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy) Phenyl]methyl}urea;Trifluoroacetic acid (90) [ka]

[0463] 2-[(tert-butyldiphenylsilyl)oxy]-4-(trifluoromethyl) Benzaldehyde [ka]

[0464] tert-Butyl(chloro)diphenylsilane (210 μl, 0.808 mmol) , 2-hydroxy-4-(trifluoromethyl)benzaldehyde in dichloromethane (2 ml) aldehyde (102 mg, 0.536 mmol), 4-dimethylaminopyridine (12.6 mg, 0.103 mmol), and triethylamine (220 μl, 1.58 mmol). After stirring at room temperature for 17 hours, HCl (2 ml, 1M aqueous solution) was added. The mixture was extracted with dichloromethane (3 x 2 ml) and the combined organic phases were separated using a phase separator. The crude material was dissolved in 3-25% ethyl acetate in petroleum ether and concentrated to dryness. The desired product is obtained by purification by column chromatography using silica gel. The intermediate was obtained as an oil (248 mg).

[0465] N-({2-[(tert-butyldiphenylsilyl)oxy]-4-(trifluoro methyl)phenyl}methyl)-1-methylpiperidin-4-amine [ka]

[0466] 1-Methylpiperidin-4-amine (72.6 μl, 0.579 mmol) was dissolved in dichloromethane 2-[(tert-butyldiphenylsilyl)oxy]-4-(triphenylsilyl) (trifluoromethyl)benzaldehyde (248 mg, 0.579 mmol) Then, sodium triacetoxyborohydride (193 mg, 0.911 mmol) was added once. After stirring at room temperature for 18 hours, NaOH (2 ml, 1M aqueous solution) was added. The mixture was extracted with dichloromethane (3 x 2 ml) and the combined organic phases were separated using a phase separator. It was dried and concentrated to give the desired intermediate as an oil (219 mg).

[0467] 1-({2-[(tert-butyldiphenylsilyl)oxy]-4-(trifluoro methyl)phenyl}methyl)-1-(1-methylpiperidin-4-yl)-3-{[4- (2-Methylpropoxy)phenyl]methyl}urea [ka]

[0468] 1-(isocyanatomethyl)-4-(2-methyl) A solution of (propoxy)benzene (48 mg, 0.187 mmol) in dichloromethane (1 N-({2-[(tert-butyldiphenylsilyl)oxy]-4-( (trifluoromethyl)phenyl}methyl)-1-methylpiperidin-4-amine (54m g, 0.103 mmol) solution. After stirring at room temperature for 3 h, NaOH (2m The mixture was extracted with dichloromethane (3 x 2 ml) and the combined The combined organic phase was dried using a phase separator and concentrated to give the desired intermediate (114 mg). Ta.

[0469] 1-{[2-hydroxy-4-(trifluoromethyl)phenyl]methyl}-1-(1 -Methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl Thiol}urea;Trifluoroacetic acid

[0470] Tetrabutylammonium fluoride (0.5 ml, 1M in tetrahydrofuran) was added to the tetrahydrofuran. 1-({2-[(tert-butyldiphenylsilyl) )oxy]-4-(trifluoromethyl)phenyl}methyl)-1-(1-methylpiperidin 1-Dimethyl-4-phenyl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea (1 After stirring at room temperature for 2 hours, the mixture was The crude material was purified by elution with 30-70% acetonitrile in water (0.1% trifluoroacetate). Purification was performed by HPLC eluting with 10% methanol in dichloromethane (containing acetic acid) followed by 10% methanol in dichloromethane. The product was purified by column chromatography on silica gel, eluting with ethanol. followed by 30–60% acetonitrile in water (containing 0.1% trifluoroacetic acid). Purification by HPLC eluting with 5% COOH gave the title compound (4.4 mg, 5%): 1 H NMR( 400MHz, chloroform-d) δ12.10(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,6 H);LCMS:494.3[M+H] + obtained.

[0471] Example 91: 1-[(4-fluoro-2-methoxyphenyl)methyl]-1-(1-methylphenyl) ethylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl }Urea;Trifluoroacetic acid (90) [ka]

[0472] Trimethylsilyldiazomethane (49.8 μl, 0.099 mmol) was added to the 1-[(4-fluorophenyl)-2-(2-(4-phenyl)phenyl]phenyl]-2-(2-(4-fluorophenyl)phenyl]-2-(2-(4- ...)-2-(2-( -2-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl)-3- {[4-(2-methylpropoxy)phenyl]methyl}urea (36.8 mg, 0.083 After stirring for 4 h while reaching room temperature, HCl (2 ml, 1 M aqueous The aqueous phase was diluted with ethyl acetate (1 ml, 1M aqueous solution) and then NaOH (5 ml, 1M aqueous solution) was added. The mixture was extracted with ethyl acetate (3×3 ml) and the combined organic phases were dried and concentrated using a phase separator. The crude material was purified by elution with 30-60% acetonitrile in water (containing 0.1% trifluoroacetic acid). Purification by preparative HPLC eluting with 5% COOH gave the title compound (8.7 mg, 18%): 1 H NMR (400MHz, chloroform-d) δ 12.67(bs,1H), 7.02(d ,3H),6.79(d,2H),6.61-6.52(m,2H),4.86(s,1 H),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),2.09-1.9 7(m,1H),1.89(d,2H),1.01(d,6H);LCMS:458.3 [M+H] + obtained.

[0473] Example 92: 5-Fluoro-2-{[1-(1-methylpiperidin-4-yl)({[ 4-(2-Methylpropoxy)phenyl]methyl}carbamoyl)amino]methyl}acetic acid Phenyl;Trifluoroacetic acid (92) [ka]

[0474] 5-Fluoro-2-{[1-(1-methylpiperidin-4-yl)({[4-(2-methyl phenyl]methyl}carbamoyl)amino]methyl}acetate; Trifluoroacetic acid

[0475] Acetic anhydride (15 mg, 147 μmol) was dissolved in dichloromethane (1 ml) in 1-[(4 -fluoro-2-hydroxyphenyl)methyl]-1-(1-methylpiperidin-4-yl (42.4 mg, After stirring at room temperature for 20 hours, NaOH (2 ml, 1M Aqueous solution) was added and the mixture was extracted with dichloromethane (3×2 ml). The combined organic phase The crude material was concentrated and dried using a phase separator. The compounds were purified by preparative HPLC eluting with trifluoroacetic acid (containing 0.1% trifluoroacetic acid) to give the following compounds: Title compound (7 mg, 15%): 1 H NMR (400MHz, chloroform-d) δ1 2.55(bs,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),2.3 5(s,3H),2.30-2.15(m,2H),2.13-1.98(m,1H), 1.91(d,2H),1.01(d,6H);LCMS:486.4[M+H] + Get Ta.

[0476] Example 93: 1-[(2,4-difluorophenyl)methyl]-3-[(1H-indane 1-(1-methylpiperidin-4-yl)urea; Oroacetic acid (93) [ka]

[0477] tert-Butyl 4-[(chlorocarbonyl)[(2,4 -Difluorophenyl)methyl]amino]piperidine-1-carboxylate (50mg , 129 μmol) and diisopropylethylamine (33.6 μl, 193 μmol) (1H-indazol-5-yl)methanamine was added to the mixture. The mixture was sonicated for 2 hours. The crude product was then collected by filtration. TFA was added and the reaction was heated to 60° C. for 1.5 h. The mixture was concentrated and then The material was suspended in ethanol, filtered and concentrated. 155 μmol) and sodium triacetoxyborohydride (54.7 mg, 258 μmol) mol) was stirred in tetrahydrofuran (1.0 ml) for 2 hours, and then formaldehyde was added. (17.3 μl, 233 μmol) and sodium triacetoxyborohydride (10 9 mg, 516 μmol) was added and the reaction was stirred for 1 h. Aqueous solution, 1 ml) was added and the reaction was stirred overnight. The reaction was concentrated and the crude material was dissolved in water. HPLC eluted with 10-40% acetonitrile (containing 0.1% trifluoroacetic acid) C. Yield: 9% from the carbamoyl chloride. 1 H NMR (400MHz, Tanol-d 4 )δ7.97(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);LCMS:414.3[M+H] + .

