RU2791533C2 - Heterocyclic compound - Google Patents

Abstract

FIELD: medicine; therapy.

SUBSTANCE: group of inventions relates to the field of medicine, namely to therapy; it is intended for the use in prevention or treatment of constipation. A heterocyclic compound of the formula (I) is presented, as well as following heterocyclic compounds: N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazole-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide, 7-(3-fluor-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide, 7-(3-fluor-4-((((S)-tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide. In another embodiment, drugs containing these compounds are provided. A method for positive allosteric modulation of a cholinergic muscarinic M1 receptor, a method for prevention or treatment of constipation, using these compounds, and the use of the specified compounds for the production of a preventive or therapeutic drug for constipation are also provided.

EFFECT: group of inventions provides new heterocyclic compounds characterized by positive allosteric modulating activity relatively to cholinergic muscarinic M1 receptor and used as a drug, such as a preventive or therapeutic drug for constipation.

16 cl, 6 tbl, 113 ex

Description

The field of technology to which the invention belongs

[0001]

The present invention relates to a heterocyclic compound putatively having a positive allosteric modulating activity on M1 cholinergic muscarinic receptor, and putatively useful as a drug such as a prophylactic or therapeutic drug for constipation, etc. As used herein, positive allosteric modulating activity refers to the potentiation of receptor function by binding to a moiety other than the endogenous activator moiety (acetylcholine for that receptor).

[0002]

BACKGROUND OF THE INVENTION

Acetylcholine is a neurotransmitter that induces signaling in the central nervous system and neuromuscular connections (parasympathetic nerve and motor nerve). In the gastrointestinal tract, intermuscular plexus, submucosal plexus, etc. forms a neural network and regulates the function of the gastrointestinal tract. Of the neurotransmitters, acetylcholine is the main neurotransmitter in gastrointestinal function and plays a key role in gastrointestinal motility.

The acetylcholine receptor is divided into a ligand-dependent ion channel (cholinergic nicotinic receptor) and a G-protein-conjugated receptor (cholinergic muscarinic receptor). The cholinergic muscarinic receptor is one type of receptor for the excitatory neurotransmitter acetylcholine, and is named for the selective activation of the receptor by muscarine. The muscarinic receptor is further subdivided into subtypes M1 to M5, and the M1 receptor is known to be widely distributed, predominantly in the brain. On the other hand, expression of the M1 receptor in the gastrointestinal plexus is also known, and its role in regulating the functions of the gastrointestinal tract has also been noted (Non-Patent Document 1). According to the results of studies in recent years, an increase in gastrointestinal motility by an agonist of the cholinergic receptor M1 has also been reported.

In general, peristalsis of the gastrointestinal tract consists of coordinated contraction and relaxation in adjacent areas. It is also known that the M1 cholinergic receptor is expressed in the gastrointestinal plexus in both the excitatory nerve and the inhibitory nerve (Non-Patent Document 1).

[0003]

WO2013/129622 (Patent Document 1) discloses the following compound having positive allosteric modulating activity for M1 muscarinic receptor (M1PAM) and useful for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disorders, etc.

[0004]

,

,

[0005]

in which the meaning of each character is defined in the specified document.

[0006]

WO2014/077401 (Patent Document 2) discloses the following compound having M1PAM activity and useful for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disturbance, etc.

[0007]

,

,

[0008]

in which the meaning of each character is defined in the specified document.

[0009]

WO2015/174534 (Patent Document 3) discloses the following compound having M1PAM activity and useful for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disturbance, Parkinson's disease dementia, Lewy body dementia, etc.

[0010]

,

,

[0011]

in which the meaning of each character is defined in the specified document.

[0012]

WO2015/163485 (Patent Document 4) discloses the following compound having M1PAM activity and useful for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disturbance, Parkinson's disease dementia, Lewy body dementia, etc.

[0013]

,

,

[0014]

in which the meaning of each character is defined in the specified document.

[0015]

WO2016/208775 (Patent Document 5) discloses the following compound having M1PAM activity and useful for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disturbance, Parkinson's disease dementia, Lewy body dementia, etc.

[0016]

,

,

[0017]

in which the meaning of each character is defined in the specified document.

[0018]

WO2015/190564 (Patent Document 6) discloses the following compound having M1PAM activity and useful for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disturbance, Parkinson's disease dementia, Lewy body dementia, etc.

[0019]

[0020]

in which the meaning of each character is defined in the specified document.

List of documents

Patent Documents:

[0021]

patent document 1: WO2013/129622

patent document 2: WO2014/077401

patent document 3: WO2015/174534

patent document 4: WO2015/163485

patent document 5: WO2016/208775

patent document 6: WO2015/190564

Non-Patent Document:

[0022]

non-patent document 1: Journal of Chemical Neuroanatomy, 2007 Jul, 33(4), 193–201

BRIEF DESCRIPTION OF THE INVENTION

Problems to be solved by the present invention

[0023]

What is needed is the development of a compound having positive allosteric modulating activity at the M1 cholinergic muscarinic receptor (M1 receptor) and useful as a prophylactic or therapeutic agent for constipation, e.g., constipation associated with a neurological disease (e.g., Parkinson's disease, spinal cord injury, multiple sclerosis). ), idiopathic constipation, age-related constipation, opioid-induced constipation, etc. In the context of this document, positive allosteric modulating activity means the action of binding to a site other than the endogenous activator (acetylcholine for a given receptor) and potentiation of receptor function.

Ways to solve problems

[0024]

The inventors of the present invention have carried out intensive studies in an attempt to solve the above problems, and have found that the compound represented by the following formula (I) can have a positive allosteric modulating activity of the M1 cholinergic muscarinic receptor, which has led to the completion of the present invention.

[0025]

Based on the foregoing, the present invention relates to the following.

[1] The compound represented by formula (I):

[0026]

,

,

[0027]

in which

R ¹ is an optionally substituted cyclic group;

R ² represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group;

[0028]

[0029]

is a single bond or a double bond;

ring A is an additionally substituted ring; And

each of R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group,

or a salt thereof (sometimes abbreviated herein as "compound (I)").

[2] The compound described in [1] above, wherein

R ¹ is

(1) an optionally substituted 3-14 membered non-aromatic heterocyclic group, or

(2) an optionally substituted C _3-10 cycloalkyl group;

R ² represents a hydrogen atom or an optionally substituted C _1-6 alkyl group;

ring A represents

(1) an optionally further substituted benzene ring,

(2) an optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle,

(3) an optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle, or

(4) an optionally further substituted 9-14 membered fused polycyclic non-aromatic heterocycle; And

each of R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom or an optionally substituted C _1-6 alkyl group,

or its salt.

[3] The compound described in [1] above, wherein

R ¹ is

(1) a 3-14 membered non-aromatic heterocyclic group optionally substituted with 1-3 hydroxy groups, or

(2) a C _3-10 cycloalkyl group optionally substituted with 1-3 substituents selected from hydroxy and halogen;

R ² represents a hydrogen atom or a C _1-6 alkyl group;

ring A represents

(1) a benzene ring optionally further substituted with 1-3 substituents selected from (a) a halogen atom, (b) a C _1-6 alkoxy group, (c) a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with 1 or 2 substituents selected from (i) a C _1-6 alkoxy group, (ii) a C _3-10 cycloalkyl group, (iii) a 3-14 membered non-aromatic heterocyclic group, (iv) a C _6-14 aryl group optionally substituted with 1- 3 hydroxy groups, (v) C _1-6 alkoxycarbonyl group, (vi) carboxy groups, (vii) C _1-6 alkylthio groups, (viii) mono- or di-C _1-6 alkylcarbamoyl group and (ix) 3-14-membered a non-aromatic heterocyclylcarbonyl group, (d) a mono- or di-C _3-10 cycloalkylcarbamoyl group, (e) a C _6-14 arylcarbamoyl group optionally substituted with 1-3 hydroxy groups, and (f) a 5-14 membered aromatic heterocyclic group, optionally substituted with 1–3 C _1–6 alkyl groups,

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted with 1-3 substituents selected from (a) a C _1-6 alkoxy group and (b) a 5-14 membered aromatic heterocyclic group optionally substituted with 1-3 C _1–6 alkyl groups,

(3) a 4-6 membered monocyclic non-aromatic heterocycle, optionally further substituted with one oxo group, or

(4) a 9-14 membered fused polycyclic non-aromatic heterocycle optionally further substituted with 1-3 substituents selected from a C _1-6 alkyl group and an oxo group; And

each of R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom or a C _1-6 alkyl group,

or its salt.

[4] The compound described in [3] above, wherein

R ¹ is

[0030]

[0031]

or its salt.

[5] The compound described in [3] above, wherein

ring A represents

(1) a benzene ring further substituted with 1-3 substituents selected from (a) a halogen atom, (b) a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with 1 or 2 substituents selected from (i) C _{1 -6} alkoxy group and (ii) a 3-14 membered non-aromatic heterocyclic group, and (c) a 5-14 membered aromatic heterocyclic group optionally substituted with 1-3 C _1-6 alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle further substituted with one 5-14 membered aromatic heterocyclic group optionally substituted with 1-3 C _1-6 alkyl groups,

or its salt.

[6] The compound described in [3] above, wherein

ring A represents

[0032]

[0033]

where R ^5A is a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with 1 or 2 substituents selected from C _1-6 alkoxy and a 3-14 membered non-aromatic heterocyclic group;

X is CR ^6A or N; And

R ^6A represents a hydrogen atom or a halogen atom,

or its salt.

[7] The compound described in [3] above, wherein

ring A represents

[0034]

[0035]

where R ^5A is a 5-14 membered aromatic heterocyclic group optionally substituted with 1-3 C _1-6 alkyl groups;

X is CR ^6A or N; And

R ^6A represents a hydrogen atom or a halogen atom,

or its salt.

[8] The compound described in [1] above, wherein

R ¹ is a 3-14 membered non-aromatic heterocyclic group substituted with one hydroxy group;

R ² represents a hydrogen atom;

ring A represents

(1) a benzene ring further substituted with 1-3 substituents selected from (a) a halogen atom, (b) a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with 1 or 2 substituents selected from (i) C _{1 -6} alkoxy group and (ii) a 3-14 membered non-aromatic heterocyclic group, and (c) a 5-14 membered aromatic heterocyclic group optionally substituted with 1-3 C _1-6 alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle further substituted with one 5-14-membered aromatic heterocyclic group optionally substituted with 1-3 C _1-6 alkyl groups; And

each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom,

or its salt.

[9] N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–1,2,3–triazol–4–yl)benzyl )furo[3,2-b]pyridine-5-carboxamide or a salt thereof.

[10] N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–1,2,3–triazol–4–yl)benzyl )-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide or a salt thereof.

[11] 7–(3–Fluoro–4–((2–methoxyethyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–2,3–dihydrofuro [3,2-b]pyridine-5-carboxamide or its salt.

[12] 7–(3–Fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4 -yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide or a salt thereof.

[13] 7–(3–Fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4 -yl)furo[3,2-b]pyridine-5-carboxamide or a salt thereof.

[14] A drug containing the compound described in the above paragraph 1, or a salt thereof.

[15] The drug described in [14] above, which is a positive allosteric modulator of the M1 cholinergic muscarinic receptor.

[16] The drug described in [14] above, which is a prophylactic or therapeutic agent for constipation.

[17] A method for positive allosteric modulation of the M1 cholinergic muscarinic receptor in a mammal, comprising administering to said mammal an effective amount of a compound described in the above-mentioned [1] or a salt thereof.

[18] A method for preventing or treating constipation in a mammal, comprising administering to said mammal an effective amount of a compound described in the above-mentioned [1] or a salt thereof.

[19] The use of the compound described in the above [1] or a salt thereof for the preparation of a prophylactic or therapeutic agent for constipation.

[20] The compound described in [1] above, or a salt thereof, for use in the prevention or treatment of constipation.

Invention Effect

[0036]

The compound of the present invention may have a positive allosteric modulating activity at the M1 cholinergic muscarinic receptor and may be useful as a drug, such as a prophylactic or therapeutic agent, for example, for constipation, such as constipation associated with a neurological disease (for example, Parkinson's disease). , spinal cord injury, multiple sclerosis), idiopathic constipation, age-related constipation, opioid-induced constipation, etc.

[0037]

Detailed description of the present invention

The definition of each substituent used in the present description is described in detail in the following. Unless otherwise indicated, each substituent is characterized by the following definition.

In the present description, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

As used herein, examples of "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

As used herein, examples of the "optionally halogenated C _1-6 alkyl group" include a C _1-6 alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

As used herein, examples of "C _2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl- 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

As used herein, examples of "C _2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

In the present specification, examples of "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1] octyl and adamantyl.

As used herein, examples of the "optionally halogenated C _3-10 cycloalkyl group" include a C _3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In the present specification, examples of the "C _3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

As used herein, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

As used herein, examples of the "C _7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl-, and phenylpropyl.

[0038]

As used herein, examples of "C _1-6 alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, and hexyloxy.

In the present specification, examples of the "optionally halogenated C _1-6 alkoxy group" include a C _1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec- butoxy, pentyloxy, and hexyloxy.

In the present specification, examples of "C _3-10 cycloalkyloxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

As used herein, examples of "C _1-6 alkylthio" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio, t- butylthio, pentylthio, and hexylthio.

In the present specification, examples of the "optionally halogenated C _1-6 alkylthio group" include a C _1-6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

As used herein, examples of "C _1-6 alkylcarbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

As used herein, examples of the "optionally halogenated C _1-6 alkylcarbonyl group" include a C _1-6 alkylcarbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl.

As used herein, examples of the "C _1-6 alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, t- butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

As used herein, examples of "C _6-14 arylcarbonyl group" include benzoyl, 1-naphthoyl, and 2-naphthoyl.

In the present description, examples of "C _7-16 aralkylcarbonyl group" include phenylacetyl and phenylpropionyl.

As used herein, examples of the "5-14 membered aromatic heterocyclylcarbonyl group" include nicotinoyl, isonicotinoyl, thenoyl, and furoyl.

As used herein, examples of the "3-14 membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0039]

As used herein, examples of the "mono- or di-C _1-6 alkylcarbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

As used herein, examples of the "mono- or di-C _7-16 aralkylcarbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of "C _1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl, and tert- butylsulfonyl.

In the present specification, examples of the "optionally halogenated C _1-6 alkylsulfonyl group" include a C _1-6 alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

In the present specification, examples of the "C _6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0040]

As used herein, examples of a "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group.

As used herein, examples of a "hydrocarbon group" (including a "hydrocarbon group" of an "optionally substituted hydrocarbon group") include a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 a cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, and a C _7-16 aralkoxy group.

[0041]

As used herein, examples of "optionally substituted hydrocarbon group" include a hydrocarbon group optionally containing a substituent(s) selected from the following substituent group A.

[substitution group A]

(1) a halogen atom,

(2) nitro group,

(3) cyano group,

(4) oxo group,

(5) hydroxy group,

(6) an optionally halogenated C _1-6 alkoxy group,

(7) C _6-14 aryloxy (eg phenoxy, naphthoxy),

(8) C _7-16 aralkyloxy (e.g. benzyloxy),

(9) 5-14 membered aromatic heterocyclyloxy group (e.g. pyridyloxy),

(10) 3-14 membered non-aromatic heterocyclyloxy group (e.g. morpholinyloxy, piperidinyloxy),

(12) C _6-14 arylcarbonyloxy group (e.g. benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),

(13) C _1-6 alkoxycarbonyloxy group (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) mono- or di-C _1-6 alkylcarbamoyloxy group (e.g. methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

(15) C _6-14 arylcarbamoyloxy group (e.g. phenylcarbamoyloxy, naphthylcarbamoyloxy),

(16) 5-14 membered aromatic heterocyclylcarbonyloxy group (e.g. nicotinoyloxy),

(17) 3-14 membered non-aromatic heterocyclylcarbonyloxy group (e.g. morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C _1-6 alkylsulfonyloxy group (eg methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C _6-14 arylsulfonyloxy group optionally substituted with a C _1-6 alkyl group (eg phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C _1-6 alkylthio group,

(21) 5–14 membered aromatic heterocyclic group,

(22) 3-14 membered non-aromatic heterocyclic group,

(23) formyl group,

(24) carboxy group,

(25) an optionally halogenated C _1-6 alkylcarbonyl group,

(26) C _6–14 arylcarbonyl group,

(27) 5–14 membered aromatic heterocyclylcarbonyl group,

(28) 3-14-membered non-aromatic heterocyclylcarbonyl group,

(29) C _1–6 alkoxycarbonyl group,

(30) C _6-14 aryloxycarbonyl group (e.g. phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) C _7-16 aralkyloxycarbonyl group (e.g. benzyloxycarbonyl, phenethyloxycarbonyl),

(32) carbamoyl group,

(33) thiocarbamoyl group,

(34) mono- or di-C _1-6 alkylcarbamoyl group,

(35) C _6-14 arylcarbamoyl group (e.g. phenylcarbamoyl),

(36) 5-14 membered aromatic heterocyclylcarbamoyl group (e.g. pyridylcarbamoyl, thienylcarbamoyl),

(37) 3-14 membered non-aromatic heterocyclylcarbamoyl group (e.g. morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C _1-6 alkylsulfonyl group,

(39) C _6–14 arylsulfonyl group,

(40) 5-14 membered aromatic heterocyclylsulfonyl group (e.g. pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C _1-6 alkylsulfinyl group,

(42) C _6-14 arylsulfinyl group (e.g. phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) 5-14 membered aromatic heterocyclylsulfinyl group (e.g. pyridylsulfinyl, thienylsulfinyl),

(44) amino group,

(45) mono- or di-C _1-6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) mono- or di-C _6-14 arylamino group (e.g. phenylamino),

(47) 5–14 membered aromatic heterocyclylamino group (e.g. pyridylamino),

(48) C _7–16 aralkylamino (e.g. benzylamino),

(49) formylamino group,

(50) C _1-6 alkylcarbonylamino group (for example, acetylamino, propanoylamino, butanoylamino),

(51) (C _1-6 alkyl) (C _1-6 alkylcarbonyl) amino group (for example, N-acetyl-N-methylamino),

(52) C _6-14 arylcarbonylamino (e.g. phenylcarbonylamino, naphthylcarbonylamino),

(53) C _1-6 alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, t- butoxycarbonylamino),

(54) C _7-16 aralkyloxycarbonylamino group (e.g. benzyloxycarbonylamino),

(55) C _1-6 alkylsulfonylamino (e.g. methylsulfonylamino, ethylsulfonylamino),

(56) C _6-14 arylsulfonylamino group optionally substituted with C _1-6 alkyl group (e.g. phenylsulfonylamino, toluenesulfonylamino),

(56) C _6-14 arylsulfonylamino group optionally substituted with C _1-6 alkyl group (e.g. phenylsulfonylamino, toluenesulfonylamino),

(57) optionally halogenated C _1-6 alkyl group,

(58) C _2–6 alkenyl group,

(59) C _2–6 alkynyl group,

(60) C _3–10 cycloalkyl group,

(61) C _3–10 cycloalkenyl group and

(62) C _6–14 aryl group.

[0042]

The number of substituents mentioned above in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. If the number of substituents is greater than or equal to two, then the respective substituents may be the same or different.

As used herein, examples of a "heterocyclic group" (including a "heterocyclic group" of an "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered bridged heterocyclic a group each containing, as a ring-forming atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, in addition to carbon atoms.

[0043]

In the present specification, examples of an "aromatic heterocyclic group" (including a "5-14 membered aromatic heterocyclic group") include a 5-14 membered (preferably 5-10 membered) aromatic heterocyclic group containing as a ring-forming atom from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms.

Preferred examples of "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; And

8-14 membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, имидазопиразинил, имидазопиримидинил, тиенопиримидинил, фуропиримидинил, пирролопиримидинил, пиразолопиримидинил, оксазолопиримидинил, тиазолопиримидинил, пиразолотриазинил, нафто[2,3–b]тиенил, феноксатиинил, индолил, изоиндолил, 1H–индазолил, пуринил, изохинолил, хинолил, фталазинил, нафтиридинил, хиноксалинил, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinil, etc.

[0044]

In the present specification, examples of a "non-aromatic heterocyclic group" (including a "3-14 membered non-aromatic heterocyclic group") include a 3-14-membered (preferably 4-10-membered) non-aromatic heterocyclic group containing as a ring-forming atom from 1 up to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms.

Preferred examples of "aromatic heterocyclic group" include 3-8 membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, пиразолинил, пиразолидинил, тиазолинил, тиазолидинил, тетрагидроизотиазолил, тетрагидрооксазолил, тетрагидроизоксазолил, пиперидинил, пиперазинил, тетрагидропиридинил, дигидропиридинил, дигидротиопиранил, тетрагидропиримидинил, тетрагидропиридазинил, дигидропиранил, тетрагидропиранил, тетрагидротиопиранил, морфолинил, тиоморфолинил, азепанил, диазепанил, азепинил, оксепанил, азоканил, диазоканил, etc.; And

9-14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolisinyl, indolinyl, изоиндолинил, тетрагидротиено[2,3–c]пиридинил, тетрагидробензазепинил, тетрагидрохиноксалинил, тетрагидрофенантридинил, гексагидрофенотиазинил, гексагидрофеноксазинил, тетрагидрофталазинил, тетрагидронафтиридинил, тетрагидрохиназолинил, тетрагидроциннолинил, тетрагидрокарбазолил, тетрагидро–β–карболинил, тетрагидроакридинил, тетрагидрофеназинил, тетрагидротиоксантенил, октагидроизохинолил, и т.д .

[0045]

As used herein, preferred examples of the "7-10 membered bridged heterocyclic group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the "nitrogen-containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring-forming atom.

As used herein, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having a substituent(s) selected from the above substituent group A.

The number of substituents in the "optionally substituted heterocyclic group" is, for example, from 1 to 3. If the number of substituents is greater than or equal to two, then the respective substituents may be the same or different.

[0046]

As used herein, examples of an "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally contains "1 or 2 substituents selected from a C _1-6 alkyl group , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl group, C _7-16 aralkyl group, 5-14-membered aromatic heterocyclic group and 3-14-membered a non-aromatic heterocyclic group each optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group."

Examples of the "acyl group" also include a hydrocarbonsulfonyl group, a heterocyclylsulfonyl group, a hydrocarbonsulfinyl group, and a heterocyclylsulfinyl group.

In this case, a hydrocarbonsulfonyl group means a hydrocarbon-linked sulfonyl group, a heterocyclylsulfonyl group means a heterocyclic-linked sulfonyl group, a hydrocarbonsulfinyl group means a hydrocarbon-linked sulfinyl group, and a heterocyclylsulfinyl group means a heterocyclic-linked sulfinyl group.

Preferred examples of "acyl group" include formyl group, carboxy group, C _1-6 alkylcarbonyl group, C _2-6 alkenylcarbonyl group (e.g. crotonoyl), C _3-10 cycloalkylcarbonyl group (e.g. cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl) , C _3-10 cycloalkenylcarbonyl group (for example, 2-cyclohexenecarbonyl), C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14-membered aromatic heterocyclylcarbonyl group, 3-14-membered non-aromatic heterocyclylcarbonyl group, C _{1- 6} alkoxycarbonyl group, C _6-14 aryloxycarbonyl group (for example, phenyloxycarbonyl, naphthyloxycarbonyl), C _7-16 aralkyloxycarbonyl group (for example, benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, mono- or di-C _2-6 alkenylcarbamoyl group (eg diallylcarbamoyl), mono- or di-C _3-10 cycloalkylcarbamoyl group (eg cyclo propylcarbamoyl), mono- or di-C _6-14 arylcarbamoyl group (e.g. phenylcarbamoyl), mono- or di-C _7-16 aralkylcarbamoyl group, 5-14 membered aromatic heterocyclylcarbamoyl group (e.g. pyridylcarbamoyl), thiocarbamoyl group, mono - or di-C _1-6 alkylthiocarbamoyl group (for example, methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenylthiocarbamoyl group (for example, diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkylthiocarbamoyl group (e.g. cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 arylthiocarbamoyl group (e.g. phenylthiocarbamoyl), mono- or di-C _7-16 aralkylthiocarbamoyl group (e.g. benzylthiocarbamoyl, phenethylthiocarbamoyl), 5-14- membered aromatic heterocyclylthiocarbamoyl group (e.g. pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (e.g. methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 alkylsulfonyl group, C _6-14 arylsulfonyl th group, a phosphono group and a mono- or di-C _1-6 alkylphosphono group (eg dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0047]

As used herein, examples of an "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkylcarbonyl group, C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14-membered aromatic heterocyclylcarbonyl group, 3-14-membered non-aromatic heterocyclylcarbonyl group, C _{1 -6} alkoxycarbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, mono- or di-C _7-16 aralkylcarbamoyl group, C _1-6 alkylsulfonyl group and C _{6 -14} arylsulfonyl groups, each optionally having 1 to 3 substituents selected from substituent group A."

Preferred examples of the optionally substituted amino group include amino, mono- or di-(optionally halogenated C _1-6 alkyl) amino (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _{2 –6} alkenylamino group (for example, diallylamino), mono- or di-C _3-10 cycloalkylamino group (for example, cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino group (for example, phenylamino), mono- or di-C _{7 –16} aralkylamino group (e.g. benzylamino, dibenzylamino), mono- or di-(optionally halogenated C _1-6 alkyl)-carbonylamino group (e.g. acetylamino, propionylamino), mono- or di-C _6-14 arylcarbonylamino group (e.g. benzoylamino) , mono- or di-C _7-16 aralkylcarbonylamino group (for example, benzylcarbonylamino), mono- or di-(5-14 membered aromatic heterocyclyl)-carbonylamino group (for example, nicotinoylamino, isonicotinoylamino), mono- or di-(3-14 -membered non-aromatic het erocyclyl)-carbonylamino group (for example, piperidinylcarbonylamino), mono- or di-C _1-6 alkoxycarbonylamino group (for example, tert- butoxycarbonylamino), 5-14-membered aromatic heterocyclylamino group (for example, pyridylamino), carbamoylamino group, (mono- or di-C _1-6 alkylcarbamoyl)amino (e.g. methylcarbamoylamino), (mono- or di-C _7-16 aralkylcarbamoyl)amino (e.g. benzylcarbamoylamino), C _1-6 alkylsulfonylamino (e.g. methylsulfonylamino, ethylsulfonylamino), C _6-14 arylsulfonylamino ( e.g. phenylsulfonylamino), (C _1-6 alkyl)(C _1-6 alkylcarbonyl)amino group (e.g. N-acetyl-N-methylamino) and (C _1-6 alkyl)(C _6-14 arylcarbonyl)amino group (e.g. N-benzoyl-N-methylamino).

