RU2795513C2 - D-amino acid oxidase inhibitors and their therapeutic use - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where

represents

,

or

; each of X and Z is independent aryl selected from phenyl and naphthyl, H, or absent; Y represents

or

; each of L₁ and L₂ is independently a moiety selected from CH₂, C_2-10 alkyl, -((CH₂)_n-W)-, where n=1 and W is O or absent. The invention also relates to a pharmaceutical composition based on a compound of formula (I) and a method for inhibiting D-amino acid oxidase (DAAO) by a compound of formula (I).

EFFECT: effective inhibition of D-amino acids (DAAO) by the compound of formula (I), useful in the treatment of CNS disorders.

10 cl, 9 dwg, 1 tbl, 26 ex

Description

RELATED APPLICATIONS

This application claims priority to a US patent application, U.S.S.N. 15/787557, registered October 18, 2017, the entire content of which is incorporated into the present invention by reference to it.

BACKGROUND OF THE INVENTION

The central nervous system (CNS) includes the brain and spinal cord. The CNS is subject to various disorders that can be caused by various factors, including genetic factors, trauma, infections, degeneration, structural defects and/or damage, tumors, impaired blood flow, and autoimmune disorders. Symptoms of CNS disorders depend on the area of the nervous system that is involved in the pathological process and the cause of the disorder.

The development of effective therapies for CNS disorders has lagged behind other areas of therapy due to the complexity of such disorders and the lack of an effective technology for delivering therapeutic agents across the blood-brain barrier. In this regard, it is of great interest to develop new approaches to the treatment of CNS disorders.

D-amino acid oxidase (DAAO) is a peroxisomal enzyme that oxidizes D-amino acids to the corresponding imino acids. DAAO has been reported to be involved in the metabolism of brain D-amino acids, including D-serine, and in the regulation of glutamatergic neurotransmission. In this regard, DAAO may be a target for the treatment of central nervous system (CNS) disorders that are associated with D-serine and/or glutamatergic neurotransmission.

SUMMARY OF THE INVENTION

The present invention is based, at least inter alia, on the creation of compounds capable of effectively inhibiting DAAO activity in a subject. Therefore, such compounds could be beneficial in the treatment of diseases and disorders associated with DAAO and/or glutamatergic neurotransmission, such as CNS disorders.

Accordingly, the invention provides compounds of formula (I) and their use for inhibiting DAAO activity in a subject and/or treating or reducing the risk of a neuropsychiatric disorder.

In one aspect, the present invention provides a compound of formula (I):

представляет собой фрагмент, выбранный из O, CH₂, C=O, C_2-10 алкила, C_2-10 алкенила, C_2-10 алкинила, -((CH₂)_n-W)-, где n=0, 1, 2, 3, 4 или 5, и W представляет собой O или S, или отсутствует; и когда L₂ отсутствует, Z представляет собой арил или гетероарил, конденсированный с B

C.or a pharmaceutically acceptable salt thereof, wherein A, B, C, D, and E are each independently C, N, NH, O, S, or absent; depicts a single or double chemical bond; each of X, Y and Z is independently aryl, heteroaryl, aralkyl, H, or absent; each of L ₁ and L ₂ independently

is a fragment selected from O, CH ₂ , C=O, C _2-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, -((CH ₂ ) _n -W)-, where n=0, 1, 2, 3, 4 or 5, and W is O or S, or absent; and when L ₂ is absent, Z is aryl or heteroaryl fused to B

C.

In another aspect, the present invention provides compositions (eg, pharmaceutical compositions, nutraceutical compositions, dietary foods, or health foods) comprising an effective amount of a compound of formula (I) and a carrier.

In yet another aspect, the present invention provides methods for inhibiting DAAO in a subject and/or treating or reducing the risk of a neuropsychiatric disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or an effective amount of a composition described herein.

In the following, one or more embodiments of the invention will be described in more detail. Other features, objects, and advantages of the invention will become apparent upon reading the detailed description, examples, and claims.

Definitions

Below is a more detailed description of the definitions of specific functional groups and chemical terms. The chemical elements are designated according to the Periodic Table of the Elements, CAS version, given on the inside cover of the Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are usually defined as described in the invention. In addition, the general principles of organic chemistry, as well as specific functional fragments and reactivity, are described in manuals and monographs by Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, ^5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, ^3rd Edition, Cambridge University Press, Cambridge, 1987. The present invention is not intended to be limited in any way by the list of substituents provided herein by way of example.

The compounds described in the invention may include one or more centers of asymmetry and, therefore, may exist in various isomeric forms, for example, in the form of enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of an individual enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, which include chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be obtained by asymmetric synthesis, see, for example, the manuals and monographs of Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). In addition, the invention includes the compounds described in the invention in the form of individual isomers, which practically do not contain other isomers, and, alternatively, in the form of mixtures of different isomers.

одинарную химическую связь в тех случаях, когда тут же не указана стереохимия фрагментов,

обозначает одинарную химическую связь или ее отсутствие, и

или

обозначает одинарную или двойную химическую связь.In the formula, means

a single chemical bond in cases where the stereochemistry of the fragments is not immediately indicated,

denotes a single chemical bond or its absence, and

or

denotes a single or double chemical bond.

In cases where a range of values is specified, it is assumed to include each value and subrange within the range. For example, "C _1-6 " is assumed to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _{1- 3} , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C 3-6 , C _3-5 , C _3-4 , C _4-6 , _{C 4- 5} and C _5-6 .

The term "aliphatic" includes both saturated and unsaturated, linear (ie, straight), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons that are optionally substituted with one or more functional groups. For any person skilled in the art it is obvious that in the present invention, the term "aliphatic" includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl fragments. Thus, the term "alkyl" includes linear, branched and cyclic alkyl groups. A similar rule applies to other general terms such as "alkenyl", "alkynyl", and other similar terms. In addition, the terms "alkyl", "alkenyl", "alkynyl" and other similar terms include both substituted and unsubstituted groups. In some embodiments, the term "lower alkyl" is used to refer to alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

In specific embodiments, the alkyl, alkenyl and alkynyl groups used in the invention contain 1-20 aliphatic carbon atoms. In other specific embodiments, the alkyl, alkenyl and alkynyl groups used in the invention contain 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain 1-6 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain 1-4 carbon atoms. Thus, illustrative examples of aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH ₂ -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH ₂ -cyclobutyl, n-pentyl, secopentyl, isopentyl, tert-pentyl, cyclopentyl, -CH ₂ -cyclopentyl, n-hexyl, storhexyl, cyclohexyl, -CH ₂ -cyclohexyl moieties and the like, which may also carry one or more deputies. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C _1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C _1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C _1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C _1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C _1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C _2-6 alkyl"). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ) (eg n-propyl, isopropyl), butyl (C4) (eg n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C ₅ ) (eg n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl) and hexyl (C ₆ ) (eg n-hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), and other similar groups. Unless otherwise indicated, in each occurrence, an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (for example, with a halogen such as F, or -OH ). In specific embodiments, the alkyl group is unsubstituted C _1-10 alkyl (such as unsubstituted C _1-6 alkyl or C _1-3 alkyl, eg -CH ₃ ). In specific embodiments, the alkyl group is a substituted C _1-10 alkyl (such as a substituted C _1-6 alkyl or C _1-3 alkyl, eg, -CF ₃ or CH ₂ OH).

), может быть (E)- или (Z)-двойной связью."Alkenyl" refers to a radical of a straight or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C _2-20 alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C _2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C _2-9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C _2-8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C _2-7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C _2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C _2-3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C ₂ alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C _2-4 alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and other similar groups. Examples of C _2-6 alkenyl groups include the C _2-4 alkenyl groups mentioned above, as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ), and other similar groups. Unless otherwise indicated, in each occurrence, the alkenyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In specific embodiments, the alkenyl group is an unsubstituted C _2-10 alkenyl. In specific embodiments, the alkenyl group is a substituted C _2-10 alkenyl. In an alkenyl group, a C=C double bond for which no stereochemistry is specified (for example, -CH=CHCH ₃ or

), may be an (E)- or (Z)-double bond.

"Alkynyl" refers to a radical of a straight or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C _2-20 alkynyl"). In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C _2-10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C _2-9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C _2-8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C _2-7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C _2-5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C _2-4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C _2-3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C ₂ alkynyl"). The one or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C _2-4 alkynyl groups include, without limitation, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and other similar groups. Examples of C _2-6 alkynyl groups include the aforementioned C _2-4 alkynyl groups, as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl include heptynyl (C ₇ ), octynyl (C ₈ ), and other similar groups. Unless otherwise indicated, in each occurrence, the alkynyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents. In specific embodiments, the alkynyl group is an unsubstituted C _2-10 alkynyl. In specific embodiments, the alkynyl group is C _2-10 alkynyl.

"Aralkyl" is a subclass of alkyl and aryl and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group. In specific embodiments, aralkyl is an optionally substituted benzyl. In specific embodiments, aralkyl is benzyl. In specific embodiments, aralkyl is an optionally substituted phenethyl. In particular embodiments, the aralkyl is phenethyl.

"Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons evenly distributed between the ring atoms) having 6-14 ring carbon atoms and zero heteroatoms forming an aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl group has six ring carbons ("C ₆ aryl", eg phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C ₁₀ aryl", eg, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C ₁₄ aryl", eg anthracyl). "Aryl" also includes ring systems in which the aryl ring defined above is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, in which case the carbon number continues to refer to the number of carbon atoms in the aryl ring system. . Unless otherwise indicated, in each occurrence, the aryl group is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In specific embodiments, the aryl group is an unsubstituted C _6-14 aryl. In specific embodiments, the aryl group is a substituted C _6-14 aryl.

"Heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g. having 6, 10 or 14 π electrons evenly distributed between the ring atoms) having ring carbon atoms and 1-4 ring heteroatoms forming aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, if this does not contradict the rules of valency. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused to one or more aryl groups, where the point of attachment is either on the aryl or heteroaryl ring, and in such cases, the number of ring members means the number of ring members in the fused (aryl/ heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment may be on any ring, i.e., or on a ring containing a heteroatom (e.g., 2-indolyl ), or on a ring that does not contain a heteroatom (eg 5-indolyl). They also include polycyclic heteroaryl groups in which two or three rings independently contain a heteroatom (eg, furopyrrolyl, thianopyrrolyl, and the like).

In some embodiments, the heteroaryl group is a 5-14 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms forming an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl". In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms forming an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5 -8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms forming an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl") In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, when present, a heteroaryl group is independently optionally substituted, that is, unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In specific embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In specific embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

Examples of 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, in dolysinil and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

"Unsaturated" or "partially unsaturated" refers to a group that includes at least one double or triple bond. A "partially unsaturated" ring system is contemplated to further include rings having many sites of unsaturation, but does not include aromatic groups (eg, an aryl or heteroaryl group). Similarly, "saturated" refers to a group that does not contain a double or triple bond, that is, contains all single bonds.

An atom, fragment or group described in the invention may be unsubstituted or substituted, unless this is contrary to the rules of valence, and unless explicitly provided otherwise. The term "optionally substituted" refers to substituted or unsubstituted.

The group is optionally substituted unless expressly stated otherwise. The term "optionally substituted" refers to the case of substitution or non-substitution. In specific embodiments, the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted", whether it follows the term "optional" or not, means that at least one hydrogen atom present in the group (for example, a carbon or nitrogen atom) is substituted with the appropriate substituent. , for example, a substituent which, after substitution has been carried out, results in the formation of a stable compound, for example, a compound which does not spontaneously undergo transformation such as rearrangement, cyclization, cleavage, or other reaction. Unless otherwise indicated, a "substituted" group is substituted at one or more substitutable positions in the group, and when more than one position in any given structure is substituted, the substituent at each position may be the same or different. The term "substituted" is intended to include substitution, with all possible substituents for organic compounds, with any of the substituents described herein, which results in the formation of a stable compound. The present invention contemplates the use of all possible such combinations to obtain a stable connection. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent described herein that does not violate the valence rule for heteroatoms and results in a stable moiety. In particular embodiments, the substituent is a substituent for a carbon atom. In particular embodiments, the substituent is a substituent for a nitrogen atom. In particular embodiments, the substituent is an oxygen atom substituent. In particular embodiments, the substituent is a substituent for a sulfur atom.

Examples of carbon atom substituents include, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC (=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , - OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa ,-P(=O)(R ^aa ) ₂ , − P(=O)(OR ^cc ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^bb ) ₂ ) ₂ , -OP(=O)(N(R ^bb ) ₂ ) ₂ , −NR ^bb P(=O)(R ^aa ) ₂ , -NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P( =O)(N(R ^bb ) ₂ ) ₂ , -P(R ^cc ) ₂ , −P(OR ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(R ^cc ) ₄ , −P(OR ^cc ) ₄ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ ⁺ X ⁻ , −OP(OR ^cc ) ₂ , −OP(OR ^cc ) ₃ ⁺ X ⁻ , −OP(R ^cc ) ₄ , −OP(OR ^cc ) ₄ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), C _1-10 alkyl , C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl , carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups; where X ⁻ is a counterion, or two non-minal hydrogens on a carbon atom are substituted with the group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O )OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc ;

in each occurrence, R ^aa is independently selected from C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^aa groups are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^dd ;

in each occurrence, R ^bb is independently selected from hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O )(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ ,-P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _{2- 10} alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^bb groups are combined to form a 3-14 membered heterocyclyl or 5-14 a membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; where ^X is a counterion;

in each occurrence, R ^cc is independently selected from hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl and 5-14 membered heteroaryl, or two R ^cc groups are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^dd ;

in each occurrence, R ^dd is independently selected from halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N (R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H , -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , -NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff )R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff )N (R ^ff ) ₂ ,-NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , -SC (=S)SR ^ee , -P(=O)(OR ^ee ) ₂ , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)( OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal substituents R ^dd can be combined to form =O or =S; where ^X is a counterion;

in each occurrence, R ^ee is independently selected from C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

in each occurrence, R ^ff is independently selected from hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _{6 -10} aryl and 5-10 membered heteroaryl, or two R ^ff are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 , 1, 2, 3, 4 or 5 groups R ^gg ; And

in each occurrence, R ^gg is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _{1- 6} alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)( C _1-6 alkyl) , -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N (C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , - OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N (C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ -C(=S)N( C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S )SC _1-6 alkyl, -SC(=S)SC _1-6 alkyl, -P(=O)(OC _1-6 alkyl) ₂ , -P(=O)(C _1-6 alkyl) ₂ , - OP(=O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents R ^gg can be combined to form ═O or ═S; where X ^- represents a counterion.

A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electrical neutrality. The anionic counterion may be monovalent (ie, including one formal negative charge). The anionic counterion may also be multivalent (ie, including more than one formal negative charge), such as divalent or trivalent. Examples of counterions include halide ions (eg F ^- , Cl ^- , Br ^- , I ^- ), NO ₃ ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , sulfonate ions (eg methanesulfonate, trifluoromethanesulfonate , p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, and other similar counterions), carboxylate ions (for example, acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and other similar ions), BF ₄ ^- , PF ₄ ^- , PF ₆ ^- , AsF ₆ ^- , SbF ₆ ^- , B[3,5-(CF ₃ ) ₂ C ₆ H ₃ ] ₄ ] ^- , BPh ₄ ^- , Al(OC(CF ₃ ) ₃ ) ₄ ^- , and carborane ions (for example, CB ₁₁ H ₁₂ ^- or (HCB ₁₁ Me ₅ Br ₆ ) ^- ) . Examples of counterions that may be multivalent include CO ₃ ²⁻ , HPO ₄ ²⁻ , PO ₄ ³⁻ _, B ₄ O ₇ ²⁻ , SO ₄ ²⁻ , S ₂ O ₃ ²⁻ , carboxylate anions (e.g. tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and other similar counterions), and carboranes.

"Halo" or "halogen" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br), or iodine (iodine, -I).

"Acyl" refers to a moiety selected from the group consisting of -C(=O)R ^aa , -CHO, -CO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa or -C(=S)SR ^aa , where R ^aa and R ^bb are defined in the invention.

Nitrogen atoms may be substituted or unsubstituted, as long as this does not conflict with the rules of valency, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Examples of substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C (=S)SR ^cc , -P(=O)(OR ^cc ) ₂ , -P(=O)(R ^aa ) ₂ ,-P(=O)(N(R ^cc ) ₂ ) ₂ , C _{1- 10} alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^cc groups , attached to the nitrogen atom, combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, and where R ^aa , R ^bb , R ^cc and R ^dd are defined above.

In specific embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , C _1-10 alkyl (for example, aralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and where R ^aa , R ^bb , R ^cc and R ^dd are defined above . Nitrogen protecting groups are well known and include those described in more detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, the contents of which are incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)R ^aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (Nʽ-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide , 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide; and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR ^aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9 -(2,7-dibromo)fluorenylmethyl-carbamate, 2,7-ditretbutyl-[9-(10,10-dioxo-10,10,10,10-tetra-hydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1.1 -dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-( 4-biphenylyl)ethylcarbamate (Bpoc), 1-(3,5-ditertbutylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2ʽ- and 4ʽ-pyridyl)ethylcarbamate (Pyoc), 2-(N, N- dicyclohexylcarboxamido)ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyllyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc) , 8-quinolylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzylcarbamate (Cbz), p-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2-(p-toluenesulfonyl)ethylcarbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc ), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl) benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o -nitro-phenyl)methylcarbamate, tertamylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxy-benzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N, N-dimethyl-carboxamido)benzylcarbamate, 1,1-dimethyl-3-(N, N-dimethyl-carboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinyl carbamate , p-(pʽ-methoxyphenylazo)benzylcarbamate, 1-methyl-cyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1 -(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tritertbutylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O) ₂ R ^aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxy-benzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-penta-methylchroman-6-sulfonamide (Pmc ), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3 -oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisylasecyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro -4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3 -pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxy-phenyl) diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethylenamine, N-ferrocenylmethylamine (Fcm), N-2-picolinamine Nʽ-oxide, N-1,1- dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(Nʽ,Nʽ-dimethylaminomethylene)-amine, N, Nʽ-isopropylidene diamine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxy-phenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylboric acid derivative, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, N-amine oxide, diphenylphosphinamide ( Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylalkylphosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3- nitropyridine sulfenamide (Npys).

Examples of substituents on the oxygen atom include, but are not limited to, -R ^aa , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O)R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) _3, -P(R ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₂ , −P(OR ^cc ) ₃ ⁺ X ⁻ , -P (=O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ and -P(=O)(N(R ^bb ) ₂ ) ₂ , where X ⁻ , R ^aa , R ^bb and R ^cc defined in the invention. In particular embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known and include those described in more detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, the contents of which are incorporated herein by reference. Examples of oxygen protecting groups include, but are not limited to, methyl, tert-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl ( PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis( 2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydro-pyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S , S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydro-furanyl, tetrahydrothiofuranyl, 2.3 ,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl- 1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, tert-butyl, allyl, p -chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halo-benzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, pʽ-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p -methoxy-phenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacil-oxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)-methyl, 4,4' ,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis (4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S, S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl , diphenylmethylsilyl (DPMS), tert-butylmethoxy-phenylsilyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4, 4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2 ,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkylisobutyl carbonate, alkylvinyl carbonate, alkylallyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2 -iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N, N,Nʽ,Nʽ-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulphenate, sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate (Ts).