[0478] Example 94: 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1R )-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidine- 4-yl)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) [ka]

[0479] 1-[(2,4-difluorophenyl)methyl]-3-[(4-ethenylphenyl)methyl] 1-(1-methylpiperidin-4-yl)urea [ka]

[0480] The compounds were (4-ethenylphenyl)methanamine and N-[(2,4-difluorophenyl)phenyl]- phenyl)methyl]-1-methylpiperidin-4-amine (1:1.2) was used to Prepared as in A.

[0481] 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1R)-1,2- Dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urine Trifluoroacetic acid and 1-[(2,4-difluorophenyl)methyl]-3-({4 -[(1S)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpi Peridine-4-yl)urea; Trifluoroacetic acid

[0482] 1-[(2,4-difluorophenyl)methyl]-3-[(4 -ethenylphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (39. 9 mg, 100 μmol) in water (2 ml) with potassium osmate(VI) dihydrate (1.8 mg, 5 μmol) and N-methylmorpholine N-oxide (50% aqueous solution, After stirring at ambient temperature for 21 hours, the reaction was Quench with sodium sulfate (aq) and filter through a plug of Celite. The solvent was removed under reduced pressure and the resulting mixture was diluted with sodium hydroxide (aqueous, 1M, 1 ml). The product was extracted with dichloromethane (3 x 1 ml), dried (phase separator) and concentrated. The product was dissolved in 10–40% acetonitrile in water (containing 0.1% trifluoroacetic acid). The compound was isolated as a racemic mixture. Yield: 43. 1mg, 79%. 1 H NMR (400MHz, methanol-d 4 ) δ7.30(d,2 H),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),2.8 3(s,3H),2.09-1.83(m,4H);LCMS:434.3[M+H] + .

[0483] Example 95: 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-difluorophenyl)methyl] 1-(1-methylpiperidin-4-yl)-2-benzofuran-5-yl)methyl ) Urea; Trifluoroacetic acid (95) [ka]

[0484] (1,3-Dihydro-2-benzofuran-5-yl)methanamine [ka]

[0485] Oxalyl chloride (56.7 μl, 660 μmol) and dimethylformamide (2.3 μl, 30 μmol) in dichloromethane (2 ml) Furan-5-carboxylic acid (98.5 mg, 600 μmol) was added. After stirring for 1 min, ammonia (27% aqueous solution, 1.02 ml, 54 mmol) was added. The resulting two-phase system was stirred vigorously for 30 min and then filtered through a plug of Celite. The aqueous phase was extracted with dichloromethane (2 ml). The combined organic phases were dried (phase separator). Borane (1M in tetrahydrofuran, 2.4 ml, 2.4 mmol) was added. The mixture was stirred at ambient temperature for 14 hours and then heated to 50°C. After 7 hours, more bora Add 1.2 mL of 1M tetrahydrofuran (1.2 mmol) and further mix the reaction. The mixture was stirred at rt for 17 h, then quenched with methanol and concentrated. The product was extracted with dichloromethane (3×10 ml) and dried. The crude material was dissolved in dichloromethane (10 ml) and concentrated with hydrochloric acid. (1M, aq., 10 ml). The aqueous phase was extracted with sodium hydroxide (5M). It was basified and extracted with dichloromethane (3 x 10 ml). The organic phase was dried (phase separator). and concentrated to give the desired benzylamine (27.4 mg, 31%).

[0486] 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-dihydro-2-phenyl) Triphenylfuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea; Fluoroacetic acid was reacted with (1,3-dihydro-2-benzofuran-5-yl)methanamine and N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine ( 1:1.5) was used and prepared similarly to GPC. Yield: 69%. 1 H NMR(4 00MHz, chloroform-d) δ12.64(bs,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),4.44-4.3 2(m,4H),3.60(d,2H),2.94-2.70(m,5H),2.20( qd,2H),1.91(d,2H);LCMS:415.9[M+H] + .

[0487] Example 96: 1-[(2,4-difluorophenyl)methyl]-3-{[4-(3-methylphenyl)methyl] (1-methylpiperidin-4-yl)urea ;Trifluoroacetic acid (96) [ka]

[0488] The compound was prepared as in Example 15 (1-[(2, 4-difluorophenyl)methyl]-3-{[4-(2-fluoroethoxy)phenyl] The compound was prepared in the same manner as in Example 1. 5%. 1 H NMR (400MHz, chloroform-d) δ 12.62 (bs, 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,2 H),2.04(p,2H),1.91(d,2H);LCMS:462.3[M+H] + .

[0489] Example 97: 1-[(2,4-difluorophenyl)methyl]-3-[(2-fluoro -4-nitrophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; Fluoroacetic acid (97) [ka]

[0490] The compound was prepared by dissolving (2-fluoro-4-nitrophenyl)methanamine hydrochloride and N -[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine(1 :1) was used and prepared similarly to GPA. Yield: 75%. 1 H NMR (400M Hz, chloroform-d) δ 12.36 (bs, 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(d dd,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,2 H);LCMS:437.3[M+H] + .

[0491] Example 98: 3-[(4-chloro-3-methoxyphenyl)methyl]-1-[(2,4 -difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea; Fluoroacetic acid (98) [ka]

[0492] The compounds were (4-chloro-3-methoxyphenyl)methanamine and N-[(2,4- difluorophenyl)methyl]-1-methylpiperidin-4-amine (1:1) It was prepared in the same manner as GPA. Yield: 69%. 1 H NMR (400MHz, chloroform Room-d) δ12.22(s,1H),7.29-7.22(m,1H),7.22-7 .11(m,1H),6.93-6.79(m,2H),6.73(s,1H),6.6 4(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),1.9 2(d,2H);LCMS:438.3[M+H] + .

[0493] Example 99: 1-[(2,4-difluorophenyl)methyl]-3-{[4-fluoro -2-(trifluoromethoxy)phenyl]methyl}-1-(1-methylpiperidine-4 -yl)urea;Trifluoroacetic acid(99) [ka]

[0494] The compound was prepared as follows: N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine- 4-Amine and [4-fluoro-2-(trifluoromethoxy)phenyl]methanamine (1:1) was used and prepared similarly to GPA. Yield: 70%. 1 H NMR(40 0MHz, chloroform-d) δ12.19(bs,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),2.96-2.8 2(m,2H),2.80(s,3H),2.47-2.30(m,2H),1.92( d,2H);LCMS:476.2[M+H] + .

[0495] Example 100: 3-[(2,4-difluorophenyl)methyl]-1-[(4-fluorophenyl)methyl] [1-(1-methylpiperidin-4-yl)urea;Trifluoroacetic acid Acid(100) [ka]

[0496] The compounds were (2,4-difluorophenyl)methanamine and N-[(4-fluorophenyl)- phenyl)methyl]-1-methylpiperidin-4-amine (1:1) was used to Prepared as above. Yield: 57%. 1 H NMR (400MHz, chloroform-d) δ 12.50(bs,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);LCMS:392.3[M+H] + .

[0497] Example 101: 1-{[2-(difluoromethoxy)-4-fluorophenyl]methyl }-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy) Phenyl]methyl}urea;Trifluoroacetic acid (101 [ka]

[0498] tert-Butyl 4-{[(4-fluoro-2-hydroxyphenyl)methyl]({[ 4-(2-methylpropoxy)phenyl]methyl}carbamoyl)amino}piperidine- 1-Carboxylate [ka]

[0499] The compound was synthesized using tert-butyl 4-oxopiperidine-1-carboxylate. , Example 13 (1-[(4-fluoro-2-hydroxyphenyl)methyl]-1-(1- Methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl The solution was prepared in the same manner as in Example 1, except that the urea was 100%.

