NZ614321B2 - Glycine transporter-inhibiting substances - Google Patents

Glycine transporter-inhibiting substances Download PDF

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NZ614321B2
NZ614321B2 NZ614321A NZ61432112A NZ614321B2 NZ 614321 B2 NZ614321 B2 NZ 614321B2 NZ 614321 A NZ614321 A NZ 614321A NZ 61432112 A NZ61432112 A NZ 61432112A NZ 614321 B2 NZ614321 B2 NZ 614321B2
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group
acetamide
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compound
trifluoromethyl
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NZ614321A
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NZ614321A (en
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Kumi Abe
Yuko Araki
Minoru Moriya
Hiroshi Ohta
Xiangmin Sun
Daisuke Wakasugi
Shuji Yamamoto
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Taisho Pharmaceutical Co Ltd
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Priority claimed from PCT/JP2012/054110 external-priority patent/WO2012115097A1/en
Publication of NZ614321A publication Critical patent/NZ614321A/en
Publication of NZ614321B2 publication Critical patent/NZ614321B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The disclosure relates to a imidazolidin-2-one derivative represented by formula [I] or a pharmacologically-permitted salt thereof, wherein the variables are as defined in the specification. This compound, on the basis of the glycine-uptake-inhibiting effect thereof, is useful in the prevention or therapy of disorders such as schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, specific phobias, acute stress disorder, and the like), depression, drug dependence, seizures, tremors, pain, Parkinson's disease, attention-deficit hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders. herapy of disorders such as schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, specific phobias, acute stress disorder, and the like), depression, drug dependence, seizures, tremors, pain, Parkinson's disease, attention-deficit hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders.

Description

DESCRIPTION GLYCINE TRANSPORTER-INHIBITTNG SUBSTANCES TECHNICAL FIELD The present invention relates to compounds having a e transporter-inhibiting action.
BACKGROUND ART The NMDA receptor, which is one of glutamate receptors, is located on the nerve cell membranes in the brain and involved in s neurophysiologic events such as neuronal plasticity, cognition, attention, and . The NMDA receptor has a plurality of allosteric binding sites, one of which is the glycine binding site (glycine binding site on NMDA receptor complex). It has been reported that the glycine binding site on NMDA receptor complex is involved in the activation ofNMDA receptors (Non-Patent Document 1).
Action potential arriving at the presynaptic terminals of glycinergic nerves triggers the release of glycine into synaptic clefts. The released glycine binds to the postsynaptic receptors or the like and is then removed from the synaptic clefts by transporters. Based on this fact, e transporters are ed to regulate the functions ofNMDA receptors through regulation ofthe amount of glycine in the extracellular fluid. e transporters (GlyTs) are proteins involved in the reuptake of extracellular glycine into cells, and two subtypes, GlyTl and GlyT2, have so far been identified. GlyTl, which is sed primarily in the cerebral cortex, hippocampus, thalamus and the like, has been reported to be associated with diseases such as schizophrenia, Alzheimer’s disease, cognitive impairment, dementia, anxiety disorders (e.g., lized anxiety disorder, panic er, obsessive-compulsive disorder, social anxiety er, post-traumatic stress disorder, c phobias, acute stress disorder), depression, drug dependence, spasm, , pain, Parkinson’s disease, attention deficit hyperactivity disorder, bipolar disorder, eating disorder, and sleep disorders (Non—Patent Documents 2—4). nds having a GlyTl ~inhibiting action and having an imidazolidinone structure have been reported in the documents shown below (Patent Documents 1 and 2).
These compounds bed in Patent Documents 1 and 2 are characterized in that a phenyl group is attached via amide or carbonyl to one of the endocyclic nitrogen atoms of the imidazolidine, While another phenyl group is attached to the other endocyclic nitrogen atom of the imidazolidine, and that an endocyclic carbon atom of the imidazolidinone is a spiro carbon atom.