[0048]

As used herein, examples of an "optionally substituted carbamoyl group" include a carbamoyl group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _{6- 14} aryl group, C _7-16 aralkyl group, C _1-6 alkylcarbonyl group, C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxycarbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, and mono- or di-C _7-16 aralkylcarbamoyl group, each of which optionally contains from 1 up to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C _1-6 alkylcarbamoyl group, a mono- or di-C _2-6 alkenylcarbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C _3-10 cycloalkylcarbamoyl group (e.g. cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14 arylcarbamoyl group (e.g. phenylcarbamoyl), mono- or di-C _7-16 aralkylcarbamoyl group, mono- or di-C _1-6 alkylcarbonylcarbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C _6-14 arylcarbonylcarbamoyl group (eg benzoylcarbamoyl) and a 5-14 membered aromatic heterocyclylcarbamoyl group (eg pyridylcarbamoyl).

[0049]

As used herein, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _{6- 14} aryl group, C _7-16 aralkyl group, C _1-6 alkylcarbonyl group, C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxycarbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, and mono- or di-C _7-16 aralkylcarbamoyl group, each of which optionally contains from 1 up to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C _1-6 alkylthiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _{2 –6} alkenylthiocarbamoyl group (e.g. diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkylthiocarbamoyl group (e.g. cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 arylthiocarbamoyl group (e.g. phenylthiocarbamoyl), mono- or di –C _7-16 aralkylthiocarbamoyl group (e.g. benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C _1-6 alkylcarbonylthiocarbamoyl group (e.g. acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C _6-14 arylcarbonylthiocarbamoyl group (e.g. benzoylthiocarbamoyl) and a 5-14 membered aromatic heterocyclylthiocarbamoyl group (eg, pyridylthiocarbamoyl).

[0050]

As used herein, examples of an "optionally substituted sulfamoyl group" include a sulfamoyl group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _{6- 14} aryl group, C _7-16 aralkyl group, C _1-6 alkylcarbonyl group, C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxycarbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, and mono- or di-C _7-16 aralkylcarbamoyl group, each of which optionally contains from 1 up to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C _1-6 alkylsulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _{2 –6} alkenylsulfamoyl group (e.g. diallylsulfamoyl), mono- or di-C _3-10 cycloalkylsulfamoyl group (e.g. cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 arylsulfamoyl group (e.g. phenylsulfamoyl), mono- or di –C _7-16 aralkylsulfamoyl group (e.g. benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C _1-6 alkylcarbonylsulfamoyl group (e.g. acetylsulfamoyl, propionylsulfamoyl), mono- or di-C _6-14 arylcarbonylsulfamoyl group (e.g. benzoylsulfamoyl) and a 5-14 membered aromatic heterocyclylsulfamoyl group (eg, pyridylsulfamoyl).

[0051]

As used herein, examples of the "optionally substituted hydroxy group" include a hydroxy group optionally having "a substituent selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7–16 aralkyl group, C _1–6 alkylcarbonyl group, C _6–14 arylcarbonyl group, C _7–16 aralkylcarbonyl group, 5–14 membered aromatic heterocyclylcarbonyl group, 3–14 membered non-aromatic heterocyclylcarbonyl group, C _1–6 alkoxycarbonyl group group, 5-14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, mono- or di-C _7-16 aralkylcarbamoyl group, C _1-6 alkylsulfonyl group and C _6-14 arylsulfonyl groups, each of which optionally contains from 1 to 3 substituents selected from the substituent group A".

Preferred examples of optionally substituted hydroxy include hydroxy, C _1-6 alkoxy, C _2-6 alkenyloxy (e.g. allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C _3-10 cycloalkyloxy (e.g. cyclohexyloxy), C _6-14 aryloxy (e.g. phenoxy, naphthyloxy), C _7-16 aralkyloxy (e.g. benzyloxy, phenethyloxy), C _1-6 alkylcarbonyloxy (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 arylcarbonyloxy (e.g. benzoyloxy), C _7-16 aralkylcarbonyloxy (e.g. benzylcarbonyloxy), 5-14 membered aromatic heterocyclylcarbonyloxy (e.g. nicotinoyloxy), 3-14 membered non-aromatic heterocyclylcarbonyloxy (e.g. piperidinylcarbonyloxy), C _1-6 alkoxycarbonyloxy (e.g. , tert- butoxycarbonyloxy), 5-14-membered aromatic heterocyclyloxy group (for example, pyridyloxy), carbamoyloxy group, C _1-6 alkylcarbamoyloxy group ( eg, methylcarbamoyloxy), a C _7-16 aralkylcarbamoyloxy group (eg, benzylcarbamoyloxy), a C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), and a C _6-14 arylsulfonyloxy group (eg, phenylsulfonyloxy).

[0052]

As used herein, examples of the "optionally substituted sulfanyl group" include a sulfanyl group optionally having "a substituent selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group , C _7-16 aralkyl group, C _1-6 alkylcarbonyl group, C _6-14 arylcarbonyl group, and 5-14 membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from substituent group A" and halogenated sulfanyl group.

Preferred examples of an optionally substituted sulfanyl group include a sulfanyl (–SH) group, a C _1-6 alkylthio group, a C _2-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C _3-10 cycloalkylthio group (e.g. cyclohexylthio), C _6-14 arylthio (e.g. phenylthio, naphthylthio), C _7-16 aralkylthio (e.g. benzylthio, phenethylthio), C _1-6 alkylcarbonylthio (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio) , C _6-14 arylcarbonylthio (eg benzoylthio), 5-14 membered aromatic heterocyclylthio (eg pyridylthio), and halogenated thio (eg pentafluorothio).

[0053]

As used herein, examples of the "optionally substituted silyl group" include a silyl group optionally having "1 to 3 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _{6 -14} aryl group and C _7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted silyl group include a tri-C _1-6 alkylsilyl group (eg trimethylsilyl, t- butyl(dimethyl)silyl).

[0054]

As used herein, examples of a "hydrocarbon ring" include a C _6-14 aromatic hydrocarbon ring, a C _3-10 cycloalkane, and a C _3-10 cycloalkene.

In the present description, examples of "C _6-14 aromatic hydrocarbon ring" include benzene and naphthalene.

In the present specification, examples of "C _3-10 cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

In the present specification, examples of "C _3-10 cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

In the present specification, examples of "heterocycle" include an aromatic heterocycle and a non-aromatic heterocycle, each of which contains, as a ring-forming atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, in addition to carbon atoms.

[0055]

As used herein, examples of "aromatic heterocycle" include a 5-14 membered (preferably 5-10 membered) aromatic heterocycle containing, as a ring-forming atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, apart from carbon atoms. Preferred examples of "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2 ,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine, etc.; And

8-14 membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiasol, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, thiazolopyridine , imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine , quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine, etc.

[0056]

As used herein, examples of a "non-aromatic heterocycle" include a 3-14-membered (preferably 4-10-membered) non-aromatic heterocycle containing, as a ring-forming atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom apart from carbon atoms. Preferred examples of "non-aromatic heterocycle" include 3-8 membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, diazepan, azepine, azocan, and t .d.; and 9-14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazol, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolysine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline .

In the present specification, examples of a "nitrogen-containing heterocycle" include a "heterocycle" containing at least one nitrogen atom as a ring-forming atom.

[0057]

The meaning of each symbol in compound (I) is explained below.

[0058]

R ¹ is an optionally substituted cyclic group.

With respect to R ¹ , as "optionally substituted cyclic group", there may be mentioned an optionally substituted heterocyclic group and an optionally substituted non-aromatic hydrocarbon ring group.

With respect to R ¹ , as the "heterocyclic group" of the "optionally substituted heterocyclic group", a 3 to 14-membered non-aromatic heterocyclic group (eg, tetrahydropyranyl) is preferred. As a substituent, 1 to 3 (preferably 1) hydroxy groups are preferred.

With respect to R ¹ , as the "non-aromatic hydrocarbon ring group" of the "optionally substituted non-aromatic hydrocarbon ring group", a C _3-10 cycloalkyl group (eg, cyclobutyl, cyclopentyl, cyclohexyl) is preferred. As a substituent, 1 to 3 (preferably 1) substituents selected from hydroxy and a halogen atom (eg, fluorine atom) are preferred.

[0059]

R ¹ is preferably

(1) an optionally substituted 3-14 membered non-aromatic heterocyclic group, or

(2) an optionally substituted C _3-10 cycloalkyl group.

R ¹ is more preferably

(1) a 3-14 membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl) optionally substituted with 1-3 (preferably 1) hydroxy groups, or

(2) a C _3-10 cycloalkyl group (eg cyclobutyl, cyclopentyl, cyclohexyl) optionally substituted with 1-3 (preferably 1) substituents selected from hydroxy and a halogen atom (eg fluorine atom).

R ¹ is more preferably

(1) a 3-14 membered non-aromatic heterocyclic group (e.g. tetrahydropyranyl) substituted with one hydroxyl group, or

(2) a C _3-10 cycloalkyl group (eg cyclohexyl) substituted with 1-3 (preferably 1) substituents selected from those selected from hydroxy and a halogen atom (eg fluorine atom).

R ¹ is even more preferably a 3-14 membered non-aromatic heterocyclic group (eg tetrahydropyranyl) substituted with one hydroxy group.

[0060]

According to another embodiment of the present invention, R ¹ is preferably

[0061]

[0062]

more preferably

[0063]

[0064]

even more preferably

[0065]

[0066]

especially preferred

[0067]

.

.

[0068]

According to another embodiment of the present invention, R ¹ is preferably

[0069]

[0070]

more preferably

[0071]

[0072]

even more preferably

[0073]

[0074]

even more preferably

[0075]

[0076]

especially preferred

[0077]

.

.

[0078]

R ² represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group.

R ² is preferably a hydrogen atom, a halogen atom (eg chlorine atom, fluorine atom), a C _1-6 alkyl group (eg methyl) or a C _1-6 alkoxy group (eg methoxy), more preferably a hydrogen atom or C _1-6 alkyl group (eg methyl), even more preferably a hydrogen atom.

[0079]

[0080]

is a single bond or a double bond.

According to one embodiment of the present invention,

[0081]

[0082]

is a single bond.

According to another embodiment of the present invention,

[0083]

[0084]

is a double bond.

[0085]

Ring A is an optionally further substituted ring.

With reference to ring A, as "optionally further substituted ring", there may be mentioned an optionally further substituted 4-6 membered monocyclic hydrocarbon ring, an optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle, an optionally further substituted 4-6 membered monocyclic a non-aromatic heterocycle; and an optionally further substituted 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle.

[0086]

With regard to ring A, as "4-6 membered monocyclic hydrocarbon ring""optionally further substituted 4-6 membered monocyclic hydrocarbon ring" benzene ring, C _4-6 cycloalkane ring (e.g. cyclobutane ring, cyclopentane ring) , cyclohexane ring) and a C _4-6 cycloalkene ring (eg cyclobutene ring, cyclopentene ring, cyclohexene ring). As "4 to 6 membered monocyclic hydrocarbon ring", a benzene ring may preferably be mentioned.

With reference to ring A, as the substituent of the "optionally further substituted 4-6 membered monocyclic hydrocarbon ring", 1 to 3 substituents selected from (1) cyano group, (2) halogen atom, (3) carboxy group, (4 ) an optionally substituted hydroxy group, (5) an optionally substituted carbamoyl group, (6) an optionally substituted amino group, (7) an optionally substituted heterocyclic group, and (8) an optionally substituted hydrocarbon group.

[0087]

With reference to ring A, as "5- or 6-membered monocyclic aromatic heterocycle" "optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle" may be mentioned a 5- or 6-membered monocyclic aromatic heterocycle containing as ring-forming atoms from 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, in addition to carbon atoms (for example, thiophene ring, furan ring, pyrrole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isooxazole ring , pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, 1,2,4-oxadiazole ring, 1,3,4-oxadiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, triazole ring, tetrazole ring, triazine ring). As "5- or 6-membered monocyclic aromatic heterocycle", a pyridine ring may preferably be mentioned.

With respect to ring A, as the "optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle" substituent, there may be mentioned from 1 to 3 substituents selected from (1) cyano, (2) halogen, (3) carboxy, ( 4) an optionally substituted hydroxy group, (5) an optionally substituted carbamoyl group, (6) an optionally substituted amino group, (7) an optionally substituted heterocyclic group, and (8) an optionally substituted hydrocarbon group.

[0088]

With reference to ring A, as "4-6 membered monocyclic non-aromatic heterocycle" "optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle" may be mentioned a 4-6-membered monocyclic non-aromatic heterocycle containing as ring-forming atoms from 1 up to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, in addition to carbon atoms (e.g., azetidine ring, oxetane ring, thietane ring, tetrahydrothiophene ring, tetrahydrofuran ring, pyrroline ring, pyrrolidine ring, imidazoline ring, imidazolidine ring, oxazoline ring , oxazolidine ring, pyrazoline ring, pyrazolidine ring, thiazoline ring, thiazolidine ring, tetrahydroisothiazole ring, tetrahydroisoxazole ring, piperidine ring, piperazine ring, tetrahydropyridine ring, dihydropyridine ring, dihydrothiopyran ring, tetrahydropyrimidine ring, tetrahydropyridazine ring, dihydropyran ring, tetrahydropyran ring, tetrahydrothiopyran ring, morpholine ring, thiomorpholine ring). As "4 to 6-membered monocyclic non-aromatic heterocycle", a dihydropyridine ring may preferably be mentioned.

With reference to ring A, as the substituent of the "optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle" there may be mentioned from 1 to 3 substituents selected from (1) cyano, (2) halogen, (3) carboxy, (4 ) an optionally substituted hydroxy group, (5) an optionally substituted carbamoyl group, (6) an optionally substituted amino group, (7) an optionally substituted heterocyclic group, and (8) an optionally substituted hydrocarbon group, and (9) an oxo group.

[0089]

Referring to ring A, as "9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle" "optionally further substituted 9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle" may be mentioned 9-14 -membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle containing as ring-forming atoms from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to carbon atoms (for example, dihydrobenzofuran ring, dihydrobenzimidazole ring, dihydrobenzoxazole ring , dihydrobenzothiazole ring, dihydrobenzisothiazole ring, dihydronaphtho[2,3-b]thiophene ring, tetrahydroisoquinoline ring, tetrahydroquinoline ring, 4H-quinolysine ring, indoline ring, isoindoline ring, tetrahydrothieno[2,3-c]pi ridine ring, tetrahydrobenzazepine ring, tetrahydroquinoxaline ring, tetrahydrophenanthridine ring, hexahydrophenothiazine ring, hexahydrophenoxazine ring, tetrahydrophthalazine ring, tetrahydronaphthyridine ring, tetrahydroquinazoline ring, tetrahydrocinnoline ring, tetrahydrocarbazole ring, tetrahydro-β-carboline ring, tetrahydroacridine ring, tetrahydrophenazoline ring, tetrahydrophenazine ring ring). As "9-14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle", an isoindoline ring may preferably be mentioned.

With respect to ring A, as the substituent of the "optionally further substituted 9 to 14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle" there may be mentioned from 1 to 3 substituents selected from (1) cyano, (2) halogen, (3) a carboxy group, (4) an optionally substituted hydroxy group, (5) an optionally substituted carbamoyl group, (6) an optionally substituted amino group, (7) an optionally substituted heterocyclic group, and (8) an optionally substituted hydrocarbon group, and (9) an oxo group.

[0090]

As an "optionally substituted hydroxy group" which is a substituent of "optionally further substituted 4-6 membered monocyclic hydrocarbon heterocycle", "optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle", "optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle" or "optionally further substituted 9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle", C _1-6 alkoxy is preferred.

As an "optionally substituted carbamoyl group" which is a substituent of "optionally further substituted 4-6 membered monocyclic hydrocarbon heterocycle", "optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle", "optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle" or "optionally further substituted 9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle", mono- or di-C _1-6 alkylcarbamoyl group, mono- or di-C _3-10 cycloalkylcarbamoyl group is preferred. group, or C _6-14 arylcarbamoyl group, each of which is optionally substituted.

As an "optionally substituted heterocyclic group" which is a substituent of "optionally further substituted 4-6 membered monocyclic hydrocarbon heterocycle", "optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle", "optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle" or "optionally further substituted 9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle", a 5-14 membered aromatic heterocyclic group is preferred (e.g., pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl ) optionally substituted with 1-3 C _1-6 alkyl groups.

[0091]

Ring A is preferably

(1) an optionally further substituted benzene ring,

(2) an optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle,

(3) an optionally further substituted 4-6 membered monocyclic non-aromatic heterocycle, or

(4) optionally further substituted 9-14 membered fused polycyclic non-aromatic heterocycle.

[0092]

Ring A is more preferably

(1) a benzene ring optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) C _1-6 alkoxy groups (e.g. methoxy),

(c) a mono- or di-C _1-6 alkylcarbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from

(i) C _1-6 alkoxy groups (e.g. methoxy, ethoxy, t- butoxy),

(ii) C _3-10 cycloalkyl group (eg cyclopropyl, cyclopentyl),

(iii) a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl, tetrahydropyranyl),

(iv) a C _6-14 aryl group (eg phenyl) optionally substituted with 1-3 (preferably 1) hydroxy groups,

(v) C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl),

(vi) carboxy groups,

(vii) C _1-6 alkylthio groups (e.g. isopropylthio, t- butylthio),

(viii) a mono- or di-C _1-6 alkylcarbamoyl group (eg dimethylcarbamoyl, diethylcarbamoyl) and

(ix) a 3-14 membered non-aromatic heterocyclylcarbonyl group (e.g. pyrrolidin-1-ylcarbonyl),

(d) a mono- or di-C _3-10 cycloalkylcarbamoyl group (eg cyclopropylcarbamoyl),

(e) a C _6-14 arylcarbamoyl group (eg phenylcarbamoyl) optionally substituted with 1-3 (preferably 1) hydroxy groups, and

(f) a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (e.g. , methyl),

(2) A 5- or 6-membered monocyclic aromatic heterocycle (e.g., a pyridine ring) optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) C _1-6 alkoxy groups (eg methoxy) and

(b) a 5-14 membered aromatic heterocyclic group (eg pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl),

(3) a 4-6 membered monocyclic non-aromatic heterocycle (e.g. dihydropyridine ring) optionally further substituted with one oxo group, or

(4) 9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle (e.g., isoindoline ring) optionally further substituted with 1-3 (preferably 1 or 2) substituents selected from a C _1-6 alkyl group (e.g., methyl) and oxo groups.

[0093]

Ring A is even more preferably

(1) a benzene ring optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) C _1-6 alkoxy groups (e.g. methoxy),

(c) a mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl, ethylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from

(i) C _1-6 alkoxy groups (eg methoxy) and

(ii) a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl) and

(d) a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (e.g. , methyl),

(2) A 5- or 6-membered monocyclic aromatic heterocycle (e.g., a pyridine ring) optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) C _1-6 alkoxy groups (eg methoxy) and

(b) a 5-14 membered aromatic heterocyclic group (eg pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl), or

(3) 4-6 membered monocyclic non-aromatic heterocycle (eg dihydropyridine ring) optionally further substituted with one oxo group.

[0094]

Ring A is even more preferably

(1) a benzene ring further substituted with 1-3 (preferably 1 or 2) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) a mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl, ethylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from

(i) C _1-6 alkoxy groups (eg methoxy) and

(ii) a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl) and

(c) 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl, preferably pyrazolyl, triazolyl, imidazolyl) optionally substituted 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl), or

(2) 5- or 6-membered monocyclic aromatic heterocycle (e.g. pyridine ring) optionally further substituted with one 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl).

[0095]

According to a preferred embodiment of the present invention, ring A is

[0096]

[0097]

where R ^5A is a mono- or di-C _1-6 alkylcarbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from C _{1– 6} alkoxy (eg methoxy, ethoxy, t- butoxy) and 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl, tetrahydropyranyl);

X is CR ^6A or N; And

R ^6A represents a hydrogen atom or a halogen atom (for example, a fluorine atom).

[0098]

According to another preferred embodiment of the present invention, ring A is

[0099]

[0100]

where R ^5A is a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl);

X is CR ^6A or N; And

R ^6A represents a hydrogen atom or a halogen atom (for example, a fluorine atom).

[0101]

Each R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group.

Examples of the halogen atom for R ³ or R ⁴ include a fluorine atom, a chlorine atom and a bromine atom, and preferably a fluorine atom.

Preferably, each of R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkyl group or a C _1-6 alkoxy group, more preferably each independently represents a hydrogen atom, a halogen atom (for example, a fluorine atom ) or a C _1-6 alkyl group (eg, methyl), even more preferably each independently represents a hydrogen atom or a halogen atom (eg, a fluorine atom).

According to a preferred embodiment of the present invention, R ³ and R ⁴ are both hydrogen atoms, or one of R ³ and R ⁴ is a hydrogen atom and the other is a halogen atom (for example, a fluorine atom), or one of R ³ and R ⁴ is a hydrogen atom and the other is a C _1-6 alkyl group (eg methyl).

According to a more preferred embodiment of the present invention, R ³ and R ⁴ are both hydrogen atoms.

[0102]

As preferred embodiments of compound (I), the following compounds may be mentioned.

[Compound I–1]

Compound (I), in which

R ¹ is

(1) a 3-14 membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl) optionally substituted with 1-3 (preferably 1) hydroxy groups, or

(2) a C _3-10 cycloalkyl group (eg cyclobutyl, cyclopentyl, cyclohexyl) optionally substituted with 1-3 (preferably 1) substituents selected from hydroxy and a halogen atom (eg fluorine atom);

R ² represents a hydrogen atom or a C _1-6 alkyl group (eg methyl);

ring A represents

(1) a benzene ring optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) C _1-6 alkoxy groups (e.g. methoxy),

(c) a mono- or di-C _1-6 alkylcarbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from

(i) C _1-6 alkoxy groups (e.g. methoxy, ethoxy, t- butoxy),

(ii) C _3-10 cycloalkyl group (eg cyclopropyl, cyclopentyl),

(iii) a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl, tetrahydropyranyl),

(iv) a C _6-14 aryl group (eg phenyl) optionally substituted with 1-3 (preferably 1) hydroxy groups,

(v) C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl),

(vi) carboxy groups,

(vii) C _1-6 alkylthio groups (e.g. isopropylthio, t- butylthio),

(viii) a mono- or di-C _1-6 alkylcarbamoyl group (eg dimethylcarbamoyl, diethylcarbamoyl) and

(ix) a 3-14 membered non-aromatic heterocyclylcarbonyl group group (e.g. pyrrolidin-1-ylcarbonyl),

(d) a mono- or di-C _3-10 cycloalkylcarbamoyl group (eg cyclopropylcarbamoyl),

(e) a C _6-14 arylcarbamoyl group (eg phenylcarbamoyl) optionally substituted with 1-3 (preferably 1) hydroxy groups, and

(f) a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (e.g. , methyl),

(2) A 5- or 6-membered monocyclic aromatic heterocycle (e.g., a pyridine ring) optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) C _1-6 alkoxy groups (eg methoxy) and

(b) a 5-14 membered aromatic heterocyclic group (eg pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl),

(3) a 4-6 membered monocyclic non-aromatic heterocycle (e.g. a dihydropyridine ring) optionally further substituted with one oxo group, or

(4) 9-14 membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycle (e.g. isoindoline ring) optionally further substituted with 1-3 (preferably 1 or 2) substituents selected from a C _1-6 alkyl group (e.g. methyl) and oxo groups; And

each of R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom (eg, a fluorine atom), or a C _1-6 alkyl group (eg, methyl).

[0103]

[Compound I–2]

Compound (I), in which

R ¹ is

(1) a 3-14 membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl) optionally substituted with 1-3 (preferably 1) hydroxy groups, or

(2) a C _3-10 cycloalkyl group (eg cyclobutyl, cyclopentyl, cyclohexyl) optionally substituted with 1-3 (preferably 1) substituents selected from hydroxy and a halogen atom (eg fluorine atom);

R ² represents a hydrogen atom;

ring A represents

(1) a benzene ring optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) C _1-6 alkoxy groups (e.g. methoxy),

(c) a mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl) and

(d) a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (e.g. methyl ),

(2) A 5- or 6-membered monocyclic aromatic heterocycle (e.g., a pyridine ring) optionally further substituted with 1-3 (preferably 1 or 2, more preferably 1) substituents selected from

(a) C _1-6 alkoxy groups (eg methoxy) and

(b) a 5-14 membered aromatic heterocyclic group (eg pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl), or

(3) a 4-6 membered monocyclic non-aromatic heterocycle (eg dihydropyridine ring) optionally further substituted with one oxo group; And

each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom (eg, a fluorine atom).

[0104]

[Compound I–3]

Compound (I), in which

R ¹ is

(1) a 3-14 membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl) substituted with one hydroxyl group, or

(2) a C _3-10 cycloalkyl group (eg cyclohexyl) substituted with 1-3 (preferably 1) substituents selected from hydroxy or a halogen atom (eg fluorine atom);

R ² represents a hydrogen atom;

ring A represents

(1) a benzene ring further substituted with 1-3 (preferably 1 or 2) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) a mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl, ethylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from

(i) C _1-6 alkoxy groups (eg methoxy) and

(ii) a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl), and

(c) a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (e.g. , methyl), or

(2) 5- or 6-membered monocyclic aromatic heterocycle (e.g. pyridine ring) further substituted with one 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl); And

each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom (eg, a fluorine atom).

[0105]

[Compound I–4]

Compound (I), in which

R ¹ is a 3-14 membered non-aromatic heterocyclic group (eg tetrahydropyranyl) substituted with one hydroxy group;

R ² represents a hydrogen atom;

ring A represents

(1) a benzene ring further substituted with 1-3 (preferably 1 or 2) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) a mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl, ethylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from

(i) C _1-6 alkoxy groups (eg methoxy) and

(ii) a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl), and

(c) a 5-14 membered aromatic heterocyclic group (eg pyrazolyl, triazolyl, imidazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl), or

(2) 5- or 6-membered monocyclic aromatic heterocycle (e.g. pyridine ring) further substituted with one 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl); And

each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom (eg, a fluorine atom).

[0106]

[Compound I–5]

Compound (I), in which

R ¹ is a 3-14 membered non-aromatic heterocyclic group (eg tetrahydropyranyl) substituted with one hydroxy group;

R ² represents a hydrogen atom;

ring A is a benzene ring further substituted with 1-3 (preferably 1 or 2) substituents selected from

(a) a halogen atom (for example, a fluorine atom),

(b) a mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from a 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl), and

(c) a 5-14 membered aromatic heterocyclic group (eg triazolyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl); And

each of R ³ and R ⁴ represents a hydrogen atom.