[0500] 1-{[2-(difluoromethoxy)-4-fluorophenyl]methyl}-1-(1- Methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl urea; trifluoroacetic acid

[0501] Sodium chlorodifluoroacetate (76.2 mg, 500 μmol), tert-butyl 4-{[(4-fluoro-2-hydroxyphenyl)methyl]({[4-(2-methyl Propoxy)phenyl]methyl}carbamoyl)amino}piperidine-1-carboxylate phosphate (106 mg, 200 μmol) and cesium carbonate (130 mg, 400 μmol). The mixture was suspended in water (200 μl) and dimethylformamide (2 ml). Heat to 80°C for 10 min, then cool to ambient temperature, dilute with ethyl acetate (20 ml) and add water (5 ml). × 20 ml), dried (phase separator) and concentrated. The crude was purified with dichloromethane (1 ml) and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene Zene (41 mg, 200 μmol) was added. After 1 h, the mixture was concentrated to give the crude product. , silica gel chromatography eluting with 25-100% ethyl acetate in petroleum ether The product-containing fractions were pooled and concentrated. The material was purified by dichloromethane ( The mixture was dissolved in 1.5 ml of trifluoroacetic acid and trifluoroacetic acid (0.5 ml) was added. After 15 min, the mixture was stirred for 15 min. The product was concentrated and redissolved in tetrahydrofuran (2 ml). Formaldehyde (37% (aqueous solution of 29.8 μl, 400 μmol) and sodium triacetoxyborohydride (84.8 mg, 400 μl) was added. After 1 h, the mixture was diluted with sodium hydroxide (aqueous The mixture was diluted with 1M HCl (1 ml) and extracted with dichloromethane (3 x 1 ml). The organic phase was dried. The crude material was purified by elution with 30-70% acetonitrile in water (0.1 The product was purified by HPLC eluting with 26% trifluoroacetic acid. Yield: 32 mg, 26% trifluoroacetic acid. %. 1 H NMR (400MHz, chloroform-d) δ 12.50 (bs, 1H), 7 .15(t,1H),7.03(d,2H),6.96-6.83(m,2H),6.8 0(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,2 H),2.07(dt,1H),1.90(d,2H),1.02(d,6H);LCM S:494.3[M+H] + .

[0502] Example 102: 1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl} -1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)furan Phenyl]methyl}urea;Trifluoroacetic acid (102) [ka]

[0503] The compound was N-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1 -Methylpiperidin-4-amine ([4-chloro-2-(trifluoromethyl)phenyl ]methanamine to give intermediate 6 (N-[(2,4-difluorophenyl)methyl] 1-(isocyanatomethyl)-1-methylpiperidin-4-amine) It was prepared in the same manner as GPB using 2-(4-(2-methylpropoxy)benzene. Rate: 91%. 1 H NMR (400MHz, chloroform-d) δ 13.09 (bs, 1 H),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);LCMS:512.3[ M+H] + .

[0504] Example 103: 1-{[4-fluoro-2-(trifluoromethoxy)phenyl]methyl 1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy )phenyl]methyl}urea;Trifluoroacetic acid (103) [ka]

[0505] The compound was prepared by the method of formulating N-{[(4-fluoro-2-(trifluoromethoxy)phenyl]methyl }-1-Methylpiperidin-4-amine ([4-fluoro-2-(trifluoromethoxy Prepared similarly to intermediate 6 using 1-(phenyl)methanamine) and 1-(isocyanamine). Prepared as for GP B using (trimethyl)-4-(2-methylpropoxy)benzene Yield: 85%. 1 H NMR (400MHz, chloroform-d) δ 13.09 ( bs,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,1 H),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] + .

[0506] Example 104: 1-[(4-fluoro-2-methylphenyl)methyl]-1-(1-methylphenyl) ethylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl }Urea;Trifluoroacetic acid (104) [ka]

[0507] The compound was synthesized as N-[(4-fluoro-2-methylphenyl)methyl]-1-methylpiperidinyl Using diamine-4-amine ((4-fluoro-2-methylphenyl)methanamine), (Prepared similarly to intermediate 6) and 1-(isocyanatomethyl)-4-(2-methylpropoxy) ) Prepared similarly to GP B using benzene. Yield: 76%. 1 H NMR(40 0MHz, chloroform-d) δ12.59(bs,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);LCMS:442.3[M+H] + .

[0508] Example 105: 1-[(2-chloro-4-methoxyphenyl)methyl]-1-(1-methylphenyl) ethylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl }Urea;Trifluoroacetic acid (105) [ka]

[0509] The compound was synthesized as N-[(2-chloro-4-methoxyphenyl)methyl]-1-methylpiperidinyl Using dimethyl-4-amine ((2-chloro-4-methoxyphenyl)methanamine), (Prepared similarly to intermediate 6) and 1-(isocyanatomethyl)-4-(2-methylpropoxy) ) Prepared similarly to GP B using benzene. Yield: 78%. 1 H NMR(40 0MHz, chloroform-d) δ13.05(bs,1H),7.09-7.00(m, 3H),6.92(s,1H),6.79(d,2H),6.74(d,1H),4.7 4(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); LCMS: 474.3 [M+H] + .

[0510] Example 106: 1-[(2,4-dichlorophenyl)methyl]-1-(1-methylpiperidine) Lysin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urine Trifluoroacetic acid (106) [ka]

[0511] The compound was synthesized as follows: N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidine-4 -Amine ((2,4-dichlorophenyl)methanamine) was used to prepare the compound in the same manner as intermediate 6. (manufactured by Sigma-Aldrich) and 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene Prepared similarly to GP B using 1,2-dichlorophenyl ether. Yield: 78%. 1 H NMR (400MHz, Fluoroform-d) δ 12.28 (bs, 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,1 H),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);LCMS:463.9[M+H] + .

[0512] Example 107: 1-[(2,4-dichlorophenyl)methyl]-1-(1-methylpiperidine) Lysine-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea ( 107) [ka]

[0513] The compound was synthesized as follows: N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidine-4 -Amine ((2,4-dichlorophenyl)methanamine) was used to prepare the compound in the same manner as intermediate 6. (manufactured by Sigma-Aldrich) and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene were used. and prepared in the same manner as for GPB. Yield: 68%. 1 H NMR (400MHz, chloro Form-d) δ7.36(s,1H),7.18(s,2H),7.09(d,2H), 6.84-6.77(m,2H),4.49-4.41(m,1H),4.41-4.3 3(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=6.7Hz,6H);LCMS:478.0[M+H] + .

[0514] Example 108: 1-[(2,4-dichlorophenyl)methyl]-1-(piperidine-4 -yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; Luoroacetic acid (108) [ka]

[0515] The compound was synthesized as follows: N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidine-4 -Amine ((2,4-dichlorophenyl)methanamine) was used to prepare the compound in the same manner as intermediate 6. (manufactured by Sigma-Aldrich) and 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene Using Example 4 (1-[(2,4-difluorophenyl)methyl]-3-{[4-( 2-Methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea The product was prepared as above. Yield: 61%. 1 H NMR (400 MHz, chloroform-d) δ 9. 48(bs,1H),9.03(bs,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(dq,2H),4.36(s,2H),4.2 8(s,2H),3.41(d,2H),3.06-2.87(m,2H),2.04- 1.87(m,4H),1.32(d,6H);LCMS:450.2[M+H] + .

[0516] Example 109: 1-[(2-chloro-4-fluorophenyl)methyl]-3-{[4- (2-Methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea; Trifluoroacetic acid (109) [ka]

[0517] The compound was synthesized by the method of the present invention using the formula: N-[(2-chloro-4-fluorophenyl)methyl]-1-methylpiperidinyl Methanamine-4-amine ((2-chloro-4-fluorophenyl)methanamine) was used to Example 4 (1-[(2,4-difluorophenyl)methyl]phenyl]-2-(2,4-difluorophenyl)-2-propanediol (prepared in the same manner as intermediate 6) was used to ethyl]-3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidine Prepared similarly to (4-yl)urea). Yield: 45%. 1 H NMR (400MHz, Roloform-d) δ 9.44 (bs, 1H), 9.08 (bs, 1H), 7.21-7. 11(m,2H),7.04(d,2H),6.94(td,1H),6.84-6.7 6(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),2.0 4-1.73(m,4H),1.02(d,6H);LCMS:448.3[M+H] + .