In particular embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C( =O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O) R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) _{3 ,} -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(=O) ₂ R ^aa , -P(=O)( R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ , and -P(=O)(NR ^bb ) ₂ , where R ^aa , R ^bb and R ^cc are defined in the invention. Sulfur protecting groups are well known and include those described in more detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, the contents of which are incorporated herein by reference.

Used in the invention, the term "salt" refers to all possible salts and includes pharmaceutically acceptable salts.

The term "pharmaceutically acceptable salt" refers to salts which, after careful medical evaluation, can be used in cases of contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, or the like, and which satisfy an acceptable benefit/risk ratio. Pharmaceutically acceptable salts are well known. For example, pharmaceutically acceptable salts are described in detail in Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, the contents of which are incorporated herein by reference.

Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid. , citric acid, succinic acid, or malonic acid, or formed by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate nye, glycerophosphate, gluconate, semisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per sulfate, 3-phenylpropionate , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and other similar salts. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ ^- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and other similar metal salts. In addition, pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine salts formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

The terms "inhibition", "inhibitory", "inhibit" or "inhibitor" refer to the ability of a compound of formula (I) to reduce, slow down, stop or prevent the activity of a particular biological process in a cell compared to placebo.

The term "subject" to which the drug is intended to be administered refers to a human (i.e., a male or female of any age group, e.g., a pediatric patient (e.g., an infant, child, or adolescent) or an adult (e.g., a young adult, human middle-aged or elderly person)) or to a lower primate. The term "patient" refers to a person who needs treatment for their disease.

The terms "administer" or "administration" refer to implantation, absorption, ingestion, injection, inhalation, or otherwise administering a compound of formula (I) described herein, or a composition thereof, to a subject.

The terms "treatment" and "treat" refer to the regression, alleviation, delay in onset or slowing of the progression of the disease described in the invention. In some embodiments, treatment may be administered following the development or discovery of one or more signs or symptoms of a disease. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a subject predisposed to a disease prior to the onset of symptoms (eg, given a history of symptoms and/or exposure to a pathogen) in order to delay or prevent the onset of the disease. Treatment may also be continued after symptoms have resolved, for example to delay or prevent recurrence of symptoms.

The terms "condition", "disease" and "disorder" are used interchangeably throughout the invention.

An "effective amount" of a compound of formula (I) as described herein refers to an amount sufficient to achieve the desired biological response (ie, treatment of the disease state). It will be appreciated by those of ordinary skill in the art that an effective amount of a compound of formula (I) as described herein may vary depending on factors such as the expected biological outcome, the pharmacokinetics of the compound of formula (I), the condition being treated, the route of administration, age and condition. subject's health. In specific embodiments, the effective amount is a therapeutically effective amount. In specific embodiments, the effective amount is a prophylactically effective amount. In specific embodiments, the effective amount is the amount of the compound of formula (I) described in the invention in a single dose. In specific embodiments, the effective amount is the total amount of the inventive compound of formula (I) in divided, multiple doses.

A "therapeutically effective amount" of a compound of formula (I) as described herein is an amount that is sufficient to achieve a beneficial therapeutic effect in the treatment of a disease state or to delay or minimize one or more of the symptoms associated with the disease state. A therapeutically effective amount of a compound of formula (I) means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a beneficial therapeutic effect in the treatment of a disease state. The term "therapeutically effective amount" may include an amount that improves the overall results of therapy, reduce or eliminate the symptoms, signs or causes of the condition and/or increase the therapeutic efficacy of another therapeutic agent.

A "prophylactically effective amount" of a compound of formula (I) as described herein is an amount that is sufficient to prevent the onset of the disease state or one or more symptoms associated with the disease state or to prevent its recurrence. A prophylactically effective amount of a compound of formula (I) means an amount of a therapeutic agent, alone or in combination with other agents, which provides a beneficial prophylactic effect in preventing the onset of a disease state. The term "prophylactically effective amount" may include an amount that improves the overall prophylactic effect or enhances the prophylactic efficacy of another prophylactic agent.

The term "psycho-neurological disorder" includes neurological diseases or mental disorders or disorders of the CNS (central nervous system), or refers to a disorder that includes either psychiatric symptoms or syndromes, or syndromes caused by organic disorders of the brain. The main characteristics of neuropsychiatric symptoms include the occurrence of various psychiatric symptoms or the likelihood of developing early cerebral symptoms. For example, a neuropsychiatric disorder may include, but is not limited to, schizophrenia, psychotic disorders, Alzheimer's disease, dementia, frontotemporal dementia, mild cognitive impairment, mild forgetfulness, closed head trauma, autism spectrum disorder, Asperger's syndrome, attention deficit disorder with hyperactivity disorder, obsessive-compulsive disorder, tic disorders, childhood learning disabilities, premenstrual syndrome, depression, suicidal mood and/or behavior, bipolar disorder, anxiety disorders, post-traumatic stress disorder, chronic pain, eating disorders, drugs and drug addictions, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis or amyotrophic lateral sclerosis.

As used herein, the term "schizophrenia" refers to a mental disorder that includes at least two of the following disorders: delusions, hallucinations, disorganized speech, extremely disorganized or catatonic behavior, or negative symptoms. Patients may be diagnosed as having schizophrenia by using the DSMIV Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), Washington, D.C. classification or the DSMV criteria (APA, 2013, Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), Washington, D.C.).

The term "personal disorders" used in the invention refers to mental disorders that are characterized by persistent, insufficiently adapted forms of behavior, cognitive activity and internal experiences, manifested in many situations and significantly deviating from those forms that are accepted in the sphere of human spiritual activity. These forms appear early, they are not adaptable and are associated with significant distress or limitation of physical and mental capabilities. Personality disorders include, but are not limited to, paranoid, schizophrenic, schizotypal, antisocial, borderline, hysterical, narcissistic, non-contact, dependent, and obsessive-compulsive personality disorders.

The terms "diet food" or "health food" refers to any type of liquid and solid/semi-solid materials that are used in the nutrition of humans and animals to improve basic behavioral functions, hyperactivity states, anxiety, depression, sensorimotor filtration, to improve pain threshold, memory and/or cognitive functioning, body weight index or to facilitate the treatment of any of the target diseases mentioned in the invention. The term "nutraceutical composition" refers to compositions containing components from food sources that provide additional beneficial health effects in addition to the main nutritional value provided by foods.

The terms "therapeutic food" or "therapeutic food product" refers to a food product prepared for consumption or enteral administration, including a food product that is usually used under the direction of the attending physician for the purpose of specific dietary therapy for a target disease, such as the diseases described in the invention. A "health food" composition may refer to a composition that is specially prepared and processed (as opposed to natural foods used in their natural state) for a patient in need of treatment (for example, for people suffering from a disease, or for those people who require the use of the product as their primary active agent in alleviating a disease or condition through specific dietary therapy).

In the following, one or more embodiments of the invention will be described in more detail. Other features, objects, and advantages of the invention will become apparent upon reading the detailed description, examples, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 graphically shows an example of the design of an experiment to study locomotion in open space.

Figure 2 graphically shows the results of spontaneous locomotion of mice after administration of the compound from example 1.

The figure 3 is a graphical representation of an example of the design of experiments on the study of unlimited space and prepulse inhibition.

Figure 4 is a graph showing the effects of the compound of Example 1 on locomotion in mice treated with MK801.

Figure 5 is a graph showing the effects of the compound of Example 1 on prepulse inhibition in mice treated with MK801.

Figure 6 is a graph showing the effects of Compound 56 on locomotion in mice treated with MK801.

Figure 7 is a graph showing the effects of Compound 56 on prepulse inhibition in mice treated with MK801.

Figure 8 is a graph showing the effects of compound 78 on locomotion in mice treated with MK801.

Figure 9 is a graph showing the effects of compound 78 on prepulse inhibition in mice treated with MK801.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula (I) capable of effectively inhibiting D-amino acid oxidase (DAAO) and their use in inhibiting, treating and/or reducing the risk of a neuropsychiatric disorder.

I. Compounds and compositions

In one aspect of the present invention, features of a compound of formula (I) are provided:

or a pharmaceutically acceptable salt thereof, wherein

each of A, B, C, D and E is independently C, N, N-H, O, S, or absent;

изображает одинарную или двойную химическую связь;

depicts a single or double chemical bond;

each of X, Y and Z is independently aryl, heteroaryl, aralkyl, H, or absent;

C.each of L ₁ and L ₂ is independently a fragment selected from O, CH ₂ , C=O, C _2-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, -((CH ₂ ) _n - W) - where n=0, 1, 2, 3, 4 or 5 and W is O or S or absent; and when L ₂ is absent, Z is aryl or heteroaryl fused to B

C.

In some embodiments, the compounds of formula (I), D and E are independently carbon and are connected through a double bond, and each of A, B and C is independently C, N, N-H, O or S.

соединения формулы (I) представляет собой

или

. В некоторых вариантах осуществления, фрагмент

соединения формулы (I) представляет собой

. В некоторых вариантах осуществления, фрагмент

соединения формулы (I) представляет собой

. В некоторых вариантах осуществления, фрагмент

соединения формулы (I) представляет собой

.In some embodiments, the fragment

compounds of formula (I) is

or

. In some embodiments, the fragment

compounds of formula (I) is

. In some embodiments, the fragment

compounds of formula (I) is

. In some embodiments, the fragment

compounds of formula (I) is

.

In some embodiments, the compounds of formula (I), L ₁ and L ₂ are independently selected from CH ₂ , C _2-10 alkyl, -((CH ₂ ) _n -W)-, where n=0, 1, 2, 3, 4 or 5, and W is O or S, or none. In some embodiments, L ₁ is -(CH ₂ )- or -(CH ₂ ) ₂ -. In some embodiments, L ₁ is -(CH ₂ )-. In some embodiments, L ₁ is -(CH ₂ ) ₂ -. In some embodiments, L ₂ is -(CH ₂ )-, -(CH ₂ ) ₂ - or -(CH ₂ )S-. In some embodiments, L ₂ is -(CH ₂ )-. In some embodiments, L ₂ is -(CH ₂ ) ₂ -. In some embodiments, L ₂ is -(CH ₂ )S-.

C. В некоторых вариантах осуществления, L₂ отсутствует, и Z представляет собой необязательно замещенный фенил, конденсированный с B

C с образованием фрагмента формулы:

.In some embodiments of a compound of formula (I), L ₂ is absent and Z is aryl or heteroaryl fused to B

C. In some embodiments, L ₂ is absent and Z is an optionally substituted phenyl fused to B

C to form a fragment of the formula:

.

,

. В некоторых вариантах осуществления, X имеет формулу:

. В некоторых вариантах осуществления, X представляет собой нафтил. В некоторых вариантах осуществления, X имеет формулу:

. В некоторых вариантах осуществления, Y представляет собой

или

. В некоторых вариантах осуществления, Y представляет собой

. В некоторых вариантах осуществления, Y представляет собой

. В некоторых вариантах осуществления, Z представляет собой необязательно замещенный фенил или необязательно замещенный нафтил. В некоторых вариантах осуществления, Z представляет собой необязательно замещенный фенил. В некоторых вариантах осуществления, Z представляет собой необязательно замещенный нафтил. В некоторых вариантах осуществления, Z представляет собой незамещенный нафтил. В некоторых вариантах осуществления, Z представляет собой фенил, необязательно замещенный с помощью галогена. В некоторых вариантах осуществления, Z представляет собой фенил, необязательно замещенный с помощью хлора или фтора. В некоторых вариантах осуществления, Z имеет формулу:

или

. В некоторых вариантах осуществления, Z имеет формулу:

. В некоторых вариантах осуществления, Z имеет формулу:

. In some embodiments of the compounds of formula (I), X, Y, and Z are each independently selected from benzyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, naphthyl, furopyrrolyl, thianopyrrolyl, indolyl, or absent. In some embodiments, X is an optionally substituted phenyl. In some embodiments, X is phenyl optionally substituted with halo. In some embodiments, X is phenyl optionally substituted with chlorine or fluorine. In some embodiments, X has the formula:

,

. In some embodiments, X has the formula:

. In some embodiments, X is naphthyl. In some embodiments, X has the formula:

. In some embodiments, Y is

or

. In some embodiments, Y is

. In some embodiments, Y is

. In some embodiments, Z is an optionally substituted phenyl or an optionally substituted naphthyl. In some embodiments, Z is an optionally substituted phenyl. In some embodiments, Z is an optionally substituted naphthyl. In some embodiments, Z is unsubstituted naphthyl. In some embodiments, Z is phenyl optionally substituted with halo. In some embodiments, Z is phenyl optionally substituted with chlorine or fluorine. In some embodiments, Z has the formula:

or

. In some embodiments, Z has the formula:

. In some embodiments, Z has the formula:

.

In some embodiments, the compound of formula (I) is a compound of formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein B and F are independently C or N; C is C, X and Z are independently aryl or heteroaryl; each of L ₁ and L ₂ is independently a C ₁ -C ₁₀ fragment, or is absent; and when L ₂ is absent, Z is aryl or heteroaryl fused to B=C. In some embodiments, F is C. In some embodiments, the compound of formula (Ia) has the formula:

, или его фармацевтически приемлемая соль.

, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) is a compound of formula (I-b):

or a pharmaceutically acceptable salt thereof, wherein X and Z are each independently aryl; and each of L ₁ and L ₂ independently represents a C ₁ -C ₁₀ fragment.

In some embodiments, the compound of formula (I) may be one of the following compounds:

,

,

In some embodiments, any one of the compounds in Examples 1-26 or any one of the compounds in Table 1 is a compound of the present invention. Any of the compounds of formula (I) described herein may be formulated as a pharmaceutical composition, nutraceutical composition, dietary food or health food.

In some examples, the composition described herein is a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier, excipient, or stabilizer (Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. KE Hoover). Acceptable carriers, excipients or stabilizers are non-toxic to recipients at the doses and concentrations employed and may include buffers such as phosphate, citrate and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride , benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechin, resorcinol, cyclohexanol, 3-pentanol, benzoates, sorbate, and m-cresol), low molecular weight polypeptides (less than about 10 residues ), proteins such as serum albumin, gelatin or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, serine, alanine or lysine, monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrans, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose or sorbitol, salt-forming counterions such as sodium, metal complexes (eg Zn-protein complexes) and/or nonionic surfactants such as TWEEN ^TM , PLURONICS ^TM or polyethylene glycol (PEG).

In other examples, the pharmaceutical composition described herein may be formulated in a sustained release form. Suitable examples of sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing tannic acids, these matrices being in the form of shaped articles such as films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or polyvinyl alcohol, polylactides (US Pat. No. 3,773,919), copolymers of L-glutamic acid and ethyl-L-glutamate, a non-degradable copolymer of ethylene, and vinyl acetate, degradable copolymers of lactic acid and glycolic acid, such as LUPRON DEPOT ^TM (injectable microspheres consisting of a copolymer of lactic acid, glycolic acid and leuprolide acetate), sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

Pharmaceutical compositions used for in vivo administration must be sterile. This is easily achieved, for example, by filtration through sterile filter membranes. Therapeutic compositions are usually placed in a container with a sterile opening, such as an intravenous solution bag or vial with a hypodermic stopper.

The pharmaceutical compositions described herein may be in unit dose dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation, or for intramuscular or intracerebral administration.

For the preparation of solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier, for example conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, with water, to form a pre-formulated solid composition, then used for molding, containing a homogeneous mixture of the compound of the present invention or its non-toxic pharmaceutically acceptable salt. When these pre-formulated compositions are referred to as homogeneous, it is meant that the active ingredient is evenly distributed throughout the composition, whereby the composition can be readily divided into equally effective single dose dosage forms such as tablets, pills and capsules. This preformed solid composition is then subdivided into single dose dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Tablets or pills of this new composition can be coated or otherwise compounded to obtain a dosage form that allows you to take advantage of prolonged action. For example, a tablet or pill may include an internal dose component and an external dose component, the latter being in the form of a shell over the first component. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass unaltered into the duodenum or be retained upon release. Various materials can be used for such enteric layers or coatings, such as materials including a range of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

Suitable surfactants include, in particular, nonionic surfactants such as polyoxyethylene sorbitans (eg Tween ^TM 20, 40, 60, 80 or 85) and other sorbitans (eg Span ^TM 20, 40, 60, 80 or 85). Surfactant compositions typically include 0.05 to 5% surfactant, and may contain 0.1 to 2.5% surfactant. Obviously, other ingredients may be added as needed, such as mannitol or other pharmaceutically acceptable media.

Suitable emulsions can be prepared using commercially available fat emulsions such as Intralipid ^TM , Liposyn ^TM , Infonutrol ^TM , Lipofundin ^TM and Lipiphysan ^TM . The active ingredient may either be dissolved in the premixed emulsion composition, or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and the emulsion formed when mixed with a phospholipid (eg egg phospholipids, soy phospholipids or soy lecithin) and water. Obviously, other ingredients, such as glycerol or glucose, may be added to adjust the tonicity of the emulsion. The emulsions used typically contain up to 20% oil, for example 5 to 20%.

Pharmaceutical compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain the above-mentioned suitable pharmaceutically acceptable excipients. In some embodiments, the compositions are administered orally or respiratory through the nose for local or systemic exposure.

Compositions, preferably in sterile pharmaceutically acceptable solvents, can be nebulized by the use of gases. Nebulized solutions can be administered by inhalation directly from a nebulizing device, or the nebulizing device can be attached to a face mask, tent, or positive pressure intermittent breathing ventilator. The solution, suspension or powder composition is preferably administered orally or nasally by means of devices that deliver the dosage form in an appropriate manner.

In some embodiments, the compositions described in the invention may be a dietary food product, or may be a dietary food product, which is any kind of liquid and solid/semi-solid materials that are used to feed humans and animals, to correct basic behavioral functions, hyperactivity, anxiety, depressive state, sensorimotor filtration, pain threshold, memory and/or cognitive functions, or to perform an auxiliary function in the treatment of any of the target diseases specified in the invention (for example, a neuropsychiatric disorder, including neuropsychiatric disorders described in the invention). The dietary food product may be a food product (e.g., tea-based drinks, juices, soft drinks, coffee, milk, jellies, cookies, cereal products, chocolate, snacks, herbal extracts, dairy products (e.g., ice cream and yogurt) ), food/dietary supplement or nutraceutical composition.

The dietary product described herein may include one or more edible carriers that provide the product with one or more of the benefits described herein. Examples of edible carriers include starch, cyclodextrin, maltodextrin, methylcellulose, carboxymethylcellulose, xanthan gum, and aqueous solutions thereof. Other examples include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, stabilizers, gelatin, binders, excipients, disintegrators, lubricants, sweeteners, flavors, colors, and other similar materials, and combinations thereof, known to any person skilled in the art. In some examples, the dietary products described herein may further include neuroprotective products such as fish oil, linseed oil, and/or benzoate.