[0107]

[Compound I–6]

Compound (I), in which

R ¹ is a 3-14 membered non-aromatic heterocyclic group (eg tetrahydropyranyl) substituted with one hydroxy group;

R ² represents a hydrogen atom;

ring A represents

[0108]

[0109]

where R ^5A is a mono- or di-C _1-6 alkylcarbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl) optionally substituted with 1 or 2 (preferably 1) substituents selected from C _{1– 6} alkoxy (eg methoxy, ethoxy, t- butoxy) and 3-14 membered non-aromatic heterocyclic group (eg tetrahydrofuranyl, tetrahydropyranyl);

X is CR ^6A or N; And

R ^6A represents a hydrogen atom or a halogen atom (for example, a fluorine atom); And

each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom (eg, a fluorine atom).

[0110]

[Compound I–7]

Compound (I), in which

R ¹ is a 3-14 membered non-aromatic heterocyclic group (eg tetrahydropyranyl) substituted with one hydroxy group;

R ² represents a hydrogen atom;

ring A represents

[0111]

[0112]

where R ^5A is a 5-14 membered aromatic heterocyclic group (e.g. pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionally substituted with 1-3 (preferably 1 or 2, more preferably 1) C _1-6 alkyl groups (eg methyl);

X is CR ^6A or N; And

R ^6A represents a hydrogen atom or a halogen atom (for example, a fluorine atom); And

each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom (eg, a fluorine atom).

[0113]

Specific preferred examples of the compound represented by formula (I) include the compounds of Examples 1-113.

[0114]

When the compound (I) is in the form of a salt, examples of such a salt include salts of an inorganic base, ammonium salt, salts of an organic base, salts of an inorganic acid, salts of an organic acid, salts of a basic or acidic amino acid, etc.

[0115]

Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt, etc.; aluminum salt, etc.

[0116]

Preferred examples of the organic base salt include salts of trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.

[0117]

Preferred examples of the inorganic acid salt include salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0118]

Preferred examples of the organic acid salt include salts of formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, para -toluenesulfonic acid, etc.

[0119]

Preferred examples of the basic amino acid salt include salts of arginine, lysine, ornithine, etc.

[0120]

Preferred examples of the acidic amino acid salt include salts of aspartic acid, glutamic acid, etc.

[0121]

Among these salts, a pharmaceutically acceptable salt is preferred. If the compound contains a basic functional group, examples of its preferred pharmaceutically acceptable salt include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and organic acid salts such as such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, para -toluenesulfonic acid, etc. In addition, if the compound contains an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt , magnesium salt, barium salt, etc.), etc., ammonium salt, etc.

[0122]

The compound (I) may be a crystalline form, and both a single crystalline form and a mixture of crystalline forms are covered by the compound (I).

Compound (I) may be a pharmaceutically acceptable co-crystal or salt of the co-crystal. In this document, co-crystal or co-crystal salt means a crystalline substance composed of two or more specific substances that are solids at room temperature and each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability, etc.). The co-crystal and co-crystal salt can be obtained according to the co-crystallization method known per se .

Compound (I) encompasses solvates (eg, hydrate) and non-solvates within its scope. Compound (I) may be a compound labeled or substituted with an isotope (eg ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I). The compound labeled or substituted with an isotope can be used, for example, as a marker (PET marker) used in positron emission tomography (PET), and applicable in the field of medical diagnosis, etc.

[0123]

If the compound (I) of the present invention contains an asymmetric center, then isomers such as enantiomer, diastereoisomer, etc. may be present. Such isomers and mixtures thereof are also within the scope of the present invention. If the isomer is formed due to conformation or tautomerism, then such isomers and their mixture are covered by the compound (I) according to the present invention.

[0124]

Next, a method for producing the compound of the present invention will be explained.

[0125]

Each of the starting materials and reagents used in each step in the subsequent production process and the resulting compounds can form a salt. Examples of the salt include salts similar to the aforementioned salts of the compound of the present invention, and so on.

[0126]

If the compound obtained in each step is in free base form, then it can be converted to the desired salt according to a method known per se . Conversely, if the compound obtained in each step is a salt, then it can be converted to the free base form or other desired salt form in accordance with a method known per se .

[0127]

The compound obtained in each step can also be used in the subsequent reaction, either directly as a reaction solution containing it, or after obtaining its crude product. Alternatively, the compound obtained in each step can be isolated and purified from the reaction mixture according to separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. according to the traditional way.

[0128]

If the starting materials and reagents used in each step are commercially available, then commercially available products can be used as received.

[0129]

In the reaction in each step, although the reaction time varies depending on the kind of reagents and solvents to be used, it is generally 1 minute to 48 hours, preferably 10 minutes to 8 hours, unless otherwise indicated.

[0130]

In the reaction in each step, although the reaction temperature varies depending on the kind of reagents and solvents to be used, it is generally -78°C to 300°C, preferably -78°C to 150°C, unless otherwise indicated.

[0131]

In the reaction at each stage, although the pressure varies depending on the kind of reagents and solvents to be used, it is generally from 1 atm to 20 atm, preferably from 1 atm to 3 atm, unless otherwise indicated.

[0132]

In the reaction at each stage, for example, microwave reactors such as Biotage's Initiator, etc. can sometimes be used. Although the reaction temperature varies depending on the reagents and solvents to be used, it is generally from room temperature to 300°C, preferably from 50°C to 250°C, unless otherwise indicated. Although the reaction time varies depending on the reagents and solvents to be used, it is generally from 1 minute to 48 hours, preferably from 1 minute to 8 hours, unless otherwise indicated.

[0133]

In the reaction in each step, the reagent is used in an amount of 0.5 equivalents to 20 equivalents, preferably 0.8 equivalents to 5 equivalents, relative to the substrate, unless otherwise indicated. If the reagent is used as a catalyst, then the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. If a reagent is used as a reaction solvent, then the reagent is used in the volume of the solvent.

[0134]

Unless otherwise indicated, the reaction in each step is carried out without solvent, or by dissolving or suspending the starting material in a suitable solvent. Examples of the solvent include the solvents described in the Examples and the following solvents:

alcohols: methanol, ethanol, tert- butyl alcohol, 2-methoxyethanol, etc.;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.;

aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.;

saturated hydrocarbons: cyclohexane, hexane, etc.;

amides: N, N-dimethylformamide, N-methylpyrrolidone, etc.;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

nitriles: acetonitrile, etc.;

sulfoxides: dimethyl sulfoxide, etc.;

aromatic organic bases: pyridine, etc.;

acid anhydrides: acetic anhydride, etc.;

organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;

inorganic acids: hydrochloric acid, sulfuric acid, etc.;

esters: ethyl acetate, etc.;

ketones: acetone, methyl ethyl ketone, etc.;

water.

The solvents mentioned above may be used in a mixture of two or more kinds in the appropriate ratio.

[0135]

If a base is used for the reaction in each step, then, for example, the bases below and the bases described in the Examples are used:

inorganic bases: sodium hydroxide, magnesium hydroxide, etc.;

organic bases: sodium carbonate, calcium carbonate, sodium bicarbonate, etc.;

organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.;

metal alkoxides: sodium ethoxide, potassium tert- butoxide, etc.;

alkali metal hydrides: sodium hydride, etc.;

metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.;

lithium-organic compounds: n -butyllithium, etc.

[0136]

If an acid or an acid catalyst is used for the reaction in each step, then, for example, the acids or acid catalysts listed below or those described in the Examples are used:

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;

organic acids: acetic acid, trifluoroacetic acid, citric acid, para -toluenesulfonic acid, 10-camphorsulfonic acid, etc.;

Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0137]

Unless otherwise indicated, the reaction of each step is carried out according to the method known per se , for example, the methods described in Jikken Kagaku Kouza 5th edition, vol. 13-vol. 19 (The Chemical Society of Japan ed.); Shinjikken Kagaku Kouza (Courses in Experimental Chemistry), vol. 14-vol. 15 (The Chemical Society of Japan ed.); Fine Organic Chemistry rev. 2nd edition (LF Tietze, Th. Eicher, NANKODO); rev. Organic Name Reactions, Their Mechanism and Essence (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I–VII (John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory, A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1 - Vol. 14 (Elsevier Japan KK); Strategic Applications of Named Reactions in Organic Synthesis (translation supervisor Kiyoshi Tomioka, KAGAKUDOJIN); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, etc., or by the methods described in the Examples.

[0138]

At each step, the reaction of protection and deprotection of the functional group is carried out in accordance with the method known per se , for example, the methods described in "Protective Groups in Organic Synthesis, 4 ^th Ed", Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups ^3rd Ed.” Thieme, 2004 (PJ Kocienski), etc., or by the methods described in the Examples.

Examples of a protecting group for an alcohol hydroxyl group, etc., and a phenol hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t- butyldimethylsilyl ether, tetrahydropyranyl ether, etc.; carboxylate-type protecting groups such as acetic acid ester, etc.; sulfonic acid ester type protecting groups such as methanesulfonic acid ester, etc.; carbonate-type protecting groups such as tert- butyl carbonate, etc., etc.

Examples of a protecting group for an aldehyde carbonyl group include acetal-type protecting groups such as dimethyl acetal, etc.; cyclic acetal-type protecting groups such as 1,3-dioxane, etc., etc.

Examples of the protecting group for the carbonyl group of a ketone include ketal-type protecting groups such as dimethylketal, etc.; cyclic ketal protecting groups such as 1,3-dioxane, etc.; oxime-type protecting groups such as O-methyloxime, etc.; hydrazone-type protecting groups such as N, N-dimethylhydrazone, etc., etc.

Examples of a protecting group for a carboxyl group include ester-type protecting groups such as methyl ester, etc.; amide-type protecting groups such as N, N-dimethylamide, etc., etc.

Examples of a protecting group for a thiol include ether-type protecting groups such as benzylthioether, etc.; ester type protecting groups such as thioacetic acid ester, thiocarbonate, thiocarbamate, etc., etc.

Examples of a protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole, etc. include carbamate-type protecting groups such as benzyl carbamate, etc.; amide type protecting groups such as acetamide, etc.; alkylamine-type protecting groups such as N-triphenylmethylamine, etc., sulfonamide-type protecting groups such as methanesulfonamide, etc., etc.

The protecting groups can be removed according to a method known per se , for example by using an acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide ), etc., recovery method, etc.

[0139]

If a reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride, etc. .d.; boranes such as the borane-tetrahydrofuran complex, etc.; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane, etc. If a carbon–carbon double bond or triple bond is reduced, then a method using a catalyst such as palladium carbon, Lindlar's catalyst, etc. is used.

[0140]

If an oxidation reaction is carried out in each step, examples of an oxidizing agent to be used include peroxy acids such as meta -chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, t- butyl hydroperoxide, etc.; perchlorates such as tetrabutylammonium perchlorate, etc.; chlorates such as sodium chlorate, etc.; chlorites such as sodium chlorite, etc.; periodates such as sodium periodate, etc.; hypervalent iodine reagents such as iodosylbenzene, etc.; manganese-containing reagents such as manganese dioxide, potassium permanganate, etc.; lead-containing reagents such as lead tetraacetate, etc.; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent, etc.; halogen-containing compounds such as N-bromosuccinimide (NBS), etc.; oxygen; ozone; complex of sulfur trioxide and pyridine; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc.

[0141]

If a radical cyclization reaction is carried out in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN), etc.; water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), etc.; triethylboron in the presence of boron or oxygen; benzoyl peroxide, etc. In addition, examples of the radical reagent to be used include tributylstannan, tristrimethylsilylstannan, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0142]

If a Wittig reaction is carried out in each step, examples of the Wittig reagent to be used include alkylidenephosphoranes, etc. Alkylidene phosphoranes can be prepared according to a method known per se , for example by reacting a phosphonium salt with a strong base.

[0143]

If a Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetic acid esters such as methyldimethylphosphonoacetate, ethyldiethylphosphonoacetate, etc.; and bases such as alkali metal hydrides, organolithium compounds, etc.

[0144]

If a Friedel-Crafts reaction is carried out in each step, examples of a reagent to be used include a combination of Lewis acid and acid chloride, a combination of Lewis acid and an alkylating agent (eg, alkyl halide, alcohol, olefins, etc.). Alternatively, an organic acid or an inorganic acid may also be used in place of Lewis acid, and an anhydride such as acetic anhydride, etc. may also be used in place of an acid chloride.

[0145]

If an aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (eg amines, imidazole, etc.) and a base (eg organic bases, etc.) are used as reagents.

[0146]

If the nucleophilic addition reaction of a carboanion, the nucleophilic 1,4-addition (Michael addition reaction) of a carboanion, or the nucleophilic substitution reaction of a carboanion are carried out in each step, examples of the base to be used to generate the carboanion include organolithium compounds, metal alkoxides, inorganic bases, organic bases, etc.

[0147]

If a Grignard reaction is carried out in each step, examples of the Grignard reagent to be used include aryl magnesium halides such as phenyl magnesium bromide, etc.; and alkyl magnesium halides such as ethyl magnesium bromide, etc. The Grignard reagent can be prepared according to a method known per se , for example by reacting an alkyl halide or an aryl halide with magnesium metal in ether or tetrahydrofuran as solvent.

[0148]

If a Knoevenagel condensation reaction is carried out in each step, the reactants used are a compound with an activated methylene group between two electron withdrawing groups (e.g. malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g. organic bases, metal alkoxides, inorganic bases).

[0149]

If the Vilsmeier-Haack reaction is carried out at each stage, then phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0150]

If an azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating reagent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, for the alcohol azidation reaction, the method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), the method using trimethylsilyl azide and Lewis acid, etc. is used.

[0151]

If a reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. If the substrate is an amine compound, examples of the carbonyl compound to be used in addition to paraformaldehyde include aldehydes such as acetaldehyde, etc., and ketones, such as cyclohexanone, etc. If the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine, etc.; secondary amines such as dimethylamine, etc., etc.

[0152]

If a Mitsunobu reaction is carried out in each step, azodicarboxylates (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as the reactant.

[0153]

If an esterification reaction, an amidation reaction or a urea reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chloride, acid bromide, etc.; and activated carboxylic acids such as anhydride, activated ester, sulfuric acid ester, etc. Examples of the carboxylic acid activator reagent include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD), etc.; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n -hydrate (DMT-MM), etc.; carbonate-condensing agents such as 1,1-carbonyldiimidazole (CDI), etc.; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukayama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate, etc.; O–(7–azabenzotriazol–1–yl)–N, N,N',N'–tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; their combinations, etc. If a carbodiimide condensing agent is used, then an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), etc. can be added to the reaction system.

[0154]

If a coupling reaction is carried out in each step, examples of the metal-containing catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, etc.; nickel compounds such as tetrakis(triphenylphosphine)nickel(0), etc.; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride, etc.; cobalt compounds; copper compounds such as copper oxide, copper (I) iodide, etc.; platinum compounds, etc. A base may be further added to the reaction system, and examples thereof include inorganic bases, etc.

[0155]

If a thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is usually used as the thiocarbonylating agent. If a thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is usually used as the thiocarbonylating agent. In addition to phosphorus pentasulfide, a reagent having the structure 1,3,2,4-dithiadiphosphetane-2,4-disulfide, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane can also be used. -2,4-disulfide (Lavesson's reagent), etc.

[0156]

If the Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. In addition, the reaction can be accelerated by exposing the reaction system to heat, light, radical initiators such as benzoyl peroxide, azobisisobutyronitrile, etc.

[0157]

If a hydroxy group halogenation reaction is carried out in each step, examples of the halogenating reagent to be used include a hydrohalic acid halide and an inorganic acid halide; in particular hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. for chlorination, 48% hydrobromic acid, etc. for bromination. In addition, a method for producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc., can be used. Alternatively, a two-step process for producing an alkyl halide can also be used, comprising converting an alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride, or sodium iodide.

[0158]

If an Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate, etc.; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite, etc.

[0159]

If a sulfonate esterification reaction is carried out in each step, examples of the sulfonating reagent to be used include methanesulfonyl chloride, p -toluenesulfonyl chloride, methanesulfonic anhydride, p -toluenesulfonic anhydride, etc.

[0160]

If a hydrolysis reaction is carried out at each stage, then an acid or a base is used as a reagent. In addition, if the acid hydrolysis reaction of tert-butyl ester is carried out, formic acid, triethylsilane, etc. are sometimes added to reductively intercept the tert-butyl cation that is obtained as a by-product.

[0161]

If a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, etc.

[0162]

Compound (I) can be obtained by the method shown in the following schemes, or by a similar method, or by the method described in the Examples.

Compound (IA) can be obtained from compound (1) according to the following method.

[0163]

[0164]

In the reaction formulas, each of R ⁵ and R ⁶ is a C _1-6 alkyl group, each of R ⁷ and R ¹⁰ is a halogen atom, R ⁸ is an optionally substituted C _1-6 alkyl group, R ⁹ is a cyano group , an optionally substituted C _1-6 alkyl group or an optionally substituted C _1-6 alkoxy group, R ¹¹ is a hydrogen atom, a cyano group, an optionally substituted C _1-6 alkyl group or an optionally substituted C _1-6 alkoxy group, TMS is a trimethylsilyl group, and R ¹ , R ³ , R ⁴ and ring A are defined above.

Compound (2) can be obtained by deprotecting R ⁵ , which is the protecting group of the hydroxyl group of compound (1).

Compound (3) can be obtained by halogenating compound (2) with a halogenating agent such as bromine, iodine, etc.

Compound (4) can be synthesized by the Sonogashira coupling reaction of compound (3) and trimethylsilylacetylene in the presence of a metal-containing catalyst and an organic base. As a metal-containing catalyst, palladium compounds such as tetrakis(triphenylphosphine)palladium (0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, etc., and copper compounds can be used in combination, such as copper(I) iodide, etc. As the organic base, triethylamine and diethylamine, etc., may be mentioned.

Compound (5) can be obtained by desilylation reaction of compound (4) with a fluoride ion such as potassium fluoride, tetra- n -butylammonium fluoride, etc., or by desilylation reaction of compound (4) under basic conditions such as potassium carbonate, etc., or under acidic conditions such as hydrochloric acid, etc.

Compound (6) can be obtained by the coupling reaction of compound (5) and bis(pinacolato)diboron in the presence of a metal-containing catalyst.

Compound (7) can be obtained by halogenation of compound (4) with N-iodosuccinimide. Fluoride such as potassium fluoride, etc. may be added to the reaction system.

Compound (10) can be obtained by the coupling reaction of compound (7) and compound (8), compound (9), or zinc cyanide in the presence of a metal-containing catalyst.

Compound (11) can be obtained by the coupling reaction of compound (10) and bis(pinacolato)diboron in the presence of a metal-containing catalyst.

Compound (13) can be obtained by the coupling reaction of compound (6) or compound (11) and compound (12) in the presence of a metal-containing catalyst.

Compound (14) can be obtained by hydrolysis of compound (13).

Compound (IA) can be obtained by an amidation reaction of compound (14) and compound (15).

[0165]

Compound (13) in the above scheme can also be obtained from compound (16) in the following way.

[0166]

[0167]

In the reaction formulas, R ¹² represents a halogen atom, and the meanings of R ³ , R ⁴ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ and ring A are as defined above.

Compound (17) can be obtained by halogenating compound (16) with a halogenating agent such as bromine, iodine, etc.

Compound (18) can be obtained by esterification of compound (17).

Compound (19) can be prepared by Sonogashira coupling of compound (18) and trimethylsilylacetylene in the presence of a metal-containing catalyst and an organic base. As a metal-containing catalyst, palladium compounds such as tetrakis(triphenylphosphine)palladium (0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, etc., and copper compounds can be used in combination, such as copper(I) iodide, etc. As the organic base, triethylamine, diethylamine, etc. can be mentioned.

Compound (20) can be obtained via the activation reaction of the C–H bond of compound (19) in the presence of a metal-containing catalyst. As a metal-containing catalyst, iridium compounds such as bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I), bis(1,5-cyclooctadiene)diiridium (I) dichloride, etc. can be mentioned. , which can be used together with a ligand such as 2,2'-bipyridine, 4,4'-di -tert -butyl-2,2'-pipyridine, etc. for reaction purposes.

Compound (21) can be obtained by the coupling reaction of compound (20) and compound (12) in the presence of a metal-containing catalyst.

Compound (23) can be obtained by halogenating compound (21) with a halogenating agent such as N-iodosuccinimide, NBS, NCS, etc. A fluoride such as potassium fluoride, etc. may be added to the reaction system.

Compound (22) can be obtained by desilylation reaction of compound (21) with a fluoride ion such as potassium fluoride, tetra- n -butylammonium fluoride, etc., or by desilylation reaction of compound (21) under basic conditions such as potassium carbonate, etc., or under acidic conditions such as hydrochloric acid, etc., or through the coupling reaction of compound (23) and compound (8), compound (9) or zinc cyanide in the presence of metal– containing a catalyst.

[0168]

Compound (IB) can be obtained from compound (23) by the following method.

[0169]

[0170]

In the reaction formulas, the meanings of R ¹ , R ³ , R ⁴ , R ⁶ , R ¹² and ring A are as defined above.

Compound (24) can be obtained by hydrolysis of compound (23).

Compound (IB) can be obtained by an amidation reaction of compound (24) and compound (15).

[0171]

Compound (I') can be obtained from compound (25) by the following method.

[0172]

[0173]

In the reaction formulas, the meanings of R ¹ , R ² , R ³ , R ⁴ , R ⁶ and ring A are as defined above.

Compound (26) can be produced by a reduction reaction of compound (25).

Compound (27) can be obtained by hydrolysis of compound (26).

Compound (I') can be obtained by an amidation reaction of compound (27) and compound (15).

[0174]

Compound (26) in the above scheme can also be obtained from compound (28) in the following way.

[0175]

[0176]

In the reaction formulas, the meanings of R ² , R ³ , R ⁴ , R ⁶ , R ⁹ , R ¹⁰ and ring A are as defined above.

Compound (29) can be produced by a reduction reaction of compound (28).

Compound (30) can be obtained via the activation reaction of the C–H bond of compound (29) in the presence of a metal-containing catalyst. As a metal-containing catalyst, iridium compounds such as bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I), bis(1,5-cyclooctadiene)diiridium (I) dichloride, etc. can be mentioned. , which can be used together with a ligand such as 2,2'-bipyridine, 4,4'-di -tert -butyl-2,2'-pipyridine, etc. for reaction purposes. In addition, compound (30) can also be obtained by reduction reaction of compound (6) or compound (11).

Compound (26) can be obtained by a coupling reaction of compound (30) and compound (12) in the presence of a metal-containing catalyst.

[0177]

Compound (II), which is a compound (IA) in which one of R ³ and R ⁴ is a fluorine atom and the other is a hydrogen atom, can be synthesized from compound (31) which is a compound ( 13) or compound (23), in which each of R ³ and R ⁴ represents a hydrogen atom.

[0178]

[0179]

In the reaction formulas, the meanings of R ¹ , R ² , R ⁶ and ring A are as defined above.

Compound (32) can be obtained by a Wohl-Ziegler reaction of compound (31) followed by hydrolysis using acetone/water.

Compound (33) can be obtained by fluorination of the hydroxy group of compound (32). As the fluorinating agent, (diethylamino)sulfur trifluoride, etc. can be mentioned.

Compound (34) can be obtained by hydrolysis of compound (33).

Compound (II) can be obtained by an amidation reaction of compound (34) and compound (15).

[0180]

Compounds (III) and (III') can be obtained from compound (32) by the following method.

[0181]

[0182]

In the reaction formulas, R ¹³ is an optionally substituted C _1-6 alkyl group, R ¹⁴ is a halogen atom, and R ¹ , R ² , R ⁶ and the A ring are as defined above.

Compound (35) can be obtained by hydrolysis of compound (32).

Compound (III) can be obtained by an amidation reaction of compound (35) and compound (15).

Compound (37) can be obtained by alkylating compound (32) with an alkyl halide (36).

Compound (38) can be obtained by hydrolysis of compound (37).

Compound (III') can be obtained by amidation reaction of compound (38) and compound (15).

[0183]

Among the compounds (I), the compound (IV) in which ring A contains an optionally substituted carbamoyl group can be obtained from compound (6), compound (11) or compound (30) by the following method.

[0184]

[0185]

In the reaction formulas, X is CR ^6A or N, each of R ¹⁴ and R ¹⁵ independently represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group, R ¹⁶ is a protective a carboxyl group, R ¹⁷ is, and R ¹ , R ² , R ⁶ , R ¹⁰ and R ^6A are as defined above.

Compound (40) can be obtained by the coupling reaction of compound (6), compound (11), or compound (30) and compound (39) in the presence of a metal-containing catalyst.

Compound (41) can be obtained by hydrolysis of compound (40).

Compound (42) can be obtained by an amidation reaction of compound (41) and compound (15).

Compound (43) can be obtained by hydrolysis of compound (42).

Compound (IV) can be obtained by an amidation reaction of compound (43) and compound (44).

[0186]

Among compounds (I), compound (V) and compound (V') in which R ³ and R ⁴ each is a C _1-6 alkyl group and the other is a hydrogen atom, and ring A contains an optionally substituted carbamoyl group , can be obtained from compound (6) or compound (11) in the following way.

[0187]

[0188]

In the reaction formulas, R ¹⁸ is a C _1–6 alkyl group, P is a phenolic hydroxyl protecting group, Tf is a trifluoromethylsulfonyl group, TMS is a trimethylsilyl group, and the values X, R ¹ , R ² , R ⁶ , R ¹⁴ , R ¹⁵ and R ¹⁷ as defined above.

Compound (46) can be prepared by combining compound (6) or compound (11) and compound (45) in the presence of p -toluenesulfonyl hydrazide and an inorganic base according to the method described in the literature - Tetrahedron, 73, 785–793 (2017 ). As the inorganic base, potassium carbonate, potassium phosphate, etc. can be mentioned.

Compound (47) can be obtained by deprotecting compound (46).

Compound (48) can be obtained by preparing a sulfonic ester of compound (47) using trifluoromethanesulfonic anhydride.

Compound (49) can be obtained by the reaction of incorporation of carbon monoxide into compound (48) in the presence of 2-(trimethylsilyl)ethanol, carbon monoxide, base, and a metal-containing catalyst.

Compound (50) can be obtained by deprotecting compound (49).