[0518] Example 110: 1-[(2-chloro-4-fluorophenyl)methyl]-1-(piperidinyl) (4-(diphenyl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea ;Trifluoroacetic acid (110) [ka]

[0519] The compound was synthesized by the method of the present invention using the formula: N-[(2-chloro-4-fluorophenyl)methyl]-1-methylpiperidinyl Methanamine-4-amine ((2-chloro-4-fluorophenyl)methanamine) was used to (Prepared similarly to intermediate 6) and 1-(isocyanatomethyl)-4-(propan-2-yl) Example 4 (1-[(2,4-difluorophenyl)methyl] -3-{[4-(2-methylpropoxy)phenyl]methyl}-1-(piperidine-4- Prepared similarly to (yl)urea). Yield: 60%. 1 H NMR (400MHz, chloroform Lum-d)δ9.57(bs,1H),9.10(bs,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,2 H),4.28(s,2H),3.42(d,2H),3.02-2.85(m,2H) ,2.07-1.84(m,4H),1.32(d,6H);LCMS:434.3[M +H] + .

[0520] Example 111: 1-[(2,4-dichlorophenyl)methyl]-3-{[4-(2-methylphenyl)methyl] 1-(piperidin-4-yl)urea; Acetic acid (111) [ka]

[0521] The compound was synthesized as follows: N-[(2,4-dichlorophenyl)methyl]-1-methylpiperidine-4 -Amine ((2,4-dichlorophenyl)methanamine) was used to prepare the compound in the same manner as intermediate 6. Example 4 (1-[(2,4-difluorophenyl)methyl]-3-{[ 4-(2-Methylpropoxy)phenyl]methyl}-1-(piperidin-4-yl)urea ) was prepared as above. Yield: 40%. 1 H NMR (400MHz, chloroform-d) δ9.51(bs,1H),9.11(bs,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,1 H),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);LCMS:464.2[M+ H] + .

[0522] 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) [ka]

[0523] The compound was designated as N-[(2,6-difluoro-3-methylphenyl)methyl]-1-methyl Piperidin-4-amine ((2,6-difluoro-3-methylphenyl)methanamine) Using this, intermediate 6 (N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine) Lysine-4-amine) and 1-(isocyanatomethyl)-4-(propane) Prepared similarly to GP B using (phenyl-2-yloxy)benzene. Yield: 57%. 1 H NMR (400MHz, chloroform-d) δ 12.45 (bs, 1H), 7.1 9-7.06(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 (qd,2H),2.16(s,3H),1.94(d,2H),1.32(d,6H) LCMS: 446.3 [M+H] + .

[0524] Example 113 (Comparative): 1-(1-methylpiperidin-4-yl)-3-{[4-(propanol) 1-[(2,3,6-trifluorophenyl)propan-2-yloxy)phenyl]methyl] (Nyl)methyl]urea;Trifluoroacetic acid (113) [ka]

[0525] The compound was synthesized as 1-methyl-N-[(2,3,6-trifluorophenyl)methyl]piperidinyl Using diamine-4-amine ((2,3,6-trifluorophenyl)methanamine), Intermediate 6 (N-[(2,4-difluorophenyl)methyl]-1-methylpiperidine-4- amine) and 1-(isocyanatomethyl)-4-(propan-2-yl Prepared similarly to GP B using (oxy)benzene. Yield: 58%. 1H NMR (400MHz, chloroform-d) δ12.69(bs,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,2 H),3.62(d,2H),2.90-2.75(m,5H),2.47-2.27( m,2H),1.96(d,2H),1.33(d,6H);LCMS:450.3[M +H] + .

[0526] Example 114: 1-[(2,4-difluoro-3-methylphenyl)methyl]-1-( 1-Methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl Trifluoroacetic acid (114) [ka]

[0527] The compound was designated as N-[(2,4-difluoro-3-methylphenyl)methyl]-1-methyl Piperidin-4-amine ((2,4-difluoro-3-methylphenyl)methanamine) Prepared similarly to intermediate 6 using 1-(isocyanatomethyl)-4-(propanediol) Prepared similarly to GP B using (-2-yloxy)benzene. Yield: 55%. 1 H NMR (400MHz, chloroform-d) δ 12.39 (bs, 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);LCMS:446.3[M+H] + .

[0528] Example 115: 1-[(2-fluoro-4-methylphenyl)methyl]-1-(1-methylphenyl) methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl Thiol}urea;Trifluoroacetic acid (115) [ka]

[0529] The compound was synthesized as N-[(2-fluoro-4-methylphenyl)methyl]-1-methylpiperidinyl Using diamine-4-amine ((2-fluoro-4-methylphenyl)methanamine), (Prepared similarly to intermediate 6) and 1-(isocyanatomethyl)-4-(propan-2-yl) Prepared similarly to GP B using (oxy)benzene. Yield: 59%. 1 H NMR( 400 MHz, chloroform-d) δ12.15(bs,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);LCMS:428.3[M+H] + .

[0530] Example 116: 1-[(2,4-difluorophenyl)methyl]-3-{[2-methyl -4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidine -4-yl)urea;Hemitartrate(116) [ka]

[0531] 4-Hydroxy-2-methyl-benzonitrile (1011 mg, 7.2 mmol), charcoal Potassium iodide (18.0 mmol, 2.49 g), tetrabutylammonium iodide (0. 5mmol, 190mg), 2-iodopropane (18mmol, 1.82ml) and D MF (5.0 ml) was stirred at 70° C. for 3 hours, and then 0.5 M NaOH and diethyl ether were added. The organic phase was washed several times with water, then dried and evaporated to give the intermediate nitrile. (1.34 g), which was dissolved in refluxing tetrahydrofuran (6 ml) and concentrated to give The mixture was reduced with muriutium (14.4 mmol, 552 mg) for 1 hour, and then worked up to give the intermediate. The intermediate benzylamine (1.29 g, 7.2 mmol, 100% yield) was obtained. Dissolve in dichloromethane (10 ml) and pyridine (14.4 mmol, 1.20 ml) phenyl chloroformate (9.4 mmol) dissolved in dichloromethane (4.0 ml) 1.22 ml) was added dropwise in an ice bath, and the mixture was stirred for 30 minutes, then diluted with dichloromethane. Partition between 1M HCl and the organic phase, separate, dry and evaporate to give the phenyl N-{[2- Methyl-4-(propan-2-yloxy)phenyl]methyl}carbamate (2.39 g, 100% yield) was obtained as an oil which slowly crystallized.

[0532] N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (2.24mmol, 539mg), Phenyl N-{[2-methyl-4-(propane-2 -yloxy)phenyl]methyl}carbamate (750 mg, 2.51 mmol) and Potassium carbonate (4.5 mmol, 625 mg) was 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 to obtain The organic phase is separated and concentrated, and the crude product is eluted with 5-50% methanol in ethyl acetate. The mixture was purified by column chromatography using silica gel to obtain a pure fraction. These fractions were collected and evaporated, and the residue was dissolved in diethyl ether (10.0 ml) for 20 min. The suspension was stirred for 10 minutes to allow all the silica to settle, the suspension was filtered and the clear filtrate was evaporated to give the title compound. The compound was obtained as a free base (703 mg, 1.57 mmol, 70% yield). (667 mg, 1.497 mmol) and L-(+)-tartaric acid (0.7485 mmol) , 113 mg) was dissolved in methanol (4 ml), the solvent was removed by evaporation, and the residue was The mixture was stirred in 2-propanol (4 ml) and treated in an ultrasonic bath. The solvent was removed and the residue was After treatment in vacuum (0.5-1.0 mbar) for 20 hours, the title compound (840 mg, yield) was obtained. rate 100%): 1 H NMR (400MHz, 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),2.6 9-2.57(m,5H),2.30(s,3H),2.11(m,2H),1.76( d,2H),1.10(d,6H);LC-MS:446.3[M+H]+ obtained.