CITATION LIST PATENT DOCUMENTS Patent Document 1: W02008092878 Patent Document 2: 034062 NON~PATENT DOCUMENTS Non-Patent Document 1: Molecular Psychiatry (2004) 9, 984-997 Non-Patent nt 2: Current nal Chemistry, 2006, 13, 1017—1044 Non-Patent Document 3: Neuropsychopharmacology (2005), 30, 1963-1985 Non~Patent Document 4: Expert Opinion on Therapeutic Patents (2004) 14 (2) 201- SUMMARY OF INVENTION TECHNICAL PROBLEM [000 8] The present invention aims to provide novel compounds or pharmaceutically acceptable salts thereof which are useful in the prevention or treatment of diseases such as schizophrenia, Alzheimer’s disease, cognitive ment, dementia, y disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety er, post—traumatic stress disorder, c phobias, acute stress disorder), depression, drug dependence, spasm, tremor, pain, Parkinson’s disease, attention deficit hyperactivity disorder, r disorder, eating disorder, or sleep disorders, which is based on the glycine uptake-inhibiting action.
SOLUTION TO PROBLEM As a result of extensive and intensive studies on structurally novel compounds with an inhibitory action against GlyTl the t inventors found that the compounds represented by the following formula, in which a nitrogen—containing aromatic ring group is attached to one of the endocyclic nitrogen atoms of the imidazolidine and the clic carbon atoms ofthe imidazolidinone are not spiro carbon atoms, are superior GlyTl- inhibiting substances. This finding has led to the completion of the present invention.
The present invention will be described below in detail. Embodiments ofthe present invention (hereinafter each referred to as “the ive compound”) are as shown below (1) A compound of formula [I] or a pharmaceutically acceptable salt thereof: [001 1] [Formula 1] \ O 3,N o R ‘7 R6 E I R1 and R1, are the same or different, and each represent a hydrogen atom, a halogen atom, a 01.6 alkoxy group, a haloC1.6 alkyl group, a cyano group, a heteroaryl group (which may be substituted by a C1.6 alkyl group), a CH, alkyl group, a C34, cycloalkyl group, a CH, alkylamino group, or the formula 8 (R7 and R8 are the same or different, and each represent a hydrogen atom or a C1-6 alkyl group), R2 represents a hydrogen atom or a CM alkyl group, R3 ents a phenyl group (which may be substituted by 1 to 3 substituents selected from halogen atoms, cyano groups, C1_6 alkyl groups, C1_6 alkoxy groups, CM alkylamino , C14, alkylsulfonyl groups, haloC1-6 alkyl groups, haloC1.6 alkoxy groups, haloCH’J alkylsulfanyl groups, phenyl groups, phenoxy groups, heteroaryl groups (which may be substituted by a cm alkyl group), and the formula ~802NR9R1° (R9 and R10 are the same or different, and each represent a hydrogen atom or a CM alkyl group)) or a heteroaryl group or a bicyclic heteroaryl group (the each heteroaryl group may be substituted by l to 3 substituents selected from halogen atoms, Cm alkyl groups, C343 cycloalkyl groups, C1-6 alkoxy groups, cyano groups, CM alkanoyl groups, and haloC1-6 alkyl groups), R4 represents a (31-6 alkyl group (which may be substituted by l to 3 halogen atoms, a CM alkoxy group, a C3.5 cycloalkyl group, or a phenyl group), a C3_6 lkyl group, or a phenyl group, R5 and R6 are the same or different, and each represent a hydrogen atom or a C16 alkyl group, and A], A2, A3, and A4 are the same or different, and each represent the formula CH or a