Compound (51) can be obtained by an amidation reaction of compound (50) and compound (44).

Compound (52) can be obtained by hydrolysis of compound (51).

Compound (V) can be obtained by an amidation reaction of compound (52) and compound (15).

Compound (53) can be produced by a reduction reaction of compound (51).

Compound (54) can be obtained by hydrolysis of compound (53).

Compound (V') can be obtained by an amidation reaction of compound (54) and compound (15).

[0189]

Compound (1), Compound (8), Compound (9), Compound (12), Compound (15), Compound (16), Compound (28), Compound (39), Compound (44), Compound (45), alkyl halide (36), zinc cyanide, trimethylsilylacetylene, bis(pinacolato)diboron, para -toluenesulfonylhydrazide and 2-(trimethylsilyl)ethanol used as starting materials for the preparation of compounds (IA), (IB), (I'), (II ), (III), (III'), (IV), (V) and (V'), may be commercially available products or may be prepared according to a method known per se .

[0190]

If the compound (I) has an optical isomer, a stereoisomer, a regioisomer or a rotamer, then these are also covered by the compound (I), and can be obtained as a separate product in accordance with the synthesis method and the separation method known per se . For example, if compound (I) contains an optical isomer, then the optical isomer separated from the compound is also covered by compound (I).

[0191]

The optical isomer can be obtained according to a method known per se . More specifically, the optical isomer is obtained using an optically active synthetic intermediate, or by subjecting the racemic end product to optical resolution using a known method.

[0192]

For example, the optical resolution method may be a method known per se , such as a fractional recrystallization method, a chiral column method, a diastereoisomer resolution method, and so on.

1) Fractional recrystallization method

Method by which a racemate salt of an optically active compound (e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-l-phenethylamine, ( -)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), which is separated by fractional recrystallization, with a neutralization step if desired, to obtain a pure optical isomer.

[0193]

2) Method using a chiral column

A method in which a racemate or a salt thereof is applied to a column (chiral column) to separate the optical isomer for separation. In the case of liquid chromatography, for example, a mixture of optical isomers is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.), etc., and developed using water, various buffers (eg phosphate buffer, etc.) and organic solvents (eg ethanol, methanol, 2-propanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as eluent, singly or in mixture, with separation of the optical isomer.

[0194]

3) Method of cleavage through diastereoisomers

A method in which a racemic mixture is converted by chemical reaction with an optically active reagent into a diastereomeric mixture, which is converted to a single substance by standard separation methods (for example, fractional recrystallization, chromatography, etc.), etc., and subjected to chemical treatment such as a hydrolysis reaction, etc., to separate the optically active reagent moiety, thereby obtaining an optical isomer. For example, if the compound (I) contains a hydroxy group or a primary or secondary amino group in the molecule, then the compound and an optically active organic acid (for example, MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid], (-)-methoxyacetic acid, etc.), etc. subjected to a condensation reaction to give diastereoisomers of an ester compound or an amide compound, respectively. If the compound (I) contains a carboxy group, then this compound and an optically active amine or an optically active alcohol are subjected to a condensation reaction to obtain diastereoisomers of an amide compound or an ester compound, respectively. The separated diastereoisomer is converted to the optical isomer of the parent compound by acid hydrolysis or alkaline hydrolysis.

[0195]

If the compound (I) is obtained as a free base, then the compound can be converted to the desired salt according to a method known per se or a similar method. Conversely, if the compound is obtained as a salt, then the salt of the compound may be converted to the free base or other desired salt in a manner known per se or in a similar manner.

[0196]

Compound (I) may be a prodrug, and a prodrug of compound (I) refers to a compound that is converted to compound (I) by interaction with an enzyme, gastric juice, etc., under physiological conditions in vivo , that is, a compound , which undergoes enzymatic oxidation, reduction, hydrolysis, etc. with conversion to a compound (I), and a compound that undergoes a hydrolysis reaction, etc. under the influence of gastric juice, etc. with conversion to compound (I).

[0197]

Examples of a prodrug of compound (I) include a compound obtained by attacking the amino group of compound (I) by acylation, alkylation, or phosphorylation (for example, a compound obtained by attacking the amino group of compound (I) by eicosanoylation, alanylation, pentylaminocarbonylation, (5– methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation, tert -butylation, etc.); a compound obtained by attacking the hydroxy group of compound (I) by acylation, alkylation, phosphorylation or boronation (for example, a compound obtained by attacking the hydroxy group of compound (I) by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation, etc.); a compound obtained by treating the carboxyl group of compound (I) by esterification or amidation (for example, a compound obtained by treating the carboxyl group of compound (I) by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl– esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterification, cyclohexyloxycarbonylethyl-esterification or methylamidation, etc.), etc.) etc. Any of these compounds can be obtained from the compound (I) in accordance with the method known per se .

The prodrug of compound (I) can also be a compound that is converted to compound (I) under physiological conditions, as described in “IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p. 163–198, Published by HIROKAWA SHOTEN (1990).

[0198]

Compound (I) can be used for the prevention or treatment of diseases, for example,

(1) constipation, such as neurogenic constipation (constipation associated with diseases such as Parkinson's disease, multiple sclerosis, spinal cord injury, Alzheimer's disease, Hirschsprung's syndrome, Chagas' disease, etc.), idiopathic constipation, functional constipation, atonic constipation , irritable bowel syndrome with constipation, constipation possibly complicated by another disease (Parkinson's disease, spinal cord injury, multiple sclerosis, etc.), age-related constipation, constipation induced by various drugs (constipation induced by opioid agonists, etc. ), primary chronic constipation, drug-induced constipation (opioids, anticholinergics, calcium antagonists, anticancer agents, heavy metal poisoning, etc.), constipation associated with underlying diseases such as endocrine diseases or metabolic abnormalities (hypopituitarism, hypothyroidism , pheochromocytoma, etc.), diseases of muscle abnormalities (hereditary atro visceral skeletal muscles, scleroderma, amyloidosis, progressive systemic sclerosis, etc.), metabolic diseases (diabetes, porphyria, uremia, hypokalemia, hypercalcemia, etc.), etc.,

(2) diseases of the digestive tract [for example, gastric ulcers, ulcers of the small intestine, gastric hypomotility such as gastroparalysis, etc., postoperative gastrointestinal paralysis, upper gastrointestinal motility disorder and discomfort, nausea, vomiting, erosive esophagitis, gastrointestinal disorder induced by anti-inflammatory drugs (non-steroidal anti-inflammatory drugs), irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress gastrointestinal disorder, diarrhea, postoperative ileus],

(3) psychiatric disorders [eg, depression, major depression, bipolar depression, dysthymic disorder, emotional disorder (seasonal affective disorder, etc.), recurrent depression, postpartum depression, stress disorder, depressive symptom, mania, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessional disorder, post-traumatic stress disorder, post-traumatic stress disorder, Tourette syndrome, autism, autism spectrum syndrome, fragile X syndrome, Rett syndrome, adjustment disorders, bipolar disorder, neurosis, schizophrenia (eg, positive symptom, negative symptom, and cognitive impairment), schizophrenia-associated cognitive impairment, chronic fatigue syndrome, anxiety neurosis, compulsive neurosis, epilepsy, anxiety symptom, mental anxiety, emotional anomaly, c iclothymia, erethism nervosa, unconsciousness, addiction, low libido, attention deficit hyperactivity disorder (ADHD), psychotic major depression, intractable major depression, treatment-resistant depression],

(4) neurodegenerative diseases [eg, Alzheimer's disease, Alzheimer's disease-type senile dementia, Parkinson's disease, Parkinson's disease dementia, Huntington's disease, multi-infarct dementia, frontotemporal dementia, Parkinson's disease-type frontotemporal dementia, progressive supranuclear palsy, Pick's syndrome, Niemann's syndrome— Peak, corticobasal degeneration, Down's syndrome, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy, multiple sclerosis] ,

(5) age-related cognitive and memory impairment [eg, age-related memory impairment, senile dementia],

(6) sleep disorders [eg, congenital sleep disorders (eg, psychophysiological insomnia, etc.), acquired sleep disorder, circadian rhythm disorders (eg, jet lag, shift work sleep disorders, irregular sleep patterns –wakefulness, delayed sleep phase syndrome, prolonged sleep phase syndrome, non-24-hour sleep-wake, etc.), parasomnias, sleep disorders associated with an internal medical or psychiatric disorder (for example, chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, anxiety neurosis), stress insomnia, insomnia, insomnia neurosis, sleep apnea syndrome],

(7) respiratory depression caused by anesthetics, traumatic disease or neurodegenerative disease, etc.,

(8) traumatic brain injury, stroke, anorexia nervosa, eating disorder, anorexia nervosa, bulimia, other eating disorder, alcohol addiction, alcohol overdose, alcohol amnesia, alcohol paranoia, alcohol preference, alcohol withdrawal, alcohol addiction, alcohol poisoning, alcohol delusions of jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcohol dependence, pharmacophilia, pharmacophobia, pharmacophobia, drug withdrawal, migraine, stress headache, catatonic headache, diabetic neuropathy, obesity, diabetes mellitus, muscle cramps, Minier's disease, autonomic ataxia , alopecia, glaucoma, arterial hypertension, heart disease, tachycardia, congestive heart failure, hyperventilation of the lungs, bronchial asthma, sleep apnea, sudden infant death syndrome, inflammatory disease, allergic disease, impotence, menopause disorders, infertility, malignancy, HIV immunodeficiency syndrome, stress-induced immunodeficiency syndrome, cerebrospinal meningitis, acromegaly, metabolic syndrome, osteoporosis, incontinence, dysuria, functional bladder disorder,

(9) pain, etc. in mammals (eg mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.).

Particularly preferably, the compound (I) can be used in the prevention or treatment of neurogenic constipation (constipation associated with diseases such as Parkinson's disease, multiple sclerosis, spinal cord injury, Alzheimer's disease, Hirschsprung's syndrome, Chagas' disease, etc.), idiopathic constipation, functional constipation, atonic constipation, irritable bowel syndrome with constipation, constipation possibly complicated by another disease (Parkinson's disease, spinal cord injury, multiple sclerosis, etc.), age-related constipation, constipation induced by various drugs (constipation induced by opioid agonists and etc.), primary chronic constipation, drug-induced constipation (opioids, anticholinergics, calcium antagonists, anticancer agents, heavy metal poisoning, etc.), constipation associated with underlying diseases such as endocrine diseases or metabolic abnormalities (hypopituitarism, hypothyroidism, feochr homocytoma, etc.), diseases of muscle abnormalities (hereditary atrophy of visceral skeletal muscles, scleroderma, amyloidosis, progressive systemic sclerosis, etc.), metabolic diseases (diabetes, porphyria, uremia, hypokalemia, hypercalcemia, etc.) and so on.

[0199]

Since the compound (I) can have a positive allosteric modulating activity on the M1 cholinergic muscarinic receptor, it is expected to provide an excellent prophylactic or therapeutic effect for the aforementioned diseases.

[0200]

It is generally desirable that therapeutic drugs for constipation show an effect immediately after administration, and that the effect then quickly disappears. It is believed that the compound (I) will show better pharmacokinetics as a therapeutic drug for constipation, and is considered to show an effect, for example, within 3 hours after administration, preferably within 2 hours after administration, even more preferably within 1 hour after the injection, and the effect is believed to disappear immediately after the effect appears.

[0201]

It is known that the cholinergic muscarinic receptor M1 is expressed in the brain and gastrointestinal tract. Compound (I) is believed to show low central nervous system permeability, effective action in the periphery, and excellent effect as a therapeutic drug for constipation. With regard to the permeability to the central nervous system, for example, the corrected MDR1 permeability in the MDR1 membrane permeability test is preferably not less than 2.0, more preferably not less than 3.0, and even more preferably not less than 5.0 .

[0202]

Since Compound (I) is considered to be excellently characterized in water dissolution test, Japanese Pharmacopoeia 2nd liquid dissolution test, or Japanese Pharmacopoeia 2nd liquid disintegration test, by pharmacokinetics (e.g. drug half-life in plasma, metabolic stability, CYP inhibition) will show low toxicity (e.g., more excellent as a drug in terms of acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interactions, carcinogenicity, phototoxicity, etc.) , and can also have excellent properties as a pharmaceutical product, such as few side effects, etc., it can be safely administered orally or parenterally to mammals (for example, mouse, rat, hamster, rabbit, cat, dog, cattle , sheep, monkey, human, etc.). Examples of "parenteral" administration include intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal administration, instrillation, intracerebral, intrarectal, intravaginal, intraperitoneal, and intratumoral administration, administration to a region surrounding a tumor, etc., and direct administration to hearth.

[0203]

The drug containing Compound (I) (sometimes abbreviated in the present description to "the drug of the present invention") may be in any form (dosage form) of a solid preparation, such as powder, granule, tablet, capsule, disintegrating film in the oral cavity, etc., or a liquid agent such as syrup, emulsion, injection, etc.

[0204]

The drug according to the present invention can be produced by a conventional method such as blending, kneading, granulating, tableting, coating, sterilizing processing, emulsifying, and so on. in accordance with the form of the drug. With regard to the preparation of the preparation, references may be given, for example, to each item of the Japanese Pharmacopoeia Preparation General Rules, etc. In addition, the medicament of the present invention may be formulated as a sustained release formulation containing the active ingredient and a biodegradable polymer compound. The sustained release preparation can be prepared according to the method described in JP-A-9-263545.

[0205]

In the drug according to the present invention, the content of the compound (I) varies depending on the form of the drug, but, as a rule, is from 0.01 to 100 wt.% of the compound (I) relative to the total drug (complete drug).

[0206]

Compound (I) may be used alone or in admixture with a suitable pharmacologically acceptable carrier, e.g. fillers (e.g. starch, lactose, white soft sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g. starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), lubricants (for example, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (for example, calcium carboxymethylcellulose, talc, etc.), diluents (e.g. water for injection, physiological saline, etc.) and, if desired, with additives (e.g., stabilizer, preservative, color, flavor, solubilizer, emulsifier, buffer, isotonic agent, etc.), etc., by a conventional method, which is formulated into a solid dosage form such as a powder , fine granules, granules, tablets, capsules, etc., or a liquid form such as injection, etc., and is administered orally or parenterally. If Compound (I) is included in a topical formulation, it can also be administered directly to the diseased part of the joint. In this case, injection is preferred. Compound (I) can also be administered as a topical parenteral (e.g., intramuscular injection, subcutaneous injection, organ injection, joint surrounding area injection, etc., solid preparation such as implant, granule, powder, etc.). etc., liquid such as suspension, etc., ointment, etc.), etc.

[0207]

When preparing a formulation for injection, compound (I), for example, is formulated in an aqueous suspension together with a dispersing agent (for example, a surfactant such as Tween 80, HCO-60, etc., polysaccharides such as carboxymethyl cellulose , sodium alginate, hyaluronic acid, etc., polysorbate, etc.), a preservative (e.g., methylparaben, propylparaben, etc.), an isotonic agent (e.g., sodium chloride, mannitol, sorbitol, glucose, etc.). etc.), a buffer (eg, calcium carbonate, etc.), a pH adjuster (eg, sodium phosphate, potassium phosphate, etc.), etc., to obtain a practical injection preparation. In addition, an oil suspension can be obtained by dispersing the compound together with vegetable oil such as sesame oil, corn oil, etc. or mixtures thereof with a phospholipid such as lecithin, etc., or a medium chain fatty acid triglyceride (eg, miglyol 812, etc.) to obtain a practical injectable preparation.

[0208]

The dose of compound (I) varies depending on the subject of administration, route of administration and symptoms, and is not specifically limited. For example, for oral administration to adult patients (adult weight 40 to 80 kg, eg 60 kg) with constipation, the dose of compound (I) may be, for example, 0.001 to 1000 mg/kg body weight per day, preferably 0.01 up to 100 mg/kg of body weight per day, more preferably from 0.1 to 10 mg/kg of body weight per day. Such an amount can be administered in one to three parts during the day.

[0209]

In the medicament of the present invention, compound (I) can be used alone or as a pharmaceutical composition of compound (I) mixed with a pharmacologically acceptable carrier according to a method known per se (for example, a method described in the Japanese Pharmacopoeia, etc.). ) as a method of preparing a pharmaceutical preparation. The medicament of the present invention can be administered safely, for example, in the form of a pharmaceutical composition such as tablet (including sugar-coated tablets, film-coated tablets, sublingual tablets, oral disintegrating tablets, buccal tablets, etc.), pill , powder, granule, capsule (including softgels, microcapsules), lozenge, syrup, liquid, emulsion, suspension, controlled release formulation (eg, immediate release formulation, sustained release formulation, sustained release microcapsule), aerosol, film (eg, film , oral mucosal adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, percutaneous absorption type preparation, ointment, lotion, adhesive preparation, suppository (eg, rectal suppository, vaginal suppository), sediment, nasal preparation, pulmonary preparation (inhalant), eye drops, etc., orally or parenterally (for example, intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, instillation, intracerebral, intrarectal, intravaginally, intraperitoneally, into the damaged area, and etc.).

[0210]

As the aforementioned "pharmacologically acceptable carrier", various organic or inorganic carriers conventionally used as preparation materials (raw materials) can be used. For example, for solid preparations, a filler, lubricant, binder, disintegrant, etc. can be used, and for liquid preparations, a solvent, solubilizer, suspending agent, isotonic agent, buffer, soothing agent, etc. can be used. Additives such as a preservative, an antioxidant, a coloring agent, a sweetener, etc., may also be used for preparation if necessary.

[0211]

Examples of the filler include lactose, white soft sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.

[0212]

Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silicon, and so on.

[0213]

Examples of the binder include crystalline cellulose, white soft sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.

[0214]

Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.

[0215]

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and so on.

[0216]

Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and so on.

[0217]

Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl amino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc.; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.; etc.

[0218]

Examples of an isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.

[0219]

Examples of the buffer include buffer solutions such as phosphate salts, acetate salts, carbonate salts, citrate salts, and so on.

[0220]

Examples of the soothing agent include benzyl alcohol, and so on.

[0221]

Examples of the preservative include paraoxybenzoate esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and so on.

[0222]

Examples of the antioxidant include sulfite salts, ascorbic acid, α-tocopherol, etc.

[0223]

Although the pharmaceutical composition varies according to dosage form, route of administration, carrier, etc., it can be obtained according to the conventional method by adding the compound (I) in a proportion of usually 0.01-100% (by mass), preferably 0.1-95% (by mass), relative to the total amount of the drug.

[0224]

Compound (I) may be used in combination with other active ingredients (hereinafter referred to as the concomitant drug).

[0225]

Examples of concomitant medication include the following.

Prokinetic agent (cholinesterase inhibitor (neostigmine, physostigmine, etc.), 5-HT ₄ agonist, ghrelin agonist (capromorelin, etc.), motilin receptor agonist (camycinal, erythromycin, etc.), opioid antagonist ( naltrexone, naloxegol, etc.)), enhancer of intestinal water secretion (guanylate cyclase C agonist (linaclotide, etc.), chloride channel 2 opener (lubiprostone, etc.), sodium/proton 3 inhibitor (tenapanor etc.)), anti-constipation medicine (sennoside, magnesium oxide, magnesium hydroxide, bisacodyl, calcium polycarbophil, laxative sugars (lactulose, etc.), laxoberone, medicinal raw material with anti-constipation effect (psyllium, etc.). etc.), benzodiazepine (chlordiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type potassium channel inhibitor (pregabalin, etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.) d.), selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-norepinephrine reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride and etc.), norepinephrine reuptake inhibitor (reboxetine mesilate, etc.), noradrenaline-dopamine reuptake inhibitor (bupropion hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, sepittyline maleate, 5-HT _1A agonist (buspirone hydrochloride, tandospirone citrate, osemozotane hydrochloride, etc.), 5-HT ₃ antagonist (cyamemazine, etc.), non-cardioselective β blocker (propranolol hydrochloride, oxprenolol hydrochloride, etc. ), a histamine H ₁ antagonist (hydroxyzine hydrochloride, etc.), a therapeutic drug for schizophrenia (chlorpromazine, haloperidol, sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, etc.), CRF antagonist, other anti-anxiety drug (meprobamate, etc.), tachykinin antagonist (aprepitant, saredutant, etc.), drug , which acts on the metabotropic glutamate receptor, CCK antagonist, β3 adrenaline antagonist (amibegron hydrochloride, etc.), GAT-1 inhibitor (tiagabine hydrochloride, etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine fragment agonist, NMDA antagonist (memantine, etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1a antagonist, phosphodiesterase inhibitor, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT _2A antagonist, 5-HT _2A inverse agonist, COMT inhibitor (entacapone, etc.), ter bipolar disorder apeutic drug (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonist (rimonabant, etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride , methamphetamine hydrochloride, etc.), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for seizures, therapeutic drug for fibromyalgia syndrome, therapeutic drug for headache, therapeutic drug for insomnia (etizolam , zopiclone, triazolam, zolpidem, ramelteon, indiplon, etc.), therapeutic drug for smoking cessation, therapeutic drug for myasthenia gravis, therapeutic drug for stroke, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for sexual dysfunction in men and women, therapeutic drug for migraine, therapeutic drug for pathological gambling, therapeutic drug for restless legs syndrome, therapeutic drug for drug addiction, therapeutic drug for alcohol-related syndrome, therapeutic drug for syndrome irritable bowel, Alzheimer's therapeutic drug (denepezil, galantamine, memantine, rivastigmine, etc.), Parkinson's therapeutic drug (levodopa, carbidopa, benserazide, selegiline, rasagiline, zonisamide, entacapone, amantadine, talipexol, pramipexole, ropinirole , rotigotine, apomorphine, cabergoline, pergolide, bromocriptine, istradephylline, trihexyphenidyl, biperiden, pyroheptin, prophenamine, promethazine, droxidopa, a combination of these drugs, etc.), therapeutic drug for dementia in Parkinson's disease (rivastigmine), therapeutic drug for dementia with calves and Levi (donepezil), a therapeutic drug for ALS (riluzole, neurotrophic factor, etc.), a therapeutic drug for lipid abnormality such as a cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.). d.), fibrate (clofibrate, etc.), squalene synthetase inhibitor), therapeutic drug for behavioral abnormalities or suppressant of dromomania caused by dementia (sedative drugs, anti-anxiety drug, etc.), apoptosis inhibitor, anti-obesity drug, therapeutic drug for diabetes mellitus, therapeutic drug for arterial hypertension, therapeutic drug for hypotension, therapeutic drug for rheumatism (DMARD), anti-cancer agent, therapeutic drug for hypothyroidism (PTH), calcium receptor antagonist, sex hormone or its derivative (progesterone, estradiol, estradiol benzoate, etc.), neuronal differentiation enhancer, neural regeneration enhancer, n nonsteroidal anti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroids (dexamethasone, cortisone acetate, etc.), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitor, etc.) .d.), antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, etc.

[0226]

By combining the compound (I) and the concomitant drug, an excellent effect such as

(1) the dose can be reduced compared to the separate administration of the compound (I) or the concomitant drug,

(2) the drug to be combined with the compound (I) can be selected according to the condition of the patients (mild case, severe case, etc.),

(3) the treatment period can be lengthened by choosing a concomitant drug having a different action and mechanism from compound (I),

(4) a delayed treatment effect can be envisaged by selecting a concomitant drug having a different action and mechanism from Compound (I),

(5) a synergistic effect can be envisaged through the combined use of the compound (I) and a concomitant drug, etc.

[0227]

Hereinafter, the compound (I) and the concomitant drug used in combination are referred to as the "combination agent of the present invention".

[0228]

When using the combination agent according to the present invention, the administration time of the compound (I) and the concomitant drug is not limited, and the compound (I) or the pharmaceutical composition containing it, and the concomitant drug or the pharmaceutical composition containing it, can be administered to the administered object at the same time, or can be introduced at different times. The dosage of the concomitant drug may be determined according to the clinically used dose, and may be appropriately selected depending on the administration subject, route of administration, disease, combination, and so on.

[0229]

The administration method of the combination agent of the present invention is not particularly limited, and it is sufficient that the compound (I) and the concomitant drug be combined when administered. Examples of the route of administration include the following methods:

(1) administration of a single preparation obtained by simultaneous processing of the compound (I) and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound (I) and the concomitant drug, which were produced separately, through the same route of administration, ( 3) administering two kinds of preparations of compound (I) and a concomitant drug, which were produced separately, through the same route of administration with a difference in time, (4) simultaneous administration of two kinds of preparations of compound (I) and a concomitant drug, which were produced separately, by different routes of administration, (5) the administration of two kinds of preparations of the compound (I) and the concomitant drug, which were produced separately, by different routes of administration with a difference in time (for example, the administration of the compound (I) and the concomitant drug in in that order or in reverse order), etc.

[0230]

It is believed that the combination agent of the present invention will exhibit low toxicity. For example, the compound (I) and/or the aforementioned concomitant drug can be combined with a pharmacologically acceptable carrier according to a known method for preparing a pharmaceutical composition such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules. (including softgels), liquids, injections, suppositories, sustained release products, etc. Such compositions can be safely administered orally or non-orally (eg, topical, rectal, intravenous, etc.). The injection can be administered intravenously, intramuscularly, subcutaneously or by intraorganic injection or directly into the damaged area.

[0231]

As pharmacologically acceptable carriers that can be used to prepare the combination agent of the present invention, various organic or inorganic carrier materials conventionally used as formulation agents can be used. For solid preparations, for example, filler, lubricant, binder and disintegrant can be used. For liquid preparations, for example, a solvent, a solubilizer, a suspending agent, an isotonic agent, a buffering agent, a soothing agent, etc. can be used. If necessary, a suitable amount of a conventional preservative, antioxidant, coloring agent, sweetener, adsorbent, humectant, etc. may be appropriately used.

[0232]

Examples of the filler include lactose, white soft sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.

[0233]

Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silicon, and so on.

[0234]

Examples of the binder include crystalline cellulose, white soft sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.

[0235]

Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.

[0236]

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and so on.

[0237]

Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and so on.

[0238]

Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl amino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc.; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.; etc.

[0239]

Examples of an isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.

[0240]

Examples of the buffer include buffer solutions such as phosphate salts, acetate salts, carbonate salts, citrate salts, and so on.

[0241]

Examples of the soothing agent include benzyl alcohol, and so on.

[0242]

Examples of the preservative include paraoxybenzoate esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and so on.

[0243]

Examples of the antioxidant include sulfite salts, ascorbic acid, α-tocopherol, etc.

[0244]

The mixture ratio of compound (I) to concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, diseases, etc.