[0533] Example 117: 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4- Difluorophenyl)methyl]-3-[(3S,4R)-3-fluoro-1-methylpiperidine Lysin-4-yl]urea and 1-[(4-cyclopropoxyphenyl)methyl]-3-[ (2,4-difluorophenyl)methyl]-3-[(3R,4S)-3-fluoro-1- Methylpiperidin-4-yl]urea (117) [ka]

[0534] tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate (3. 0g, 13.12mmol), dichloromethane (15ml), 2,4-difluorobenzene dimethylamine (13.8 mmol, 2.04 g) and acetic acid (300 μl) were stirred for 10 minutes. Sodium triacetoxyborohydride (22.3 mmol, 4.87 g) was added. The mixture was stirred for 1 h and then partitioned between 0.5 M NaOH and dichloromethane. The phases were separated, dried and the solvent removed. The crude was purified by elution with 30-50% acetic acid in petroleum ether. Purified by column chromatography on silica gel eluted with ethyl acetate The pure fractions of the desired compound were obtained by collecting these fractions, evaporating them, and diluting the residue with EtO. Recrystallization from Ac / petroleum ether gave tert-butyl 4-{[(2,4-difluorophenyl) phenyl)methyl]amino}-3-fluoropiperidine-1-carboxylate (racemic The cis compound (2.394 g, 53% yield) was obtained. .53mmol), Phenyl N-[(4-cyclopropoxyphenyl)methyl]carbamate phosphate (150 mg, 0.53 mmol) and potassium carbonate (1.0 mmol, 138 mg ) was suspended in toluene (1.0 ml). The mixture was stirred at 70°C for 14 hours and then The mixture was partitioned between toluene and 0.5M NaOH, the organic phase was separated, washed with water and dried, and then The crude product was purified by column chromatography on silica gel, eluting with 30-50% ethyl acetate in petroleum ether. The desired protected urea intermediate was obtained by purification using column chromatography on silica gel. The solvent was removed and the residue was dissolved in dichloromethane (2.0 ml) and trifluoroacetic acid (2 The mixture was stirred in 0.0 ml) for 30 minutes, then evaporated and diluted with dichloromethane and 1M NaOH. The residue after evaporation of the organic phase was dissolved in ethyl acetate and Column chromatography using silica gel, eluted with 10-100% methanol. The intermediate (156 mg, 0.36 mmol, 68% yield) was obtained by chromatographic purification. This material (149 mg, 0.34 mmol), formaldehyde (1.08 mmol) , 81 μl) and sodium triacetoxyborohydride (1.1 mmol, 241 mg ) was dissolved in tetrahydrofuran (3.0 ml) for 2 h, then diluted with ether and 1M N The organic phase was separated, dried and evaporated, and the residue was dissolved in 10 mL of ethyl acetate. Column chromatography using silica gel eluted with ~50% methanol Purification by HPLC gave the title compound (110 mg, 0.246 mmol, 72%): 1 H NMR (400MHz, chloroform-d) δ 7.19 (q, 1H), 7.04 (d, 2 H),6.94(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),2.4 0(s,3H),1.63(d,1H),0.81-0.69(m,4H);LC-MS :448.3[M+H] + obtained.

[0535] Example 118: 1-[(2,4-difluorophenyl)methyl]-3-[(3-fluorophenyl)methyl] 1-(1-methylpiperidin-4-yl)urea ( 118) [ka]

[0536] 3-Fluoro-4-methoxybenzoic acid (975 mg, 5.73 mmol), dichloromethane A mixture of 17 mmol, 1.4 mmol, 1.0 mmol, 1.5 ... 5 ml) was refluxed for 1 hour, the volatiles were removed and the residue was dissolved in ammonium hydroxide (28% solution The solution was concentrated to give a solid. The solid was allowed to settle and the solid was collected by filtration to give the intermediate carboxamide (713 mg, 4. This material (705 mg, 4.16 mmol) was reduced to give 21 mmol, 74% yield. Lithium aluminum hydride (2 equivalents, 8.3 mmHg) in flowing tetrahydrofuran (5 ml) ol, 323 mg) for 1 h, and then the reaction was quenched with 2 M NaOH. The organic phase was collected and extracted with 1M HCl, and the aqueous phase was separated. The solution was then basified with 5M NaOH, extracted with diethyl ether, and the organic phase was collected and dried. Drying and evaporation afforded crude 3-fluoro-4-methoxy-benzylamine (495 mg, 3.1 This material was dissolved in dichloromethane (2 ml) and the pipet Lysine (4.5 mmol, 360 μl) was added, followed by dichloromethane (2.0 ml). Phenyl chloroformate (3.5 mmol, 455 μl) dissolved in was added dropwise in an ice bath and mixed. The mixture was stirred for 30 min and then partitioned between dichloromethane and 0.5 M HCl, and the organic phase was The mixture was separated, dried and evaporated, and the residue was crystallized from ethanol / water to give the phenyl N-[3- fluoro-4-methoxyphenyl)methyl]carbamate (357 mg, 1.3 mmol The compound was synthesized with the aid of a 41% yield.

[0537] N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.5mmol, 95%, 127mg), Phenyl N-[(3-fluoro-4-methoxy (152 mg, 0.55 mmol) and potassium carbonate (1.0 mmol, 139 mg) was suspended in toluene (2.0 ml). The mixture was The mixture was stirred at 4° C. for 16 hours, then partitioned between toluene and 0.5 M NaOH and the organic phase was separated. The product was dissolved in 5-100% methanol in ethyl acetate in petroleum ether. The fraction was purified by column chromatography using silica gel. The residue was stirred in ether (5.0 ml) for 20 min to remove all the cyano groups. The precipitate was allowed to settle, the suspension was filtered, and the clear filtrate was evaporated to give the title compound (123 mg , 0.292 mmol, 58% yield): 1H NMR (400 MHz, chloroform- d)δ7.21(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),2.24-1.8 6(m,2H),1.80-1.65(m,4H);LC-MS:422.2[M+H] + obtained.

[0538] Example 119: 1-[(2,4-difluorophenyl)methyl]-3-[(2-fluorophenyl)methyl] 1-(1-methylpiperidin-4-yl)urea (119) [ka]

[0539] N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (0.42mmol, 108mg), Phenyl N-({4-[(tert-butyldimethyl (2-fluorophenyl)methyl)carbamate (0.42mmol , 160 mg) and potassium carbonate (0.7 mmol, 100 mg) in toluene (1.5 The mixture was stirred at 60° C. for 20 hours in a 100 ml flask, then partitioned between toluene and water, the organic phase was separated and concentrated. The residue was concentrated on silica gel and eluted with 5-100% methanol in ethyl acetate. The mixture was purified by column chromatography using a column of ethyl acetate, and the fraction was collected and evaporated to give a residue. The residue was stirred in ether for 20 min to precipitate all the silica, and the suspension was filtered to obtain a clear The filtrate was evaporated to give the intermediate silylated compound (91 mg, 0.174 mmol, 41% yield). This material was dissolved in tetrahydrofuran (1 ml) and tetrabutyl fluoride was added. ammonium (1M solution in tetrahydrofuran, 1.0 mmol, 1.0 ml) was added. The mixture was stirred for 4 hours, then concentrated and diluted with saturated potassium carbonate, water and pH 10-10. The organic phase was collected, dried and evaporated to give the crude product. Columns using silica gel eluted with 5-100% methanol in ethyl acetate. The mixture was purified by column chromatography to obtain a fraction which was evaporated and the residue was treated with diethyl ether. Stir in ether / EtOAc for 20 min to precipitate all the silica, filter the suspension, The clear filtrate was evaporated to give the title compound (40 mg, 0.098 mmol, 56% yield). : 1 H NMR (400MHz, 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),4.29-4.1 8(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] + obtained.