In some examples, the dietary food product is a nutraceutical composition, which refers to compositions containing components from dietary sources and providing additional beneficial health effects in addition to the main nutritional value found in foods. The nutraceutical composition described herein comprises a compound of formula (I) as described in the invention and additional ingredients and additives that promote good health and/or enhance the stability and biological activity of the compound of formula (I).

The effects of nutraceutical compositions may be rapid and/or short-term, or may contribute to the achievement of the long-term treatment goals described in the invention, such as, for example, the correction of basic behavioral functions, hyperactivity, anxiety, depressive state, sensorimotor filtration, pain threshold, memory and/ or cognitive function, for example, in people who already have a neuropsychiatric disorder or are at risk of developing a neuropsychiatric disorder. These nutraceutical compositions may be contained in an edible material, for example as a dietary supplement or pharmaceutical composition. As a dietary supplement, additional nutrients such as vitamins, minerals or amino acids may be included. The composition may also be a beverage or food product, such as tea, soft drink, juice, milk, coffee, biscuits, cereal, chocolate, and snack food. If necessary, the composition may be sweetened by adding a sweetener such as sorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starch hydrolyzate, high fructose corn syrup, cane sugar, beet sugar, pectin or sucralose.

The nutraceutical composition disclosed in the invention may be prepared in the form of a solution. For example, a nutraceutical composition may be formulated in a medium such as a buffer, solvent, diluent, inert carrier, oil, or cream. In some examples, the composition is present in an aqueous solution, which optionally contains a non-aqueous co-solvent such as an alcohol. The nutraceutical composition may also be in the form of a powder, paste, jelly, capsule or tablet. Lactose and cornstarch are commonly used as capsule diluents and as tablet carriers. Lubricants such as magnesium stearate are commonly added to form tablets.

Dietary foods may be prepared for an appropriate route of administration, such as oral administration. The composition for oral administration may, for example, take the form of tablets or capsules prepared by conventional methods using appropriate excipients, such as binders (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (for example, lactose, microcrystalline cellulose or hydrogen phosphate calcium), lubricants (eg magnesium stearate, talc or silica), disintegrants (eg potato starch or sodium starch glycolate), or wetting agents (eg sodium lauryl sulfate). Tablets may be coated by methods well known in the art. In addition, dosage forms of compositions for oral administration include chewing gums and other chewable forms.

In some examples, the dietary food product may be in liquid form and one or more edible carriers may be a solvent or dispersion medium including, but not limited to, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol), lipids (eg triglycerides, vegetable oils, liposomes) or combinations thereof. Appropriate fluidity can be achieved, for example, by using a coating agent such as lecithin, by maintaining the desired particle size as a result of dispersion in carriers, such as, for example, liquid polyol or lipids, by using surfactants, such as, for example , hydroxypropyl cellulose, or combinations thereof. In many cases, it is advisable to add an isotonic agent such as, for example, sugars, sodium chloride, or combinations thereof.

Liquid preparations for oral administration may, for example, take the form of solutions, syrups or suspensions, or they may be formulated as a dry product for reconstitution with water or other suitable vehicle before use. In one embodiment, liquid preparations may be formulated for administration with fruit juice. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifiers (for example, lecithin or gum arabic), non-aqueous vehicles (for example, almond oil, butyric esters, ethyl alcohol or fractionated vegetable oils) and preservatives (eg methyl or propyl p-hydroxybenzoates, benzoate or sorbate).

In specific embodiments, the composition is a health food product, which may be a food product prepared for consumption or enteral administration. Such food product is usually used under the supervision of a physician for specific dietary treatment of the target disease described in the invention. In some cases, such a health food composition is specially prepared and processed (as opposed to natural foods used in their natural state) for a patient in need of treatment (for example, for people suffering from a disease, or for those people who require the use of the product as the main active agent for the relief of a disease or condition through specific dietary therapy). In some instances, the health food composition described herein is not one that a physician simply recommends as part of a general diet to treat symptoms or reduce the risk of a disease or condition.

Any of the health food products described herein, comprising a compound of formula (I) and at least one carrier (for example, the carrier described in the invention), can be prepared in the form of a liquid solution, powder, bar, implant capsule, suspension in in a suitable liquid or in a suitable emulsion, as detailed below. At least one carrier, which may be naturally occurring or synthetic (not naturally occurring), may provide one or more beneficial properties to the compound of formula (I) in the composition, such as stability, bioavailability and/or biological activity. Any of the carriers described herein may be used to formulate a health food composition. In some embodiments, the health food composition may further include one or more additional ingredients selected from the group including, but not limited to, natural flavors, artificial flavors, trace and trace amounts of essential minerals, minerals, vitamins, oats. , nuts, spices, milk, egg, salt, flour, lecithin, xanthan gum and/or sweeteners. The health food composition may be placed in a suitable container, which may further contain at least an additional therapeutic agent, such as additional therapeutic agents described herein.

In specific embodiments, the compound of formula (I) described herein is incorporated into a pharmaceutical composition in an effective amount. In specific embodiments, the effective amount is a therapeutically effective amount (eg, an amount that is effective to treat and/or reduce the risk of a neuropsychiatric disorder in a subject in need thereof). In specific embodiments, the neuropsychiatric disorder is a neurological disorder, such as Alzheimer's disease. In particular embodiments, the neuropsychiatric disorder is schizophrenia. In specific embodiments, the effective amount is a prophylactically effective amount (e.g., an amount that is effective to inhibit D-amino acid oxidase (DAAO) in a subject in need thereof, or an amount that is effective to treat or reduce the risk of a neuropsychiatric disorder in subject in need).

The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. Generally, such preparations involve bringing into association the compound of formula (I) described herein (i.e., the "active ingredient") with a carrier or excipient, and/or with one or more other accessory ingredients, and then, if necessary and/or desirably, shaping and/or packaging the product into the desired single dose or multi-dose dosage form.

Pharmaceutical compositions may be formulated, packaged and/or marketed as bulk pharmaceuticals in single dose and/or multiple unit dose form. A "single dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of active ingredient is usually equal to the dose of the active ingredient that is administered to the subject and/or a convenient fraction of such dose to administer, for example, half or one third of such dose.

The relative amounts of the active ingredient, pharmaceutically acceptable excipient and/or any additional ingredients in the pharmaceutical composition described in the invention will vary depending on the individual characteristics, size and/or health of the subject being treated, and, in addition, depending on the intended route of administration compositions. The composition may include from 0.1 to 100% (by weight) of the active ingredient.

Pharmaceutically acceptable excipients used in the manufacture of the pharmaceutical compositions of the invention include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrants, binders, preservatives, buffering agents, lubricants and/or oils. Adjuvants such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents and perfumes may also be present in the composition.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to active ingredients, liquid dosage forms may include inert diluents commonly used in pharmaceuticals such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol , 1,3-butylene glycol, dimethylformamide, oils (eg, cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfumes. In specific embodiments, for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as ^Cremophor® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

Injectable preparations, for example sterile injectable aqueous or oily suspensions, may be prepared by known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as the solvent or suspending medium. Any emollient fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable dosage forms can be sterilized, for example, by filtration through a bacteria-retaining filter, or by administering sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the action of a drug, it is often desirable to slow down the absorption of a drug administered by subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the drug in this case depends on the rate of its dissolution, which, in turn, may depend on the size of the crystal and its crystalline form. Alternatively, delayed absorption of a parenteral dosage form can be accomplished by dissolving or suspending the drug in an oily medium.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) excipients or solid diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, (c) humectants such as glycerol, (d) disintegrants such as agar, calcium carbonate, potato or corn starch, alginic acid, certain silicates and sodium carbonate, (f) dissolution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (d) wetting agents such as, for example , cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may include a buffering agent.

Solid compositions of this type can be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coated layers and shells such as enteric coatings and other coatings well known in pharmacology. They may optionally include opacifiers and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally with a delay. Examples of encapsulating compositions that can be used include polymeric materials and waxes. Solid compositions of this type can be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active ingredient may be in microencapsulated form with one or more of the excipients mentioned above. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coated layers and coatings such as enteric coatings, controlled release coatings, and other coatings well known in pharmacology. In such solid dosage forms, the active ingredient may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may include, as is common practice, additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may include buffer substances. They may optionally include opacifiers and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally with a delay. Examples of encapsulating materials that may be used include, but are not limited to, polymeric materials and waxes.

Although the descriptions of pharmaceutical compositions given in the invention generally relate to pharmaceutical compositions that are used for administration to humans, nevertheless, such compositions, as a rule, can be used for administration to animals of all kinds. Modification of pharmaceutical compositions used for administration to humans, in order to create compositions that can be used for administration to various animals, is well known, and such a modification can be developed and/or carried out by a person of ordinary skill in the veterinary pharmacology by routine experimentation.

The compound of formula (I) according to the invention is usually formulated in a single dose dosage form for ease of administration and consistency of dosing. However, it should be borne in mind that the total daily dose of the composition described in the invention should be determined by the attending physician on the basis of a thorough medical assessment. The specific level of therapeutically effective dose for any particular subject or organism will depend on a number of factors including the disease being treated and its severity, the activity of the particular active ingredient used, the particular composition used, age, body weight, general health, sex and diet of the subject, the time of administration, route of administration and rate of excretion of the particular active ingredient used, duration of treatment, drugs used in combination or simultaneously with the particular active ingredient, and other such factors well known in medicine.

II. Methods of treatment

In another aspect, the present invention provides a method for inhibiting D-amino acid oxidase (DAAO) activity in a subject and/or treating or reducing the risk of a neuropsychiatric disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) mentioned above or a composition containing the same .

A compound of formula (I) as described herein is used to inhibit DAAO activity in a subject and/or to treat or reduce the risk of a neuropsychiatric disorder in a subject (e.g., a person suspected of having a neuropsychiatric disorder or at risk of developing a neuropsychiatric disorder). In some embodiments, the neuropsychiatric disorder includes schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, dementia, mild cognitive impairment, mild forgetfulness, closed head injury, autism spectrum disorder, Asperger's syndrome, attention deficit hyperactivity disorder, obsessive-compulsive disorder, tic disorders, learning disabilities in childhood, premenstrual syndrome, depression, suicidal mood and/or behavior, bipolar disorder, anxiety disorders, post-traumatic stress disorder, chronic pain, eating disorders, drug and drug addictions , personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis or amyotrophic lateral sclerosis.

The compound of formula (I) according to the invention, or a composition containing it, may be administered by an appropriate route known to those skilled in the art, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (eg, powders, ointments, creams and/or drops) administration. In particular, contemplated routes of administration include oral administration, intravenous administration (eg, systemic intravenous administration), regional administration by delivery to the blood and/or lymph, and/or direct administration to an affected area of the body. Generally, selection of the most appropriate route of administration will depend on a number of factors including the properties of the drug (eg, stability in the gastrointestinal environment) and/or the condition of the subject (eg, the subject's ability to tolerate oral administration).

The exact amount of the compound of formula (I) contained in the above composition required to achieve an effective amount will vary from subject to subject, depending, for example, on the species, age and general health of the subject, the severity of side effects or disorders, special properties the particular compound of formula (I), the route of administration, and the like. An effective amount can be included in a single dose dosage form (eg, a single dose oral dosage form) or a multiple dose dosage form (eg, a multiple dose oral dosage form). In particular embodiments, where multiple doses are administered to a subject or are administered to a biological sample, tissue, or cell, any two of the multiple doses comprise different or substantially the same amounts of the inventive compound of formula (I). In specific embodiments, in cases where multiple doses are administered to a subject or administered to a biological sample, tissue, or cell, the frequency of multiple doses to a subject or multiple doses to a tissue or cell is three doses per day, two doses per day, one dose per day, one dose every other day, one dose every three days, one dose every week, one dose every two weeks, one dose per month, or one dose every other month. In specific embodiments, the frequency of administration of multiple doses to a subject or administration of multiple doses to a tissue or cell is one dose per day. In specific embodiments, the frequency of administration of multiple doses to a subject or administration of multiple doses to a tissue or cell is two doses per day. In specific embodiments, in cases where multiple doses are administered to a subject or administered to a biological sample, tissue, or cell, the time interval between administration of the first dose and the last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years or the lifespan of a subject, biological sample, tissue, or cell. In specific embodiments, the time interval between the first dose and the last dose of multiple doses is three months, six months, or one year. In specific embodiments, the time interval between the first dose and the last dose of multiple doses is equal to the lifespan of the subject, biological sample, tissue, or cell. In specific embodiments, the dose described herein (e.g., a single dose or any of multiple doses) independently comprises 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg , from 100 mg to 300 mg, from 300 mg to 1000 mg or from 1 g to 10 g inclusive of the compound of formula (I) described in the invention. In specific embodiments, the inventive dose independently comprises 3 mg to 10 mg, inclusive, of the inventive compound of formula (I). In specific embodiments, the inventive dose independently comprises 10 mg to 30 mg, inclusive, of the inventive compound of formula (I). In particular embodiments, the inventive dose independently comprises 30 mg to 100 mg, inclusive, of the inventive compound of formula (I). In specific embodiments, the inventive dose independently comprises 100 mg to 300 mg, inclusive, of the inventive compound of formula (I). In particular embodiments, the inventive dose independently comprises 300 mg to 1000 mg, inclusive, of the inventive compound of formula (I).

The dosage ranges described herein are recommended for administering the pharmaceutical compositions of the invention to an adult human. The amount that may be administered to, for example, a child or adolescent may be determined by the attending physician or one of skill in the art and may be lower or the same as for an adult.

III. Combined treatment

The compound of formula (I) described herein may be administered in combination with one or more additional pharmaceutical agents (eg, therapeutic and/or prophylactic agents) used to treat and/or reduce the risk of a neuropsychiatric disorder. Additional pharmaceutical agents can increase the potency (e.g., potency (e.g., potency and/or efficacy) of a compound in treating and/or reducing the risk of a neuropsychiatric disorder in a subject in need thereof), increase bioavailability, increase safety, reduce drug resistance , reduce and/or alter metabolism, slow excretion and/or modify the distribution of a compound in a subject's body, biological sample, tissue, or cell. It should also be borne in mind that the applied therapy may achieve the desired effect for the same disorder, and/or it may achieve different effects. In specific embodiments, the inventive compound of formula (I) and the additional pharmaceutical agent exhibit a synergistic effect that is not present when treated with one of the compounds of formula (I) and one additional pharmaceutical agent alone, but not both.

The compound of formula (I) can be administered concurrently, before, simultaneously with or after the administration of one or more additional pharmaceutical agents, which can be used as, for example, combination therapy in the treatment and/or reduction of the risk of a neuropsychiatric disorder in a subject. In some examples, the compound and the additional pharmaceutical agent(s) are formulated as a single composition. In other examples, the compound and the additional pharmaceutical agent(s) are formulated as separate compositions.

Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceuticals include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the US Food and Drug Administration (US FDA) under the US Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, antibodies, small molecules associated with proteins such as antibodies, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In specific embodiments, the additional pharmaceutical agent is a pharmaceutical agent used to treat and/or reduce the risk of a neuropsychiatric disorder in a subject. In specific embodiments, the additional pharmaceutical agent is a pharmaceutical approved by a government regulatory agency (eg, the US FDA) for the treatment and/or reduction of the risk of a neuropsychiatric disorder in a subject. Each additional pharmaceutical agent may be administered in the form of a dose and/or in accordance with the mode of administration defined for that pharmaceutical agent. Additional pharmaceutical agents can also be administered together with each other and/or with a composition containing the compound of formula (I) described in the invention, in a single dose or administered separately in different doses. The specific combination for use in a dosing regimen will be selected based on the compatibility of the inventive compound of formula (I) with the additional pharmaceutical agent(s) and/or the possibility of achieving the desired therapeutic and/or prophylactic effect. Generally, it is contemplated that the additional pharmaceutical agent(s) in combination should be used at dose levels that do not exceed the dose levels at which they are used in monotherapy. In some embodiments, the levels used in combination will be lower than those used in monotherapy.

In specific embodiments, the additional pharmaceutical agent is selected from agents for treating and/or reducing the risk of a neuropsychiatric disorder, or combinations thereof. In specific embodiments, pharmaceutical compositions containing a compound of formula (I) as described herein may be administered in combination with therapy to treat and/or reduce the risk of a neuropsychiatric disorder.

In specific embodiments, the additional pharmaceutical agent is an agent for the treatment and/or reduction of the risk of a neuropsychiatric disorder, which may be an antipsychotic agent, an antidepressant, a mood stabilizer (normotimic), an anxiolytic agent, a psychostimulant, and an agent for the treatment of attention deficit hyperactivity disorder (ADHD), or an agent for the treatment of Alzheimer's disease (AD).

Antipsychotic includes, but is not limited to, butyrophenone, phenothiazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthene, chlorprothixene, flupentixol, thiothixene, zuclopenthixol, clozapine, olanza pin, risperidone, quetiapine , ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, asenapine, cariprazine, iloperidone, pimavanserin, luradisone, brexpiprazole, cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate and tetrabenazine.

Antidepressant includes, but is not limited to, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and serotonergic specific antidepressants (NASSA), norepinephrine (noradrenaline) reuptake inhibitors ), norepinephrine-dopamine reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors (SNRIs). Examples of antidepressants include, but are not limited to, fluoxetine, paroxetine, escitalopram, citalopram, sertraline, fluvoxamine, venlafaxine, desvenlafaxine, vortioxetine, levomilnacipran, vilazodone, selegiline, ketamine, milnacipine, duloxetine, mirtazapine, mianserin, reboxetine, bupropion, amitriptyline, nortriptyline , protriptyline, desipramine, trimipramine, amoxapine, bupropion, clomipramine, desipramine, doxepin, isocarboxazid, tranylcypromine, trazodone, nefazodone, phenelzine, lamatrogin, lithium, topiramate, gabapentin, carbamazepine, oxcarbazepine, valproate, maprotiline, brofaromine, gepirone, moclobemide, isoniazid and iproniazid.

A psychostimulant or treatment for attention deficit hyperactivity disorder (ADHD) includes, but is not limited to, methylphenidate, dextro-threo-methylphenidate, isopropylphenidate, cocaine, amphetamine, methamphetamine, dextroamphetamine, 3,4-methylenedioxymethamphetamine, pemoline, phenmetrazine, diethylpropion, chlorphentermine, pipradol, p-hydroxymorphedrine, fenfluramine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane, bupropion, statins, modafinil, arecoline, dexmethylphenidate, lisdexamphetamine dimesilate, amphetamine mixed salts, atomoxetine, clonidine hydrochloride, guanfacine hydrochloride and arecoline.

The mood stabilizer (normothymic) includes, but is not limited to, lithium, lamotrigine, carbamazepine, oxcarbazepine, topiramate, zolpidem, carbamazepine, and valproate.