nitrogen atom, provided that one or two of A], A2, A3, and A4 represent a nitrogen atom. (2) The compound or ceutically acceptable salt thereof according to (1), wherein R1 is a en atom, a halogen atom, a C1-6 alkoxy group, a haloC1.6 alkyl group, a cyano group, a heteroaryl group (which may be substituted by a C1.6 alkyl group), a Cm alkyl group, a C1_6 alkylarnino group, or the formula CONR7R8 (R7 and R8 are the same or different, and each represent a hydrogen atom or a CM alkyl group), R1, is a hydrogen atom, R3 is a phenyl group (which may be substituted by 1 to 3 substituents selected from halogen atoms, cyano groups, CH, alkyl groups, C1.6 alkoxy groups, C1-6 alkylamino , CH, alkylsulfonyl groups, haloC1.6 alkyl groups, haloC1.6 alkoxy groups, _6 alkylsulfanyl groups, phenyl groups, phenoxy groups, heteroaryl groups (which may be substituted by a Cm alkyl group), and the formula ~SOZNR9RI0 (R9 and R10 are the same or different, and each ent a hydrogen atom or a CM, alkyl group)) or a heteroaryl group (which may be substituted by 1 to 3 substituents selected from halogen atoms, C1-6 alkyl groups, C1_6 alkoxy groups, cyano groups, and haloCH, alkyl ), and R4 is a C1-6 alkyl group (which may be tuted by a C3_6 cycloalkyl group or a phenyl group) or a phenyl group. (3) The compound or pharmaceutically acceptable salt thereof according to (1), wherein R4 is a C1_6 alkyl group which may be substituted by 1 to 3 halogen atoms. (4) The nd or pharmaceutically acceptable salt thereof according to (l) or (2), wherein R4 is a CM, alkyl group. (5) The compound or ceutically acceptable salt thereof according to any one of (l) to (4), wherein R2 is a hydrogen atom, and R5 and R6 are both a hydrogen atom. (6) The compound or pharmaceutically acceptable salt thereof according to (5), wherein R1 is a halogen atom, a C1.6 alkoxy group, a haloC1_6 alkyl group, a cyano group, a aryl group (which may be substituted by a C1-6 alkyl group), a C1_6 alkyl group, a CM alkylamino group, or the formula CONR7R8 (R7 and R8 are the same or ent, and each ent a hydrogen atom or a CM alkyl group), and R1‘ is a hydrogen atom. (7) The compound or pharmaceutically acceptable salt thereof according to any one of (1) and (3) to (5), wherein R1 is a halogen atom, a C1-6 alkoxy group, a haloC1.6 alkyl group, a CM, alkyl group, or a C3.6 cycloalkyl group, and R1, is a hydrogen atom, a halogen atom, a C1-6 alkoxy group, a haloC1.6 alkyl group, a C1-6 alkyl group, or a C3-6 cycloalkyl group. (8) The nd or pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein R1 is attached in the para position. (9) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein any one of A], A2, A3 and A4 is a nitrogen atom or A] and A3 are both a nitrogen atom. (10) The nd or pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein Al is a nitrogen atom, A2 and A4 are both the a CH, and A3 is the formula CH or a nitrogen atom. (11) The compound or pharmaceutically acceptable salt thereof according to any one of (l) and (3) to (10), wherein R3 is a heteroaryl group (which may be substituted by l to 3 substituents selected from halogen atoms, C1-6 alkyl groups, C3-6 cycloalkyl groups, CH, alkoxy groups, cyano groups, CH, alkanoyl groups, and haloC1.5 alkyl groups). (12) The compound or ceutically acceptable salt thereof ing to any one of (1) and (3) to (10), wherein R3 is a pyridyl group (which may be