[0540] Example 120: 3-[(2,4-difluorophenyl)methyl]-3-(1-methylphenyl) Peridine-4-yl)-1-[(4-phenoxyphenyl)methyl]urea (120) [ka]

[0541] p-(phenoxy)-benzylamine (2.88 mmol, 575 mg) and pyridine (8.3 mmol, 670 μl) was dissolved in dichloromethane (5 ml) and Add dropwise to an ice-cold solution of triphosgene (1.152 mmol, 342 mg) in ethanol (3 ml). The mixture was stirred for 1 h and then partitioned between dichloromethane and 1M sulfuric acid, and the organic phase was Separate, dry and evaporate to give crude 1-(isocyanatomethyl)-4-phenoxybenzene. (0.5 g) was obtained and used in the next step. Methyl]-1-methylpiperidin-4-amine (0.66 mmol, 167 mg) was added to dichloromethane. Dissolve in dichloromethane (2 ml) and 1-(isocyanatomethyl)-4-phenoxyben Zene (300 mg, 1.3 mmol) was added. The mixture was stirred for 18 hours and then diluted with acetic acid. Column chromatography using silica gel, eluted with 0-30% methanol in ethyl acetate. The residue was purified by chromatography to give a residue. Diethyl ether was added to the residue, and the solution The mixture was filtered to remove any solids. The clear solution was evaporated to give 182 mg. The material was triturated with hexane to give the title compound (152 mg, 49% yield): 1 H NMR(4 00MHz, chloroform-d) δ7.33(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),1.8 7(d,2H),1.75(m,2H);LC-MS:466.3[M+H] + obtained.

[0542] Example 121: 3-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl }-3-(1-methylpiperidin-4-yl)-1-{[4-(2-methylpropoxy) Phenyl]methyl}urea (121) [ka]

[0543] N-Methyl-4-piperidone (5.0 mmol, 583 mg) was dissolved in ethanol (5.0 ml) l) and dissolved in [4-methoxy-2-(trifluoromethyl)phenyl]methanamine (5.0 mmol, 1026 mg), followed by sodium triacetoxyborohydride (2 0.0 equiv., 10.0 mmol, 2.2 g) was added. The mixture was stirred at 20° C. for 3 h. It was then concentrated and partitioned between diethyl ether and 0.5 M aqueous NaOH, and the organic phase was collected. The extract was collected and extracted with 2M aqueous HCl, the aqueous phase was separated and made basic with 5M NaOH, and then The organic phase was collected and concentrated to give N-{[4-methoxy-2 -(trifluoromethyl)phenyl]methyl}-1-methylpiperidin-4-amine(1 This material (150 mg, 0.496 mmol) was mixed with dichloromethane to give 1.466 g (96% yield). Dissolve in dichloromethane (2 ml) and 1-(isocyanatomethyl)-4-(2-methylpropanediol) (phenyloxy)benzene (0.595 mmol, 123 mg) was added. The mixture was stirred for 1 hour. The mixture was stirred, concentrated, and the residue was extracted with 0-30% methanol in ethyl acetate in petroleum ether. The compound was purified by column chromatography on silica gel, eluting with hexane. Title compound (164 mg, 65% yield): 1 H NMR (400MHz, chloroform -d)δ7.36(d,1H),7.16(s,1H),7.04(d,2H),6.9 7(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),1.7 9-1.59(m,4H),1.01(d,6H);LC-MS:508.4[M+H] + obtained.

[0544] Example 122: 1-[(2-fluoro-4-methoxyphenyl)methyl]-1-(1- Methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl] Methyl}urea;Trifluoroacetic acid (122) [ka]

[0545] (2-Fluoro-4-methoxyphenyl)methanamine hydrochloride (1.0 g, 5 0.2 mmol) was partitioned between diethyl ether and 0.5 M NaOH. The organic phase was separated. The mixture was dried and evaporated to liberate (2-fluoro-4-methoxyphenyl)methanamine. This material was treated with N-methyl-4-piperidinyl chloride to give the base (699 mg, 4.50 mmol). Don (5.0 mmol, 583 mg), ethanol (5.0 ml) and triacetoxy water Sodium borohydride (9.0 mmol, 1.97 g) was added and the mixture was incubated at 20° C. for 1 The mixture was stirred for 8 hours, then partitioned between diethyl ether and 0.5M aqueous NaOH, and the organic phase was separated and extracted with 2M aqueous HCl, the aqueous phase was separated and made basic with 5M NaOH, It was then extracted with diethyl ether. The organic phase was separated and concentrated to give N-[(2-fluoro -4-Methoxyphenyl)methyl]-1-methylpiperidin-4-amine (1.059g This compound (132 mg, 0.497 mmol) was dissolved in dichloromethane (93%). Dissolve in 2 ml of ethanol and add 1-(isocyanatomethyl)-4-(propan-2-yl) (oxy)benzene (0.596 mmol, 114 mg) was added. The mixture was stirred for 1 hour. Use silica gel, then elute with 0-30% methanol in ethyl acetate. The fractions were then purified by column chromatography using a 100% alcohol-based solvent. Diethyl ether was added to the residue and the solution was filtered to remove solids. The liquid 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) and Trifluoroacetic acid (1 M solution in dioxane, 1.1 equiv., 0.102 mmol, 10 2 μl) was added and the mixture was lyophilized to give the title compound (49 mg): 1 H NMR(4 00MHz,DMSO-d 6 ) δ9.19(s,1H),7.12(d,2H),7.0 8(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] + obtained.

[0546] Example 123: 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl) (phenyl)methyl]-1-(piperidin-4-yl)urea;Hemitartrate (123) [ka]

[0547] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidinyl 1.00 g, 3.06 mmol) was dissolved in dichloromethane (10 mL) l) and 1-butoxy-4-(isocyanate) dissolved in dichloromethane (2 ml). (methyl)naphthalene (735 mg, 3.4 mmol) was added. The mixture was stirred for 18 h. Stir, evaporate, and elute the residue with 30-50% ethyl acetate in petroleum ether. The intermediate ( This material was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (4 ml). l) for 20 min, then evaporated and partitioned between EtOAc and 0.5 M NaOH. The organic phase was collected and evaporated, and the residue was crystallized from hexane / EtOAc to give a simple solid. The mixture was separated and triturated in ether to give 3-[(4-butoxyphenyl)methyl]-1-[(2,4 -difluorophenyl)methyl]-1-(piperidin-4-yl)urea (765 mg, yield This material (71.8 mg, 0.166 mmol) was dissolved in 2-propanol (1 ml), L-(+)-tartaric acid (2M solution in ethanol, 1.1 equivalents, After 1 min, a precipitate formed and the suspension was Stir for 20 minutes, then filter and dry to give the title compound (62.9 mg, 0.124 mm ol, yield 75%): 1 H NMR (400MHz, methanol-d 4)δ7.21(q ,1H),7.14(d,2H),6.98-6.85(m,2H),6.82(d,2 H),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(p,2H),1.50(sex t,2H),0.98(t,3H);LC-MS:432.3[M+H] + obtained.

[0548] Example 124: 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl) [1-(1-methylphenyl)methyl]-1-(1-methylpiperidin-4-yl)urea (124) [ka]

[0549] 3-[(4-butoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl] [0.14-tyl]-1-(piperidin-4-yl)urea (200 mg, 0.463 mmol) was added to tetrahydrofuran. Dissolve in trihydrofuran (3.0 ml) and add formaldehyde (1.16 mmol, 87 μl), followed by sodium triacetoxyborohydride (1.16 mmol, 254 mg ) was added. The mixture was stirred for 2 h and partitioned between diethyl ether and 0.5 M NaOH. The organic phase was then evaporated and the residue was suspended in diethyl ether. 166 mg was obtained by filtration. which was crystallized from ethanol / water to give the title compound (108 mg, 52% yield). : 1 H NMR (400MHz, 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,2 H),2.88(d,2H),2.27(s,3H),2.08(m,2H),1.80 -1.60(m,6H),1.48(h,2H),0.97(t,3H);LC-MS: 446.3[M+H] + obtained.

[0550] Example 125: 3-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl) [1-(1-phenyl)methyl]-3-(1-methylpiperidin-4-yl)urea (125) [ka]

[0551] 1-Methoxy-4-(isocyanatomethyl)benzene in dichloromethane (1 ml) A solution of (172 mg, 1.03 mmol) of N-[(2 ,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (Intermediate 2, The mixture was stirred for 1 h and then evaporated to give The residue was eluted with 0-25% methanol in ethyl acetate using silica gel. The product was purified by column chromatography to give the title compound (192 mg, 60% yield). ): 1 H NMR (400MHz, 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] + obtained.