The anxiolytic agent includes, but is not limited to, diazepam, alprazolam, triazolam, indiplon, zaleplon, bromazepam, oxazepam, buspiron, hydroxyzine, mecloqualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, al let's go, Alseroxlon , amphenidone, azacyclonol, bromisovalum, clorazepate, calcium N-carbamoyl aspartate, captodiamine, capuride, carbcloral, carbromal, chloral betaine, ensiprazine, flesinoxan, ipsapiraone, ipsapirone, lesopitron, loxapine, methaqualone, metprilon, propanolol, tandospirone, trazodone, zopiclone and zolpidem .

The Alzheimer's disease (AD) agent includes, but is not limited to, donepezil, rivastigmine, galantamine, memantine, selfotel, midaphotel, tacrine, selegiline, and vitamin E.

IV. Treatment Kits

The present invention also includes kits for use in the treatment of any of the target diseases described herein. The kits according to the invention may include the compound of formula (I) described in the invention or a composition containing it. The kit may optionally further include one or more additional pharmaceutical agents described in the invention.

Any of the kits described herein may include one or more containers (eg, vial, ampoule, vial, syringe and/or dispenser pack or other suitable container) containing the active ingredients of the invention. In some embodiments, the kits provided may further comprise a container containing a pharmaceutical diluent or suspension of a pharmaceutical composition comprising a compound of formula (I) as described herein, and optionally additional pharmaceuticals. In some embodiments, a pharmaceutical composition comprising a compound of formula (I) described in the invention in one or more containers is combined to form a single dosage form with a single dose.

In specific embodiments, the implementation described in the invention, the kit further contains instructions for use included in the kit composition containing the compound of formula (I). The set described in the invention may also include information that is required by a government regulatory body, such as the US Food and Drug Administration (FDA). In specific embodiments, the information included in the kits is an instruction for the medical use of the drug. In specific embodiments, the kits and instructions provide treatment and/or reduction in the risk of a neuropsychiatric disorder. The kit described in the invention may include one or more additional pharmaceutical agents described in the invention in the form of a separate composition.

It is assumed that any person skilled in the art as a result of reading the above description of the invention can apply the present invention to its fullest extent without additional research. Therefore, the following specific embodiments should be interpreted as illustrative only and not limiting in any way the remainder of the invention. The entire content of all publications cited in the invention is incorporated into the present invention by reference to them.

EXAMPLES

All chemicals used were purchased from suppliers such as Sigma Aldrich and Alfa Aesar. The NMDA receptor antagonist MK801 used in the experiments was supplied by Sigma (Sigma-Aldrich, USA). Male C57BL/6J mice were purchased from the Laboratory Animal Center in the College of Medicine, National Taiwan University. Mice were divided into groups and housed with ad libitum access to food and water in ventilated polysulfone cages (Alternative Design, AR, USA) (3-5 mice/cage) in animal facilities from SyneuRx International (Taiwan) Corp. ¹ H NMR spectra were recorded on a Bruker 300 MHz or BRUKER 400 MHz spectrometer and chemical shifts were expressed in δ (ppm) values using trimethylsilane as an internal standard. Mass spectra were recorded on a Shimadzu LCMS-2020 Quadrupole LC/MS single quadrupole chromato-mass spectrometer.

Example 1: Synthesis of 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl 1H-pyrrol-2-carboxylate (1)

6-(Hydroxymethyl)-4-oxo-4H-pyran-3-yl 1H-pyrrol-2-carboxylate (1)

To a stirred suspension of pyrrole-2-carboxylic acid (3.0 g, 27.1 mmol) in dichloromethane (18 ml) at room temperature (RT) was added oxalyl chloride (8.5 ml, 99.0 mmol) in one portion. After 2-3 hours, dichloromethane and oxalyl chloride were removed under reduced pressure. Benzene was added to the residue and removed under reduced pressure. Dichloromethane (20 ml) was added to the residue and the resulting solution was added dropwise to a solution of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (5.8 g, 40.5 mmol) in pyridine (20 ml ) at 0°C for 2 hours. The mixture was warmed to room temperature and stirred overnight. The dichloromethane was removed by evaporation under reduced pressure and the residue was diluted with an equivalent volume of water. The precipitate was filtered off and the filtrate was poured into 1 L of water, then kept at 4° C. overnight. The solid was suction filtered and washed with ethanol. Drying under vacuum gave 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl 1H-pyrrol-2-carboxylate (1) as an off-white solid (2.2 g, 34.5% ), which is confirmed by the ¹ H NMR spectrum (DMSO-d ₆ , 300 MHz) δ 12.14 (br. s, 1H), 8.53 (s, 1H), 7.14 (m, 1H), 6.98 (m, 1H), 6.45 (s, 1H), 6.26 (s, 1H), 5.89 (t, J=6.0 Hz, 1H), 4.36 (d, J=6, 0 Hz, 2H). ESI-MS, m/z=236 [M+H] ⁺ .

Example 2: Synthesis of 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl 4-(4-chlorophenethyl)-1H-pyrrole-2-carboxylate (5)

Ethyl 4-(2-(4-chlorophenyl)acetyl)-1H-pyrrole-2-carboxylate (2)

To a solution of 4-chlorobenzeneacetyl chloride (54.0 g, 300.0 mmol) in dichloromethane (500 ml) was added aluminum chloride (38.0 g, 280.0 mmol) at 0°C under N ₂ atmosphere. Then, a solution of ethylpyrrole-2-carboxylate (20.0 g, 140.0 mmol) in dichloromethane (200 ml) was added dropwise to the mixture at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with saturated aqueous NH ₄ Cl. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using 0-30% ethyl acetate in petroleum ether to give ethyl 4-(2-(4-chlorophenyl)acetyl)-1H-pyrrole-2-carboxylate (2) as a brown solid (23, 0 g, 55%). ESI-MS, m/z=292 [M+H] ⁺ .

Ethyl 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (3)

Triethylsilane (40 ml, 244 .3 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was evaporated under vacuum. The residue was purified by flash column chromatography using 0-30% ethyl acetate in petroleum ether to give ethyl 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (3) as a purple solid (12 g, 55%). ESI-MS, m/z=278 [M+H] ⁺ .

4-(4-Chlorophenethyl)-1H-pyrrole-2-carboxylic acid (4)

To a solution of ethyl 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (3, 2.0 g, 8.3 mmol) in tetrahydrofuran (50 ml) was added a solution of lithium hydroxide (1.0 g, 41.5 mmol) in water (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The pH was adjusted to 5-6 with 1N HCl. The mixture was filtered and the solid was collected and dried to give 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylic acid (4) as an off-white solid (0.91 g, 48%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.08 (s, 1H), 11.4 (s, 1H), 7.33-7.23 (m, 4H), 6.73 (s, 1H), 6.58 (s, 1H), 2.84-2.80 (m, 2H), 2.71-2.67 (m, 2H). ESI-MS, m/z=278 [M+H] ⁺ .

6-(Hydroxymethyl)-4-oxo-4H-pyran-3-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (5)

5-Hydroxy-2-( hydroxymethyl)-4H-pyran-4-one (0.3 g, 2.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.4 g, 2.0 mmol) and hydroxybenzotriazole (0. 3 mg, 2.0 mmol). The resulting mixture was stirred at 60°C for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using dichloromethane/methanol (95:5) to give 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl 4-(4-chlorophenetyl)-1H-pyrrole-2 -carboxylate (5) as a white solid (0.4 g, 53%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.91 (s, 1H), 8.57 (s, 1H), 7.34-7.32 (m, 2H), 7.26-7, 24 (m, 2H), 6.92-6.91 (m, 1H), 6.87-6.86 (m, 1H), 6.45 (s, 1H), 5.79-5.76 ( m, 1H), 4.38 (d, J=6.1 Hz, 2H), 2.87-2.80 (m, 2H), 2.76-2.72 (m, 2H). ESI-MS, m/z=374 [M+H] ⁺ .

Example 3 Synthesis of 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl 4H-furo[3,2-b]pyrrole-5-carboxylate (9)

Ethyl (Z)-2-azido-3(furan-2-yl)acrylate (6)

To a stirred solution of ethanol (200 ml) was added sodium (8.3 g, 360.9 mmol) in an ice bath, and then slowly added ethyl 2-azidoacetate (44.8 g, 347.0 mmol) and furan-2-carbaldehyde (28.8 g, 299.7 mmol). The reaction mixture was stirred at room temperature for 3 hours, then quenched by adding a saturated aqueous solution of NH ₄ Cl (30 ml). The resulting solution was extracted with ethyl acetate (2×100 ml) and the organic layers were combined. The organic layer was then washed with brine (50 ml). The mixture was dried over anhydrous sodium sulfate and filtered. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:9) to give ethyl (Z)-2-azido-3(furan-2-yl)acrylate (6) as a yellow oil (10.0 g , 16%). ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.54-7.46 (m, 1H), 7.11 (d, J=3.7 Hz, 1H), 6.88 (s, 1H), 6 .54 (m, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).

Ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (7)

A solution of ethyl (Z)-2-azido-3(furan-2-yl)acrylate (6, 10.0 g, 48.3 mmol) in xylene (100 ml) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:9) to give ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (7) as a yellow solid substances (7.2 g, 83%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.64 (s, 1H), 7.79 (d, J=2.2 Hz, 1H), 6.74 (dd, J=1.8, 0.9Hz, 1H), 6.61(dd, J=2.2, 0.9Hz, 1H), 4.26(kv, J=7.1Hz, 2H), 1.30(t, J=7.1 Hz, 3H). ESI-MS, m/z=180 [M+H] ⁺ .

4H-Furo[3,2-b]pyrrole-5-carboxylic acid (8)

To a stirred solution of ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (7.1.8 g, 10.1 mmol) in methanol (20 ml) was added sodium hydroxide solution (1.2 g, 30. 0 mmol) in water (10 ml). The resulting mixture was stirred at 80°C for 3 hours, then cooled to room temperature. The pH of the mixture was adjusted to 1 with 1N HCl. The mixture was filtered. The solid was collected and purified by recrystallization using acetate/petroleum ether (1:4) to give 4H-furo[3,2-b]pyrrole-5-carboxylic acid (8) as a brown solid (1.6 g , 100%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.36 (s, 1H), 11.51 (s, 1H), 7.76 (d, J=2.1 Hz, 1H), 6.69 (dd, J=1.8, 0.9 Hz, 1H), 6.58 (dd, J=2.1, 0.9 Hz, 1H). ESI-MS, m/z=152 [M+H] ⁺ .

6-(Hydroxymethyl)-4-oxo-4H-pyran-3-yl 4H-furo[3,2-b]pyrrole-5-carboxylate (9)

5-Hydroxy-2-( hydroxymethyl)-4H-pyran-4-one (0.3 g, 2.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.4 g, 2.0 mmol) and hydroxybenzotriazole (0. 3 g, 2.0 mmol). The reaction mixture was stirred at 60°C for 4 hours and then diluted with ethyl acetate (50 ml). The mixture was washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) to give 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl 4H-furo[3,2-b]pyrrole-5- carboxylate (9) as a white solid (0.2 g, 28%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.62 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 6.97 (d, J=0.9 Hz , 1H), 6.67 (dd, J=2.2, 0.9 Hz, 1H), 6.47 (s, 1H), 5.80 (s, 1H), 4.39 (s, 2H) . ESI-MS, m/z=276 [M+H] ⁺ .

Example 4 Synthesis of 6-(((4-chlorophenyl)thio)methyl)-4-oxo-4H-pyran-3-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (14)

A mixture of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (90.0 g, 630.0 mmol), 4-methoxybenzyl chloride (110.0 g, 700.0 mmol) and potassium carbonate (132, 0 g, 1000.0 mmol) in N,N-dimethylformamide (500 ml) was stirred at 50° C. for 16 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (2:8) to give 2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (10) as yellow solid (130.0 g, 78%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.15 (s, 1H), 7.35 (d, J=6.3 Hz, 2H), 6.95 (d, J=6.3 Hz , 2H), 6.32 (s, 1H), 5.75-5.70 (m, 1H), 4.87 (s, 2H), 4.30 (d, J=4.0 Hz, 2H) , 3.77 (s, 3H). ESI-MS, m/z=263 [M+H] ⁺ .

2-(Bromomethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (11)

To a solution of 2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (10, 30.0 g, 110.0 mmol) in dichloromethane (500 ml) dimethylpyridine (26.0 ml, 170.0 mmol), triphenylphosphine (51.0 g, 170.0 mmol) and tetrabromomethane (57.0 g, 170.0 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:4) to give 2-(bromomethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (11) as yellow solids (20.0 g, 54%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.57 (s, 1H), 7.35-7.32 (m, 2H), 6.92-6.90 (m, 2H), 6, 47 (s, 1H), 5.03 (s, 2H), 4.16 (s, 2H), 3.83 (s, 3H). ESI-MS, m/z=325 [M+H] ⁺ .

2-(((4-Chlorophenyl)thio)methyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (12)

To a mixture of 2-(bromomethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (11, 19.5 g, 60.0 mmol), 4-chlorobenzenethiol (11.0 g, 76 .0 mmol) in N,N-dimethylformamide (100 ml) was added potassium carbonate (12.0 g, 80.0 mmol). The resulting mixture was stirred at room temperature for 10 hours and then concentrated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:2) to give 2-(((4-chlorophenyl)thio)methyl)-5-((4-methoxybenzyl)-oxy)-4H-pyran- 4-one (12) as a yellow solid (20.0 g, 84%). ¹ H NMR (CDCl ₃ -d, 400 MHz) δ 7.50 (s, 1H), 7.34-7.32 (m, 6H), 6.93-6.91 (m, 2H), 6, 20 (s, 1H), 5.02 (s, 2H), 3.84-3.79 (m, 5H). ESI-MS, m/z=389 [M+H] ⁺ .

2-(((4-Chlorophenyl)thio)methyl)-5-hydroxy-4H-pyran-4-one (13)

To a stirred solution of 2-(((4-chlorophenyl)thio)methyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (12, 1.3 g, 3.0 mmol) in dichloromethane (50 ml) trifluoroacetic acid (5.0 ml, 66.0 mmol) was added. The resulting solution was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was triturated with diethyl ether to give 2-(((4-chlorophenyl)thio)methyl)-5-hydroxy-4H-pyran-4-one (13) as an off-white solid (0.13 g, 16% ). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.15 (s, 1H), 8.03 (s, 1H), 7.44-7.39 (m, 4H), 6.28 (s, 1H), 4.18 (s, 2H). ESI-MS, m/z=269 [M+H] ⁺ .

6-(((4-Chlorophenyl)thio)methyl)-4-oxo-4H-pyran-3-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (14)

To a stirred solution of 2-(((4-chlorophenyl)thio)methyl)-5-hydroxy-4H-pyran-4-one (13, 280.0 mg, 1.0 mmol) in N,N-dimethylformamide (10 ml ) 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylic acid (4, 200.0 mg, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (153.0 mg, 0.8 mmol) and hydroxybenzotriazole (108.0 mg, 0.8 mmol). The reaction mixture was stirred at 60°C for 4 hours and then diluted with ethyl acetate (30 ml). The resulting mixture was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexane (3:7) to give 6-(((4-chlorophenyl)thio)methyl)-4-oxo-4H-pyran-3-yl 4-(4-chlorophenetyl) -1H-pyrrole-2-carboxylate (14) as a white solid (150.0 mg, 37%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.89 (s, 1H), 8.56 (s, 1H), 7.55-7.35 (m, 4H), 7.32 (dd, J=6.2, 2.0 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.91 (d, J=2.7 Hz, 1H), 6.87- 6.80 (m, 1H), 6.42 (s, 1H), 4.27 (s, 2H), 2.95-2.80 (m, 2H), 2.76-2.65 (m, 2H). ESI-MS, m/z=500 [M+H] ⁺ .

Example 5 Synthesis of 6-(((4-chlorophenyl)thio)methyl)-4-oxo-4H-pyran-3-yl 4H-furo[3,2-b]pyrrole-5-carboxylate (15)

6-(((4-Chlorophenyl)thio)methyl)-4-oxo-4H-pyran-3-yl 4H-furo-[3,2-b]pyrrole-5-carboxylate (15)

4H- furo[3,2-b]pyrrole-5-carboxylic acid (8, 360.0 mg, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (450.0 mg, 2.4 mmol) and hydroxybenzotriazole (320.0 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC to give 6-(((4-chlorophenyl)thio)methyl)-4-oxo-4H-pyran-3-yl 4H-furo[3,2-b]pyrrole-5-carboxylate (15) as an off-white solid (159.1 mg, 24%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.99 (s, 1H), 8.62 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.49 -7.42 (m, 4H), 6.95 (s, 1H), 6.67 (s, 1H), 6.64 (s, 1H), 4.29 (s, 2H). ESI-MS, m/z=402 [M+H] ⁺ .

Example 6 Synthesis of 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 4-(4-chlorophenethyl)-1H-pyrrole-2-carboxylate (18)

5-Chloro-3-methoxyquinoline-2(1H)-one (16)

To a stirred solution of 4-chloroindoline-2,3-dione (3.6 g, 20.0 mmol), diethylamine (25.0 ml, 240.0 mmol) in ethanol (30 ml) was added (trimethylsilyl)diazomethane (20 0 ml, 30.0 mmol) and the resulting mixture was stirred at room temperature for 16 hours. A solid precipitated from the reaction mixture and was collected by filtration and rinsed with ethanol (3×10 ml) to give 5-chloro-3-methoxyquinolin-2(1H)-one (16) as a gray solid (2.6 g, 65% ). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.5 (s, 1H), 7.36-7.20 (m, 4H), 3.88 (s, 3H). ESI-MS, m/z=210 [M+H] ⁺ .

5-Chloro-3-hydroxyquinolin-2(1H)-one (17)

Boron tribromide (62.4 g, 248.0 mmol) was added to a stirred solution of 5-chloro-3-methoxyquinolin-2(1H)-one (16, 2.6 g, 12.4 mmol) in dichloromethane (50 ml) . The resulting solution was stirred at room temperature for 16 hours. The solid was collected by filtration and rinsed with methanol (2×20 ml) to give 5-chloro-3-hydroxyquinolin-2(1H)-one (17) as a gray solid (1.2 g, 50%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.26 (s, 1H), 10.07 (s, 1H), 7.32-7.23 (m, 4H). ESI-MS, m/z=196 [M+H] ⁺

5-Chloro-2-oxo-1,2-dihydroquinolin-3-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (18)

A mixture of 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylic acid (4, 0.4 g, 1.7 mmol), N, N-dicyclohexylcarbodiimide (0.35 g, 1.7 mmol), 5- chloro-3-hydroxyquinolin-2(1H)-one (17, 0.3 g, 1.5 mmol) and 4-pyrrolidinopyridine (0.24 g, 0.2 mmol) in 50 ml dichloromethane was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the crude product was purified by preparative HPLC to give 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (18) as yellowish white solid (0.15 g, 23%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.50 (s, 1H), 11.93 (s, 1H), 7.99 (s, 1H), 7.54 (m, 1H), 7 .48-7.13(m, 6H), 6.72-6.52(m, 2H), 2.97-2.86(m, 2H), 2.76-2.40(m, 2H) . ESI-MS, m/z=427 [M+H] ⁺ .