[0245]

For example, the content of compound (I) in the combination agent according to the present invention varies depending on the form of the preparation and is usually about 0.01 to 100 wt.%, preferably about 0.1 to 50 wt.%, even more preferably about 0.5 to 20 wt% of the preparation as a whole.

[0246]

The content of the concomitant drug in the combination agent according to the present invention varies depending on the form of the drug and is usually from about 0.01 to 100 wt.%, preferably from about 0.1 to 50 wt.%, even more preferably from about 0.5 to 20 wt.% of the drug as a whole.

[0247]

The content of additives such as carrier, etc., in the combined agent according to the present invention varies depending on the form of preparation and is usually from about 1 to 99.99 wt.%, preferably from about 10 to 90 wt.% of the drug in in general.

[0248]

If the compound (I) and the concomitant drug are included in the composition of separate preparations, then their content is similar to that indicated above.

examples

[0249]

The present invention is explained in detail hereinafter by reference to Examples, Experimental Examples and Formulation Examples, which should not be construed as limiting, and the present invention may be changed within the scope of the present invention.

In the following Examples, the term "room temperature" generally means a temperature of about 10°C to about 35°C. Unless otherwise indicated, ratios given for mixed solvents are mixing ratios by volume. Unless otherwise indicated, % means mass%.

Unless otherwise indicated, the column chromatography elution in the Examples was carried out under the control of TLC (thin layer chromatography). For TLC control, Merck 60 F ₂₅₄ was used as a TLC plate, and the solvent used in column chromatography was used as the eluent. A UV detector was used for detection. For silica gel column chromatography, "NH" means using aminopropylsilanyl modified silica gel and "Diol" means using 3-(2,3-dihydroxypropoxy)propylsilane modified silica gel. For preparative HPLC (high performance liquid chromatography), "C18" indicates the use of octadecyl-modified silica gel. Unless otherwise indicated, eluent ratios are mixing ratios by volume.

¹ H-NMR spectra were analyzed using ACD/SpecManager (trade name), etc. software. Very weak proton peaks of the hydroxy group, amino group, etc., may sometimes not be described.

Mass spectrometry was carried out in the LC/MS mode. As the ionization method, the ESI method or the APCI method was used. The received data are presented. As a rule, a molecular ion peak is observed, but sometimes it can be observed as a fragment ion peak. In the case of a salt, a molecular ion peak or a fragment ion peak of the free base form is generally observed.

The unit of sample concentration (c) in optical rotation ([α] _D ) is g/100 ml.

As elemental analysis values (Element. analysis:), calculated values (Calc.) and measured values (Detected) were described.

In the Examples, an X-ray powder diffractometry peak means a peak measured at room temperature using an Ultima IV instrument (Rigaku Corporation, Japan) using Cu-Kα as the radiation source. The measurement conditions were as follows:

Electrical voltage/electric current: 40 kV/50 mA

Scanning speed: 6 degrees/min

Scatter Angle Scan Range: 2-35 degrees

In the Examples, the degree of crystallinity from powder X-ray diffraction was calculated by the Hermann method.

[0250]

The following abbreviations have been used in the Examples:

m.p.: melting point

MS: mass spectrum

M: molar concentration

n: normal concentration

CDCl ₃ : deuterochloroform

DMSO–d ₆ : hexadeuterodimethyl sulfoxide

CD ₃ OD: deuterated methanol

¹ H-NMR: proton nuclear magnetic resonance

LC/MS: liquid chromatography/mass spectrometry

ESI: electrospray ionization

APCI: atmospheric pressure chemical ionization

AIBN: 2,2'-azobis(isobutyronitrile)

DAST: (diethylamino)sulfur trifluoride

DCM: dichloromethane

DIPEA: N, N-diisopropylethylamine

DMA: N, N-dimethylacetamide

DME: 1,2-dimethoxyethane

DMF: N, N-dimethylformamide

DMSO: dimethyl sulfoxide

DMT–MM: n -hydrate of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

EtOH: ethanol

HATU: O–(7–azabenzotriazol–1–yl)–N, N,N’,N’–tetramethyluronium hexafluorophosphate

HOBt: 1-hydroxybenzotriazole

HOBt H ₂ O: 1-hydroxybenzotriazole hydrate

IPE: diisopropyl ether

LAH: lithium aluminum hydride

MeOH: methanol

MEK: methyl ethyl ketone

NBS: N-bromosuccinimide

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium (0)

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium (0)

PdCl ₂ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]-palladium (II) dichloride

PdCl ₂ (dppf) DCM: complex of [1,1'–bis(diphenylphosphino)–ferrocene]palladium(II) dichloride and dichloromethane

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

WSC HCl: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

tRn(n=1-4): HPLC retention time (number indicates elution sequence)

Example 1

N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

[0252]

A) methyl-4-chloro-5-hydroxypyridine-2-carboxylate

Aluminum chloride (25.5 g) was added to a mixture of methyl 4-chloro-5-methoxypyridine-2-carboxylate (3.85 g) and anhydrous DCM (200 ml) at room temperature, and the mixture was refluxed under nitrogen within 16 hours the Reaction mixture was added to ice water (150 ml) to stop the reaction, and was extracted with a mixture of DCM/THF (10:1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3.15 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.98 (3H, s), 5.61 (1H, br s), 8.18 (1H, s), 8.46 (1H, s).

[0253]

B) methyl-4-chloro-5-hydroxy-6-iodopyridine-2-carboxylate

Iodine (30.8 g) was added to a mixture of methyl 4-chloro-5-hydroxypyridine-2-carboxylate (15.1 g), potassium carbonate (11.1 g) and water (150 ml) at room temperature and stirred mixture at 50° C. for 16 hours. The solid was filtered off and the filtrate was washed with ethyl acetate. A saturated aqueous sodium thiosulfate solution was added to the aqueous layer, and the mixture was adjusted to pH=1 by adding concentrated hydrochloric acid and extracted with ethyl acetate/THF (1/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (23.5 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.95 (3H, s), 5.90 (1H, br s), 8.06 (1H, s).

[0254]

C) methyl-7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl-4-chloro-5-hydroxy-6-iodopyridine-2-carboxylate (24.5 g), trimethylsilylacetylene (8.05 g), PdCl ₂ (dppf) (2.75 g), copper (I) iodide (745 mg), TEA (31.6 ml) and anhydrous THF (300 ml) were stirred under nitrogen at 10° C. for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ petroleum ether) to give the title compound (14.4 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.41 (9H, s), 4.04 (3H, s), 7.25 (1H, s), 8.14 (1H, s).

[0255]

D) methyl-7-chlorofuro[3,2-b]pyridine-5-carboxylate

Potassium fluoride (8.85 g) was added to a mixture of methyl 7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (14.4 g) and anhydrous MeOH (200 ml) and the mixture was stirred at 10° C. for 16 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate/THF (1/1). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (9.12 g).

MS: [M+H] ⁺ 211.8.

[0256]

E) methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of bis(pinacolato)diboron (9.00 g), methyl-7-chlorofuro[3,2-b]pyridine-5-carboxylate (5.00 g), 2-dicyclohexyl-phosphino-2',4', 6'-triisopropyl-1,1'-biphenyl (0.811 g), potassium acetate (4.64 g) and anhydrous THF (100 ml) were added Pd ₂ (dba) ₃ (0.782 g) at room temperature. The mixture was stirred under nitrogen at 65° C. for 3 hours and cooled to room temperature. The mixture was diluted with ethyl acetate and added to water, and the precipitated solid was filtered off. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. IPE was added to the residue and the solid was collected by filtration and washed with IPE to give the title compound (3.77 g).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.43 (12H, s), 4.04 (3H, s), 7.11 (1H, d, J=2.6 Hz), 8.02 ( 1 H, d, J=2.3 Hz), 8.50 (1H, s).

[0257]

F) methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (150 mg), 1-( 4-(chloromethyl)phenyl)-1H-pyrazole (95 mg), sodium carbonate (105 mg), DME (3.0 ml) and water (1.0 ml) at room temperature were added PdCl ₂ (dppf) (18, 1 mg). Under argon atmosphere, the mixture was stirred at 80°C for 1 h, diluted with ethyl acetate at room temperature and added to water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (114 mg).

MS: [M+H] ⁺ 334.2.

[0258]

G) methyl-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl 7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate (2.55 g), 10% palladium charcoal (1.25 g) and EtOH (150 ml) was stirred in a hydrogen atmosphere at a pressure of 55 psi (3.79 kPa) at 20°C for 3 days. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (2.04 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.42 (2H, t, J=8.8 Hz), 3.91-3.96 (5H, m), 4.76 (2H, t, J =8.8Hz), 6.45(1H, t, J=2.0Hz), 7.30(2H, d, J=8.4Hz), 7.62(2H, d, J=8 .4 Hz), 7.71 (1H, d, J=1.2 Hz), 7.79 (1H, s), 7.89 (1H, d, J=2.4 Hz).

[0259]

H) 7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

A mixture of methyl-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (2.04 g), lithium hydroxide monohydrate (1, 28 g) and THF/MeOH/water (3/1/1, 35 ml) were stirred at 10° C. for 16 hours. The solvent was evaporated under reduced pressure. To a mixture of the residue and water (50 ml) was added concentrated hydrochloric acid to adjust to pH=1, and the mixture was stirred at 10°C for 5 hours. The precipitated solid was collected by filtration and dried to give the title compound (1 .50 g).

MS: [M+H] ⁺ 321.9.

[0260]

I) N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

A mixture of 7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid (360 mg), hydrochloride (1S,2S)–2– aminocyclopentanol (232 mg), WSC HCl (439 mg), HOBt (151 mg), DIPEA (433 mg) and DMF (10 ml) were stirred under nitrogen at 10°C for 16 h. The mixture was added to water and extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate) to give the title compound (310 mg).

[0261]

Example 4

N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)furo[3,2–b]pyridine–5–carboxamide

[0262]

A) 7–(4–(1H–pyrazol–1–yl)benzyl)furo[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 320.2.

[0263]

B) N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0264]

Example 5

N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1–methyl–1H–pyrazol–3–yl)benzyl)furo[3,2–b]pyridine–5–carboxamide

[0265]

A) methyl-7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 348.1.

[0266]

B) 7–(4–(1–methyl–1H–pyrazol–3–yl)benzyl)furo[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 334.1.

[0267]

C) N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0268]

Example 8

1,5-Anhydro-2,4- dideoxy -2-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L- threo-pentitol

[0269]

A) methyl-7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 350.1.

[0270]

B) 7–(4–(1–methyl–1H–pyrazol–3–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 336.1.

[0271]

C) 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0272]

Example 10

N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–methoxypyridin–3–yl)methyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

[0273]

A) methyl-7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ^+299.1 .

[0274]

B) methyl-7-((6-methoxypyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 301.1.

[0275]

C) 7-((6-methoxypyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 287.2.

[0276]

D) N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–methoxypyridin–3–yl)methyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0277]

Example 12

N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–methoxybenzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

[0278]

A) methyl-7-(4-methoxybenzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ^+298.0 .

[0279]

B) methyl-7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 300.0.

[0280]

C) 7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 286.1.

[0281]

D) N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0282]

Example 14

N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(5–methyl–1,3–thiazol–2–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine –5–carboxamide

[0283]

A) (4-(5-methyl-1,3-thiazol-2-yl)phenyl)methanol

The title compound was prepared from (4-(hydroxymethyl)phenyl)boronic acid and 2-bromo-5-methyl-1,3-thiazole in a manner similar to that described in step F of Example 1.

MS: [M+H] ⁺ 206.1.

[0284]

B) 2–(4–(chloromethyl)phenyl)–5–methyl–1,3–thiazole

To a mixture of (4-(5-methyl-1,3-thiazol-2-yl)phenyl)methanol (3.3 g) and DCM (120 ml) was added thionyl chloride (3.83 g) at 0°C. After stirring at room temperature for 3 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.8 g).

MS: [M+H] ⁺ 224.1.

[0285]

C) methyl-7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 365.0.

[0286]

D) methyl-7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 367.1.

[0287]

E) 7–(4–(5–methyl–1,3–thiazol–2–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ^+353.0 .

[0288]

F) N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b ]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0289]

Example 16

N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(4–methyl–1,3–thiazol–2–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine –5–carboxamide

[0290]

A) (4-(4-methyl-1,3-thiazol-2-yl)phenyl)methanol

The title compound was prepared from (4-(hydroxymethyl)phenyl)boronic acid and 2-bromo-4-methyl-1,3-thiazole in a manner similar to that described in step F of Example 1.

MS: [M+H] ⁺ 206.1.

[0291]

B) 2–(4–(chloromethyl)phenyl)–4–methyl–1,3–thiazole

The title compound was prepared in a manner similar to that described in Step B of Example 14.

MS: [M+H] ⁺ 224.1.

[0292]

C) methyl-7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 365.0.

[0293]

D) methyl-7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 367.0.

[0294]

E) 7–(4–(4–methyl–1,3–thiazol–2–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 353.1.

[0295]

F) N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b ]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0296]

Example 18

N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(2–methyl–1,3–thiazol–5–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine –5–carboxamide

[0297]

A) methyl-4-(2-methyl-1,3-thiazol-5-yl)benzoate

A mixture of methyl-4-iodobenzoate (1.75 g), 2-methyl-1,3-thiazole (0.99 g), potassium acetate (1.96 g), Pd (PPh ₃ ) ₄ (35 mg) and DMA (60 ml) was stirred at 100°C overnight. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/DCM) to give the title compound (500 mg).

MS: [M+H] ⁺ 234.1.

[0298]

B) (4–(2–methyl–1,3–thiazol–5–yl)phenyl)methanol

LAH (147 mg) was added to a mixture of methyl 4-(2-methyl-1,3-thiazol-5-yl)benzoate (450 mg) and THF (30 ml) at 0°C, and the mixture was stirred at room temperature in over 2 hours. Water (0.15 ml), 30% aqueous sodium hydroxide solution (0.15 ml) and water (0.45 ml) were added dropwise successively to the mixture. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (330 mg).

MS: [M+H] ⁺ 206.1.

[0299]

C) 5–(4–(chloromethyl)phenyl)–2–methyl–1,3–thiazole

The title compound was prepared in a manner similar to that described in Step B of Example 14.

MS: [M+H] ⁺ 224.1.

[0300]

D) methyl-7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 365.1.

[0301]

E) methyl-7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 367.1.

[0302]

F) 7–(4–(2–methyl–1,3–thiazol–5–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 353.1.

[0303]

G) N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b ]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0304]

Example 20

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl )furo[3,2-b]pyridine-5-carboxamide

[0305]

A) 5-hydroxy-6-iodopyridine-2-carboxylic acid

Iodine (17.88 G). The mixture was stirred at 0° C. for 3 hours, the reaction temperature was raised to room temperature, and the mixture was stirred at room temperature overnight. Citric acid monohydrate (32.6 g) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (13.1 g).

MS: [M+H] ⁺ 266.0.

[0306]

B) methyl-5-hydroxy-6-iodopyridine-2-carboxylate

To a mixture of 5-hydroxy-6-iodopyridine-2-carboxylic acid (20.0 g) and MeOH (100 ml) was added concentrated sulfuric acid (8.05 ml) at room temperature. The mixture was stirred at 50° C. for 3 h and a solution of sodium citrate (39.0 g) in water (100 ml) was added dropwise at 0° C. The precipitated solid was collected by filtration and washed with water to give the title compound (17.7 g).

MS: [M+H] ⁺ 280.0.

[0307]

C) methyl-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

PdCl ₂ (dppf) (1.31 g) was added to a mixture of methyl 5-hydroxy-6-iodopyridine-2-carboxylate (10.0 g), TEA (36.3 g) and ethyl acetate (150 ml) at room temperature and copper(I) iodide (0.341 g). The mixture was stirred under argon at 15° C. for 5 minutes. While maintaining the internal temperature at 15–18°C, trimethylsilylacetylene (9.93 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature overnight. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.0 g).

MS: [M+H] ⁺ 250.1.

[0308]

D) methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of bis(1,5-cyclooctadiene)di- μ -methoxydiiridium (I) (0.052 g), 4,4'-di- tert- butyl-2,2'-bipyridine (0.042 g) and tert- butyl methyl ether ( 40 ml) was added bis(pinacolato)diboron (4.17 g) and the mixture was stirred under argon at room temperature for 5 minutes. Methyl 2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (3.90 g) was added to the mixture, and the mixture was stirred at 80°C for 4 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.87 g).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.40 (9H, s), 1.42 (12H, s), 4.03 (3H, s), 7.23 (1H, s), 8, 41 (1H, s).

[0309]

E) methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (5, 87 g), 4-(4-(bromomethyl)phenyl)-1-methyl-1H-1,2,3-triazole (4.13 g), PdCl ₂ (dppf) (0.114 g), sodium carbonate (2.486 g ), DME (50 ml) and water (10 ml) were stirred under argon at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.2 g).

MS: [M+H] ⁺ 421.1.

[0310]

F) methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

To a solution of methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate ( 4.2 g) in MeOH (50 ml) was added potassium fluoride (0.87 g) at room temperature, and the mixture was stirred at 80°C for 4 h. While stirring at room temperature, water (100 ml) was added to the reaction mixture . The precipitated solid was collected by filtration, washed with water and IPE, and dried under reduced pressure to give the title compound (3.14 g).

MS: [M+H] ⁺ 349.2.

[0311]

G) 7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylic acid

To a mixture of methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate (13.6 g), water (180 ml) and MeOH (30 ml) at room temperature was added 2 M aqueous sodium hydroxide solution (39.0 ml). After stirring at 60° C. for 1 hour, the reaction mixture was filtered through Celite to remove insoluble matter. Water (80 ml) and 2 M hydrochloric acid (50 ml) were added to the filtrate. The mixture was stirred at room temperature for 30 minutes and the precipitated solid was collected by filtration. The solid was washed with water and dried under reduced pressure to give the title compound (13.30 g).

MS: [M+H] ⁺ 335.1.

[0312]

H) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2 –b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7-(4-(1H-pyrazol-1-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3, 2–b]pyridine–5–carboxamide

To a mixture of 7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylic acid (14.1 g), hydrochloride (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol (7.13 g), TEA (8.82 ml) and EtOH (200 ml) at room temperature was added DMT-MM (20.36 g) . After stirring at room temperature for 3 hours, water was added to the mixture. The precipitated solid was collected by filtration, washed with water (20 ml) and dried under reduced pressure to give the title compound (14.2 g).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.64 (1H, qd, J=12.1, 4.5 Hz), 1.84 (1H, dd, J=13.0, 4.3 Hz), 3.03 (1H, t, J=10.4 Hz), 3.26–3.41 (1H, m), 3.59 (1H, tt, J=9.8, 5 .1 Hz), 3.72–3.89 (3H, m), 4.07 (3H, s), 4.37 (2H, s), 4.96 (1H, d, J=5.7 Hz ), 7.23 (1H, d, J=2.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.78 (2H, d, J=8.3 Hz), 7.92 (1H, s), 8.43–8.50 (2H, m), 8.55 (1H, d, J=8.3 Hz).

[0313]

Example 22

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5- yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7-(4-(1H-pyrazol-1-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3, 2–b]pyridine–5–carboxamide

A mixture of 7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid (106 mg), (3R,4S)–4–aminotetrahydro -2H-pyran-3-ol hydrochloride (60.8 mg), HATU (163 mg), TEA (0.115 ml) and DMF (3.0 ml) were stirred at room temperature overnight. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (75 mg).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.59 (1H, qd, J=12.3, 4.7 Hz), 1.81 (1H, dd, J=13.0, 4.3 Hz), 3.01 (1H, t, J=10.4 Hz), 3.25–3.40 (3H, m), 3.46–3.61 (1H, m), 3, 66–3.85 (3H, m), 3.97 (2H, s), 4.76 (2H, t, J=8.9 Hz), 4.92 (1H, d, J=5.7 Hz ), 6.48–6.56 (1H, m), 7.36 (2H, d, J=8.7 Hz), 7.65–7.80 (4H, m), 8.25 (1H, d, J=8.3 Hz), 8.44 (1H, d, J=2.3 Hz).

[0314]

Example 25

N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0315]

Example 26

N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: short retention time)

N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (71 mg) prepared in Example 25 was optically resolved by HPLC (CHIRALPAK AD, id 50 mm x length 500 mm, mobile phase: hexane/EtOH=200/800) and triturated with a low retention time (tR1 ) with ethyl acetate-IPE to give the title compound (30 mg).

[0316]

Example 27

N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: long retention time)

N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (71 mg) prepared in Example 25 was optically resolved by HPLC (CHIRALPAK AD, id 50 mm x length 500 mm, mobile phase: hexane/EtOH=200/800) and triturated with a long retention time (tR2 ) with ethyl acetate-IPE to give the title compound (33 mg).

[0317]

Example 29

1,5-Anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro [3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

[0318]

A) 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde

The title compound was prepared from 6-chloronicotinaldehyde and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a manner similar to that described in Step F Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.01 (3H, s), 6.97 (1H, d, J=2.45 Hz), 7.45 (1H, d, J=2.45 Hz), 8.08 (1H, d, J=8.4 Hz), 8.19 (1H, dd, J=8.31, 1.96 Hz), 9.05 (1H, d, J=1 .47 Hz), 10.09 (1H, s).

[0319]

B) (6–(1–methyl–1H–pyrazol–3–yl)pyridin–3–yl)methanol

Sodium borohydride (10.16 g) was added to a mixture of 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde (25.0 g) and MeOH (375 ml) at 0°C, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (18.0 g).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.81 (1H, br s), 3.98 (3H, s), 4.74 (2H, d, J=4.88 Hz), 6, 85 (1H, d, J=2.44 Hz), 7.41 (1H, d, J=2.44 Hz), 7.74 (1H, dd, J=8.09, 2.29 Hz), 7.90 (1H, d, J=7.93 Hz), 8.59 (1H, d, J=1.83 Hz).

[0320]

C) 5–(chloromethyl)–2–(1–methyl–1H–pyrazol–3–yl)pyridine

To a mixture of (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol (18.0 g), TEA (11.16 ml) and DCM (270 ml) at 0 ° C for methanesulfonyl chloride (7.3 ml) was added dropwise. The mixture was stirred at room temperature for 16 hours, water was added and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.0 g).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 3.98 (3H, s), 4.61 (2H, s), 6.86 (1H, d, J=2.44 Hz), 7.41 ( 1H, d, J=2.14 Hz), 7.75 (1H, dd, J=8.09, 2.29 Hz), 7.91 (1H, d, J=8.24 Hz), 8, 60 (1H, d, J=2.14 Hz).

[0321]

D) methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 349.1.

[0322]

E) methyl-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 351.1.

[0323]

F) 7–((6–(1–methyl–1H–pyrazol–3–yl)pyridin–3–yl)methyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 337.1.

[0324]

G) 1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3 -dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0325]

Example 31

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[ 3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl )-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

[0326]

A) methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-furo[3,2-b]pyridine-5-carboxylate (1.92 g), 10% palladium charcoal (NX type, 50% water wet, 400 mg) and MeOH (400 ml) were stirred under a hydrogen atmosphere at 5 MPa at 50° C. for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. A mixture of the residue, 10% palladium charcoal (NX type, 50% water wet, 400 mg) and MeOH (400 ml) was stirred under a hydrogen atmosphere at 5 MPa at 50° C. for 2 hours. The catalyst was filtered off and the filtrate was concentrated to obtain the title compound (1.90 g).

MS: [M+H] ⁺ 351.2.

[0327]

B) 7–(4–(1–methyl–1H–1,2,3–triazol–4–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

To a mixture of methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (2 .72 g), MeOH (27 ml) and THF (13 ml) were added 2 M aqueous sodium hydroxide solution (23.29 ml) at room temperature. After stirring at room temperature overnight, 1 M hydrochloric acid (55 ml) was added and the precipitated solid was collected by filtration to give the title compound (2.31 g).

MS: [M+H] ⁺ 337.2.

[0328]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3- dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl )-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of 7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid (350 mg ), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (192 mg), WSC HCl (299 mg), HOBt H ₂ O (191 mg) and DMF (7.0 ml) at room temperature temperature, TEA (0.653 ml) was added. After stirring at room temperature overnight, water was added to the reaction mixture. The precipitated solid was collected by filtration and washed with water. The solid was recrystallized from MEK/heptane to give the title compound (277 mg).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.49-1.69 (1H, m), 1.75-1.87 (1H, m), 3.00 (1H, t, J= 10.4 Hz), 3.34–3.40 (3H, m), 3.54 (1H, tt, J=9.8, 5.1 Hz), 3.67–3.85 (3H, m ), 3.95(2H, s), 4.08(3H, s), 4.76(2H, t, J=8.9Hz), 4.92(1H, d, J=5.7Hz ), 7.31 (2H, d, J=8.3 Hz), 7.67 (1H, s), 7.76 (2H, d, J=8.3 Hz), 8.26 (1H, d , J=8.3 Hz), 8.46 (1H, s).

[0329]

Example 33

N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–(1–methyl–1H–1,2,3–triazol–4–yl)pyridin–3–yl)methyl)furo[3 ,2–b]pyridine–5–carboxamide

[0330]

A) methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 350.1.

[0331]

B) 7–((6–(1–methyl–1H–1,2,3–triazol–4–yl)pyridin–3–yl)methyl)furo[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 336.1.

[0332]

C) N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo [3,2-b]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.18–1.51 (4H, m), 1.78 (2H, d, J=7.9 Hz), 2.01–2.23 (2H , m), 3.44–3.59 (2H, m), 3.85 (1H, br s), 4.15 (3H, s), 4.31 (2H, s), 6.99 (1H, d, J=2.3 Hz), 7.67 (1H, dd, J=8.1, 2.1 Hz), 7.93 (1H, d, J=2.3 Hz), 8 .01–8.13 (4H, m), 8.56 (1H, d, J=1.9 Hz).

[0333]

Example 35

N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)furo[3,2–b]pyridine –5–carboxamide

[0334]

A) methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (800 mg), 5-( chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (603 mg), sodium carbonate (559 mg), DME (13 ml) and water (4.0 ml) PdCl ₂ was added at room temperature (dppf) (97 mg), and the mixture was stirred under argon atmosphere at 80° C. for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (543.6 mg).

MS: [M+H] ⁺ 349.1.

[0335]

B) 7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)furo[3,2–b]pyridine–5–carboxylic acid

To a mixture of methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate (150 mg), MeOH (3.0 ml) and THF (1.0 ml) at room temperature was added 2 M aqueous sodium hydroxide solution (1.0 ml). After stirring at room temperature for 19 hours, the solvent was evaporated under reduced pressure. Water (6.0 ml) was added to the residue, and the mixture was neutralized by adding 1 M hydrochloric acid (2.0 ml). The mixture was stirred at room temperature for 3 hours and the precipitated solid was collected by filtration to give the title compound (143 mg).