substituted by l to 3 substituents selected from n atoms, CH, alkyl groups, C3_6 cycloalkyl groups, C]_5 alkoxy groups, cyano groups, CM alkanoyl groups, and haloCH’> alkyl ). (13) The compound or phannaceutically acceptable salt thereof according to any one of (I) and (3) to (10), n R3 is a pyridyl group (which may be substituted by 1 to 3 substituents selected from halogen atoms, CH; alkyl groups, C3_6 lkyl groups, and haloC1.6 alkyl groups). (14) The compound or pharmaceutically acceptable salt thereof according to (1), wherein the compound is selected from the group consisting of: 2-[(5S)(S-methoxypyrimidinyl)oxo-5~(propan—Z-yl)imidazolidin-l-yl]-N- [4-(t1'ifluoromethyl)pyridinyl]acetarnide, )(5-ethylpyrimidin-Z-yl)~2-oxo(propanyl)imidazolidinyl]-N-[4- (trifluoromethyl)pyridinyl]acetamide, 2-[(5S)—3-(5-chloropyrimidin—2-yl)-2—oxopropylimidazolidin~l-yl]—N-[4- (trifluoromethyl)pyridin—2—yl]acetarnide, N-(4~chloropyridin~2-yl)[(5S)(5-chloropyrimidin—2—y1)—2-oxo propylimidazolidinyl]acetamide, 2-[(5S)—3-(5-chloropyrimidinyl)oxopropylimidazolidin~1~yl]~N—(4- ethylpyridin—Z-yi)acetamide, 2-[(SS)(5-fluoropyrimidin—2-yl)0x0propylimidazolidin-l-yl]—N—[4- (trifluoromethyl)pyridiny1]acetamide, 2-[(5 S)—3 —(5-fluoropyrimidinyl)—2—oxo—5~(propan—2—yl)imidazolidin—1 -yl]~N-[4- (trifluoromethyl)pyridin—2-yl]acetamide, N-(4-cyclopropylpyridin—Z—yl)—2—{(5S)ox0(propan-2—yl)—3—[5— (trifluoromethyl)pyrimidinyl]imidazolidin~1~yl}acetamide, 2-[(5 S)—5— [(28)-butan—2-yl]-3—(5~chloropyrimidiny1)-2~oxoimidazolidin— 1 ~y1]-N- {4—(trifluoromethyl)pyridiny1]acetamide, h10ropyridin—2-y1)~2~[(SS)(5-chloropyrimidin-2~y1)-2~0xo(propan y1)imidazolidin- l -y1]acetamide, h10ropyridiny1){ (5 S)oxo(pr0pan—2—yl)[5- (trifluoromethyl)pyrimidin—2-y1]imidazolidin—1 —y1}acetamide, 2—[(5 S)—3—(5~cycl0pr0py1pyrimidin-2—yl)—2—0xo(propanyl)imidazolidin—1 -yI]~ N-[4-(trifluoromethyl)pyridin—Z-yl]acetamide, N—(4-ch10ropyridin—2~y1)-2—[(SS)(5-cyclopropylpyrimidin—2-y1)oxo-5~(propan- 2-y1)imidazolidin—1-yl]acetamide, 2-[(5 S)—5-[(2 S)-butan—2—y1]~3~(5~ch10ropyrimidinyI)-2—oxoimidazolidin— 1 ~y1]—N— (4—cyc10propy1pyridin~2~y1)acetamide, 2—[(5S)¥5-[(2S)-butany1](5-ch10ropyrimidiny1)oxoimidazolidiny1]—N- (4-chloropyridinyl)acetamide, 2-[(5S)[(ZS)-butany1](5-ch1oropyrimidinyl)ox0imidazolidin—1-yl]-N-(4- ethylpyridiny1)acetamide, N-(4-ch10ropyridin—2~y1) {(5R)[(1 S)- 1 propy1]ox0[5- (trifluoromethyl)pyrimidin—2-yl]imidazolidiny1} acetamide, N—(4—ch10ropyridinyl) {(5R)-3~(5-ch10ropyrimidinyl)[(1 S)—1~ fluoropropyl]oxoimidazolidiny1}acetamide, N~(4—cycl0propy1pyridinyl)—2-{(5R)[(1S)-1~flu0r0propyl]oxo[5~ (trifluoromethyl)pyrimidiny1]imidazolidin—1-yl}acetamide, 2-{(5R)[(1S)fluoropropy1]0x0[5-(trifluoromethy1)pyrimidin y1]imidazolidiny1} -N-[4-(trifluoromethyl)pyridinyl]acetamide, )—3~(5-ch10r0pyrimidin—2—yl)—5—[(1S)fluor0propy1]ox0imidazolidin—1— yl} -N- [4-(trifluoromethy1)pyridinyl]acetamide, 2~[(5R)-5— [(1 S)~ 1~fluoropropyl](5-fluoropyrimidin~2-y1)oxoimidazolidin—1- y1]-N—[4-(trifluoromethyl)pyridin-2~yl]acetamide, 2—{(5R)—3-(5—cyclopropylpyrimidin-Z-yl)~5—[(1 S)fluoropropy1]-2~ oxoimidazolidin—1~y1}—N—[4-(trifluoromethyl)pyridin—2-yl]acetamide, 2~{(5R)—3-(5—eth0xypyrimidin»2—y1)-5—[(1S)fluoropropyl]oxoimidazolidin—1- yl } —N— [4-(trifluor0methy1)pyridin~2~yl] acetamide, N—(4-cyc]0pr0pylpyridiny1){(5R)(5-ethoxypyrimidin~2~y1)—5-[(1 S)-1 — fluoropropyl]oxoimidazolidin—1—y1}acetarnide, N—(4—chloropyridin—2~yl) { (5R)(5-ethoxypyrimidin-2—y1)—5—[(1 