Example 7 Synthesis of 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 4H-furo[3,2-b]pyrrole-5-carboxylate (19)

5-Chloro-2-oxo-1,2-dihydroquinolin-3-yl 4H-furo[3,2-b]pyrrole-5-carboxylate (19)

A mixture of 4H-furo[3,2-b]pyrrole-5-carboxylic acid (8, 0.5 g, 3.0 mmol), N,N-dicyclohexylcarbodiimide (0.6 g, 3.0 mmol), 5- chloro-3-hydroxyquinolin-2(1H)-one (17, 0.6 g, 3.0 mmol) and 4-pyrrolidinopyridine (0.4 g, 0.3 mmol) in dichloromethane (20 ml) was stirred at room temperature within 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography using methanol/dichloromethane (5:95) to give 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 4H-furo[3,2-b ]pyrrole-5-carboxylate (19) as a white solid (0.13 g, 13%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.55 (s, 1H), 12.05 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=2, 4 Hz, 1H), 7.57-7.51(m, 1H), 7.42-7.34(m, 2H), 7.01(s, 1H), 6.69-6.68(m , 1H). ESI-MS, m/z=329 [M+H] ⁺ .

Example 8 Synthesis of 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 4-phenethyl-1H-pyrrole-2-carboxylate (23)

Ethyl 4-(2-phenylacetyl)-1H-pyrrole-2-carboxylate (20)

Ethyl 1H-pyrrole-2-carboxylate (20.0 g, 140.0 mmol) in dichloromethane (400 ml) was added to an ice-cooled stirred mixture of aluminum chloride (23.0 g, 280.0 mmol) and 2-phenylacetyl chloride (44 .0 g, 280.0 mmol) in dichloromethane (200 ml) under N ₂ atmosphere. The resulting solution was stirred at room temperature for 10 hours, then quenched by adding a saturated aqueous solution of NH ₄ Cl (200 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers were combined. The organic layer was then washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give ethyl 4-(2-phenylacetyl)-1H-pyrrole-2-carboxylate (20) as a white solid (28.0 g, 76%). ESI-MS, m/z=358 [M+H] ⁺ .

Ethyl 4-phenethyl-1H-pyrrole-2-carboxylate (21)

Triethylsilane (70.0 ml, 434.0 mmol). The resulting solution was stirred at room temperature for 10 hours. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give ethyl 4-phenethyl-1H-pyrrole-2-carboxylate (21) as a white solid (14.0 g, 78%). ESI-MS, m/z=244 [M+H] ⁺ .

4-Phenethyl-1H-pyrrole-2-carboxylic acid (22)

To a stirred solution of ethyl 4-phenethyl-1H-pyrrole-2-carboxylate (21.1.5 g, 6.2 mmol) in tetrahydrofuran (30 ml) was added a solution of lithium hydroxide (0.7 g, 31.0 mmol) in water (15 ml). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The resulting mixture was acidified (pH=5~6) by dropwise addition of 10% HCl. A white solid which precipitated from the reaction mixture was filtered off and washed with water. The solid was purified by preparative HPLC to give 4-phenethyl-1H-pyrrole-2-carboxylic acid (22) as a pink solid (0.13 g, 10%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.21 (s, 1H), 11.51 (s, 1H), 7.53-7.14 (m, 5H), 6.55 (s, 1H), 6.48 (s, 1H), 3.34-2.90 (m, 2H), 2.79-2.66 (m, 2H). ESI-MS, m/z=216 [M+H] ⁺ .

5-Chloro-2-oxo-1,2-dihydroquinolin-3-yl 4-phenethyl-1H-pyrrole-2-carboxylate (23)

A mixture of 4-phenethyl-1H-pyrrole-2-carboxylic acid (22, 1.2 g, 5.6 mmol), N,N-dicyclohexylcarbodiimide (1.2 g, 5.8 mmol), 5-chloro-3- hydroxyquinolin-2(1H)-one (17, 1.0 g, 5.1 mmol) and 4-pyrrolidinopyridine (0.9 g, 0.5 mmol) in dichloromethane (150 ml) was stirred at room temperature for 16 hours . The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 4-phenethyl-1H-pyrrole-2-carboxylate (23) as an off-white solid (0.13 g, 6%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.50 (s, 1H), 11.93 (s, 1H), 7.99 (s, 1H), 7.56-7.52 (m, 1H), 7.41-7.17(m, 8H), 6.96-6.92(m, 1H), 3.34-2.86(m, 2H), 2.81-2.75( m, 2H). ESI-MS, m/z=393 [M+H] ⁺ .

Example 9 Synthesis of 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-phenethyl-1H-pyrazole-5-carboxylate (27)

Methyl 2,4-dioxo-6-phenylhexanoate (24)

To a stirred solution of benzylacetone (30.0 g, 200.0 mmol) in dried methanol (300 ml) were added dimethyl oxalate (27.0 g, 230.0 mmol) and sodium methoxide (42.0 ml, 200.0 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was diluted with ethyl acetate (500 ml) and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give methyl 2,4-dioxo-6-phenylhexanoate (24) as a yellow solid (13.0 g, 27%). ESI-MS, m/z=235 [M+H] ⁺ .

Methyl 3-phenethyl-1H-pyrazole-5-carboxylate (25)

To a stirred solution of methyl 2,4-dioxo-6-phenylhexanoate (24, 13.0 g, 56.0 mmol) in ethanol (56 ml) was added hydrazine (51 wt.% aqueous solution) (10.0 ml, 213. 9 mmol). The mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography using ethyl acetate/petroleum ether (2:3) to give methyl 3-phenethyl-1H-pyrazole-5-carboxylate (25) as a yellow oil (6.0 g, 50%). ESI-MS, m/z=231 [M+H] ⁺ .

3-Phenethyl-1H-pyrazole-5-carboxylic acid (26)

To a stirred solution of methyl 3-phenethyl-1H-pyrazole-5-carboxylate (25.5.0 g, 20.0 mmol) in tetrahydrofuran (40 ml) was added a solution of lithium water (20 ml). The mixture was stirred at room temperature for 16 hours. Most of the tetrahydrofuran was evaporated under vacuum. The pH of the mixture was adjusted to 2 with 1N HCl. The mixture was filtered and the solid collected. The solid was purified by prep HPLC to give further prep HPLC purified 3-phenethyl-1H-pyrazole-5-carboxylic acid (26) as a white solid (83.9 mg, 2%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.97 (s, 2H), 7.30-7.17 (m, 5H), 6.48 (s, 1H), 2.92 (s, 4H). ESI-MS, m/z=217 [M+H] ⁺ .

5-Chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-phenethyl-1H-pyrazole-5-carboxylate (27)

A mixture of 3-phenethyl-1H-pyrazole-5-carboxylic acid (26, 100.0 mg, 0.5 mmol), N, N-dicyclohexylcarbodiimide (100 mg, 0.5 mmol), 5-chloro-3-hydroxyquinoline- 2(1H)-one (17, 84.0 mg, 0.4 mmol) and 4-pyrrolidinopyridine (7.0 mg, 0.05 mmol) in dichloromethane (20 ml) were stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the crude product was purified by preparative HPLC to give 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-phenethyl-1H-pyrazole-5-carboxylate (27) as a white solid ( 17.0 mg, 10%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 13.54 (s, 1H), 12.55 (s, 1H), 8.04 (s, 1H), 7.55 (m, 1H), 7 .42-7.19 (m, 7H), 6.72 (s, 1H), 2.99 (s, 4H). ESI-MS, m/z=394 [M+H] ⁺ .

Example 10 Synthesis of 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (32)

4-(4-Chlorophenyl)butan-2-one (28)

To a stirred solution of 1-chloro-4-(chloromethyl)benzene (22.0 g, 136.6 mmol) in ethanol (200 ml) was added potassium carbonate (19.0 g, 137.5 mmol) and -dione (14.4 g, 143.8 mmol). The resulting mixture was heated at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and then filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:9) to give 4-(4-chlorophenyl)butan-2-one (28) as a colorless solid (18.0 g, 72%). ¹ H NMR (CDCl ₃ -d, 300 MHz) δ = 7.32-7.24 (m, 2H), 7.20-7.10 (m, 2H), 2.95-2.85 (m, 2H), 2.83-2.71 (m, 2H), 2.17 (s, 3H). ESI-MS, m/z=183 [M+H] ⁺ .

Methyl 6-(4-chlorophenyl)-2,4-dioxohexanoate (29)

Sodium hydride (4.8 g, 201.3 mmol) was added in portions to a solution of methanol (90 ml), then 4-(4-chlorophenyl)butan-2-one (28, 22.0 g, 120.5 mmol) and dimethyl oxalate (14.2 g, 120.3 mmol). The resulting mixture was stirred for 5 hours at room temperature. After completion of the reaction, the mixture was quenched with 1N HCl. The mixture was evaporated under vacuum to remove most of the solvent. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using petroleum ether to give methyl 6-(4-chlorophenyl)-2,4-dioxohexanoate (29) as a yellow oil in the form of a mixture (3.7 g, 11%). ESI-MS, m/z=269 [M+H] ⁺ .

Methyl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (30)

Hydrazine (51 wt% aqueous solution) (0.1 ml, 2.1 mmol). The resulting mixture was heated at 70°C for 3 hours. After completion of the reaction, the mixture was evaporated under vacuum. The residue was purified by reverse phase flash column chromatography to give methyl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (30) as a white solid in the form of a mixture (100.0 mg, 20%). ESI-MS, m/z=265 [M+H] ⁺ .

3-(4-Chlorophenethyl)-1H-pyrazole-5-carboxylic acid (31)

To a mixture of methyl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (30, 1.1 g, 4.2 mmol) in methanol (20 ml) was added sodium hydroxide (0.7 g, 16.7 mmol ) and water (5 ml). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the pH of the mixture was adjusted to 1 with 1N HCl. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by preparative HPLC to give 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylic acid (31) as a white solid (0.9 g, 90%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.97 (s, 2H), 7.34-7.32 (m, 2H), 7.24 (d, 2H, J=8.4 Hz) , 6.48 (s, 1H), 2.95-2.87 (m, 4H). ESI-MS, m/z=250 [M+H] ⁺ .

5-Chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (32)

5-Chloro-3-hydroxyquinoline- 2(1H)-one (17, 292.5 mg, 1.5 mmol), N, N-dicyclohexylcarbodiimide (309.3 mg, 1.5 mmol) and 4-(pyrrolidin-1-yl)pyridine (27, 7 mg, 0.2 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using methanol/dichloromethane (1:9) to give 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-(4-chlorophenethyl)-1H-pyrazol-5- carboxylate (32) as a gray solid (18.9 mg, 4%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ = 13.52 (s, 1H), 12.54 (s, 1H), 8.03 (s, 1H), 7.56-7.51 (m , 1H), 7.41-7.34 (m, 4H), 7.31-7.25 (m, 2H), 6.71 (s, 1H), 3.17-2.98 (m, 4H ). ESI-MS, m/z=428 [M+H] ⁺ .

Example 11 Synthesis of 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-(naphthalen-1-ylmethyl)-1H-pyrazole-5-carboxylate (39)

2-(Naphthalen-1-yl)acetyl chloride (33)

To a stirred solution of 2-(naphthalen-1-yl)acetic acid (18.0 g, 95.0 mmol) in dichloromethane (300 ml) and N,N-dimethylformamide (0.5 ml) was added dropwise at 0°C oxalyl chloride (8.5 ml, 100.0 mmol). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 2-(naphthalen-1-yl)acetyl chloride (33) (21.0 g, crude) as a yellow oil.

N-Methoxy-N-methyl-2-(naphthalen-1-yl)acetamide (34)

To a mixture of methoxy(methyl)amine hydrochloride (6.0 g, 98.0 mmol), trimethylamine (20.0 ml, 149.0 mmol) and dichloromethane (200 ml) was added 2-(naphthalen-1-yl)acetyl chloride ( 33, 17.0 g, 83.0 mmol) in dichloromethane (50 ml) at 0°C. The resulting solution was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:1) to give N-methoxy-N-methyl-2-(naphthalen-1-yl)acetamide (34) as a yellow oil (7.0 g, 50%). ESI-MS, m/z=230 [M+H] ⁺ .

1-(Naphthalene-1-yl)propan-2-one (35)

To a stirred solution of N-methoxy-N-methyl-2-(naphthalen-1-yl)acetamide (34, 7.0 g, 31.0 mmol) in tetrahydrofuran (150 ml) was added dropwise at 0°C methyl magnesium bromide (60.0 ml, 1.0 M in tetrahydrofuran). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding saturated aqueous NH₄Cl (100 ml) and extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give 1-(naphthalen-1-yl)propan-2-one (35) as a yellow oil (3.5 g, 61%) . ESI-MS, m/z=185 [M+H]⁺.

Ethyl 5-(naphthalene-1-yl)-2,4-dioxopentanoate (36)

To a stirred solution of 1-(naphthalen-1-yl)propan-2-one (35, 3.0 g, 16.0 mmol) diethyl oxalate (3.0 g, 20.0 mmol) in toluene (100 ml) was added tert-butoxide sodium (1.5 g, 16.0 mmol) at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at 0°C for 2 hours and then warmed to room temperature overnight. The solvent was removed and the residue was dissolved in water and neutralized to pH 2 with 1N HCl and extracted with ethyl acetate. The organic phase was combined and washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:1) to give ethyl 5-(naphthalen-1-yl)-2,4-dioxopentanoate (36) as a yellow oil (1.5 g, 33 %). ESI-MS, m/z=285 [M+H] ⁺ .

Ethyl 3-(naphthalene-1-ylmethyl)-1H-pyrazole-5-carboxylate (37)

Hydrazine mixture (51 wt.% aqueous solution) (1.0 ml, 21.4 mmol), ethyl 5-(naphthalene-1-yl)-2,4-dioxopentanoate (36, 1.5 g, 5.3 mmol ) in ethanol (50 ml) was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:1) to give ethyl 3-(naphthalene-1-ylmethyl)-1H-pyrazole-5-carboxylate (37) as yellow solid (0.8 g, 57%). ESI-MS, m/z=281 [M+H] ⁺ .

3-(Naphthalene-1-ylmethyl)-1H-pyrazole-5-carboxylic acid (38)

To a stirred solution of ethyl 3-(naphthalene-1-ylmethyl)-1H-pyrazol-5-carboxylate (37, 0.8 g, 2.9 mmol) in tetrahydrofuran (30 ml) was added a solution of lithium hydroxide (0.4 g, 14.5 mmol) in water (15 ml). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and then acidified to pH 1 with 10% HCl. A white solid precipitated, collected by filtration and washed with water. The solid was then purified by preparative HPLC to give 3-(naphthalene-1-ylmethyl)-1H-pyrazole-5-carboxylic acid (38) as a white solid (79.9 mg, 11%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 13.11 (br. s, 2H), 8.14-8.12 (m, 1H), 7.75-7.73 (m, 1H), 7.93-7.85(m, 1H), 7.82-7.40(m, 4H), 6.38(s, 1H), 4.43(s, 2H). ESI-MS, m/z=253 [M+H] ⁺ .

5-Chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-(naphthalen-1-ylmethyl)-1H-pyrazole-5-carboxylate (39)

5-Chloro-3- hydroxyquinolin-2(1H)-one (17, 273.0 mg, 1.4 mmol), N,N-dicyclohexylcarbodiimide (1.9 g, 9.0 mmol) and 4-(pyrrolidin-1-yl)pyridine ( 110.0 mg, 0.8 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) to give 5-chloro-2-oxo-1,2-dihydroquinolin-3-yl 3-(naphthalen-1-ylmethyl)-1H-pyrazol- 5-carboxylate (39) as a white solid (30.0 mg, 5%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.73 (s, 1H), 12.52 (s, 1H), 8.16-7.86 (m, 4H), 7.61-7, 32 (m, 7H), 6.57 (s, 1H), 4.53 (s, 2H). ESI-MS, m/z=430 [M+H] ⁺ .

Example 12 Synthesis of 5-(((3,4-dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 1H-pyrazole-5-carboxylate (47)

2,3-Dimethoxypyridine (40)

To a stirred solution of sodium methoxide (300.0 ml, 30% in methanol) was added 2-chloro-3-methoxypyridine (55.0 g, 383.1 mmol). The reaction mixture was stirred at 80°C overnight. After completion of the reaction, the mixture was evaporated under vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using ethyl acetate/petroleum ether (1:5) to give 2,3-dimethoxypyridine (40) as a yellow oil (42.0 g, 79%). ESI-MS, m/z=140 [M+H] ⁺ .

5-Bromo-2,3-dimethoxypyridine (41)

Bromine (9.0 ml, 174.6 mmol) was added to a stirred solution of 2,3-dimethoxypyridine (40, 27.0 g, 194.0 mmol) in dichloromethane (200 ml). The reaction mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 6 with saturated aqueous NaHCO ₃ . The mixture was extracted with dichloromethane (2×300 ml), washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using ethyl acetate/petroleum ether (1:5) to give 5-bromo-2,3-dimethoxypyridine (41) as a yellow oil (22.0 g, 52%). ESI-MS, m/z=218 [M+H] ⁺ .

5,6-Dimethoxynicotinaldehyde (42)

To a solution of 5-bromo-2,3-dimethoxypyridine (41, 21.7 g, 99.5 mmol) in anhydrous tetrahydrofuran (200 ml) was added dropwise n-butyllithium (48.0 ml, 2.5 mol/l in hexane) at -78°C in an atmosphere of N ₂ . The mixture was stirred at -78 ^°C for 1 hour. Then N,N-dimethylformamide (16.2 ml) was added to the mixture at -78°C. The reaction mixture was stirred for another 30 minutes at -78°C. After completion of the reaction, the mixture was quenched with saturated aqueous NH ₄ Cl, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using ethyl acetate/petroleum ether (1:3) to give 5,6-dimethoxynicotinaldehyde (42) as a yellow solid (13.5 g, 81%). ESI-MS, m/z=168 [M+H] ⁺ .

(5,6-Dimethoxypyridin-3-yl)methanol (43)

To a stirred solution of 5,6-dimethoxynicotinaldehyde (42, 21.0 g, 125.6 mmol) in methanol (200 ml) was added portionwise NaBH ₄ (17.1 g, 452.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was quenched with saturated aqueous NH ₄ Cl. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using dichloromethane/methanol (9:1) to give (5,6-dimethoxypyridin-3-yl)methanol (43) as a yellow solid (10.5 g, 49%). ESI-MS, m/z=170 [M+H] ⁺ .