MS: [M+H] ⁺ 335.1.

[0336]

C) N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)furo[3,2–b ]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0337]

Example 36

1,5-Anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2- b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl) methyl)furo[3,2-b]pyridine-5-carboxamide

To a mixture of 7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)furo[3,2–b]pyridine–5–carboxylic acid (50 mg), (3R ,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (27.6 mg), WSC HCl (43 mg), HOBt H ₂ O (27.5 mg) and DMF (1.0 ml) were added TEA (0.073 ml), and the mixture was stirred at room temperature for 22 hours. Ethyl acetate was added to the mixture. The mixture was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was washed with IPE and dried under reduced pressure to give the title compound (32.5 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.74–1.92 (1H, m), 2.06 (1H, s), 3.23 (1H, dd, J=11.3, 9, 8 Hz), 3.42–3.53 (1H, m), 3.65 (1H, td, J=9.1, 4.2 Hz), 3.91–4.17 (6H, m), 4.25–4.32 (3H, m), 6.99 (1H, d, J=2.6 Hz), 7.37 (1H, d, J=8.7 Hz), 7.55 (1H , dd, J=8.1, 2.5 Hz), 7.89 (2H, d, J=6.8 Hz), 7.94 (1H, d, J=2.3 Hz), 8.07 (1H, s), 8.14 (1H, d, J=7.2 Hz), 8.54 (1H, d, J=2.6 Hz).

[0338]

Example 37

1,5-Anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)- L-threo-pentitol

[0339]

A) 7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 285.1.

[0340]

B) 1,5-anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0341]

Example 38

1,5-Anhydro-2,3-dideoxy-3-(((7-((6-oxo-1,6-dihydropyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

To a mixture of 1,5-anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L-threo-pentitol (115.8 mg) and acetonitrile (3.0 ml) sodium iodide (91 mg) and trimethylchlorosilane (0.116 ml) were added at room temperature. The mixture was stirred at 80°C for 1.5 h and concentrated under reduced pressure. Water was added to the residue, and the precipitated solid was collected by filtration. The solid was washed with water and dried to give the title compound (109 mg).

[0342]

Example 39

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 –b]pyridin–5–yl)carbonyl)amino)–L–threo–pentitol

[0343]

A) methyl-7-(hydroxy(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate (346.8 mg) and benzotrifluoride (7.0 ml) NBS (177 mg) and AIBN (32.7 mg) were added at room temperature. Under a nitrogen atmosphere, the reaction mixture was stirred under irradiation with a 60 W lamp at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, acetone (6.0 ml) and water (3.0 ml) were added to the residue, and the mixture was stirred at 50° C. for 5 hours. After adding ethyl acetate to the mixture, the mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate) to give the title compound (65.8 mg).

MS: [M+H] ⁺ 365.1.

[0344]

B) methyl-7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-(hydroxy(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate (65 mg) and THF (5.0 ml) at 0°C was added DAST (0.03 ml), and the mixture was stirred at room temperature for 5 h, and then at 60°C for 5 h. DAST was added to the mixture at 60°C (0.03 ml), and the mixture was stirred at the same temperature for 10 minutes. Ethyl acetate was added to the mixture, and the mixture was added to saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (22.7 mg).

MS: [M+H] ⁺ 367.1.

[0345]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in steps H and I of Example 1.

[0346]

Example 40

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

[0347]

A) methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (1000 mg), 4-( 4-(chloromethyl)phenyl)-1-methyl-1H-pyrazole (750 mg), potassium carbonate (699 mg), DME (15 ml) and water (5.0 ml) were added PdCl ₂ (dppf) at room temperature ( 121 mg). The mixture was stirred under argon at 80° C. for 1 hour. The mixture was diluted with ethyl acetate at room temperature and added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (729.0 mg).

MS: [M+H] ⁺ 348.2.

[0348]

B) 7–(4–(1–methyl–1H–pyrazol–4–yl)benzyl)furo[3,2–b]pyridine–5–carboxylic acid

To a mixture of methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate (294.2 mg), MeOH (6.0 ml ) and THF (3.0 ml) at room temperature was added 2 M aqueous sodium hydroxide solution (2.0 ml). The mixture was stirred at room temperature for 3 hours and the solvent was evaporated under reduced pressure. Water (8.0 ml) was added to the residue, and the mixture was neutralized by adding 1 M hydrochloric acid (4.0 ml). The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (306 mg).

MS: [M+H] ⁺ 334.1.

[0349]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5 -yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0350]

Example 42

N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0351]

Example 43

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

[0352]

A) methyl-7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 360.1.

[0353]

B) 7–(4–(6–methylpyridazin–4–yl)benzyl)furo[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ2.66 (3H, s), 4.42 (2H, s), 7.26 (1H, d, J=2.3 Hz), 7.52 (2H, d, J=8.3 Hz), 7.81–7.91 (3H, m), 7.94 (1H, s), 8.48 (1H, d, J=2.6 Hz) , 9.44 (1H, d, J=2.3 Hz), 13.12 (1H, br s).

[0354]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridine-5-yl)carbonyl )amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0355]

Example 44

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–pyrazol–4–yl)benzyl)–2,3– dihydrofuro[3,2-b]pyridine-5-carboxamide

[0356]

A) methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

Mixture of methyl 7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate (466 mg), 10% palladium charcoal (50% water moisture) , 93 mg) and MeOH (30 ml) were stirred under a hydrogen atmosphere at a pressure of 5 MPa at 50°C for 6 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (389.1 mg).

MS: [M+H] ⁺ 350.2.

[0357]

B) 7–(4–(1–methyl–1H–pyrazol–4–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

To a mixture of methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (389 mg), MeOH (8 .0 ml) and THF (3.0 ml) at room temperature was added 2 M aqueous sodium hydroxide solution (3.0 ml). After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. Water (12 ml) was added to the residue, and the mixture was neutralized by adding 1 M hydrochloric acid (6.0 ml). The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (364 mg).

MS: [M+H] ⁺ 336.1.

[0358]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–pyrazol–4–yl)benzyl)–2,3– dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of 7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid (55.9 mg), (3R ,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (51.2 mg), WSC HCl (128 mg), HOBt H ₂ O (51.1 mg) and DMF (1.0 ml) at room temperature, TEA (0.163 ml) was added. After stirring at room temperature for 3 days, water was added to the mixture. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (67.7 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.70-1.87 (1H, m), 1.93-2.08 (1H, m), 3.20 (1H, dd, J=11, 3, 9.8 Hz), 3.33 (2H, t, J=8.9 Hz), 3.45 (1H, td, J=11.9, 2.3 Hz), 3.52–3, 69 (1H, m), 3.81–4.03 (7H, m), 4.07 (1H, dd, J=11.3, 4.9 Hz), 4.53 (1H, d, J= 3.0 Hz), 4.76 (2H, t, J=9.1 Hz), 7.22 (2H, d, J=7.9 Hz), 7.38 (2H, d, J=8, 3 Hz), 7.57 (1H, s), 7.71 (1H, d, J=0.8 Hz), 7.85 (1H, s), 7.90 (1H, d, J=5, 7 Hz).

[0359]

Example 45

N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: short retention time)

N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (114 mg) prepared in Example 42 was optically resolved by HPLC (CHIRALPAK IC, id 50 mm x length 500 mm, mobile phase: hexane/EtOH=400/600) and triturated with a short retention time (tR1 ) with IPE to give the title compound (49.1 mg).

[0360]

Example 46

N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: long retention time)

N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (114 mg) prepared in Example 42 was optically resolved by HPLC (CHIRALPAK IC, id 50 mm x length 500 mm, mobile phase: hexane/EtOH=400/600) and triturated with a long retention time (tR2 ) with IPE to give the title compound (52.0 mg).

[0361]

Example 49

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

[0362]

A) (4-(2-methylpyrimidin-4-yl)phenyl)methanol

The title compound was prepared from (4-(hydroxymethyl)phenyl)boronic acid and 4-chloro-2-methylpyrimidine in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 201.1.

[0363]

B) 4–(4–(chloromethyl)phenyl)–2–methylpyrimidine

The title compound was prepared in a manner similar to that described in Step B of Example 14.

MS: [M+H] ⁺ 219.1.

[0364]

C) methyl-7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 360.2.

[0365]

D) 7–(4–(2–methylpyrimidin–4–yl)benzyl)furo[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 346.2.

[0366]

E) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl )amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0367]

Example 51

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 –b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (stereoisomer: short retention time)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 -b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (21.1 mg) obtained in Example 39 was digested by HPLC (CHIRALCEL OJ, id. dia. 50 mm × length 500 mm, movable phase: hexane/EtOH=150/850), and triturate the short retention time (tR1) material with IPE to give the title compound (3.1 mg).

[0368]

Example 52

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 –b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (stereoisomer: long retention time)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 -b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (21.1 mg) obtained in Example 39 was digested by HPLC (CHIRALCEL OJ, id. dia. 50 mm × length 500 mm, movable phase: hexane/EtOH=150/850) and triturated the long retention time (tR2) material with IPE to give the title compound (3.7 mg).

[0369]

Example 53

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

[0370]

A) methyl-7-(hydroxy(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-furo[3,2-b]pyridine-5-carboxylate (100 mg) and trifluorotoluene (3.0 ml) NBS (53.6 mg) and AIBN (4.71 mg) were added at room temperature. The mixture was stirred under nitrogen at 80°C for 5 hours. After concentration under reduced pressure, acetone (3.0 ml) and water (10 ml) were added to the residue, and the mixture was stirred at 50°C for 16 hours. The mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (55.1 mg).

MS: [M+H] ⁺ 365.2.

[0371]

B) methyl-7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl-7-(hydroxy(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate (212, 6 mg) and anhydrous THF (12 ml) at room temperature was added DAST (0.154 ml). After the mixture was stirred at room temperature for 15 minutes, the mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration, washed with IPE and dried under reduced pressure to give the title compound (185 mg).

MS: [M+H] ⁺ 367.2.

[0372]

C) 7–(fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)furo[3,2–b]pyridine–5–carboxylic acid

To a mixture of methyl-7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate (236 mg ), MeOH (5.0 ml) and THF (3.0 ml) were added 2 M aqueous sodium hydroxide solution (2.0 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Water (6.0 ml) was added to the residue, and the mixture was neutralized by adding 1 M hydrochloric acid (4.0 ml). The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (219 mg).

MS: [M+H] ⁺ 353.2.

[0373]

D) 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo [3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

To a mixture of 7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylic acid (160 mg) , (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol (91 mg), WSC HCl (174 mg), HOBt H ₂ O (90 mg) and DMF (3.0 ml) were added at room temperature TEA (0.253 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. IPE was added to the residue and the precipitated solid was collected by filtration. The solid was washed with IPE and dried under reduced pressure to give the title compound (200.6 mg).

[0374]

Example 54

7–(Fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0375]

Example 55

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridin-5-yl)carbonyl)-amino)-L-threo-pentitol (stereoisomer: short retention time)

(synonym) 7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran -4-yl)furo[3,2-b]pyridine-5-carboxamide (stereoisomer: short retention time)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (194.6 mg) obtained in Example 53 was digested by HPLC (CHIRALPAK IA, id 50 mm x length 500 mm , mobile phase: EtOH) and triturated the short retention time (tR1) material with IPE to give the title compound (70 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.76-1.92 (1H, m), 2.03-2.14 (1H, m), 3.25 (1H, dd, J=11, 3, 9.9 Hz), 3.50 (1H, td, J=12.0, 2.5 Hz), 3.57–3.75 (1H, m), 3.95–4.06 (2H , m), 4.06–4.18 (4H, m), 4.23 (1H, dd, J=3.5, 0.6 Hz), 6.84–7.05 (2H, m), 7.53 (2H, d, J=7.4 Hz), 7.75 (1H, s), 7.84 (2H, d, J=8.0 Hz), 7.94 (1H, d, J =2.3 Hz), 8.14 (1H, d, J=5.9 Hz), 8.38 (1H, d, J=1.8 Hz).

[0376]

Example 56

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridin-5-yl)carbonyl)-amino)-L-threo-pentitol (stereoisomer: long retention time)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (194.6 mg) obtained in Example 53 was digested by HPLC (CHIRALPAK IA, id 50 mm x length 500 mm , mobile phase: EtOH), and triturated the long retention time (tR2) material with IPE to give the title compound (80.2 mg).

[0377]

Example 57

7–(Fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide (stereoisomer: short retention time)

7–(Fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide (63 mg) obtained in Example 54 was digested by HPLC (CHIRALPAK AD, i.d. 50 mm x length 500 mm, mobile phase: EtOH) and triturated with a short retention time (tR1 ) with IPE to give the title compound (20.9 mg).

[0378]

Example 58

7–(Fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide (stereoisomer: long retention time)

7–(Fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide (63 mg) obtained in Example 54 was digested by HPLC (CHIRALPAK AD, i.d. 50 mm x length 500 mm, mobile phase: EtOH) and triturated with a long retention time (tR2 ) with IPE to give the title compound (23.0 mg).

[0379]

Example 60

1,5-Anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro [3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

[0380]

A) methyl-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

MS: [M+H] ⁺ 351.2.

[0381]

B) 7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 337.1.

[0382]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3 -dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0383]

Example 62

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)- L-threo-pentitol

[0384]

A) methyl-7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 343.2.

[0385]

B) 7–(3–fluoro–4–(methylcarbamoyl)benzyl)furo[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 329.1.

[0386]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

[0387]

Example 63

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

[0388]

A) methyl-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step G of Example 1.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.42 (2H, t, J=8.9 Hz), 3.98 (3H, s), 4.76 (2H, t, J=8.9 Hz), 7.07 (1H, d, J=8.7 Hz), 7.97 (1H, d, J=8.3 Hz).

[0389]

B) methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step D of Example 20.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.29 (12H, s), 3.24-3.32 (2H, m), 3.83 (3H, s), 4.75 (2H , t, J=8.9 Hz), 7.98 (1H, s).

[0390]

C) methyl-7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step F of Example 1.

MS: [M+H] ⁺ 345.2.

[0391]

D) 7–(3–fluoro–4–(methylcarbamoyl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 1.

MS: [M+H] ⁺ 331.1.

[0392]

E) 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5- yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step H of Example 20.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.51-1.68 (1H, m), 1.75-1.86 (1H, m), 2.75 (3H, d, J= 4.5 Hz), 2.96–3.06 (1H, m), 3.32 (3H, s), 3.49–3.61 (1H, m), 3.70–3.83 (3H , m), 3.99 (2H, s), 4.75 (2H, t, J=8.9 Hz), 4.92 (1H, d, J=5.7 Hz), 7.10–7 .20 (2H, m), 7.55 (1H, t, J=7.7 Hz), 7.68 (1H, s), 8.14–8.22 (1H, m), 8.26 ( 1H, d, J=8.3 Hz).

[0393]

Example 64

1,5-Anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

[0394]

A) methyl-7-chloro-2-iodofuro[3,2-b]pyridine-5-carboxylate

N-iodosuccinimide (71.55 g ) and potassium fluoride (7.38 g), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, an aqueous solution of sodium thiosulfate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (8.0 g).

MS: [M+H] ^+338.05 .

[0395]

B) methyl-7-chloro-2-methylfuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl-7-chloro-2-iodofuro[3,2-b]pyridine-5-carboxylate (8.00 g), methylboronic acid (2.84 g), tripotassium phosphate (15.1 g), tricyclohexylphosphine (1, 99 g), palladium (II) acetate (1.06 g) and toluene (240 ml) were stirred under argon at 120° C. for 18 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.10 g).

MS: [M+H] ⁺ 225.9.

[0396]

C) methyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of bis(pinacolato)diboron (5.84 g), methyl-7-chloro-2-methylfuro[3,2-b]pyridine-5-carboxylate (2.60 g), 2-dicyclohexylphosphino-2',4 ',6'-triisopropyl-1,1'-biphenyl (0.550 g), potassium acetate (3.39 g) and 1,4-dioxane (78 ml) at room temperature was added Pd ₂ (dba) ₃ (0.528 g) . The mixture was stirred under argon at 80° C. for 2 h and cooled to room temperature. The reaction mixture was diluted with THF and heated at 60°C. The insoluble matter was removed by filtration on Celite. The filtrate was concentrated and the resulting solid was washed with pentane to give the title compound (2.60 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (12H, s), 2.58 (3H, s), 3.90 (3H, s), 6.91 (1H, s), 8.13 (1H, s).

[0397]

D) 2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylic acid

A mixture of methyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (428 mg), 4–(4–(chloromethyl)phenyl)–1–methyl–1H–1,2,3–triazole (278 mg), Pd(PPh ₃ ) ₄ (35 mg), potassium carbonate (372 mg), 1.4 -dioxane (12 ml) and water (4.0 ml) were subjected to microwave treatment at 110°C for 1 h. The solvent was concentrated under reduced pressure. The residue was washed with ethyl acetate, 1 M hydrochloric acid was added to adjust to pH 2, and the mixture was stirred. The precipitated solid was collected by filtration and purified by silica gel column chromatography (MeOH/dichloromethane) to give the title compound (200 mg).

MS: [M+H] ^+349.41 .

[0398]

E) 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo [3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.62-1.65 (1H, m), 1.81-1.84 (1H, m), 2.57 (3H, d, J= 0.92 Hz), 3.02 (1H, t, J=10.5 Hz), 3.30–3.34 (1H, m), 3.57–3.61 (1H, m), 3, 76–3.82 (3H, m), 4.07 (3H, s), 4.32 (2H, s), 4.95 (1H, d, J=5.80 Hz), 6.87 (1H , d, J=1.22 Hz), 7.38 (2H, d, J=8.24 Hz), 7.77–7.80 (3H, m), 8.47 (1H, s), 8 .51 (1H, d, J=8.54 Hz).

[0399]

Example 65

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-methylfuro[3,2-b]pyridine-5-yl)carbonyl) amino)-L-threo-pentitol

[0400]

A) 7–(3–fluoro–4–(methylcarbamoyl)benzyl)–2–methylfuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step D of Example 64.

MS: [M+H] ^+343.33 .

[0401]

B) 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-methylfuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.62-1.68 (1H, m), 1.76-1.84 (1H, m), 2.56 (3H, s), 2 .75 (3H, d, J=4.40 Hz), 3.02 (1H, t, J=10.51 Hz), 3.34–3.35 (1H, m), 3.59 (1H, br s), 3.77–3.82 (3H, m), 4.35 (2H, s), 4.94 (1H, br s), 6.87 (1H, s), 7.19 –7.28 (2H, m), 7.56 (1H, t, J=7.83 Hz), 7.79 (1H, s), 8.18 (1H, br s), 8.51 ( 1H, d, J=8.31 Hz).

[0402]

Example 66

1,5-Anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine -5-yl)carbonyl)amino)-L-threo-pentitol

[0403]

A) 2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Step D of Example 64.

MS: [M+H] ^+348.37 .

[0404]

B) 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.62-1.67 (1H, m), 1.81-1.84 (1H, m), 2.57 (3H, s), 3 .02 (1H, t, J=10.53 Hz), 3.33–3.34 (1H, s), 3.55–3.61 (1H, m), 3.75–3.82 (3H , m), 3.84 (3H, s), 4.27 (2H, s), 4.94 (1H, d, J=5.80 Hz), 6.86 (1H, d, J=0, 92 Hz), 7.29 (2H, d, J=8.24 Hz), 7.50 (2H, d, J=7.93 Hz), 7.78 (1H, s), 7.80 (1H , s), 8.07 (1H, s), 8.49 (1H, d, J=8.24 Hz).

[0405]

Example 67

1,5-Anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

[0406]

A) 2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Step D of Example 64.

MS: [M+H] ⁺ 334.27.

[0407]

B) 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5 -yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.62-1.65 (1H, m), 1.81-1.84 (1H, m), 2.57 (3H, d, J= 0.92 Hz), 3.02 (1H, t, J=10.53 Hz), 3.29–3.31 (1H, m), 3.57–3.62 (1H, m), 3, 75–3.82 (3H, m), 4.34 (2H, s), 4.94 (1H, d, J=5.80 Hz), 6.52 (1H, dd, J=2.44, 1.83 Hz), 6.87 (1H, d, J=1.22 Hz), 7.43 (2H, d, J=9.0 Hz), 7.72 (1H, d, J=1, 83 Hz), 7.77–7.80 (3H, m), 8.45 (1H, dd, J=2.44, 0.61 Hz), 8.51 (1H, d, J=8.54 Hz).

[0408]

Example 68

1,5-Anhydro-2,3-dideoxy-3-(((2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine-3- yl)methyl)furo[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

[0409]

A) 2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5 –carboxylic acid

The title compound was prepared in a manner similar to that described in Step D of Example 64.

MS: [M+H] ^+350.35 .

[0410]

B) 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine- 3-yl)methyl)furo[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in step I of Example 1.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.63-1.67 (1H, m), 1.81-1.84 (1H, m), 2.57 (3H, s), 3 .02 (1H, t, J=10.38 Hz), 3.35–3.37 (1H, m), 3.57–3.62 (1H, m), 3.77–3.82 (3H , m), 4.10 (3H, s), 4.36 (2H, s), 4.94 (1H, d, J=5.80 Hz), 6.88 (1H, d, J=0, 92 Hz), 7.80 (1H, dd, J=8.24, 2.14 Hz), 7.83 (1H, s), 7.97 (1H, d, J=7.93 Hz), 8 .51–8.52 (2H, m), 8.62 (1H, d, J=1.83 Hz).

[0411]

Example 74

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–imidazol–4–yl)benzyl)–2,3– dihydrofuro[3,2-b]pyridine-5-carboxamide

[0412]

A) (4-(1-methyl-1H-imidazol-4-yl)phenyl)methanol

To a mixture of 4-bromo-1-methyl-1H-imidazole (25 g), (4-(hydroxymethyl)phenyl)boronic acid (47.2 g), DME (250 ml) and water (50 ml) under argon at room temperature, cesium carbonate (100.93 g) and PdCl ₂ (dppf) DCM (6.33 g) were added, and the mixture was stirred under argon at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate, and the insoluble matter was removed by filtering on Celite. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (18.0 g).

MS: [M+H] ^+189.1 .

[0413]

B) 4–(4–(chloromethyl)phenyl)–1–methyl–1H–imidazole

Thionyl chloride (17.36 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (11 g).

MS: M+H 207.06.

[0414]

C) 7–(4–(1–methyl–1H–imidazol–4–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

Mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (400 mg) , 4-(4-(chloromethyl)phenyl)-1-methyl-1H-imidazole (325 mg), Pd(PPh ₃ ) ₄ (76 mg), potassium carbonate (725 mg), DME (7.5 ml) and water (4.5 ml) was subjected to microwave treatment at 150° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate and water, and the mixture was extracted with 1 M sodium hydroxide. The resulting aqueous layer was neutralized by adding 1 M hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (164.2 mg).

MS: [M+H] ⁺ 336.1.

[0415]

D) 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–imidazol–4–yl)benzyl)–2,3– dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of 7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid (100 mg), (3R,4S )-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (55.0 mg), TEA (0.062 ml), HOBt (60.4 mg) and DMF (3.0 ml) WSC was added under ice-cooling conditions ( 0.078 ml). The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate/hexane to give the title compound (81 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (1H, qd, J=12.3, 4.5 Hz), 1.77-1.85 (1H, m), 3 .01 (1H, t, J=10.5 Hz), 3.24–3.39 (3H, m), 3.54 (1H, tt, J=9.8, 5.1 Hz), 3, 67 (3H, s), 3.69–3.83 (3H, m), 3.90 (2H, s), 4.76 (2H, t, J=8.9 Hz), 4.93 (1H , d, J=5.4 Hz), 7.20 (2H, d, J=8.3 Hz), 7.54 (1H, d, J=1.2 Hz), 7.60 (1H, d , J=1.0 Hz), 7.63–7.68 (3H, m), 8.25 (1H, d, J=8.3 Hz).

[0416]

Example 76

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine -5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro [3,2-b]pyridine-5-carboxamide

[0417]

A) tert- butyl-2-fluoro-4-methylbenzoate

A mixture of 2-fluoro-4-methylbenzoic acid (10 g) and toluene (160 ml) was stirred under argon at 80°C for 30 min. A mixture of 1,1-di- tert- butoxy-N, N-dimethylmethanamine (31.1 ml) and toluene (40 ml) was added dropwise at 80°C, and the mixture was stirred at 100°C for 2 h. mixture at 80°C was added dropwise a mixture of 1,1-di- tert- butoxy-N, N-dimethylmethanamine (15.56 ml) and toluene (20 ml), and the mixture was stirred at 100°C for 2 h. the mixture was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (11.19 g). The compound was used in the next step without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.53 (9H, s), 2.36 (3H, s), 7.06-7.20 (2H, m), 7.64-7 .75 (1H, m).

[0418]

B) tert- butyl-4-(bromomethyl)-2-fluorobenzoate

AIBN (0.867 g) was added to a mixture of tert- butyl 2-fluoro-4-methylbenzoate (11.1 g), NBS (9.40 g) and trifluorotoluene (140 ml) at room temperature. The mixture was stirred under argon at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.37 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.53-1.57 (9H, m), 4.73 (2H, s), 7.34-7.45 (2H, m), 7 .80 (1H, t, J=7.8 Hz).

[0419]

C) methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

Mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (9.56 g), 10% palladium charcoal (NX type, 50% water moisture, 1.92 g) and MeOH (300 ml) were stirred in a hydrogen atmosphere at a pressure of 0.5–0.8 MPa at 30°C for 4 h. THF was added to the reaction mixture (300 ml), and the mixture was stirred in a hydrogen atmosphere at a pressure of 0.5–0.8 MPa at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (9.52 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23-1.36 (12H, m), 3.26-3.32 (2H, m), 3.83 (3H, s), 4 .72–4.79 (2H, m), 7.98 (1H, s).

[0420]

D) methyl-7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (2.0 d), tert- butyl-4-(bromomethyl)-2-fluorobenzoate (2.09 g), Pd(PPh ₃ ) ₄ (379 mg), potassium carbonate (3.62 g), DME (20 ml) and water (12 ml) was subjected to microwave treatment at 70°C for 10 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.96 g).

MS: [M+H] ⁺ 388.2.