[0552] Example 126: 1-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl) [Diphenyl)methyl]-1-(piperidin-4-yl)urea;Hemitartrate (126) [ka]

[0553] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidinyl 1-carboxylate (300 mg, 0.873 mmol) was dissolved in dichloromethane (2 mL) l) and 1-methoxy-4-(isocyanate) dissolved in dichloromethane (1 ml). (190 mg, 1.14 mmol) dihydrogen benzene was added. The mixture was evaporated. The column was prepared using silica gel and eluted with 50% ethyl acetate in petroleum ether. The material was purified by column chromatography to give the intermediate (387 mg). The mixture was stirred in 2 ml of fluoromethane and 1 ml of trifluoroacetic acid for 1 hour, then evaporated. The mixture was partitioned between diethyl ether / EtOAc and 0.5M NaOH. The organic phase was collected. The residue was crystallized from diethyl ether / hexane to give the title compound. 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 equiv., 0.23 mmol, 575 μl) The crystals were isolated by filtration and then diluted with MeOH / ethanol. Recrystallization from this afforded the title compound (130 mg, 67% yield from the free base): 1 H.N.M. R (400MHz, methanol-d 4 ) δ7.21(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),3.7 6(s,3H),3.38(d,2H),2.98(m,2H),1.95-1.81( m, 4H); LC-MS: 390.2 [M+H] + obtained.

[0554] Example 127: 3-[(2,4-difluorophenyl)methyl]-1-[(4-ethoxy) [Diphenyl)methyl]-3-(piperidin-4-yl)urea;Hemitartrate (127) [ka]

[0555] tert-Butyl 4-{[(2,4-difluorophenyl)methyl]amino}piperidinyl 1-carboxylate (Intermediate 1, 331 mg, 1.01 mmol) was added to dichloromethane Dissolve 1-ethoxy-4-( Isocyanatomethyl)benzene (265 mg, 1.30 mmol) was added. The mixture was stirred for 20 min and then partitioned between 0.5 M NaOH and dichloromethane. The organic phase was Evaporate and wash the residue with 30-50% ethyl acetate in petroleum ether. Chromatograph on silica gel. The intermediate (365 mg, 0. The resulting material was dissolved in dichloromethane (2 ml) and trifluoromethane (1 ml). The mixture was stirred in 1 ml of oroacetic acid for 20 min, the solvent was evaporated, and the residue was diluted with ether and 0.5M The organic phase was collected, dried and evaporated, and the residue was dissolved in EtOAc / hexane. Crystallization from ethyl acetate and MeOH / water afforded 107 mg (0.26 mmol, 2% yield). 9%). This material was dissolved in 2-propanol (1.0 ml) and ethanol (0. A solution of L-(+)-tartaric acid in 4M, 1.1 equiv., 0.146 mmol, 365 μl The crystals were isolated by filtration and dried to give the title compound (119 mg, 0.248 mmol, 96% yield, 25% total yield from starting material): 1 H NMR (400MHz ,methanol-d 4 )δ7.21(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),1.95-1.81(m,4H),1. 37(t,3H);LC-MS:404.2[M+H] + obtained.

[0556] Example 128: 3-[(2H-1,3-benzodioxol-5-yl)methyl]-1 -[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl )Urea(128) [ka]

[0557] 2H-1,3-Benzodioxole-5-carbonyl in diethyl ether (15 ml) Tolyl (1.73 g, 11.75 mmol) was dissolved in hydrogen chloride in diethyl ether (15 ml). Lithium aluminum hydride (55.2 mmol, 13.8 mmol, 525 mg The mixture was refluxed for 2 hours, then cooled and worked up (H 2 HO, 15% NaOH, 3×H 2 O), crude benzylamine (1.77 g, quantitative) was obtained. The amine (1.0 g, 6.6 mmol) and pyridine (1.1 eq, 17.6 mmol) , 1.43 ml) was dissolved in dichloromethane (5.0 ml) and The mixture was added dropwise to an ice-cold mixture of triphosgene (2.7 mmol, 801 mg) in 10 ml of ethyl acetate. The material was stirred for 1 hour and then partitioned between cold 0.5M sulfuric acid and dichloromethane. is separated, dried and evaporated to give crude 5-(isocyanatomethyl)-2H-1,3-benzothiazolinone. The dioxole was obtained (1.08 g, 92% yield).

[0558] N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine (250 mg, 1.01 mmol) was dissolved in dichloromethane (1 ml) and 5-(isocyanatomethyl)-2H-1,3-benzodioxole in ethanol (1 ml) (215 mg, 1.21 mmol) was added in one portion. The mixture was stirred at room temperature for 1 h, then The column was chromatographed on silica gel, eluted with methanol, Further purification gave the title compound (275 mg, 66%): 1 H NMR (400MHz, Fluoroform-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-M S:418.2[M+H] + obtained.

[0559] Example 129 (Comparative): 1-[(2,3-difluorophenyl)methyl]-1-(1- Methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl urea; trifluoroacetic acid (129) [ka]

[0560] The compound was prepared as follows: N-[(2,3-difluorophenyl)methyl]-1-methylpiperidine- 4-Amine ((2,3-difluorophenyl)methanamine) was used as in intermediate 6. (prepared in Example 1) and 1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene Prepared similarly to GP B using 1,2-dichlorophenyl ether. Yield: 87%. 1 H NMR (400MHz, C1H-d) δ7.10-6.97(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),1.8 7(d,2H),0.99(d,6H);LCMS:446.3[M+H] + .

[0561] Example 130: 1-[(3,4-difluorophenyl)methyl]-1-(1-methylphenyl) 4-(4-(propan-2-yloxy)phenyl)-3-{[4-(propan-2-yloxy)phenyl]methyl} Urea; Trifluoroacetic acid (130) [ka]

[0562] The compound was prepared as follows: N-[(3,4-difluorophenyl)methyl]-1-methylpiperidine- As with intermediate 6, using the 4-amine ((3,4-difluorophenyl)methanamine) (prepared in advance) and 1-(isocyanatomethyl)-4-(propan-2-yloxy)benzene It was prepared in the same manner as for GP B, using 1,2-dichlorophenyl ether. Yield: 82%. 1 H NMR (400MHz , chloroform-d) δ7.15-7.05(m,1H),7.05-6.97(m,3 H),6.95-6.89(m,1H),6.81-6.75(m,2H),4.72( ddt,2H),4.50(p,1H),4.34(s,2H),4.27(s,2H) ,3.56(d,2H),2.86(t,2H),2.77(s,3H),2.18(q d,2H),1.89(d,2H),1.31(d,6H);LCMS:432.3[M +H] + .

[0563] 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) [ka]

[0564] 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3 -{[4-(propan-2-yloxy)phenyl]methyl}urea (50 mg, 0.12 The potassium carbonate (33 mg, 240 ...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, 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 , R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ are independently hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, nitro, 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 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 is selected from the group consisting of heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ２ is not hydrogen, hydroxy, or benzyloxy, or R ２ and R ２ｂ Or R ２ｃ together with the atoms to which they are attached form a ring system, or R ２ａ and R ２ｂ , or R ２ｃ and R ２ｄ form a ring system together with the atoms to which they are attached, R ３ is hydrogen, unsubstituted C １－６ Alkyl, -CD ３ , -CD ２ CDs ３ , -CD ２ CDs ２ CDs ３ , cyclopropyl, and -CDCD ３ CDs ３ is selected from the group consisting of R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ are independently hydrogen, deuterium, and unsubstituted or substituted C １－６ alkyl, and when m and n are 1, R ４ａ , R ４ｂ , R ５ａ , R ５ｂ is hydrogen, R ６ is 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 aryl, or R ６ and R ３ form a ring system together with the atoms to which they are attached, R ７ is 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 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, R １ and R １ｄ is fluoro, R １ａ , R １ｂ , and R １ｃ is hydrogen.), or a pharma- ceutically acceptable salt, stereoisomer or deuterated analog thereof.