5-(Bromomethyl)-2,3-dimethoxypyridine (44)

To a solution of (5,6-dimethoxypyridin-3-yl)methanol (43, 10.3 g, 60.9 mmol) in dichloromethane (200 ml) was added triphenylphosphine (24.0 g, 91.5 mmol) at 0°C in an atmosphere of N ₂ . The mixture was stirred for 30 minutes at 0°C. Then, tetrabromomethane (30.0 g, 91.3 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using ethyl acetate/petroleum ether (1:5) to give 5-(bromomethyl)-2,3-dimethoxypyridine (44) as a brown solid (6.6 g, 47%). ESI-MS, m/z=232 [M+H] ⁺ .

5-(((3,4-Dichlorophenyl)thio)methyl)-2,3-dimethoxypyridine (45)

To a mixture of 5-(bromomethyl)-2,3-dimethoxypyridine (44, 540.0 mg, 2.3 mmol) and 3,4-dichlorobenzene-1-thiol (498.4 mg, 2.8 mmol) in N, N-dimethylformamide (10 ml) was added potassium carbonate (646.0 mg, 4.7 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using ethyl acetate/petroleum ether (3:7) to give 5-(((3,4-dichlorophenyl)thio)methyl)-2,3-dimethoxypyridine (45) as a brown solid (640 .0 mg, 83%). ESI-MS, m/z=330 [M+H] ⁺ .

5-(((3,4-Dichlorophenyl)thio)methyl)-3-hydroxypyridin-2(1H)-one (46)

Tribromoborane (10.0 ml , 1.0 M in dichloromethane). The reaction mixture was stirred at room temperature for 48 hours. The resulting mixture was evaporated under vacuum. The pH of the mixture was adjusted to 1 with 1N HCl. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by preparative HPLC to give 5-(((3,4-dichlorophenyl)thio)methyl)-3-hydroxypyridin-2(1H)-one (46) as a pink solid (132.6 mg, 44%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.51 (s, 1H), 9.14 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.29 (dd, J=8.4, 2.4 Hz, 1H), 6.81 (s, 1H), 6.70 (d, J= 2.4 Hz, 1H), 4.03 (s, 2H). ESI-MS, m/z=302 [M+H] ⁺ .

5-(((3,4-Dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 1H-pyrazole-5-carboxylate (47)

To a stirred solution of 5-(((3,4-dichlorophenyl)thio)methyl)-3-hydroxypyridin-2(1H)-one (46, 302.0 mg, 1.0 mmol) in N,N-dimethylformamide (15 ml) was added N,N-dicyclohexylcarbodiimide (309.0 mg, 1.5 mmol), 1H-pyrazole-5-carboxylic acid (168.0.0 mg, 1.5 mmol), 4-(pyrrolidin-1-yl )pyridine (30.0 mg, 0.2 mmol). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with dichloromethane (2×50 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) followed by preparative HPLC to give 5-(((3,4-dichloro-phenyl)thio)methyl)-2-oxo-1,2- dihydropyridin-3-yl 1H-pyrazole-5-carboxylate (47) as a white solid (31.7 mg, 8%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.71 (s, 1H), 11.96 (s, 1H), 7.96 (1, 1H), 7.64-7.48 (m, 3H), 7.35-7.30(m, 2H), 6.90(s, 1H), 4.13(s, 2H). ESI-MS, m/z=396 [M+1] ⁺ .

Example 13 Synthesis of 5-(((3,4-dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (48 )

5-(((3,4-Dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylate (48)

A mixture of 3-(4-chlorophenetyl)-1H-pyrazole-5-carboxylic acid (31, 200.0 mg, 0.8 mmol), N, N-dicyclohexylcarbodiimide (198.0 mg, 1.0 mmol), 5- (((3,4-dichlorophenyl)thio)methyl)-3-hydroxypyridin-2(1H)-one (46, 240.0 mg, 0.8 mmol) and 4-(pyrrolidin-1-yl)-pyridine ( 24.0 mg, 0.2 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 16 hours. The resulting mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash chromatography using dichloromethane/methanol (95:5) and then purified by preparative HPLC under the following conditions: SunFire Prep C ₁₈ OBD 19×150 mm 5 µm 10 nm column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 52% B to 77% B in 7 minutes; 254/220 nm; R _t : 6.82 min to give 5-(((3,4-dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydro-pyridin-3-yl 3-(4-chlorophenetyl)-1H -pyrazole-5-carboxylate (48) as a white solid (60.0 mg, 14%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.45 (s, 1H), 11.94 (s, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.36-7.24 (m, 6H), 6.65 (s, 1H), 4.12 (s, 2H), 2.96 (s, 4H). ESI-MS, m/z=534 [M+H] ⁺ .

Example 14 Synthesis of 5-(((3,4-dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 3-phenethyl-1H-pyrazole-5-carboxylate (49)

5-(((3,4-Dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 3-phenethyl-1H-pyrazole-5-carboxylate (49)

To a stirred solution of 5-(((3,4-dichlorophenyl)thio)methyl)-3-hydroxypyridin-2(1H)-one (46, 300.0 mg, 1.0 mmol) in N,N-dimethylformamide (15 ml) was added N,N-dicyclohexylcarbodiimide (248.0 mg, 1.2 mmol), 3-phenethyl-1H-pyrazole-5-carboxylic acid (26, 250.0 mg, 1.2 mmol), 4-(pyrrolidine -1-yl)pyridine (30.0 mg, 0.2 mmol). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with dichloromethane (2×80 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) followed by preparative HPLC under the following conditions: SunFire Prep C ₁₈ OBD column, 19×150 mm 5 µm 10 nm; mobile phase, water (0.1% formic acid) and acetonitrile (from 53% acetonitrile to 70% after 7 minutes) to give 5-(((3,4-dichlorophenyl)thio)methyl)-2-oxo-1, 2-dihydro-pyridin-3-yl 3-phenethyl-1H-pyrazole-5-carboxylate (49) as a white solid (152.0 mg, 18%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.47 (s, 1H), 11.94 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.35-7.17 (m, 7H), 6.65 (s, 1H), 4.13 (s, 2H), 2.97 (s, 4H). ESI-MS, m/z=500 [M+H] ⁺ .

Example 15 Synthesis of 5-(((3,4-dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 4-phenethyl-1H-pyrrole-2-carboxylate (50)

5-(((3,4-Dichlorophenyl)thio)methyl)-2-oxo-1,2-dihydropyridin-3-yl 4-phenethyl-1H-pyrrole-2-carboxylate (50)

To a stirred solution of 5-(((3,4-dichlorophenyl)thio)methyl)-3-hydroxypyridin-2(1H)-one (46, 450.0 mg, 1.5 mmol) in N,N-dimethylformamide (10 ml) was added N,N-dicyclohexylcarbodiimide (371.0 mg, 1.8 mmol), 4-phenethyl-1H-pyrrole-2-carboxylic acid (323.0 mg, 1.5 mmol), 4-(pyrrolidine-1 -yl)pyridine (45.0 mg, 0.3 mmol). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with dichloromethane (2×100 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) followed by preparative HPLC to give 5-(((3,4-dichlorophenyl)-thio)methyl)-2-oxo-1,2-dihydropyridine -3-yl 4-phenethyl-1H-pyrrole-2-carboxylate (50) as a white solid (97.9 mg, 13%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.89 (s, 1H), 11.83 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.42-7.10 (m, 7H), 6.90 (d, J=2.1 Hz, 1H) , 6.83 (s, 1H), 4.12 (s, 2H), 2.92-2.80 (m, 2H), 2.80-2.70 (m, 2H). ESI-MS, m/z=499 [M+1] ⁺ .

Example 16 Synthesis of 6-(3,5-difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (56)

3-Chlorobenzo[5,6][1,4]dioxino[2, 3-c]pyridazine (51)

To a suspension of sodium hydride (15.0 g, 375.0 mmol) in 1,4-dioxane (400 ml) was added benzene-1,2-diol (36.0 g, 320.0 mmol) on an ice bath and 3 4,6-trichloropyridazine (60.0 g, 320.0 mmol). The resulting solution was stirred at 100°C for 10 hours, then quenched by adding saturated aqueous NaCl (100 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers were combined. The organic layer was then washed with brine. The mixture was dried over anhydrous sodium sulfate and filtered. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give 3-chlorobenzo[5,6]-[1,4]dioxino[2,3-c]pyridazine (51) as a white solid substances (32.0 g, 50%). ESI-MS, m/z=221 [M+H] ⁺ .

3-Vinylbenzo[5,6][1,4]dioxino[2,3-c]pyridazine (52)

To a stirred solution of 3-chlorobenzo[5,6][1,4]dioxino-[2,3-c]pyridazine (51, 30.0 g, 136.0 mmol) in 1,4-dioxane (300 ml) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (25.2 g, 164.0 mmol), Pd(dppf)Cl ₂ (20.1 g, 27.6 mmol) , sodium carbonate (28.8 g, 272.0 mmol) and water (60 ml). The resulting solution was refluxed for 3 hours. The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers were combined. The organic layer was then washed with brine. The mixture was dried over anhydrous sodium sulfate and filtered. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give 3-vinylbenzo[5,6][1,4]dioxino[2,3-c]pyridazine (52) as a white solid (18.0 g, 65%). ESI-MS, m/z=213 [M+H] ⁺ .

(E)-3-(3,5-Difluorostyryl)benzo[5,6][1,4]dioxino[2,3-c]pyridazine (53)

To a stirred solution of 3-vinylbenzo[5,6][1,4]-dioxino[2,3-c]pyridazine (52, 15.0 g, 74.0 mmol) in N,N-dimethylformamide (100 mL) was added palladium diacetate (0.81 g, 3.6 mmol), tri(o-tolyl)phosphine (4.5 g, 15.0 mmol), triethylamine (144.0 g, 1410.0 mmol) and 1-bromo- 3,5-difluorobenzene (17.1 g, 90.0 mmol). The resulting solution was stirred at 85°C for 16 hours. The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers were combined. The organic layer was then washed with brine. The mixture was dried over anhydrous sodium sulfate and filtered. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:3) to give (E)-3-(3,5-difluorostyryl)benzo[5.6]-[1.4]dioxino[2.3 -c]pyridazine (53) as an off-white solid (9.0 g, 41%). ESI-MS, m/z=325 [M+H] ⁺ .

(E)-3,4-Bis(benzyloxy)-6-(3,5-difluorostyryl)pyridazine (54)

To a solution of benzyl alcohol (6.0 g, 55.6 mmol) in toluene (50 ml) was added sodium tert-butoxide (6.4 g, 57.6 mmol) at 0°C. A solution of (E)-3-(3,5-difluorostyryl)benzo[5,6][1,4]dioxino-[2,3-c]pyridazine (53, 8.4 g, 26.0 mmol) in N,N-dimethylformamide (30 ml) and toluene (10 ml) and the reaction mixture was heated to 120° C. for 4 hours. The resulting solution was extracted with ethyl acetate (3×200 ml) and the organic layers were combined. The organic layer was then washed with brine. The mixture was dried over anhydrous sodium sulfate and filtered. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:1) to give (E)-3,4-bis(benzyloxy)-6-(3,5-difluorostyryl)pyridazine (54) as a brown solid substances (2.8 g, 25%). ESI-MS, m/z=431 [M+H] ⁺ .

6-(3,5-Difluorofenethyl)-4-hydroxypyridazin-3(2H)-one (55)

To a solution of (E)-3,4-bis(benzyloxy)-6-(3,5-difluorostyril)-pyridazine (54, 500.0 mg, 1.2 mmol) in ethanol (20 ml) was added 10% palladium per carbon (90.0 mg, 0.1 mmol). The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was passed through a pad of celite and the filtrate was concentrated in vacuo to give a solid. The crude product was purified by preparative HPLC to give 6-(3,5-difluorophenethyl)-4-hydroxypyridazin-3(2H)-one (55) as a pink solid (60.0 mg, 21%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.71 (s, 1H), 10.78 (br. s, 1H), 7.06-6.96 (m, 3H), 6.60 ( s, 1H), 6.88 (s, 1H), 2.97-2.89 (m, 2H), 2.81-2.77 (m, 2H). ESI-MS, m/z=253 [M+H] ⁺ .

6-(3,5-Difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (56)

A solution of 6-(3,5-difluorophenethyl)-4-hydroxypyridazin-3(2H)-one (55, 500.0 mg, 2.0 mmol), N, N-dicyclohexylcarbodiimide (450.0 mg, 2.2 mmol ), 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylic acid (4, 550.0 mg, 4.4 mmol), 4-pyrrolidinopyridine (30.0 mg, 0.2 mmol) in dichloromethane (50 ml) was stirred at approximately 25°C for 16 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give 6-(3,5-difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 4-(4-chlorophenetyl)-1H-pyrrole-2-carboxylate (56) as white solid (48.7 mg, 5%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ = 13.17 (s, 1H), 11.99 (s, 1H), 7.49 (s, 1H), 7.33 (d, J=8 .0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 7.17-6.98 (m, 3H), 6.97 (s, 1H), 6.89 (s , 1H), 2.99-2.84 (m, 6H), 2.76-2.72 (m, 2H). ESI-MS, m/z=484 [M+H] ⁺ .

Example 17 Synthesis of 6-(3,5-difluorophenethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl 1H-pyrazol-5-carboxylate (57)

6-(3,5-Difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 1H-pyrazole-5-carboxylate (57)

A solution of propylphosphine anhydride (50% in ethyl acetate) (1.2 ml, 2.0 mmol), pyridine (1.0 ml, 12.2 mmol) and 1H-pyrazole-5-carboxylic acid (168.0 mg, 1.5 mmol). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) and preparative HPLC (column: SunFire Prep C ₁₈ OBD 19 x 150 mm 5 μm 10 nm; mobile phase A: water (0.1% formic acid) , mobile phase B: acetonitrile, flow rate: 25 ml/min, gradient: from 27% B to 47% B in 7 minutes, 254/220 nm, R _t : 6.88 min) to give 6-(3.5- difluorofenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 1H-pyrazole-5-carboxylate (57) as a white solid (10.2 mg, 3%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.22 (s, 1H), 12.70 (s, 1H), 7.55 (s, 1H), 7.13-6.92 (m, 4H), 6.59 (s, 1H), 3.05-2.85 (m, 2H), 2.85-2.69 (m, 2H). ESI-MS, m/z=347 [M+H] ⁺ .

Example 18 Synthesis of 6-(naphthalene-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-phenethyl-1H-pyrazole-5-carboxylate (62)

(Naphthalene-1-ylmethyl)zinc(II) bromide (58)

At a pressure of 400 pascals, a mixture of lithium chloride (5.5 g, 130.0 mmol) and zinc (8.3 g, 130.0 mmol) was stirred at 170°C for 0.5 hour, cooled to room temperature, then 1,2-dibromoethane (1.9 g, 9.9 mmol) in tetrahydrofuran (100 ml) was added slowly and refluxed for 1 hour, re-cooled to room temperature, chlorotrimethylsilane (1.1 g, 9, 9 mmol) and the mixture was stirred for another 1 hour, 1-(bromomethyl)-naphthalene (11.0 g, 49.8 mmol) was added and stirred for 1 hour. After filtration, the filtrate was directly used in the next step without further purification.

3-(Naphthalen-1-ylmethyl)benzo[5,6][1,4]dioxino[2,3-c]pyridazine (59)

To a mixture of (naphthalen-1-ylmethyl)zinc(II) bromide (58) from the previous step was added 3-chlorobenzo[5,6][1,4]dioxino[2,3-c]pyridazine (51, 2.8 g , 12.5 mmol), Pd(dppf)Cl ₂ (1.5 g, 2.1 mmol). The mixture was refluxed overnight under N ₂ atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:5) to give 3-(naphthalen-1-ylmethyl)benzo[5,6][1,4]-dioxino[2,3-c]pyridazine (59) as a yellow solid (632.0 mg, 16%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.24-8.17 (m, 1H), 7.97-7.91 (m, 1H), 7.88-7.83 (m, 1H ), 7.59-7.45 (m, 4H), 7.16-7.10 (m, 2H), 7.08-6.98 (m, 3H), 4.59 (s, 2H). ESI-MS, m/z=327 [M+H] ⁺ .

3,4-Bis(benzyloxy)-6-(naphthalen-1-ylmethyl)pyridazine (60)

To a mixture of 3-(naphthalen-1-ylmethyl)benzo[5,6][1,4]dioxino[2,3-c]pyridazine (59, 632.0 mg, 1.9 mmol) in N, N-dimethylformamide (10 ml) and toluene (20 ml) were added sodium tert-butoxide (868.0 mg, 7.7 mmol) and benzyl alcohol (837.0 mg, 7.7 mmol). The reaction mixture was stirred at 120°C for 16 hours, cooled to room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (3:7) to give 3,4-bis(benzyloxy)-6-(naphthalen-1-ylmethyl)pyridazine (60) as a yellow solid ( 320 mg, 38%). ESI-MS, m/z=433 [M+H] ⁺ .

4-Hydroxy-6-(naphthalen-1-ylmethyl)pyridazin-3(2H)-one (61)

To a solution of 3,4-bis(benzyloxy)-6-(naphthalen-1-ylmethyl)-pyridazine (60, 330.0 mg, 0.8 mmol) in methanol (10 ml) was added 10% palladium on carbon (100, 0 mg, 0.1 mmol), the reaction mixture was stirred at room temperature for 16 hours under H ₂ atmosphere. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) to give 4-hydroxy-6-(naphthalen-1-ylmethyl)pyridazin-3(2H)-one (61) as a yellow solid (150 .0 mg, 78%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.68 (s, 1H), 8.13-8.06 (m, 1H), 7.96-7.89 (m, 1H), 7, 83 (dd, J=5.7, 3.8 Hz, 1H), 7.59-7.43 (m, 4H), 6.41 (s, 1H), 4.26 (s, 2H). ESI-MS, m/z=253 [M+H] ⁺ .

6-(Naphthalene-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-phenethyl-1H-pyrazole-5-carboxylate (62)

To a solution of 4-hydroxy-6-(naphthalene-1-ylmethyl)pyridazin-3(2H)-one (61, 500.0 mg, 2.0 mmol) in ethyl acetate (10 ml) was added a solution of propylphosphine anhydride (50% in ethyl acetate) (1.2 ml, 2.0 mmol), pyridine (1.0 ml, 12.2 mmol) and 3-phenethyl-1H-pyrazole-5-carboxylic acid (26, 428.0 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) and then purified by preparative HPLC (column: XBridge Prep C ₁₈ OBD 19 x 150 mm 5 µm C0013; mobile phase A: water (0.1% formic acid ), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: from 45% B to 67% B after 7 minutes; 254/220 nm) to give 6-(naphthalen-1-ylmethyl)-3-oxo- 2,3-dihydropyridazin-4-yl 3-phenethyl-1H-pyrazole-5-carboxylate (62) as an off-white solid (50.5 mg, 5%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.54 (s, 1H), 13.24 (s, 1H), 8.15-8.12 (m, 1H), 7.97-7, 93 (m, 1H), 7.88-7.84 (m, 1H), 7.60-7.44 (m, 5H), 7.31-7.16 (m, 5H), 6.65 ( s, 1H), 4.48 (s, 2H), 2.96 (s, 4H). ESI-MS, m/z=451 [M+H] ⁺ .