[0421]

E) 1,5-anhydro-3-(((7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino )-2,3-dideoxy-L-threo-pentitol

To a mixture of methyl 7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (1.1 g) and THF (10 ml) with 1 M sodium hydroxide aqueous solution (5.68 mL) was added at room temperature, and the mixture was stirred at room temperature for 4 h. After neutralization with 1 M hydrochloric acid, the reaction mixture was concentrated under reduced pressure to give 7–(4–( tert- butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid as a solid. A mixture of the resulting solid, (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (0.567 mg), HATU (1.62 g), TEA (1.19 ml) and DMF (10 ml) was stirred at room temperature for 5 hours. Water was added to the reaction mixture at room temperature, the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.22 g).

MS: [M+H] ^+473.2 .

[0422]

F) 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2, 3-dideoxy-L-threo-pentitol

A mixture of 1,5-anhydro-3-(((7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino) -2,3-dideoxy-L-threo-pentitol (1.44 g) and 4 M hydrochloric acid in ethyl acetate (50 ml) were stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue between ethyl acetate and 1 M sodium hydroxide. The aqueous layer was neutralized by adding 1M hydrochloric acid under ice-cooling, the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.12 g).

MS: [M+H] ^+417.2 .

[0423]

G) 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro [3,2-b]pyridine-5-carboxamide

To a mixture of 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-2, 3-dideoxy-L-threo-pentitol (1.1 g), 2-methoxyethanamine (0.344 ml), HOBt (535 mg) and DMF (30 ml) were added WSC (0.695 ml) at 0°C. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate/heptane to give the title compound (858 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (1H, qd, J=12.3, 4.6 Hz), 1.81 (1H, dd, J=13.0, 4.4 Hz), 3.01 (1H, t, J=10.5 Hz), 3.26 (3H, s), 3.30–3.43 (7H, m), 3.54 (1H, tt, J=10.0, 5.0 Hz), 3.69–3.84 (3H, m), 3.99 (2H, s), 4.75 (2H, t, J=8.8 Hz ), 4.92 (1H, d, J=5.6 Hz), 7.07–7.21 (2H, m), 7.54 (1H, t, J=7.7 Hz), 7.69 (1H, s), 8.20–8.31 (2H, m).

[0424]

Example 77

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7–(3–fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4 –yl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

A mixture of 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-2,3 -dideoxy-L-threo-pentitol (100 mg), 1-((2S)-tetrahydrofuran-2-yl)methanamine (36.4 mg), WSC (0.085 ml), HOBt H ₂ O (73.6 mg) , TEA (0.100 ml) and DMF (2.0 ml) were stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). The resulting solid was crystallized from ethyl acetate/hexane to give the title compound (91 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.47-1.68 (2H, m), 1.69-1.95 (4H, m), 3.01 (1H, t, J= 10.5 Hz), 3.21–3.32 (3H, m), 3.33–3.40 (2H, m), 3.48–3.57 (1H, m), 3.58–3 .65 (1H, m), 3.68–3.84 (4H, m), 3.89–3.96 (1H, m), 3.99 (2H, s), 4.75 (2H, t , J=8.9 Hz), 4.92 (1H, d, J=5.6 Hz), 7.09–7.24 (2H, m), 7.53 (1H, t, J=7, 8 Hz), 7.69 (1H, s), 8.16–8.36 (2H, m).

[0425]

Example 95

Methyl-((2-fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridine -7-yl)methyl)benzoyl)amino)acetate

A mixture of 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-2,3 -dideoxy-L-threo-pentitol (200 mg), glycine methyl ester hydrochloride (90 mg), WSC (112 mg), HOBt (97 mg), TEA (0.201 ml) and DMF (3.0 ml) were stirred at 50°C for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). The resulting solid was crystallized from ethyl acetate/hexane to give the title compound (183 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.51-1.68 (1H, m), 1.75-1.86 (1H, m), 3.01 (2H, t, J= 10.5 Hz), 3.26-3.32(1H, m), 3.33-3.39(2H, m), 3.49-3.60(1H, m), 3.68-3 .86 (4H, m), 3.93–4.06 (5H, m), 4.75 (2H, t, J=8.9 Hz), 4.92 (1H, d, J=5.9 Hz), 7.12–7.25 (2H, m), 7.61 (1H, t, J=7.8 Hz), 7.70 (1H, s), 8.27 (1H, d, J = 8.1 Hz), 8.52–8.73 (1H, m).

[0426]

Example 96

((2-Fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridine-7 –yl)methyl)benzoyl)amino)acetic acid

To a mixture of methyl–2–(2–fluoro–4–((5–(((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)carbamoyl)–2,3–dihydrofuro[3,2– b]pyridin-7-yl)methyl)benzamido)acetate (220 mg), MeOH (2.0 ml) and THF (2.0 ml) were added at room temperature 1 M aqueous sodium hydroxide solution (2.0 ml), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized by adding 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate/hexane to give the title compound (179 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.47-1.68 (1H, m), 1.74-1.86 (1H, m), 2.94-3.08 (1H, m), 3.26–3.32 (1H, m), 3.33–3.39 (2H, m), 3.47–3.61 (1H, m), 3.67–3.84 ( 3H, m), 3.88–3.94 (2H, m), 4.01 (2H, s), 4.75 (2H, t, J=8.8 Hz), 4.92 (1H, d , J=5.6 Hz), 7.10–7.26 (2H, m), 7.62 (1H, t, J=7.8 Hz), 7.70 (1H, s), 8.27 (1H, d, J=8.1 Hz), 8.39–8.55 (1H, m), 12.60 (1H, s).

[0427]

Example 99

1,5-Anhydro-2,3-dideoxy-3-(((7-(4-((2-(diethylamino)-2-oxoethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3, 2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

A mixture of 2–(2–fluoro–4–((5–(((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)carbamoyl)–2,3–dihydrofuro[3,2–b]pyridine -7-yl) methyl) benzamido) acetic acid (50 mg), N-ethylethanamine (23.17 mg), WSC (49.2 mg), HOBt H ₂ O (24.26 mg), TEA (0.044 ml) and DMF (2.0 ml) was stirred at room temperature overnight. HATU (80 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (18.0 mg).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 0.93-1.08 (3H, m), 1.09-1.22 (3H, m), 1.45-1.68 (1H, m), 1.68–1.92 (1H, m), 2.94–3.08 (1H, m), 3.24–3.31 (4H, m), 3.33–3.39 ( 3H, m), 3.46–3.64 (1H, m), 3.69–3.86 (3H, m), 4.01 (2H, s), 4.11 (2H, d, J= 5.3 Hz), 4.75 (2H, t, J=8.7 Hz), 4.92 (1H, d, J=6.0 Hz), 7.07–7.28 (2H, m) , 7.60–7.76 (2H, m), 8.11–8.23 (1H, m), 8.26 (1H, d, J=8.3 Hz).

[0428]

Example 102

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)furo[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7–(3–fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4 –yl)furo[3,2–b]pyridine–5–carboxamide

[0429]

A) methyl-7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (2.6 g), tert- butyl-4-(bromomethyl)-2-fluorobenzoate (2.8 g), Pd(PPh ₃ ) ₄ (466 mg), potassium carbonate (4.46 g), DME (12 ml) and water (2 ml) were subjected to microwave treatment at 80°C for 20 min. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.30 g).

MS: [M+H] ⁺ 386.2.

[0430]

B) 7–(4–( tert– butoxycarbonyl)–3–fluorobenzyl)furo[3,2–b]pyridine–5–carboxylic acid

To a mixture of methyl 7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)-furo[3,2-b]pyridine-5-carboxylate (1.63 g), THF (30 ml) and MeOH (30 ml ) at room temperature was added 1 M aqueous sodium hydroxide solution (8.46 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized by adding 1 M hydrochloric acid under ice-cooling, stirred for some time, and the precipitated solid was collected by filtration to give the title compound (1.53 g).

MS: [M+H] ⁺ 372.2.

[0431]

C) 1,5-anhydro-3-(((7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-yl)carbonyl)amino)-2,3 –dideoxy–L–threo–pentitol

To a mixture of 7–(4–( tert– butoxycarbonyl)–3–fluorobenzyl)furo[3,2–b]pyridine–5–carboxylic acid (1.53 g), (3R,4S)–4–aminotetrahydro–2H– pyran-3-ol hydrochloride (759 mg), HOBt (835 mg) and DMF (20 ml) was added WSC (1.084 ml). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate/ethanol to give the title compound (1.81 g).

MS: [M+H] ^+471.3 .

[0432]

D) 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L -threo-pentitol

A mixture of 1,5-anhydro-3-(((7-(4-( tert- butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-yl)carbonyl)amino)-2,3- dideoxy-L-threo-pentitol (1.91 g) and 4 M hydrochloric acid in ethyl acetate (50 ml) were stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and 1 M sodium hydroxide. The aqueous layer was neutralized by adding 1 M hydrochloric acid under ice-cooling, the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.32 g).

MS: [M+H] ^+415.2 .

[0433]

E) 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)furo[3,2- b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

(synonym) 7–(3–fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4 –yl)furo[3,2–b]pyridine–5–carboxamide

To a mixture of 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L -threo-pentitol (1.31 g), 1-((2S)-tetrahydrofuran-2-yl)methanamine (0.480 g), HOBt (641 mg) and DMF (30 ml) WSC (0.832 ml). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/heptane to give the title compound (1.21 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.49-1.71 (2H, m), 1.73-1.96 (4H, m), 3.03 (1H, t, J= 10.5 Hz), 3.19–3.40 (3H, m), 3.52–3.67 (2H, m), 3.70–3.85 (4H, m), 3.93 (1H , fifth, J=6.2 Hz), 4.41 (2H, s), 4.96 (1H, d, J=5.6 Hz), 7.12–7.32 (3H, m), 7 .54 (1H, t, J=7.8 Hz), 7.92 (1H, s), 8.16–8.35 (1H, m), 8.47 (1H, d, J=2.4 Hz), 8.56 (1H, d, J=8.3 Hz).

[0434]

Example 109

1,5-Anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)furo[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

(synonym) 7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2- b]pyridine-5-carboxamide

A mixture of 1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L- threo-pentitol (70 mg), 2-methoxyethanamine (38.1 mg), WSC (0.089 ml), HOBt H ₂ O (51.7 mg), TEA (0.071 ml) and DMF (2.0 ml) were stirred at room temperature overnight. HATU (128 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (31.3 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.55-1.70 (1H, m), 1.77-1.90 (1H, m), 3.03 (1H, s), 3 .23–3.27 (3H, m), 3.28–3.31 (1H, m), 3.35–3.47 (4H, m), 3.51–3.68 (1H, m) , 3.80 (3H, td, J=10.2, 4.3 Hz), 4.41 (2H, s), 4.96 (1H, d, J=5.9 Hz), 7.17– 7.24 (2H, m), 7.28 (1H, d, J=11.5 Hz), 7.55 (1H, t, J=7.8 Hz), 7.92 (1H, s), 8.19–8.31 (1H, m), 8.45–8.49 (1H, m), 8.51–8.63 (1H, m).

[0435]

Example 111

1,5-Anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridine -5-yl)carbonyl)amino)-L-threo-pentitol

[0436]

A) 1–(3–fluoro–4–(methoxymethoxy)phenyl)ethanone

A mixture of 1-(3-fluoro-4-hydroxyphenyl)ethanone (5.0 g), chloro(methoxy)methane (2.96 ml), potassium carbonate (5.38 g) and DMF (50 ml) was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (6.09 g).

MS: [M+H] ^+199.0 .

[0437]

B) methyl-7-(1-(3-fluoro-4-(methoxymethoxy)phenyl)ethyl)-furo[3,2-b]pyridine-5-carboxylate

A mixture of 1-(3-fluoro-4-(methoxymethoxy)phenyl)ethanone (1.70 g), 4-methylbenzenesulfonohydrazide (2.40 g) and toluene (34.3 ml) was stirred at 80°C for 2 h. Methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate (3.12 g) was added to the reaction mixture and potassium carbonate (2.37 g), and the mixture was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.6 g).

MS: [M+H] ⁺ 360.0.

[0438]

C) methyl–7–(1–(3–fluoro–4–hydroxyphenyl)ethyl)furo[3,2–b]pyridine–5–carboxylate

A mixture of methyl 7-(1-(3-fluoro-4-(methoxymethoxy)phenyl)ethyl)-furo[3,2-b]pyridine-5-carboxylate (2.1 g) and 2 M hydrochloric acid in methanol (4.26 g) was stirred at room temperature overnight. Saturated brine was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (960 mg). The compound was used in the next step without further purification.

MS: [M+H] ⁺ 316.0.

[0439]

D) methyl–7–(1–(3–fluoro–4–(((trifluoromethyl)sulfonyl)oxy)–phenyl)ethyl)furo[3,2–b]pyridine–5–carboxylate

Trifluoromethanesulfonic anhydride (5.46 ml), and the mixture was stirred under ice-cooling for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.01 g).

MS: [M+H] ^+448.0 .

[0440]

E) methyl–7–(1–(3–fluoro–4–((2–(trimethylsilyl)ethoxy)–carbonyl)phenyl)ethyl)furo[3,2–b]pyridine–5–carboxylate

A mixture of methyl-7-(1-(3-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate (1.01 g), 2 -(trimethylsilyl)ethanol (0.971 ml), palladium(II) acetate (76 mg), 1,3-bis(diphenylphosphino)propane (140 mg), TEA (0.629 ml) and DMF (10 ml) were stirred under carbon monoxide atmosphere at 70° C. for 4 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (801 mg).

MS: [M+H] ^+444.1 .

[0441]

F) 2-fluoro-4-(1-(5-(methoxycarbonyl)furo[3,2-b]pyridin-7-yl)ethyl)benzoic acid

To a mixture of methyl-7-(1-(3-fluoro-4-((2-(trimethylsilyl)ethoxy)-carbonyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate (810 mg) and THF (20 ml) was added 1 M solution of tetra- n -butylammonium fluoride in THF (3.65 ml) under ice-cooling conditions, and the mixture was stirred at room temperature for 3 h. acid, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate/hexane to give the title compound (361 mg).

MS: [M+H] ⁺ 344.0.

[0442]

G) methyl–7–(1–(3–fluoro–4–((2–methoxyethyl)carbamoyl)phenyl)–ethyl)furo[3,2–b]pyridine–5–carboxylate

A mixture of 2-fluoro-4-(1-(5-(methoxycarbonyl)furo[3,2-b]pyridin-7-yl)ethyl)benzoic acid (300 mg), 2-methoxyethanamine (131 mg), HATU (665 mg), TEA (0.487 ml) and DMF (3.0 ml) were stirred at room temperature for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (162 mg).

MS: [M+H] ^+401.1 .

[0443]

H) 1,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

To a mixture of methyl 7–(1–(3–fluoro–4–((2–methoxyethyl)carbamoyl)–phenyl)ethyl)furo[3,2–b]pyridine–5–carboxylate (52 mg), MeOH (1 ml) and THF (1 ml) at room temperature was added 4 M aqueous solution of lithium hydroxide (0.097 ml). After stirring at room temperature for 2 h, 6 M hydrochloric acid (0.065 ml) was added and the mixture was concentrated to give 7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo [3,2-b]pyridine-5-carboxylic acid as a solid. A mixture of the resulting solid, (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (30 mg), HATU (74.1 mg), TEA (0.036 ml) and DMF (1.0 ml) was stirred at room temperature for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52.0 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.59-1.69 (1H, m), 1.71-1.79 (3H, m), 1.80-1.90 (1H, m), 2.95–3.11 (1H, m), 3.25 (3H, s), 3.33–3.44 (5H, m), 3.52–3.67 (1H, m) , 3.72–3.89 (3H, m), 4.80 (1H, q, J=7.1 Hz), 4.97 (1H, dd, J=5.5, 4.3 Hz), 7.16–7.26 (2H, m), 7.31 (1H, dd, J=11.7, 1.5 Hz), 7.54 (1H, t, J=7.8 Hz), 7 .98 (1H, s), 8.26 (1H, br s), 8.44 (1H, d, J=2.2 Hz), 8.57 (1H, d, J=8.3 Hz) .

[0444]

Example 112

1,5-Anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)-2,3-dihydrofuro[3, 2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

[0445]

A) methyl-7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-ethyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

Mixture of methyl 7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)-phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate (160 mg), 10% palladium charcoal (type NX, 50% wetness with water, 32 mg) and MeOH (30 ml) were stirred under hydrogen atmosphere at 5 MPa at 50° C. for 4.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title in the title compound (140 mg). The compound was used in the next step without further purification.

MS: [M+H] ^+403.2 .

[0446]

B) 7–(1–(3–fluoro–4–((2–methoxyethyl)carbamoyl)phenyl)ethyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxylic acid

The title compound was prepared in a manner similar to that described in Step H of Example 111.

MS: [M+H] ⁺ 389.1.

[0447]

C) 1,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)-2,3-dihydrofuro[ 3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in Step H of Example 111.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.49-1.66 (4H, m), 1.75-1.85 (1H, m), 2.94-3.07 (2H, m), 3.25 (3H, s), 3.28–3.31 (1H, m), 3.35–3.47 (5H, m), 3.49–3.61 (1H, m) , 3.68–3.87 (3H, m), 4.34 (1H, q, J=7.0 Hz), 4.72 (2H, t, J=9.0 Hz), 4.92 ( 1H, t, J=5.4 Hz), 7.08–7.30 (2H, m), 7.48–7.59 (1H, m), 7.72 (1H, s), 8.12 –8.37 (2H, m).

[0448]

Example 113

1,5-Anhydro-2,3-dideoxy-3-(((7-(((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3- dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

[0449]

A) 2-methyl-1-oxoisoindoline-5-carbaldehyde

A mixture of 5-bromo-2-methylisoindolin-1-one (1030 mg), 2-isocyano-2-methylpropane (947 mg), sodium carbonate (579 mg), palladium (II) acetate (102 mg), biphenyl-2- yl(di- tert- butyl)phosphine (272 mg), triethylsilane (2.18 ml) and DMF (20 ml) were stirred under nitrogen at 75°C for 2.5 h. After cooling the reaction mixture to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound (690 mg).

MS: M+H 176.4.

[0450]

B) 5–(hydroxymethyl)–2–methylisoindolin–1–one

Sodium borohydride (285 mg) was added to a mixture of 2-methyl-1-oxoisoindoline-5-carbaldehyde (660 mg) and THF (20 ml) at 0°C, and the mixture was stirred at room temperature for 1 h. water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, the solvent was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound (576 mg).

MS: [M+H] ⁺ 178.4.

[0451]

C) 5–(chloromethyl)–2–methylisoindolin–1–one

Thionyl chloride (0.475 ml) was added to a mixture of 5-(hydroxymethyl)-2-methylisoindolin-1-one (576 mg), toluene (5 ml) and acetonitrile (10 ml) at 0°C. After stirring at room temperature for 1 hour, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound (126 mg).

MS: [M+H] ⁺ 196.4.

[0452]

D) methyl-7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was prepared in a manner similar to that described in Step A of Example 102.

MS: [M+H] ⁺ 339.4.

[0453]

E) 7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Step B of Example 31.

MS: [M+H] ⁺ 325.3.

[0454]

F) 1,5-anhydro-2,3-dideoxy-3-(((7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2, 3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was prepared in a manner similar to that described in Example 22.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (1H, qd, J=12.3, 4.4 Hz), 1.80 (1H, dd, J=13.2, 4.4 Hz), 2.98–3.05 (4H, m), 3.26–3.31 (1H, m), 3.33–3.38 (2H, m), 3.55 (1H , d, J=5.1 Hz), 3.77 (3H, td, J=10.8, 4.4 Hz), 4.04 (2H, s), 4.42 (2H, s), 4 .75 (2H, t, J=8.9 Hz), 4.92 (1H, d, J=5.6 Hz), 7.35 (1H, d, J=8.1 Hz), 7.43 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.67 (1H, s), 8.26 (1H, d, J=8.1 Hz).

[0455]

Example compounds are presented in the following Tables. In the tables, MS stands for measured values. Compounds of Examples 2, 3, 6, 7, 9, 11, 13, 15, 17, 19, 21, 23, 24, 28, 30, 32, 34, 41, 47, 48, 50, 59, 61, 69– 73, 75, 78-94, 97, 98, 100, 101, 103108 and 110 in the following Tables were prepared by the methods presented in the Examples mentioned above, or by a similar method.

[0456]

Table 1–1

Example
No. Name according to IUPAC Structural formula Salt MS 1 N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

405.2 2 N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

419.2 3 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5- yl)carbonyl)amino)-L-threo-pentitol

421.2 4 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)furo[3,2–b]pyridine–5–carboxamide

417.2 5 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1–methyl–1H–pyrazol–3–yl)benzyl)furo[3,2–b]pyridine–5–carboxamide

431.2

[0457]

Table 1–2

Example
No. Name according to IUPAC Structural formula Salt MS 6 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

419.1 7 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

433.1 8 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

435.2 9 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1–methyl–1H–pyrazol–3–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5 –carboxamide

433.2 10 N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–methoxypyridin–3–yl)methyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

384.3

[0458]

Table 1–3

Example
No. Name according to IUPAC Structural formula Salt MS eleven N–((1S,2S)–2–hydroxycyclopentyl)–7–((6–methoxypyridin–3–yl)methyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

370.3 12 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–methoxybenzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

383.2 13 N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

369.2 14 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(5–methyl–1,3–thiazol–2–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine –5–carboxamide

450.2 15 N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine –5–carboxamide

436.2

[0459]

Table 1–4

Example
No. Name according to IUPAC Structural formula Salt MS 16 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(4–methyl–1,3–thiazol–2–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine –5–carboxamide

450.2 17 N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine –5–carboxamide

436.2 18 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(2–methyl–1,3–thiazol–5–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine –5–carboxamide

450.2 19 N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine –5–carboxamide

436.2

[0460]

Table 1–5

Example
No. Name according to IUPAC Structural formula Salt MS 20 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl )furo[3,2-b]pyridine-5-carboxamide

434.1 21 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

434.1 22 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5- yl)carbonyl)amino)-L-threo-pentitol
(synonym) 7-(4-(1H-pyrazol-1-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3, 2–b]pyridine–5–carboxamide

421.2 23 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1–methyl–1H–1,2,3–triazol–4–yl)benzyl)furo[3,2–b]pyridine– 5-carboxamide

432.2

[0461]

Table 1–6

Example
No. Name according to IUPAC Structural formula Salt MS 24 N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)furo[3,2–b]pyridine–5–carboxamide

453.2 25 N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

455.2 26 N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: short retention time)

455.2 27 N–( trans– 5,5–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: long retention time)

455.2 28 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

435.2

[0462]

Table 1–7

Example
No. Name according to IUPAC Structural formula Salt MS 29 1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro [3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

436.2 thirty N-(2-hydroxycyclobutyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

391.2 31 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[ 3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl )-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

436.2 32 N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3, 2–b]pyridine–5–carboxamide

434.2

[0463]

Table 1–8

Example
No. Name according to IUPAC Structural formula Salt MS 33 N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–(1–methyl–1H–1,2,3–triazol–4–yl)pyridin–3–yl)methyl)furo[3 ,2–b]pyridine–5–carboxamide

433.2 34 1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl) furo[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

435.2 35 N–((1S,2S)–2–hydroxycyclohexyl)–7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)furo[3,2–b]pyridine –5–carboxamide

432.2 36 1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2- b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–((6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl) methyl)furo[3,2-b]pyridine-5-carboxamide

434.1

[0464]

Table 1–9

Example
No. Name according to IUPAC Structural formula Salt MS 37 1,5-anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)- L-threo-pentitol

384.2 38 1,5-anhydro-2,3-dideoxy-3-(((7-((6-oxo-1,6-dihydropyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

370.2 39 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 –b]pyridin–5–yl)carbonyl)amino)–L–threo–pentitol

452.2 40 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

433.2 41 1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

433.2

[0465]

Table 1–10

Example
No. Name according to IUPAC Structural formula Salt MS 42 N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

455.2 43 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

445.2 44 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–pyrazol–4–yl)benzyl)–2,3– dihydrofuro[3,2-b]pyridine-5-carboxamide

435.2 45 N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: short retention time)

455.2

[0466]

Table 1–11]

Example
No. Name according to IUPAC Structural formula Salt MS 46 N–( trans– 4,4–difluoro–2–hydroxycyclohexyl)–7–(4–(1H–pyrazol–1–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide (optical isomer: long retention time)

455.2 47 N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2 –b]pyridine–5–carboxamide

434.2 48 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

419.2 49 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino )–L–threo–pentitol

445.2 50 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(2–methylpyrimidin–4–yl)benzyl)furo[3,2–b]pyridine–5–carboxamide

443.3

[0467]

Table 1–12]

Example
No. Name according to IUPAC Structural formula Salt MS 51 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 –b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (stereoisomer: short retention time)

452.2 52 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2 –b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (stereoisomer: long retention time)

452.2 53 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

452.2 54 7–(fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide

450.2

[0468]

Table 1–13

Example
No. Name according to IUPAC Structural formula Salt MS 55 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (stereoisomer: short retention time)
(synonym) 7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran -4-yl)furo[3,2-b]pyridine-5-carboxamide (stereoisomer: short retention time)

452.2 56 1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3 ,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (stereoisomer: long retention time)

452.2 57 7–(fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide (stereoisomer: short retention time)

450.2 58 7–(fluoro(4–(1–methyl–1H–1,2,3–triazol–4–yl)phenyl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2– b]pyridine-5-carboxamide (stereoisomer: long retention time)

450.2

[0469]

Table 1–14

Example
No. Name according to IUPAC Structural formula Salt MS 59 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[ 3,2-b]pyridine-5-yl)carbonyl)amino)-D-threo-pentitol

436.2 60 1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro [3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

436.2 61 N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3, 2–b]pyridine–5–carboxamide

434.1 62 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)- L-threo-pentitol

428.1 63 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

430.1

[0470]

Table 1–15

Example
No. Name according to IUPAC Structural formula Salt MS 64 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

448.1 65 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-methylfuro[3,2-b]pyridine-5-yl)carbonyl) amino)-L-threo-pentitol

442.1 66 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine -5-yl)carbonyl)amino)-L-threo-pentitol

447.1 67 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

433.1 68 1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine-3- yl)methyl)furo[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

449.1

[0471]

Table 1–16

Example
No. Name according to IUPAC Structural formula Salt MS 69 7–(fluoro(6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2–b] pyridine-5-carboxamide

450.1 70 7–(fluoro(6–(1–methyl–1H–pyrazol–4–yl)pyridin–3–yl)methyl)–N–((1S,2S)–2–hydroxycyclohexyl)furo[3,2–b] pyridine-5-carboxamide