S)—1 - fluoropropyl]ox0imidazolidiny1}acetamide, 2-[(5 (2S)-butany1]—3 oropyrimidin-2—y1)oxoimidazolidin— 1 -y1]~N- [4—(trifluoromethy1)pyridin-2—y1]acetamide, 2- {(5 S)-5—[(ZS)-butany1]oxo—3-[5~(trifluoromethy1)pyrimidin—2- y1]imidazolidinyl} -N—(4~oyclopropylpyridinyl)acetamide, 2- {(5 S)—5-[(ZS)-butany1] oxo[5-(trifluoromethyl)pyrimidin—2— y1]imidazolidin- l -y1} -N-(4-chloropyridin~2~y1)acetamide, 2-[(5S)—3-(5-ethoxypyrimidiny1)-2~oxo(propan—Z-yl)imidazolidiny1]-N-[4— (trifluoromethyl)pyridin—2~yl}acetamide, N—(4-chloropyridin-2—yl)~2~[(SS)(5-eth0xypyrimidin-2—y1)oxo—5-(propan~2~ y1)imidazolidin—1-yl]acetamide, N—(4—cyclopropylpyridin-2—yl)[(5S)(5-ethoxypyrimidin~2—yl)-2—0x0—5-(pr0pan- 2—y1)imidazolidiny1]acetamide, 2-[(5 (ZS)-butan—2~y1]~3 ~(5—ethoxypyrimidiny1)—2-oxoimidazolidin— 1 -y1]~N- [4~(trifluoromethyl)pyridin—2-y1]acetamide, 2-[(SS)-5—[(ZS)-butanyl]—3—(5—cyclopropylpyrimidin—Z-yl)oxoimidazolidin- 1— yl]-N-[4-(trifluoromethy1)pyridiny1]acetamide, N—(S—chloropyridin—2-yl) {(5S)—2-oxopropy1-3—[5~(trifluoromethy1)pyrimidin yl] imidazolidin—l —y1 }acetamide, hIoromethylpyridin»2~y1)-2— {(5 S)—2—0X0—5-pr0pyl—3—[5- (trifluoromethyl)pyrirnidin—2-yl]imidazolidiny1}acetamide, N-(S-chloro-6~methylpyridin-2—yl)-2~[(5S)(5-chloropyrimidin—2»y1)—2-oxo-S— propylimidazolidin—1—yi]acetamide, 2-{(5S)oxo~5—(propany1)-3—[5—(propanyloxy)pyrimidin—2-yl]imidazolidin—1— yl}-N—[4-(trifluoromethyl)pyridin-2—yl]acetamide, 2—[(5 S)~5~[(2 S)-butan—2—yl]~3~(5-ethoxypyrimidiny1)-2~0x0imidazolidin-l —yl]—N- (4~chloropyridinyl)acetarnide, 2-[(5S)—5-[(2S)-butan-2—yl]~3-(5-cyclopropylpyrimidin—2~yl)~2—0xoimidazolidin—1- yl]~N~(4-chloropyridinyl)acetamide, 2~ [(5 S)-5 - [(2 S)-butan—2-yl]—3~(5 —eth0xypyrimidinyl)—2-oxoimidazolidin—1—yl]~N- (4—cyclopropy1pyridin~2~yi)acetamide, and 2-[(SS)[(ZS)-butanyl](5-cyclopropylpyrimidin—Z—yl)oxoimidazolidin yl]-N-(4-cyclopropylpyridin-2~yl)acetarnide. (15) A ceutical ition comprising, as an active ingredient, the nd or pharmaceutically acceptable salt thereof according to any one of (1) to (14). (16) An agent for preventing or treating diseases of schizophrenia, Alzheimer’s disease, cognitive impairment, dementia, y disorders, depression, drug ence, spasm, tremor, pain, Parkinson’s disease, attention deficit hyperactivity disorder, bipolar disorder, eating disorder, or sleep disorders, which comprises, as an active ient, the compound or pharmaceutically acceptable salt thereof according to any one of (1) to (14).
ADVANTAGEOUS EFFECTS OF INVENTION The inventive compounds have glycine transporter (GlyT1)-inhibiting activity.
DESCRIPTION OF EMBODIMENTS The term “Cwy (x and y each denote a natural number)” as used herein means that the number of carbon atoms is x to y.
The term “Cm alkyl group” as used herein refers to a straight-chain or branched- chain alkyl group having 1 to 6 carbon atoms, and includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tyl group, a pentyl group, an isopentyl group, and a hexyl group. -10, The term “C3-6 cycloalkyl group” as used herein refers to a cycloalkyl group having 3 t0 6 carbon atoms, which is a ropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
The term “CM alkoxy group” as used herein refers to a straight—chain or branched- chain alkoxy group having 1 to 6 carbon atoms, and includes, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group.