Example 19 Synthesis of 6-(naphthalene-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylate (67)

4-(3-Chlorophenyl)butan-2-one (63)

A mixture of 1-chloro-3-(chloromethyl)benzene (49.0 g, 304.3 mmol), pentane-2,4-dione (30.6 g, 304.3 mmol) and potassium carbonate (42.3 g, 304.3 mmol) in ethanol (500 ml) was heated at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:9) to give 4-(3-chlorophenyl)butan-2-one (63) as a yellow oil (20.0 g, 27%). ESI-MS, m/z=183 [M+H] ⁺ .

Ethyl 6-(3-chlorophenyl)-2,4-dioxohexanoate (64)

To a solution of sodium hydride (5.6 g, 232.0 mmol) in ethanol (150 ml) was added a mixture of 4-(3-chlorophenyl)butan-2-one (63, 19.6 g, 107.3 mmol) and diethyl oxalate (15.7 g, 107.4 mmol). The resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was cooled to room temperature. The pH of the mixture was adjusted to 1 with 1N HCl. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using petroleum ether to give ethyl 6-(3-chlorophenyl)-2,4-dioxohexanoate (64) as a yellow oil (17.9 g, 59%). ESI-MS, m/z=283 [M+H] ⁺ .

Ethyl 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylate (65)

To a solution of 6-(3-chlorophenyl)-2,4-dioxohexanoate (64, 17.2 g, 60.8 mmol) in ethanol (200 ml) was added hydrazine (51 wt. 213.1 mmol). The resulting mixture was heated at 80°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and then evaporated under vacuum. The residue was purified by recrystallization in ethanol/ethyl acetate/petroleum ether (1:10:1) to give ethyl 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylate (65) as a white solid (15.6 g , 90%). ESI-MS, m/z=279 [M+H] ⁺ .

3-(3-Chlorophenethyl)-1H-pyrazole-5-carboxylic acid (66)

To a solution of ethyl 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylate (65, 1.0 g, 3.6 mmol) in methanol (20 ml) was added sodium hydroxide (288.0 mg, 7.2 mmol ) in water (3 ml). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the pH of the mixture was adjusted to 1 with 1N HCl. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylic acid (66) as a white solid (700 mg, 78%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.96 (s, 2H), 7.33-7.17 (m, 4H), 6.48 (s, 1H), 2.95-2, 87 (m, 4H). ESI-MS, m/z=250 [M+H] ⁺ .

6-(Naphthalen-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylate (67)

A solution of propylphosphine anhydride ( 50% in ethyl acetate) (1.2 ml, 2.0 mmol), pyridine (1.0 ml, 12.2 mmol) and 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylic acid (66, 500 .0 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) and then purified by preparative HPLC (column: XBridge Prep C ₁₈ OBD 19 x 150 mm 5 µm C0013; mobile phase A: water (0.1% formic acid ), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: from 45% B to 65% B after 10 minutes; 254/220 nm) to give 6-(naphthalen-1-ylmethyl)-3-oxo- 2,3-dihydropyridazin-4-yl 3-(3-chlorophenetyl)-1H-pyrazole-5-carboxylate (67) as a light yellow solid (114.2 mg, 12%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.54 (s, 1H), 13.24 (s, 1H), 8.15-8.12 (m, 1H), 7.97-7, 84 (m, 2H), 7.63-7.50 (m, 5H), 7.49-7.17 (m, 4H), 6.67 (s, 1H), 4.43 (s, 2H) , 2.97 (s, 4H). ESI-MS, m/z=485 [M+H] ⁺ .

Example 20 Synthesis of 6-(naphthalen-1-ylmethyl)-3-oxo-2,3-di-hydropyridazin-4-yl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (72)

4-(4-Fluorophenyl)butan-2-one (68)

A mixture of 1-(chloromethyl)-4-fluorobenzene (30.0 g, 207.5 mmol), pentane-2,4-dione (20.8 g, 207.8 mmol) and potassium carbonate (28.8 g, 208 .4 mmol) in ethanol (200 ml) was refluxed for 16 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (6:94) to give 4-(4-fluorophenyl)butan-2-one (68) as a light yellow oil (21.0 g, 61%) . ESI-MS, m/z=167 [M+H] ⁺ .

Ethyl 6-(4-fluorophenyl)-2,4-dioxohexanoate (69)

Sodium hydride (6.6 g, 164.5 mmol) was added portionwise to an ice-cooled ethanol solution (100 ml). Then, a mixture of 4-(4-fluorophenyl)butan-2-one (68, 21.0 g, 126.4 mmol) and diethyl oxalate (18.5 g, 126.6 mmol) was added to the mixture at the same temperature. The resulting mixture was stirred at room temperature overnight. The pH of the resulting mixture was adjusted to 1 with 1N HCl. Most of the solvent was removed under vacuum. The residue of the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (1:9) to give ethyl 6-(4-fluorophenyl)-2,4-dioxo-hexanoate (69) as a yellow oil (24.3 g, 72 %). ESI-MS, m/z=267 [M+H] ⁺ .

Ethyl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (70)

To a solution of ethyl 6-(4-fluorophenyl)-2,4-dioxohexanoate (69, 24.3 g, 91.3 mmol) in ethanol (200 ml) was added hydrazine (51 wt. , 229.5 mmol). The resulting mixture was refluxed for 3 hours. After completion of the reaction, the mixture was evaporated under vacuum. The residue was purified by recrystallization in ethanol/ethyl acetate/petroleum ether (1:8:1) to give ethyl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (70) as a white solid (20.0 g , 84%). ESI-MS, m/z=263 [M+H] ⁺ .

3-(4-Fluorophenethyl)-1H-pyrazole-5-carboxylic acid (71)

Sodium hydroxide solution (836.0 mg, 20.9 mmol) in water (3 ml). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was evaporated under vacuum. The pH of the mixture was adjusted to 1 with 1N HCl. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by preparative HPLC under the following conditions: SunFire Prep C ₁₈ OBD 19×150 mm 5 µm 10 nm column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 15% B to 55% B in 7 minutes; 254/220 nm; R _t : 6.22 min to give 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylic acid (71) as a white solid (40.0 mg, 42%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.96 (s, 2H), 7.27-7.22 (m, 2H), 7.14-7.06 (m, 2H), 6, 47 (s, 1H), 2.93-2.85 (m, 4H). ESI-MS, m/z=235 [M+H] ⁺ .

6-(Naphthalene-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (72)

To a solution of 4-hydroxy-6-(naphthalene-1-ylmethyl)pyridazin-3(2H)-one (61, 300.0 mg, 1.2 mmol) in ethyl acetate (10 ml) was added a solution of propylphosphine anhydride (50% in ethyl acetate) (1.0 ml, 1.7 mmol), pyridine (0.8 ml, 9.8 mmol) and 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylic acid (71, 278.6 mg , 1.2 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) and then purified by preparative HPLC (column: XBridge Prep C ₁₈ OBD 19 x 150 mm 5 µm C0013; mobile phase A: water (0.1% formic acid ), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: from 45% B to 66% B after 7 minutes; 254/220 nm) to give 6-(naphthalen-1-ylmethyl)-3-oxo- 2,3-dihydropyridazin-4-yl 3-(4-fluorophenethyl)-1H-pyrazole-5-carboxylate (72) as an off-white solid (114.2 mg, 12%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.53 (s, 1H), 13.23 (s, 1H), 8.15-8.11 (m, 1H), 7.97-7, 92 (m, 1H), 7.88-7.84 (m, 1H), 7.60-7.44 (m, 5H), 7.27-7.23 (m, 2H), 7.13- 7.07 (m, 2H), 6.65 (s, 1H), 4.43 (s, 2H), 2.94 (s, 4H). ESI-MS, m/z=469 [M+H] ⁺ .

Example 21 Synthesis of 6-(naphthalen-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-benzyl-1H-pyrazole-5-carboxylate (77)

Ethyl 5-(4-chlorophenyl)-2,4-dioxopentanoate (73)

Sodium hydride (15.6 g, 650.0 mmol) was added portionwise to an ice-cooled ethanol solution (500 ml). Then a mixture of 1-(4-chlorophenyl)propan-2-one (50.0 g, 296.5 mmol) and diethyl oxalate (43.5 g, 297.3 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the pH of the mixture was adjusted to 1 with 1N HCl. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using ethyl acetate/petroleum ether (3:7) to give ethyl 5-(4-chlorophenyl)-2,4-dioxopentanoate (73) as a yellow oil (59.0 g, 74%) . ESI-MS, m/z=269 [M+H] ⁺ .

Ethyl 3-(4-chlorobenzyl)-1H-pyrazole-5-carboxylate (74)

To a solution of ethyl 5-(4-chlorophenyl)-2,4-dioxopentanoate (73.59.0 g, 219.6 mmol) in ethanol (260 ml) was added hydrazine (51 wt. , 180.3 mmol). The resulting mixture was refluxed for 3 hours. After completion of the reaction, the mixture was evaporated under vacuum. The residue was purified by recrystallization in ethanol/ethyl acetate/PE (1:8:1) to give ethyl 3-(4-chlorobenzyl)-1H-pyrazole-5-carboxylate (74) as an off-white solid (32.0 d, 55%). ESI-MS, m/z=265 [M+H] ⁺ .

Ethyl 3-benzyl-1H-pyrazole-5-carboxylate (75)

10% Pd/C (1.2 g, 1 .1 mmol). The reaction mixture was stirred at room temperature for 48 hours under H ₂ atmosphere. After completion of the reaction, the mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified by reverse phase flash chromatography to give ethyl 3-benzyl-1H-pyrazole-5-carboxylate (75) as a yellow solid (2.2 g, 50%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.35-7.19 (m, 5H), 6.48 (s, 1H), 4.23 (q, J=7.2 Hz, 2H) , 3.97 (s, 2H), 1.26 (t, J=7.2 Hz, 3H). ESI-MS, m/z=231 [M+H] ⁺ .

3-Benzyl-1H-pyrazole-5-carboxylic acid (76)

Sodium hydroxide (176.0 mg, 4.4 mmol). The resulting mixture was refluxed for 1 hour. After completion of the reaction, the mixture was evaporated under vacuum to remove most of the solvents. The pH of the mixture was adjusted to 1 with 1N HCl. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by preparative HPLC under the following conditions: SunFire Prep C ₁₈ OBD 19×150 mm 5 µm 10 nm column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 15% B to 35% B after 9 minutes; 254/220 nm; R _t : 8.9 min to give 3-benzyl-1H-pyrazole-5-carboxylic acid (76) as a white solid (130.0 mg, 30%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.04 (s, 2H), 7.33-7.19 (m, 5H), 6.46 (s, 1H), 3.96 (s, 2H). ESI-MS, m/z=203 [M+H] ⁺ .

6-(Naphthalen-1-ylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-benzyl-1H-pyrazole-5-carboxylate (77)

A solution of propylphosphine anhydride (50% in ethyl acetate) (1.5 ml, 2.5 mmol), pyridine (0.8 ml, 9.8 mmol) and 3-benzyl-1H-pyrazole-5-carboxylic acid (76, 404.0 mg, 2, 0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum. The residue was purified by flash column chromatography using methanol/dichloromethane (5:95) and then purified by preparative HPLC (column: XBridge Prep C ₁₈ OBD 19 x 150 mm 5 µm C0013; mobile phase A: water (0.1% formic acid ), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: from 45% B to 66% B after 7 minutes; 254/220 nm) to give 6-(naphthalen-1-ylmethyl)-3-oxo- 2,3-dihydropyridazin-4-yl 3-benzyl-1H-pyrazole-5-carboxylate (77) as an off-white solid (73.0 mg, 8%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.68 (s, 1H), 13.24 (s, 1H), 8.14-8.11 (m, 1H), 7.97-7, 92 (m, 1H), 7.88-7.83 (m, 1H), 7.59-7.44 (m, 5H), 7.34-7.20 (m, 5H), 6.63 ( s, 1H), 4.45 (s, 2H), 4.02 (s, 2H). ESI-MS, m/z=437 [M+H] ⁺ .

Example 22 In Vitro Measurements of D-Amino Acid Oxidase (DAAO) Activities

pkDAAO activity (porcine kidney DAAO) was measured using D-proline as a substrate for the production of hydrogen peroxide (H ₂ O ₂ ). The H ₂ O ₂ produced was oxidized by peroxidase and the resulting free radicals were reacted with the reagent 1,2-phenylenediamine (OPD). The reaction product was characterized by absorption at 450 nm. As an indicator of pkDAAO activity, data on measuring the optical density of OD450 were used. All compounds were dissolved in DMSO. Each compound was diluted in DMSO at 3-fold or 4-fold serial dilution to generate a 9-point dose-response curve. Each sample was added in triplicate at 10 μl/well to a 96-well assay microplate. 10 μl DMSO was added to positive control wells. The diluted compounds were incubated with pkDAAO in the dark for 10 minutes and then reacted with D-proline. The final reaction mixture consisted of 0.01 U/ml pkDAAO, 0.03% OPD, 25 μg/ml HRP and 40 mM D-proline in PBS. The reaction plates were then incubated in the dark at room temperature. OD450 absorbance readings were taken at 0 and 20 minutes using a Molecular Device Spectra Max Plus plate reader. Percent inhibition values for each well were calculated using the following equation:

Percent Inhibition = (OD450 _{sample, 20 minutes} - OD450 _{sample, 0 minutes} ) / (OD450 _{DMSO, 20 minutes} - OD450 _{DMSO, 0 minutes} ) x 100%

To calculate the IC ₅₀ value for each compound, a non-linear curve fitting model was used using the GraphPad Prism 5 software.

hDAAO activity (human DAAO) was measured using D-serine as a substrate for H ₂ O ₂ production. The H ₂ O ₂ produced was oxidized by peroxidase, and the resulting free radicals were further reacted with Amplex Red reagent to initiate fluorescent emission. As an indicator of hDAAO activity, the fluorescence intensity at 590 nm was measured. All compounds were dissolved in DMSO. Each compound was diluted in DMSO at 3-fold serial dilution to build a 9-point dose-response curve. Each sample was added in triplicate at 1 μl/well to 96-well black plates. 1 µl of DMSO was added to positive control wells. Then, 49 µl of assay buffer (100 mM Tris-HCl, pH 8.5) containing 1.2 ng/ml hDAAO, 900 nM FAD, 0.2 U/ml HRP and 100 µM Amplex Red. Then 50 μl of 100 mM D-serine in assay buffer was added. The reaction plates were then incubated in the dark at room temperature. The amount of fluorescent emission was recorded at 0 and 20 minutes using a Molecular Device Gemini EM fluorescent plate reader using the following settings: 530 nm excitation filter and 590 nm emission filter. Percent inhibition values for each well were calculated using the following equation:

Percent inhibition = (fluorescence _{sample, 20 min} - fluorescence _{sample, 0 min} ) / (fluorescence _{DMSO, 20 min} - fluorescence _{DMSO, 0 min} ) x 100%

To calculate the IC ₅₀ value for each compound, a non-linear curve fitting model was used using the GraphPad Prism 5 software.

Table 1. Inhibitory activity of compounds against DAAO

Compound
No. hDAAO IC ₅₀ (µM) pkDAAO IC ₅₀ (µM) 1 100-500 10000-50000 5 10-100 10-100 9 1-10 10-100 14 1-10 10-100 18 0.1-0.5 1-10 23 0.1-1 1-10 27 0.1-0.5 0.1-1 32 0.1-1 0.1-0.5 49 1-10 0.1-1 50 1-10 1-10 56 1-10 10-100 62 0.1-1 0.01-0.1 67 0.1-0.5 0.01-0.1 72 0.1-0.5 0.01-0.1 77 0.1-1 0.01-0.1

0.1-0.5 0.01-0.1

0.1-0.5 0.01-0.1

0.1-0.5 0.01-0.1

0.1-0.5 0.01-0.1

The IC ₅₀ values for some of the compounds are shown in Table 1. At the initial stage of the study, the compounds tested did not provide high inhibitory activity. IC ₅₀ values were greater than 100 μM. After testing compounds with a modified structure, IC ₅₀ values below 1 μM were obtained. The most active compounds were characterized by IC ₅₀ values below 0.5 μM.

Example 23 Therapeutic Effects of the Compound of Example 1

Effect of the Compound of Example 1 on Spontaneous Locomotion in Mice

Mice were divided into groups and housed with ad libitum access to food and water in ventilated polysulfone cages (Alternative Design, AR, USA) (3-5 mice per cage) in SyneuRx International (Taiwan) Corp. animal quarters. Colony mice were maintained on a 12/12 hour light/dark cycle at 22 ± 2°C, and all behavioral studies were performed during the dark cycle. All animals used in this study were adult mice (at least 2.5 months of age). All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC).

The compound from Example 1 was placed in 100% PEG400 and subjected to ultrasonic vibration until the solution became clear. An appropriate amount of PBS (Phosphate Buffered Saline) was added to a clear PEG400 solution of the compound from Example 1 to reach the final concentration for each dose level. Adult mice were randomized into three groups: placebo control (medium), administration of the compound of Example 1 at 446 mg/kg and at 892 mg/kg.

An example of an experimental design is shown in Figure 1. Mice administered orally with either placebo (medium) or a low/high dose of the compound of Example 1 were immediately tested in an open field, and spontaneous locomotion score was expressed as the total distance of movement measured over a specified period of time. period of time.

Mice were placed in a plexiglass cage (37.5 cm x 21.5 cm x 18 cm) at a light intensity of 50-65 lux and spontaneous locomotion was measured for 120 minutes using the EthoVision video surveillance system (Noldus Information Technology, the Netherlands). As an index of spontaneous locomotion, the moving distance of each mouse was measured.

The figure 2 presents the results of spontaneous locomotion after the introduction of the compound from example 1 when recording data in temporary files for 5 minutes.

The mice in each group were allowed to acclimate to the test chamber for 30 minutes. During the 120 minutes of observation, no significant differences were found between the groups.

The effect of the compound from example 1 on mice injected with MK801

Mice were housed in a group (3-5 mice/cage) with unlimited access to food and water in ventilated polysulfone cages (Alternative Design, AR, USA) in animal facilities from SyneuRx International (Taiwan) Corp.. The colony of mice was housed on a 12/12 hour light/dark cycle at 22 ± 2°C, and all behavioral studies were performed during the dark cycle. All animals used in this study were adult mice (at least 2.5 months of age). All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC). Mice were randomly divided into four groups: group 1 - placebo control, group 2 - MK801, group 3 - compound from example 1 at a dose of 446 mg/kg + MK801, group 4 - compound from example 1 at a dose of 892 mg/kg + MK801. Mice in groups 2-4 were given a single dose of MK-801 (Sigma-Aldrich USA, NMDA receptor antagonist dissolved in saline, 0.1 mg/kg, ip) 20 minutes prior to behavioral tests. On the other hand, each mouse in Groups 4-5 received 446 or 892 mg/kg of the compound of Example 1 (dissolved in PBS with 30% PEG400) orally once 20 minutes prior to administration of MK801. In addition, the dose of MK801 was adjusted depending on the requirements of each test (0.1 mg/kg for open field, 0.2 mg/kg for prepulse inhibition).