2. R ２ is 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 selected from the group consisting of heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ２ｄ is 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 selected from the group consisting of heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R ２ａ , R ２ｂ , and R ２ｃ is hydrogen, R ２ｄ is not hydrogen or R ２ａ , R ２ｃ , and R ２ｄ is hydrogen, R ２ and R ２ｂ is taken together with the atom to which they are attached to form a heteroalicyclic or heteroaryl ring system, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof.

3. R ２ｂ R ２ When R does not form a ring system with ２ａ , R ２ｃ , R ２ｄ , and R ２ｂ are independently hydrogen, deuterium, halogen, hydroxyl, methyl, -CD ３ , methoxy, -OCD ３ , -OCF ３ , and -CF ３ 3. A 5-HT2a antagonist comprising the compound of claim 1 or 2 selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof.

4. R ２ａ , R ２ｃ , and R ２ｂ is hydrogen, R ２ｄ A 5-HT2a antagonist comprising the compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen, fluoro, or hydroxyl.

5. R ２ａ and R ２ｂ is fluoro and the other is hydrogen; R ２ｃ and R ２ｄ A 5-HT2a antagonist comprising the compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen.

6. R ２ R ２ｂ When R does not form a ring system with ２ is halogen, cyano, methyl, -CD ３ , ethyl, -CD ２ CDs ３ , optionally deuterated n-propyl, optionally deuterated iso-propyl, optionally deuterated n-butyl, optionally deuterated iso-butyl, 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, deuterated Optionally deuterated iso-butoxy, optionally deuterated tert-butoxy, optionally deuterated pentyl-oxy, optionally deuterated 4-methyl-butoxy, optionally deuterated hexyl-oxy, optionally deuterated 4-methylpentoxy, optionally 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 , -OCF ２ CF ３ , -OCHF ２ , -OCDF ２ , -CF ３ , -CF ２ CF ３ , -CHF ２ , C.D.F. ２ -CH ２ CF ３ , -CD ２ CF ３ , -CH ２ F, -CF ２ CH ３ 6. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 5, selected from the group consisting of 1,1,2,2-tetrafluorobutyl, and 1,1,1,2,2-pentafluorobutyl, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analog thereof.

7. R ２ R ２ｂ When R does not form a ring system with ２ is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyl-oxy, 4-methyl-butoxy, hexyl-oxy, 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 7. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 6, selected from the group consisting of (1,3-difluoropropan-2-yl)oxy, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof.

8. R ２ methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-1-yloxy, n-butoxy, iso-butoxy, 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; R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ A 5-HT2a antagonist comprising the compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen.

9. R ２ is selected from the group consisting of ethoxy, isopropoxy, n-propoxy, allyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and 2,2-difluoroethoxy; R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ A 5-HT2a antagonist comprising the compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen.

10. R ２ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, iso-butoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2-difluoroethoxy, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof.

11. 11. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein halogen is fluoro.

12. R ３ 12. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen or methyl.

13. R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ 13. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is independently hydrogen or methyl.

14. R ４ａ , R ４ｂ , and R ５ａ is hydrogen, R ５ｂ 14. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is methyl or hydrogen.

15. R ４ａ , R ５ａ , and R ５ｂ is hydrogen, R ４ｂ 15. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is methyl or hydrogen.

16. R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ 16. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen.

17. q is 0 or R ６ is halogen and C １－４ 17. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, selected from: alkyl.

18. 18. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein q is 1.

19. R ６ 20. A 5-HT2a antagonist comprising the compound of claim 18, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is fluoro.

20. 20. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein p is 0.

21. R ８ is hydrogen, halogen, methyl, propyl, methoxy, ethoxy, C １－２ -haloalkyl, and C １－２ 21. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, selected from the group consisting of: -haloalkoxy.

22. R ８ is hydrogen, -CF ３ , -CHF ２ , -CF ２ CF ３ , -OCF ３ , -OCF ２ CF ３ , and -OCHF ２ 22. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 21 selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof.

23. R ８ 23. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen.

24. 24. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein X is O.

25. 25. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein m and n are independently selected from the group consisting of 0 and 1.

26. 26. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein m is 1 and n is 0 or 1.

27. R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ , R ７ , R ８ are hydrogen, m and n are each 1; p and q are 0 or 1; X is O, R ３ is hydrogen, methyl, -CD ３ , ethyl, -CD ２ CDs ３ , n-propyl, -CD ２ CDs ２ CDs ３ , isopropyl, cyclopropyl, and -CDCD ３ CDs ３ 11. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 10 selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof.

28. R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ , R ７ , R ８ are hydrogen, m and n are each 1; p and q are 0; X is O, R ３ 11. A 5-HT2a antagonist comprising the compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is hydrogen or methyl.

29. R ３ 28. A 5-HT2a antagonist comprising the compound of claim 27, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analogue thereof, wherein is methyl or hydrogen.

30. R ２ is selected from the group consisting of ethoxy, n-propoxy, isopropoxy, allyloxy, iso-butoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, 2-fluoroethoxy, 3-fluoropropoxy, and 2,2-difluoroethoxy, or a pharma- ceutically acceptable salt, stereoisomer, or deuterated analogue thereof.

31. 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-4-yl)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-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-[(1-methyl-2,3-dihydro-1H-indol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-[(3-methyl-1,2-benzoxazol-6-yl)methyl]-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-[(1,2-dimethyl-1H-indol-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea, 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-4-yl)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-yl)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-( ２ H ３ ) Methyl (1,1,1,3,3,3- ２ H ６ )propan-2-yl]oxy}phenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, 3-[(4-cyclopropoxyphenyl)methyl]-1-[(1R)-1-(2,4-difluorophenyl)ethyl]-1-(1-methylpiperidin-4-yl)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-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-(1-methylpiperidin-4-yl)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-4-yl)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-( ２ H 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- ２ H ６ ) propan-2-yl]piperidin-4-yl}-3-{[4-(propan-2-yloxy)phenyl]methyl}urea, 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)urea, 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-2-yloxy)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-[(3S,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}urea, 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-[(1H-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-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-({4-[(1S)-1,2-dihydroxyethyl]phenyl}methyl)-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-[(1,3-dihydro-2-benzofuran-5-yl)methyl]-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-{[4-(3-methoxypropoxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)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-4-yl)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-methylpiperidin-4-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-( ２ H 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-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-{[3-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-{[2-fluoro-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-3-{[3-methyl-4-(propan-2-yloxy)phenyl]methyl}-1-(1-methylpiperidin-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-4-yl)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, 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-(piperidin-4-yl)urea, and 1-[(2,4-difluorophenyl)methyl]-3-{[2,3-dihydro(2,2,3,3- ２ H ４ 2. A 5-HT2a antagonist comprising the compound of claim 1 selected from the group consisting of: {1-(1-benzofuran-5-yl)methyl}-1-(1-methylpiperidin-4-yl)urea, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analog thereof.

32. 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-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-(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-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-(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 10. A 5-HT2a antagonist comprising the compound of 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, or a pharma- ceutically acceptable salt, stereoisomer or deuterated analog thereof.

33. 3-{[4-(cyclopropylmethoxy)phenyl]methyl}-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea, 1-[(2,4-difluorophenyl)methyl]-1-(piperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea, 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea; 1-[(4-cyclopropoxyphenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-3-(piperidin-4-yl)urea, and 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, or a pharma- ceutically acceptable salt or stereoisomer thereof.

34. 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea, 2. A 5-HT2a antagonist comprising the compound of claim 1, which is:

35. 2. A 5-HT2a antagonist comprising the compound of claim 1, which is 1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(propan-2-yloxy)phenyl]methyl}urea, or a pharma- ceutically acceptable salt or stereoisomer thereof.

36. 3-[(4-cyclopropoxyphenyl)methyl]-1-[(2,4-difluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)urea, or a pharma- ceutically acceptable salt or stereoisomer thereof.

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