The term “Cm alkanoyl group” as used herein refers to a ht-chain or branched- chain alkanoyl group having 1 to 6 carbon atoms, and es, for example, a formyl group, an acetyl group, a propanoyl group, a butanoyl group, and a pivaloyl group.
The term “halogen (halo)” as used herein refers to fluorine, chlorine, bromine, or iodine.
The term “haloC1-6 alkyl group” as used herein refers to a straight—chain or branched-chain alkyl group which has 1 to 6 carbon atoms and which has been tuted by a halogen atom or halogen atoms. The preferred number of the substituting halogen atom(s) is 1 to 3. Examples of the haloC1.5 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluorornethyl group, and a triohloromethyl group. Among these groups, a trifluoromethyl group is preferred.
The term “C1-6 mino group” as used herein refers to a group characterized in that l or 2 straight-chain or branched-chain alkyl groups each having 1 to 6 carbon atoms are attached to an amino group. Examples of the CM alkylamino group include a methylamino group, a dimethylamino group, a diethylamino group, an N~ethy1—N—methylamino group, and the like.
The term “CM alkylamine” as used herein refers to an amine which has one or two straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms. es of the CM mine include methylamine, dimethylamine, diethylamine, N-ethyl—N~methylamine, and the like.
The term “Cm alkylsulfonyl group” as used herein refers to a straight-chain or branched—chain alkylsulfonyl group having 1 to 6 carbon atoms, and es, for example, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a tert~butylsulfonyl group, a pentylsulfonyl group, an isopentylsulfonyl group, and a hexylsulfonyl group.
The term “haloCHg alkylsulfanyl group” as used herein refers to a ht—chain or branched-chain alkylsulfanyl group which has 1 to 6 carbon atoms and which has been substituted by a n atom or n atoms. The preferred number of the substituting halogen at0m(s) is 1 to 3. Examples of the haloC1_6 alkylsulfanyl group include a fluoromethylsulfanyl group, a difluoromethylsulfanyl group, a trifluoromethylsulfanyl group, and a trichloromethylsulfanyl group.
The term “haloC1-6 alkoxy group” as used herein refers to a straight—chain or branched-chain alkoxy group which has 1 to 6 carbon atoms and which has been substituted by a n atom or halogen atoms. The preferred number of the substituting halogen atom(s) is 1 to 3. Examples ofthe haloC]_5 alkoxy group include a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.
The term “heteroaryl group” as used herein refers to a monocyclic heteroaryl group having in the ring at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. When the monocyclic heteroaryl group has a en atom or nitrogen atoms in the ring, the each en atom may be an N—oxide.
The heteroaryl group is preferably a 5- or ered heteroaryl group, and includes, for example, a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thienyl group, a triazolyl group, an oxadiazolyl group, and a thiadiazolyl group.
The term “bicyclic heteroaryl group” as used herein refers to a bicyclic heteroaryl group having in the ring at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. When the bicyclic heteroaryl group has a nitrogen atom or en atoms in the ring, the each nitrogen atom may be an N-oxide.
The bicyclic heteroaryl group is ably a 9- or 10~membered heteroaryl group, and es, for example, a quinolyl group, an isoquinolyl group, and an l group.
The term “pharmaceutically acceptable salt” as used herein refers to an acid addition salt that may be accepted in pharmaceutical terms. Examples ofthe acid that may be used include inorganic acids such as ic acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, sulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The free forms may be converted to these salts in a conventional manner.
In connection with the inventive compounds, preferred embodiments will be shown below.
Preferred nds are those wherein R1 is a halogen atom, a CH; alkoxy group, a haloC1.6 alkyl group, a cyano group, a heteroaryl group (which may be tuted by a C1-6 alkyl group), a CM alkyl group, a CM cycloalkyl group, a C1.6 alkylamino group, or the formula CONR7R8 (R7 and R8 are the same or ent, and each represent a hydrogen atom or a C16 alkyl group). More preferred compounds are those wherein R1 is a halogen atom, a CM alkoxy group, a haloC1.6 alkyl group, a C1-6 alkyl group, or a C3_6 cycloalkyl group.
The haloC1_6 alkyl group is more preferably a trifluoromethyl group, and the halogen atom is more preferably a chlorine atom. Compounds n R1 is attached in the para position are preferred.