All mice in the experiments were tested in the open field test and in the prepulse inhibition test at least one week apart between two tests. An open field test was used to evaluate the ability of the compound of Example 1 to reverse the state of hyperlocomotion induced by MK801 administration. The apparatus and registration method for the open field test was the same as described above, except for drug administration. A prepulse inhibition (PPI) test using an SR-LAB startle induction instrument (San Diego Instruments, San Diego, CA, USA) was used to determine the ability of the compound of Example 1 to alleviate MK801-induced sensorimotor filtering impairment in mice. Under background noise conditions of 72 dB, each session consisted of a 5-minute accumulation period followed by 64 trials in four blocks. The single pulse test (PA) was a 40 ms pulse of white noise with a power of 120 dB. In the case of prepulse (pp) + impulse tests, prepulse 20 ms white noise 78 dB (pp6), 82 dB (pp10), 90 dB (pp18) stimuli were delivered 100 ms before the 40 ms pulse with 120 dB power . The non-stimulus (NS) trials only represented background noise. The initial and final blocks consisted of six PA trials, respectively. The middle two blocks consisted of PA, pp+pulse and NS trials. These trials were performed in a pseudo random order and were separated by an interval between trials averaging 15 seconds (varying from 10 to 20 seconds). Percent prepulse inhibition was calculated using the following formula: % PPI=100×[(PA score)-(pp-P score)]/(PA score) where the PA score was the average of PA in the middle blocks.

An example of the design of the present experiments is shown in Figure 3. Spontaneous locomotion and sensorimotor filtering function of each mouse were tested in the open field test and prepulse inhibition, respectively, with a minimum interval between tests of 1 week. Twenty minutes prior to the injection of MK801 (or saline), each mouse was given a compound from Example 1 (or placebo) by gavage. Twenty minutes prior to behavioral testing, each mouse was intraperitoneally injected with MK801 (or saline).

Figure 4 shows the effect of the compound of Example 1 on locomotion in mice treated with MK801. Compared with the control group, the MK801-administered group exhibited hyperlocomotion in the open field test within 120 minutes of testing. Mice that received either a low or high dose of the compound of Example 1, prior to their administration of MK801, showed the same level of locomotor activity during 120 minutes of testing as mice in the control group, which indicates a decrease in hyperlocomotion in these mice, caused by the introduction of MK801.

Figure 5 shows the results of the compound of Example 1 on prepulse inhibition in mice treated with MK801. Compared to the control group, the MK801 group had a lower percentage of prepulse inhibition at each prepulse intensity. Compared to the control group, the low/high dose groups of the compound of Example 1 showed the same level of prepulse inhibition percentage at each prepulse intensity.

It has long been known that the symptoms of psychosis are difficult to observe and measure in animal models. However, recent developments in this area have greatly increased the usefulness and validity of animal models. Therefore, behaviors associated with psychosis can be tested in animal models, including psychomotor arousal, arousal symptoms, sensory filtering, and sensitivity to psychotomimetic drugs such as MK801 (Arguello & Gogos, 2006; Lai et al., 2014). In mice, parameters related to hyperlocomotion and novelty-induced change in locomotion (either due to novelty habituation disorder or increased exploratory drive) in the open field test can be used to measure psychomotor arousal and arousal symptoms, respectively (Lai et al. al. ., 2014; Powell & Miyakawa, 2006; Vardigan et al., 2010). In the present study, administration of the compound of Example 1 reversed/protected MK801-induced locomotion in the open field test (Figure 4). The result showed that the compound of example 1 is a potential drug for the treatment of symptoms of psychosis (eg, delusions and hallucinations).

Animal models incorporating MK-801-induced hyperactivity are commonly used to study various neuropsychiatric disorders and develop analyzes of conditions including, but not limited to, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, Tourette syndrome , autism spectrum disorders, fragile X syndrome, Parkinson's disease, Lewy body dementia, and senile dementia (see Rubia et al., 2010; Sheppard and Bradshaw, 1999; Bent et al., 2014; Powell and Miyakawa, 2006; Nestler and Hyman, 2010; Bubenı´kova´-Valesˇova et al., 2008; Gobira et al., 2013; Lai et al., 2014; Maio et al., 2014; Sontag et al., 2010; Ding et al. , 2014; Walitza et al., 2007; Finestone et al., 1982; Golimstok et al., 2011).

In the prepulse inhibition test, administration of the compound of Example 1 at both low and high doses alleviated/protected against MK801-induced PPI deficiencies. Deficiency in prepulse inhibition is generally considered a schizophrenic endophenotype in the mouse model, as the same deficiency manifestations can be identified in humans (Arguello & Gogos, 2006; Geyer & Braff, 1987; Lai et al., 2014). Prepulse inhibition deficiency has also been found in other central nervous system diseases including schizophrenia, autism spectrum disorder, Asperger's syndrome, obsessive-compulsive disorder, Huntington's disease, bedwetting, attention deficit disorder, attention deficit hyperactivity disorder, tic disorder, major depressive disorder. disorder, personality disorders, Tourette's syndrome, blepharospasm, non-epileptic seizures, post-traumatic stress disorder, panic disorder, bipolar disorder, mild Alzheimer's dementia, Lewy body dementia, and Alzheimer's disease (see McAlonan et al., 2002; Braff et al. , 2001; Giakoumaki et al., 2007; Ueki et al., 2006; Perriol et al., 2005; Ludewig et al., 2002; Castellanos et al., 1996; Cadenhead et al., 2000; 2017; Lai et al., 2014; McCool et al., 2003; Arguello and Gogos, 2006).

Thus, the results of the experiments described in the invention indicate that the compounds described in the invention are highly active DAAO inhibitors and are promising potential drugs for the treatment of CNS disorders, in particular, in which D-amino acid oxidase (DAAO) is involved.

Example 24 Therapeutic Effects of Compound 56

The effect of compound 56 on mice injected with MK-801

Male C57BL/6J mice were housed in a group (3-5 mice per cage) with unlimited access to food and water in ventilated polysulfone cages (Alternative Design, AR, USA) in SyneuRx animal housing. The mouse colony was maintained on a 12/12 hour light/dark cycle at 22 ± 2°C, and all behavioral studies were performed during the dark cycle. All animals used in this study were adult mice (at least 2.5 months of age). All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC).

Mice were randomly divided into five groups: group 1 - placebo control, group 2 - MK-801, group 3 - compound 56 at a dose of 10 mg/kg+MK-801, group 4 - compound 56 at a dose of 30 mg/kg+ MK-801, group 5 - compound 56 at a dose of 100 mg/kg + MK-801. Mice in group 2-5 received single injections of MK-801 (Sigma-Aldrich USA), an NMDA receptor antagonist dissolved in saline, at a dose of 0.2 mg/kg for open field and 0.3 mg/kg for prepulse inhibition (PPI ), respectively, by intraperitoneal injection 20 minutes prior to behavioral tests. Each mouse in group 3-5 received compound 56 at doses of 10, 30 and 100 mg/kg (dissolved in double distilled H ₂ O with 65% PEG400 and 10% DMSO) once orally 20 minutes prior to MK-801 administration. All mice were tested in the open field test and in the prepulse inhibition test.

The open field test is a standard method for measuring novelty-induced exploratory behavior and overall activity in mice and rats. The purpose of this experiment was to evaluate the effectiveness of the effect of compound 56 on the attenuation of hyperlocomotion caused by the introduction of MK-801. In this study, mice were placed in a plexiglass cage (37.5 cm x 21.5 cm x 18 cm) at a light intensity of 50-65 lux. Their spontaneous locomotion was measured over 60 minutes using a Photobeam Activity System (PAS)-open field (San Diego Instruments, San Diego, CA, USA) Behavior Investigation System. The total number of light beam interruptions (beam interruptions) by each mouse was measured as an index of locomotion.

To determine the effect of compound 56 in reducing MK-801-induced deficits in sensorimotor filtration function in mice, prepulse inhibition was used using the SR-LAB startle induction instrument (San Diego Instruments, San Diego, CA, USA). Under background noise conditions of 65 dB, each session consisted of a 5-minute accumulation period followed by 64 trials in four blocks. The single pulse test (PA) was a 40 ms pulse of white noise with a power of 120 dB. In the case of prepulse (pp) + impulse tests, 20 ms white noise prepulse stimuli with a power of 71 dB (pp6), 75 dB (pp10) and 83 dB (pp18) were delivered 100 ms before a 40 ms pulse with a power of 120 dB . The non-stimulus (NS) trials only represented background noise. The initial and final blocks consisted of six PA trials, respectively. The middle two blocks consisted of PA, pp+pulse and NS trials. These trials were performed in a pseudo random order and were separated by an interval between trials averaging 15 seconds (varying from 10 to 20 seconds). Percent prepulse inhibition was calculated using the following formula: % PPI=100×[(PA score)-(pp-P score)]/(PA score) where the PA score was the average of PA in the middle blocks.

Figure 6 shows the results of a study on the effect of compound 56 (administering doses of 10 mg/kg, 30 mg/kg or 100 mg/kg of compound 56) on locomotion (number of beam interruptions) in mice injected with MK-801. Compared with the placebo control group, the MK-801-only group (MK-801 group) exhibited hyperlocomotion in the open field test. Compared with the MK-801 group, no effect was found in the low dose (10 mg/kg) group of Compound 56 (and MK-801), and the middle dose (30 mg/kg) group 56 (and MK-801) had a slightly lower locomotion, while the high dose (100 mg/kg) group of Compound 56 (and MK-801) showed a significant reduction in hyperlocomotion induced by MK -801.

Figure 7 shows the results of studying the effect of compound 56 (10 mg/kg, 30 mg/kg or 100 mg/kg doses of compound 56) on prepulse inhibition in MK-801-treated mice at various levels of prepulse intensity (71 dB , 75 dB, 83 dB). Compared to the placebo control group, the MK-801 group (MK-801 group) was deficient in prepulse inhibition at all levels of prepulse intensity. At a prepulse intensity of 71 dB, administration of compound 56 at a dose of 10 mg/kg resulted in a slight improvement in prepulse inhibition deficit, but administration of compound 56 at a dose of 30 mg/kg and 100 mg/kg to mice treated with MK-801 achieved significantly more high percentage of prepulse inhibition (increased sparing effects with a deficit of prepulse inhibition). At prepulse intensities of 75 and 83 dB, the administration of compound 56 both at a dose of 30 mg/kg and at a dose of 100 mg/kg led to a decrease in the deficit of prepulse inhibition induced by the administration of MK-801 to a level similar to that in the control group, in which placebo was administered and showed improved sparing effects in prepulse inhibition deficiency.

Example 25 Synthesis of Compound (78)

Synthesis of 6-(3,5-difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 1H-pyrazole-5-carboxylate (78)

6-(3,5-difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-phenethyl-1H-pyrazole-5-carboxylate (78)

Compound 78 was synthesized by the same methods as those described in Example 17 for compound 57 and in accordance with the synthesis scheme above. The reaction was carried out with a loading of the starting reagent of 252 mg and 6-(3,5-difluorophenethyl)-3-oxo-2,3-dihydropyridazin-4-yl 3-phenethyl-1H-pyrazole-5-carboxylate (78) was obtained as white solids (30.2 mg, 7%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.56 (s, 1H), 13.19 (s, 1H), 7.51 (s, 1H), 7.32-7.17 (m, 5H), 7.00-7.08 (m, 3H), 6.69 (s, 1H), 2.98-2.73 (m, 8H). ESI-MS, m/z=451 [M+H] ⁺ .

Example 26 Therapeutic Effects of Compound 78

The effect of compound 78 on mice injected with MK-801

Male C57BL/6J mice were housed in a group (3-5 mice per cage) with unlimited access to food and water in ventilated polysulfone cages (Alternative Design, AR, USA) in SyneuRx animal housing. The mouse colony was maintained on a 12/12 hour light/dark cycle at 22 ± 2°C, and all behavioral studies were performed during the dark cycle. All animals used in this study were adult mice (at least 2.5 months of age). All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC).

Mice were randomly divided into five groups: group 1 - placebo control, group 2 - MK-801, group 3 - compound 78 at a dose of 10 mg/kg+MK-801, group 4 - compound 78 at a dose of 30 mg/kg+ MK-801, group 5 - compound 78 at a dose of 100 mg/kg + MK-801. Mice in group 2-5 received single injections of MK-801 (Sigma-Aldrich USA), an NMDA receptor antagonist dissolved in saline, at a dose of 0.2 mg/kg for open field and 0.3 mg/kg for prepulse inhibition (PPI ), respectively, by intraperitoneal injection 20 minutes prior to behavioral tests. Each mouse in group 3-5 was dosed with compound 78 at doses of 10, 30 and 100 mg/kg (dissolved in double distilled H ₂ O with 65% PEG400 and 10% DMSO) once orally 20 minutes prior to MK-801 administration.

All mice were tested in the open field test and in the prepulse inhibition test. Open field and prepulse inhibition tests were used to assess the efficacy of compound 78 in reducing MK-801 induced hyperlocomotion and sensorimotor filtration deficiency in mice, respectively. The recording apparatus and method used for the open field and prepulse inhibition tests were the same as described in Example 24 above.

Figure 8 shows the results of a study on the effect of compound 78 on locomotion in mice administered MK-801. Compared with the placebo control group, the MK-801 alone group (MK-801 group) exhibited hyperlocomotion in the open field test. Compared to the MK-801 group, the low and medium dose (10 mg/kg and 30 mg/kg) group of mice treated with Compound 78 (and MK-801) exhibited slightly lower locomotion, while mice treated with a high dose of compound 78 (and MK-801) were characterized by a significant reduction in hyperlocomotion induced by administration of MK-801.

Figure 9 shows the results of studying the effect of compound 78 (administered at doses of 10 mg/kg, 30 mg/kg or 100 mg/kg of compound 78) on prepulse inhibition in mice treated with MK-801. Compared to the placebo control group, the MK-801-only group (MK-801 group) showed a deficit in prepulse inhibition at all levels of prepulse intensity. At a prepulse intensity of 71 dB, compound 78 had a stronger effect on prepulse inhibition deficit and had a significantly higher percentage of prepulse inhibition when compound 78 was administered at doses of 10 mg/kg and 100 mg/kg. At prepulse intensities of 75 and 83 dB, administration of compound 78 resulted in a dose-dependent reduction in the prepulse inhibition deficit induced by MK-801α administration.

Equivalents and Scope of the Invention

In the claims, the use of the singular form may refer to one or more than one subject matter, unless otherwise indicated or otherwise evident from the context. Claims or descriptions that include the word "or" between one or more members of a group are deemed to satisfy the requirements for execution if one, more than one, or all of the members of the group are present in, used in, or related to the product or method. product or method, unless otherwise indicated or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, used in, or related to a given product or method. The invention includes embodiments in which more than one or all of the members of the group are present in, used in, or related to a given product or method.

In addition, the invention includes all variations, combinations and permutations in which one or more limitations, one or more elements, one or more parts of the claims and one or more descriptive terms from one or more of the listed claims are included in another claim. invention formulas. For example, any claim that is dependent on another claim may be modified to include one or more of the limitations found in any other claim that is dependent on the same main claim. In cases where elements are presented as lists, such as in the Markush group format, each subgroup of elements is also described, and any element(s) can be removed from the group. It should be appreciated that, in general, where the invention or aspects of the invention are characterized as including specific elements and/or features, the particular embodiments of the invention or aspects of the invention consist or essentially consist of such elements and/or features. For the sake of simplicity, these embodiments have not been specifically set forth in this invention. In addition, it should be noted that the terms "comprising" and "comprising" are intended to be open-ended and allow the inclusion of additional elements or steps. In cases where ranges are specified, the endpoints are within the specified range. In addition, unless otherwise indicated, or otherwise obvious from the context and to the understanding of a person skilled in the art, then values that are expressed as ranges can take on any particular value or fall within a subrange within the indicated ranges in various embodiments of the invention. up to one tenth of the lower limit of the range, unless the context clearly indicates otherwise.

This application makes reference to various patents, published patent applications, journal articles and other publications, the entire contents of which are incorporated into the present invention by reference to them. If there is a conflict between the contents of any of the references incorporated in the invention and the present invention, the invention shall control. In addition, any particular embodiment of the present invention that falls within the definition of the prior art may be expressly excluded from any one or more claims. Since such embodiments are considered to be known to any person of ordinary skill in the art, they may be excluded even if that exception is not explicitly set forth in the invention. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Those skilled in the art may recognize, or may discover using no more than routine experimentation, the existence of many equivalents to the specific embodiments described herein. It is assumed that the scope of the embodiments described in the invention is not limited to the above description, and moreover, this scope is limited only by the claims of the appended claims. It is obvious to those of ordinary skill in the art that various changes and modifications can be made to this invention without departing from the spirit or scope of the present invention as defined in the following claims.

Claims (25)

1. Compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

represents

,

or

; each of X and Z is independently aryl selected from phenyl and naphthyl, H, or absent; Y represents

or

; each of L ₁ and L ₂ is independently a moiety selected from CH ₂ , C _2-10 alkyl, -((CH ₂ ) _n -W)-, where n=1 and W is O or absent. 2. A compound according to claim 1 wherein L ₁ is -(CH ₂ )-. 3. The compound according to claim 1, where the compound has the formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein B and F are independently C or N; C is C, X and Z are independently aryl selected from phenyl and naphthyl; each of L ₁ and L ₂ is independently C ₁ -C ₁₀ alkyl or absent. 4. The compound according to claim 3, where the compound has the formula:

, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, where the compound has the formula (I-b):

(IB) or a pharmaceutically acceptable salt thereof, wherein X and Z are independently aryl selected from phenyl and naphthyl; and each of L ₁ and L ₂ is independently C ₁ -C ₁₀ alkyl. 6. The compound according to claim 1, which is selected from the group consisting of:

(62)

And

. 7. A pharmaceutical composition having inhibitory activity against D-amino acid oxidase (DAAO), comprising an effective amount of a compound according to any one of paragraphs. 1-6 and carrier. 8. A method of inhibiting D-amino acid oxidase (DAAO) in a subject, wherein the method comprises administering to a subject in need thereof an effective amount of a compound according to any one of paragraphs. 1-6. 9. The method according to claim 8, where the subject is a person with a suspicion of having a neuropsychiatric disorder or at risk of developing a psychoneurological disorder, where the neuropsychiatric disorder is selected from the group consisting of schizophrenia, Alzheimer's disease, dementia, autism spectrum disorder, Asperger's syndrome, attention deficit hyperactivity disorder, obsessive-compulsive disorder, tic disorders, depression, bipolar disorder, post-traumatic stress disorder, personality disorders, Parkinson's disease and Huntington's disease. 10. The method according to any one of paragraphs. 8, 9, where the subject is administered the compound at a frequency of from three times a day to once every two months.

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