450.1 71 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-D-threo-pentitol

434.1 72 7–(3–fluoro–4–(methylcarbamoyl)benzyl)–N–((1S,2S)–2–hydroxycyclopentyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

414.2 73 7–(3–fluoro–4–(methylcarbamoyl)benzyl)–N–((1S,2S)–2–hydroxycyclohexyl)–2,3–dihydrofuro[3,2–b]pyridine–5–carboxamide

428.2

[0472]

Table 1–17

Example
No. Name according to IUPAC Structural formula Salt MS 74 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)–7–(4–(1–methyl–1H–imidazol–4–yl)benzyl)–2,3– dihydrofuro[3,2-b]pyridine-5-carboxamide

435.1 75 N–((1S,2S)–2–hydroxycyclohexyl)–7–(4–(1–methyl–1H–imidazol–4–yl)benzyl)–2,3–dihydrofuro[3,2–b]pyridine–5 –carboxamide

433.1 76 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)-benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) 7-(3-fluoro-4-((2-methoxyethyl)-carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3- dihydrofuro[3,2-b]pyridine-5-carboxamide

474.1 77 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol
(synonym) 7–(3–fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)–benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran– 4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

500.2

[0473]

Table 1–18

Example
No. Name according to IUPAC Structural formula Salt MS 78 1,5-anhydro-3-(((7-(4-((cyclopropylmethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino) -2,3-dideoxy-L-threo-pentitol

470.2 79 1,5-anhydro-3-(((7-(4-((cyclopentylmethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino) -2,3-dideoxy-L-threo-pentitol

498.2 80 1,5-anhydro-3-(((7-(4-(butylcarbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2, 3-dideoxy-L-threo-pentitol

472.2 81 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(ethylcarbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl )amino)-L-threo-pentitol

444.2 82 1,5-anhydro-3-(((7-(4-(cyclopropylcarbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2, 3-dideoxy-L-threo-pentitol

456.2

[0474]

Table 1–19

Example
No. Name according to IUPAC Structural formula Salt MS 83 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(isopropylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

458 84 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(propylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

458.2 85 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(isobutylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

472.2 86 1,5-anhydro-2,3-dideoxy-3-(((7-(4-((2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine- 5-yl)carbonyl)amino)-L-threo-pentitol

488.2 87 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((3-methoxypropyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine -5-yl)carbonyl)amino)-L-threo-pentitol

488.2

[0475]

Table 1–20

Example
No. Name according to IUPAC Structural formula Salt MS 88 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2R)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

500.3 89 1,5-anhydro-3-(((7-(4-((2- tert- butoxyethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

514 90 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((4-hydroxybenzyl)-carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

522.2 91 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((3-hydroxybenzyl)-carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

522.2 92 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((4-hydroxyphenyl)-carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b] pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

507.9

[0476]

Table 1–21

Example
No. Name according to IUPAC Structural formula Salt MS 93 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((1-methoxypropan-2-yl)carbamoyl)-benzyl)-2,3-dihydrofuro[3, 2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

488.0 94 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(pentylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl) carbonyl)amino)-L-threo-pentitol

486 95 methyl–((2–fluoro–4–((5–(((3R,4S)–3–hydroxytetrahydro–2H–pyran–4–yl)carbamoyl)–2,3–dihydrofuro[3,2–b]pyridine -7-yl)methyl)benzoyl)amino)acetate

488.2 96 ((2-fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridine-7 –yl)methyl)benzoyl)amino)acetic acid

474.2 97 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-(isopropylsulfanyl)ethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5-yl)-carbonyl)amino)-L-threo-pentitol

518.2

[0477]

Table 1–22

Example
No. Name according to IUPAC Structural formula Salt MS 98 1,5-anhydro-3-(((7-(4-((2-( tert- butylsulfanyl)ethyl)-carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine- 5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

532.4 99 1,5-anhydro-2,3-dideoxy-3-(((7-(4-((2-(diethylamino)-2-oxoethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3, 2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

529.2 100 1,5-anhydro-2,3-dideoxy-3-(((7-(4-((2-(dimethylamino)-2-oxoethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3, 2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

501.2 101 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-oxo-2-(pyrrolidin-1-yl)ethyl)-carbamoyl)benzyl)-2 ,3-dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

527.3

[0478]

Table 1–23

Example
No. Name according to IUPAC Structural formula Salt MS 102 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-furo[3,2-b ]pyridine-5-yl)-carbonyl)amino)-L-threo-pentitol
(synonym) 7–(3–fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)–carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran– 4-yl)furo[3,2-b]pyridine-5-carboxamide

498.2 103 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(propylcarbamoyl)-benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino) -L-threo-pentitol

456.2 104 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((3-methoxypropyl)-carbamoyl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol

486.2 105 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2R)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

498.2

[0479]

Table 1–24

Example
No. Name according to IUPAC Structural formula Salt MS 106 1,5-anhydro-3-(((7-(4-(cyclopropylcarbamoyl)-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L -threo-pentitol

454.2 107 1,5-anhydro-2,3-dideoxy-3-(((7-(4-((2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-yl)carbonyl )amino)-L-threo-pentitol

486.2 108 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((tetrahydro-2H-pyran-2-ylmethyl)carbamoyl)-benzyl)furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

512.3 109 1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)-carbamoyl)benzyl)furo[3,2-b]pyridin-5-yl )carbonyl)amino)-L-threo-pentitol
(synonym) 7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2- b]pyridine-5-carboxamide

472.2

[0480]

Table 1–25

Example
No. Name according to IUPAC Structural formula Salt MS 110 1,5-anhydro-3-(((7-(4-((cyclopropylmethyl)carbamoyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-yl)carbonyl)amino)-2,3- dideoxy-L-threo-pentitol

468.3 111 1,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-ethyl)-furo[3,2-b ]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

486.3 112 1,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-ethyl)-2,3-dihydrofuro[3 ,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

488.2 113 1,5-anhydro-2,3-dideoxy-3-(((7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3- dihydrofuro[3,2-b]pyridine-5-yl)carbonyl)amino)-L-threo-pentitol

424.2

[0481]

Composition example 1

(1) The compound obtained in Example 1 10.0 g (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) magnesium stearate 2.0 g

A mixture of the compound (10.0 g) obtained in Example 1, lactose (60.0 g) and corn starch (35.0 g) is passed through a 1 mm sieve and granulated using 10 wt.% aqueous gelatin solution (30 ml) (3.0 g gelatin), the granules are dried at 40° C. and sieved again. The obtained granules are mixed with magnesium stearate (2.0 g) and the mixture is compressed. The resulting tablet core is coated with a sugar coating consisting of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are glazed with beeswax to give 1000 coated tablets.

[0482]

Composition example 2

(1) The compound obtained in Example 1 10.0 g (2) Lactose 70.0 g (3) Corn starch 50.0 g (4) Soluble Starch 7.0 g (5) magnesium stearate 3.0 g

The compound (10.0 g) obtained in Example 1 and magnesium stearate (3.0 g) are granulated using an aqueous solution of soluble starch (70 ml) (7.0 g of soluble starch), dried and mixed with lactose (70, 0 g) and corn starch (50.0 g). The mixture is compressed to give 1000 tablets.

[0483]

Experimental example 1

Measurement of positive allosteric modulating activity at the M1 receptor (M1PAM)

The activity of a test compound in the presence of acetylcholine at an EC ₂₀ concentration (final concentration 0.8-1.0 nM) that provides an effect corresponding to approximately 20% of the maximum activity was measured as PAM activity. The method is as follows. CHO-K1 cells stably expressing the human M1 receptor (hCHRM1) were plated in a 384-well black clear bottom plate (BD Falcon) at 5,000 cells per well and cultured in an incubator at 37°C and 5% CO ₂ in within 1 day. The medium in the cell plate was removed and assay buffer A containing calcium indicator (registration medium (DOJINDO LABORATORIES), 0.1% BSA (Wako Pure Chemical Industries, Ltd.), 2.5 μg/ml Fluo-4 AM (DOJINDO LABORATORIES), 0.08% Pluronic F127 (DOJINDO LABORATORIES), 1.25 mM probenecid (DOJINDO LABORATORIES)), at 30 µl per well. Cells were left in an incubator at 37°C and 5% CO ₂ for 30 minutes, and additionally left at room temperature for 30 minutes. Test compound prepared by dilution in assay buffer B (HBSS (Invitrogen), 20 mM HEPES (Invitrogen), 0.1% BSA) containing 3.2-4.0 nM acetylcholine was added at 10 µl per well, and fluorescence was measured by FDSS/μCELL (Hamamatsu Photonics KK) for 1 minute in 1 second increments. Taking the amount of fluorescence change upon addition of acetylcholine (final concentration 1 μM) as 100%, and that upon addition of DMSO instead of the test compound as 0%, the activity of the test compound (in %) was calculated, and the inflection point in the concentration curve of the test compound was calculated as the IP value . The results are presented in Table 2.

[0484]

[Table 2–1]

Example No. IP value (nM) Activity (%) at 10 µM 3 13 100 8 7.9 100 16 10 100 18 12 97 20 0.88 98 21 1.6 100 22 1.7 106 23 1.5 99 27 4.5 100 28 2.3 101 31 1.4 101 34 2.4 100 36 1.5 96 40 1.6 98 43 2.4 110 44 1.5 105 46 4.3 107 47 1.8 101 48 1.1 103 49 2.9 104 51 0.88 104 55 0.63 107 56 42 106 57 1.1 99 60 1.6 104 61 1.8 104

[0485]

[Table 2–2]

Example No. IP value (nM) Activity (%) at 10 µM 64 2.4 109 65 8.5 106 70 1.2 99 74 1.5 108 76 3.5 109 77 3.2 108 81 5.3 108 82 6.4 110 88 7.6 111 89 25 110 90 1.4 113 96 eleven 107 97 5.1 107 100 3.8 103 102 2.7 107 105 4.3 105 109 2.4 107 111 8.8 107 113 21 109

[0486]

Experimental example 2

Rat defecation experiment

Male SD rats (aged 5-6 weeks) were used after an acclimatization period of 1 week. The test drug (1 mg/kg or 3 mg/kg) was suspended in 0.5% methylcellulose solution and administered orally at a volume of 5 ml/kg, and after 2 hours the faeces were counted. The solvent group received only 0.5% methylcellulose.

The results are presented in Table 3. The results are presented as "mean ± standard error".

[0487]

[Table 3]

Example No. dose Solvent group
0 mg/kg 1 mg/kg 3 mg/kg 20 amount of feces after 2 hours 4.9±1.0 10.6±1.3 12.1 ± 1.1 31 amount of feces after 2 hours 3.5±0.6 10.0±1.4 - 76 amount of feces after 2 hours 3.3±1.0 8.3±0.8 10.3±0.9 77 amount of feces after 2 hours 2.1±0.6 13.9±1.5 12.3 ± 1.6 102 amount of feces after 2 hours 4.4 ± 1.1 8.9±1.3 12.4±0.9

[0488]

Experimental Example 3

Pharmacokinetic test in rats

As rats, 8 week old male SD rats (Japan SLC, Inc.) were used. They were fed a commercially available solid ration (CE-2, CLEA Japan, Inc.) and were allowed to freely consume tap water as drinking water. An intravenous solution for rats was prepared by weighing the test compound, dissolving it in dimethylacetamide (DMA) (Wako Pure Chemical Industries, Ltd.), adding the same volume of 1,3-butanediol (Wako Pure Chemical Industries, Ltd.), and mixing with shaking to obtain a solution of DMA:1,3-butanediol (1:1, v/v). An oral solution was prepared by weighing the test compound, pulverizing it into an agate mortar, and gradually adding 0.5% w/v methylcellulose aqueous solution to form a suspension. For intravenous administration, the solution was injected into the femoral vein of rats at 0.1 mg/0.5 ml/kg (salt converted to free base form). For oral administration, the suspension was administered to rats at 1 mg/5 ml/kg (salt converted to free base form). For both routes of administration, the cassette dosing method was used and the test compound was administered as follows.

Compound of Example 20 (intravenous: cassette administration of 8 compounds, orally: cassette administration of 5 compounds)

Compound of Example 22 (intravenously: cassette administration of 5 compounds, orally: cassette administration of 5 compounds)

Compound of Example 31 (intravenous: cassette administration of 10 compounds, orally: cassette administration of 5 compounds)

Compound of Example 36 (intravenous: cassette administration of 10 compounds, orally: cassette administration of 5 compounds)

Compound of Example 44 (intravenous: cassette administration of 10 compounds, orally: cassette administration of 5 compounds)

Compound of Example 55 (intravenous: cassette administration of 6 compounds, orally: cassette administration of 4 compounds)

Compound of Example 74 (intravenous: cassette administration of 10 compounds, orally: cassette administration of 5 compounds)

Compound of Example 76 (intravenous: cassette administration of 9 compounds, orally: cassette administration of 4 compounds)

Compound of Example 77 (intravenous: cassette administration of 10 compounds, orally: cassette administration of 5 compounds)

Compound of Example 102 (intravenous: cassette administration of 10 compounds, orally: cassette administration of 5 compounds)

Compound of Example 109 (IV: cassette administration of 7 compounds, orally: cassette administration of 4 compounds)

In the case of intravenous administration, blood samples were collected from the tail vein at 5, 10, 15, 30 minutes, 1, 2, 4, 8 hours after administration, anticoagulant treatment with sodium heparin (Shimizu Pharmaceutical Co., Ltd.), collected after centrifugation. plasma and measured the concentration of the drug. In the case of oral administration, blood samples were collected from the tail vein at 15, 30 minutes, 1, 2, 4, 8 hours after administration, anticoagulant treatment with sodium heparin was performed, plasma was collected after centrifugation, and drug concentration was measured.

All drug concentrations were measured by LC-MS/MS analysis. For the pharmacokinetic test, plasma (50 µl) was placed in a test tube, acetonitrile (150 µl) containing an internal standard solution was added, and mixed by vortexing. Then, the mixture was centrifuged (5000 rpm, 5 minutes, 4°C). The supernatant (60 μl) after centrifugation was added to the previously added 10 mM ammonium formate (160 μl) and mixed. This sample was entered into LC/MS/MS. The HPLC system used was Shimadzu LC-20A (Shimadzu Corporation), the column used was Unison UK-C18 HT (3.0 µm, 2.0×20 mm, Imtakt) at 50°C; 10 mM ammonium formate with 0.2% formic acid as mobile phase A and acetonitrile with 0.2% formic acid as mobile phase B were fed at a flow rate of 1.2 ml/min in gradient mode (concentration B: 0 min - 0.1 min, 5%, 0.1-0.75 min, 5-99%, 0.75-1.15 min, 99%, 1.15-1.16 min, 5%, 1.16- 1.5 min, 5%). The MS/MS used was AB Sciex TQ5500-MPX (Applied Biosystems).

The results are presented in Table 4.

Tmax: time to reach maximum plasma concentration

MRT: Mean Retention Time

IV: intravenous administration

General CL: total ground clearance

[0489]

[Table 4]

Example No. Tmax
(watch) MRT IV
(watch) General CL
(ml/hours/kg) 20 2.0 1.8 246 22 2.0 1.9 280 31 1.0 1.5 200 36 1.3 1.9 327 44 1.3 1.3 286 55 1.7 0.6 1814 74 0.8 0.9 843 76 0.8 1.2 335 77 1.0 0.8 488 102 1.0 0.9 703 109 1.0 1.5 404

[0490]

Experimental example 4

MDR1 membrane permeability test

If MDR1 is overexpressed in LLC-PK1 cells, which are polar cells, then MDR1 is localized to the apical membrane (A), thereby enhancing transcellular transport from the basement membrane (B) towards A. If an indicator of transcellular transport in the opposite direction is obtained and further obtain a score for a control cell into which the surrogate vector has been introduced, then the MDR1 permeability ratio by simple diffusion (adjusted permeability ratio) is calculated. By analogy, if the Mdr1(–/–) mouse brain/plasma concentration ratio is divided by the wild-type mouse brain/plasma concentration ratio, then the Mdr1 permeability ratio is obtained by simple diffusion across the blood-brain barrier (BBB) ("Kp, ratio in the brain", a higher value means lower permeability to the central nervous system). Adachi Y. et al. (Reference 1) a positive correlation was reported between the adjusted permeability ratio and the "Kp, brain ratio" value (Figure 5(C)), and the permeability ratio in an MDR1-expressing cell and the "Kp, brain ratio" value (Figure 5 (IN)). In other words, this report shows that a higher in vitro MDR1 permeability ratio results in lower central nervous system permeability.

[0491]

In order to confirm the permeability of the compounds of the present invention to the central nervous system, the MDR1 membrane permeability test was carried out in the following way.

Digoxin and lucifer yellow (LY) were purchased from Sigma-Aldrich, Diclofenac, colchicine, and alprenolol were purchased from Wako Pure Chemical Industries, Ltd, and other reagents used were specialty grade commercial products.

MDR1-expressing human LLC-PK1 cells were cultured according to Takeuchi et al. (Link 2). MDR1-expressing human LLC–PK1 cells were cultured in M199 medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen), 500 µg/mL G418 (Invitrogen), 150 ng/mL colchicine, in 5% _CO2 at 37°C. C.

Transcellular transport was performed as reported by Sugimoto et al. (Link 3). Cells were cultured for 3 days on a HTS Transwell (registered trademark) 96-well permeable base (pore size 0.4 μm, surface area 0.143 cm ² , Corning Life Sciences) with a polyethylene terephthalate membrane, on which cells were seeded in an amount of 3, 45×10 ⁴ cells per well. After preincubation in M199 medium (containing 10 mmol/L HEPES, 1% BSA, pH 7.4) for 30 minutes, 75 or 250 µl of drug solution (10 µmol/L digoxin, 200 µmol/l LY, 10 µmol/l test compound) dissolved in M199 medium, and cultured cells in 5% CO ₂ at 37°C. After 1 hour, the sample was collected from the side opposite to which the drug solution was added, and the concentration of the test compound was measured by LC-MS/MS. 100 ng/ml of aprenolol and diclofenac were used as internal standard substances. The analysis conditions were as follows.

LC: UFLC LC-20 (Shimadzu)

MS/MS: API4000 (AB Sciex Instruments)

LC Conditions: Gradient Method

[0492]

[Table 5]

Time (min) Pump B (%) 0.02 5 0.40 95 0.80 95 0.81 5 1.50 Stop

[0493]

Column: Unison UK–C18 HT (3.0 µm, 2.0×20 mm)

Column temperature: 50°C

Flow rate: 0.7 ml/min (within 1.5 min run), 1.0 ml/min (within 1.0 min run)

Mobile phase A: 50 mM CH ₃ COONH ₄ :MeCN:water=1:1:8

Mobile phase B: 50 mM CH ₃ COONH ₄ :MeCN=1:9

Injection volume: 1–20 µl

[0494]

LY fluorescence was measured on a fluorescence plate reader (Fluoroskan Ascent FL).

The values of P _app (AB) and P _app (BA) (effective permeability) were calculated by formula (1), and the permeability ratio (ER) was calculated by formula (2).

[0495]

P _app =Amount/Area×C ₀ ×Time (1)

[0496]

Quantity: amount of transferred digoxin per well

Area: surface area of the cell monolayer (0.143 cm ² )

C ₀ : concentration of the added drug solution

Time: incubation time

[0497]

ER = P _app (BA) / P _app (AB) (2)

[0498]

The results are presented in Table 6.

[0499]

[Table 6]

Example No. MDR1 substrate screening
1 μM (MDRSUB1)/Ratio (NUM) 20 4.8 22 2.6 31 eleven 36 9.1 44 5.5 55 6.5 74 eleven 76 35 77 25 102 20 109 10

[0500]

Bibliographic index of reference materials

1. Adachi Y. et al., Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein, Pharm. Res. 18:1660–1668, 2001

2. Takeuchi T., Yoshitomi S., Higuchi T., Ikemoto K., Niwa S., Ebihara T., Katoh M., Yokoi T. and Asahi S., Establishment and characterization of the transformants stably–expressing MDR1 derived from various animal species in LLC–PK1, Pharm. Res., 23(7):1460–1472, 2006

3. Sugimoto H., Hirabayashi H., Kimura Y., Furuta A., Amano N. and Moriwaki T., Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood-brain barrier in rats, Drug Metab. Dispos., 39(1):8–14, 2011

Industrial Applicability

[0501]

The compound of the present invention may have a positive allosteric modulatory activity for the M1 cholinergic muscarinic receptor, and may be useful as a drug such as an agent for the prevention or treatment of constipation, etc.

[0502]

This application is based on Japanese Patent Application Nos. 2017-120859 and 2018-005960 and United States Patent Application No. 62/683,418, the entire contents of which are incorporated herein by reference.

Claims (61)

1. The compound represented by formula (I):

, in which R ¹ is (1) a 3- to 14-membered non-aromatic heterocyclic group containing one oxygen atom and substituted with one hydroxy group, or (2) a C _3-10 cycloalkyl group substituted with 1-3 substituents selected from hydroxy and halogen; R ² represents a hydrogen atom or a C _1-6 alkyl group;

is a single bond; ring A represents (1) a benzene ring further substituted with one or two substituents selected from (a) a halogen atom, (b) a C _1-6 alkoxy group, (c) a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with one substituent, selected from (i) a C _1-6 alkoxy group, (ii) a C _3-10 cycloalkyl group, (iii) a 3-14 membered non-aromatic heterocyclic group containing one oxygen atom, (iv) a C _6-14 aryl group substituted with one a hydroxy group, (v) a C _1-6 alkoxycarbonyl group, (vi) a carboxy group, (vii) a C _1-6 alkylthio group, (viii) a di-C _1-6 alkylcarbamoyl group, and (ix) a 3-14-membered non-aromatic heterocyclylcarbonyl group, containing one nitrogen atom, (d) a mono-C _3-10 cycloalkylcarbamoyl group, (e) a C _6-14 arylcarbamoyl group substituted with one hydroxy group, and (f) a 5-14 membered aromatic heterocyclic group containing 1-3 heteroatoms, selected from a nitrogen atom and a sulfur atom, and optionally substituted with one C _1-6 alkyl group, (2) or a 6-membered monocyclic aromatic heterocycle containing one nitrogen heteroatom and further substituted with one substituent selected from (a) a C _1-6 alkoxy group and (b) a 5-14-membered aromatic heterocyclic group containing two or three nitrogen heteroatoms and substituted with one C _1–6 alkyl group, (3) a 4-6 membered monocyclic non-aromatic heterocycle containing one nitrogen heteroatom and additionally substituted with one oxo group, or (4) a 9-14 membered fused polycyclic non-aromatic heterocycle containing one nitrogen heteroatom and further substituted with two substituents selected from a C _1-6 alkyl group and an oxo group; And each of R ³ and R ⁴ independently represents a hydrogen atom, a halogen atom or a C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof. 2. The connection according to claim 1, in which R ¹ is

or a pharmaceutically acceptable salt thereof. 3. Connection according to claim 1, in which ring A represents (1) a benzene ring further substituted with one or two substituents selected from (a) a halogen atom, (b) a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with one substituent selected from (i) C _1-6 an alkoxy group and (ii) a 3-14 membered non-aromatic heterocyclic group containing one oxygen heteroatom and (c) a 5-14 membered aromatic heterocyclic group containing one to three heteroatoms selected from a nitrogen atom and a sulfur atom and optionally substituted with one C _1-6 alkyl group, or (2) a 6-membered monocyclic aromatic heterocycle containing one nitrogen heteroatom and further substituted with one 5-14-membered aromatic heterocyclic group containing two or three nitrogen heteroatoms and optionally substituted with one C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof. 4. Connection according to claim 1, in which ring A represents

where R ^5A is a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with one substituent selected from C _1-6 alkoxy and a 3-14 membered non-aromatic heterocyclic group containing one oxygen heteroatom; X is CR ^6A ; And R ^6A represents a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. 5. Connection according to claim 1, in which ring A represents

where R ^5A represents a 5-14-membered aromatic heterocyclic group containing from one to three heteroatoms selected from a nitrogen atom and a sulfur atom and optionally substituted with one C _1-6 alkyl group; X is CR ^6A or N; And R ^6A represents a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. 6. Connection according to claim 1, in which ring A represents

where R ^5A is a 5-14 membered aromatic heterocyclic group containing two or three nitrogen heteroatoms and substituted with one C _1-6 alkyl group; And X is N; or a pharmaceutically acceptable salt thereof. 7. The connection according to claim 1, in which R ¹ is a 3-14-membered non-aromatic heterocyclic group containing one oxygen heteroatom and substituted with one hydroxy group; R ² represents a hydrogen atom; ring A represents (1) a benzene ring further substituted with one or two substituents selected from (a) a halogen atom, (b) a mono- or di-C _1-6 alkylcarbamoyl group optionally substituted with one substituent selected from (i) C _1-6 an alkoxy group and (ii) a 3-14 membered non-aromatic heterocyclic group containing one oxygen heteroatom, and (c) a 5-14 membered aromatic heterocyclic group containing one to three heteroatoms selected from a nitrogen atom and a sulfur atom, and optionally substituted one C _1-6 alkyl group, or (2) a 6-membered monocyclic aromatic heterocycle containing one nitrogen heteroatom and additionally substituted with one 5-14-membered aromatic heterocyclic group containing two or three nitrogen heteroatoms and substituted with one C _1-6 alkyl group; And each of R ³ and R ⁴ independently represents a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. 8. N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl) -2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof. 9. 7-(3-Fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[ 3,2-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof. 10. 7–(3–Fluoro–4–((((S)–tetrahydrofuran–2–yl)methyl)carbamoyl)benzyl)–N–((3R,4S)–3–hydroxytetrahydro–2H–pyran–4– yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof. 11. A drug for the prevention or treatment of constipation, containing an effective amount of a compound according to any one of paragraphs. 1-10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 12. A drug that has the activity of positive allosteric modulation of the cholinergic muscarinic M1 receptor, containing an effective amount of the compound according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 13. A method for positive allosteric modulation of the M1 cholinergic muscarinic receptor in a mammal, comprising administering to said mammal an effective amount of a compound according to any one of claims. 1-10 or a pharmaceutically acceptable salt thereof. 14. A method for preventing or treating constipation in a mammal, comprising administering to said mammal an effective amount of a compound according to any one of paragraphs. 1-10 or a pharmaceutically acceptable salt thereof. 15. The use of a compound according to any one of paragraphs. 1-10 or a pharmaceutically acceptable salt thereof for the preparation of a prophylactic or therapeutic agent for constipation. 16. Connection according to any one of paragraphs. 1-10 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of constipation.