Preferred compounds are those wherein R" is a hydrogen atom, a halogen atom, a C1-6 alkoxy group, a haloC1-6 alkyl group, a C1_6 alkyl group, or a C3-5 cycloalkyl group.
More preferred compounds are those wherein R" is a hydrogen atom or a halogen atom.
When R" is an atom or group other than a hydrogen atom, R1, is preferably attached in the ortho position.
Preferred compounds are those wherein R2 is a hydrogen atom.
Preferred compounds are those wherein R3 is a phenyl group (which has been substituted by l to 3 substituents selected from halogen atoms, cyano groups, CM alkyl , C16 alkoxy groups, C1.6 alkylamino groups, CH; alkylsulfonyl , haloCH; alkyl groups, haloCM alkoxy groups, haloC1-6 alkylsulfanyl groups, phenyl groups, phenoxy groups, aryl groups (which may be substituted by a CH; alkyl group), and the formula - SOgNRgRlo (R9 and R10 are the same or different, and each represent a hydrogen atom or a C1-6 alkyl group)) or a heteroaryl group (which has been substituted by l to 3 substituents selected from halogen atoms, C1.6 alkyl groups, C3-5 cycloalkyl groups, C1_5 alkoxy groups, cyano groups, CH, alkanoyl groups, and g alkyl groups). More preferred compounds are those wherein R3 is a pyridyl group (which has been substituted by 1 to 3 substituents selected from halogen atoms, CH, alkyl groups, C3_6 cycloalkyl groups, C;_6 alkoxy groups, cyano groups, CH, alkanoyl groups, and haloCl_6 alkyl groups). Still more preferred compounds are those wherein R3 is a pyridyl group (which has been substituted by 1 to 3 tuents selected from n atoms, CH, alkyl groups, C3_6 cycloalkyl groups, and haloC1.5 alkyl ). In the embodiments of R3, the .6 alkyl group mentioned as a substituent by which a phenyi group or a heteroaryl group (more preferably, a pyridyl group) is substituted is more preferably a trifluoromethyl group, and the halogen atom also mentioned as a substituent is more preferably a chlorine atom. The pyridyl group is preferably a pyridin-Z-yl group having a substituent in the tion.
Preferred compounds are those wherein R4 is a C1_6 alkyl group which may be substituted by 1 to 3 halogen atoms, and more preferred compounds are those wherein R4 is a branched-chain C1_5 alkyl group or a straight-chain CH,- alkyl group substituted by 1 to 3 n atoms. The configuration of the carbon atom to which R4 is attached is preferably as shown below.
[Formula 2] R2 /A red compounds are those wherein R5 and R6 are both a hydrogen atom.
Preferred compounds are those wherein any one of Al, A2, A3 and A4 is a nitrogen atom or Al and A3 are both a nitrogen atom. More preferred compounds are those wherein Al is a nitrogen atom, A2 and A4 are both the a CH, and A3 is the formula CH or a nitrogen atom.
The inventive compounds may contain a plurality of asymmetric centers. Thus, the aforementioned nds may exist not only in optically active forms but also in their racemates. Further, a plurality of diastereomers may also exist. All of these forms are included in the scope of the present invention. Individual isomers may be obtained by known methods, for example, by use of optically active starting materials or intermediates, by an optically selective reaction or a diastereoselective reaction in the preparation of intermediates or final products, or by tographic separation or the like in the preparation of intermediates or final products. If the inventive compounds form hydrates or solvates, these hydrates or solvates are also included in the scope of the present invention.
Likewise, pharrnaceutically able salts of hydrates or es of the inventive compounds are also included in the scope of the present invention.
The compounds according to the present invention may be administered orally or parenterally. The dosage forms are tablets, es, granules, dispersions, powders, lozenges, ents, creams, emulsions, suspensions, suppositories, injections and the like, all of which may be produced by conventional formulation techniques (for example, the methods set forth in the 15th revised Japanese Pharmacopoeia). These dosage forms may be selected as appropriate, according to the symptoms and age of patients and the purpose of treatment.
To produce these preparations, a composition containing the compound of the present ion may be d with one or more pharmacologically acceptable carriers, namely, excipients (e. g., crystalline ose, starch, lactose, mannitol), binders (e.g., hydroxypropylcellulose, polyvinylpyrrolidone), lubricants (e.g., ium stearate, talc), disintegrants (e. g., carboxymethylcellulose calcium), and/0r various other pharmacologically -15.. acceptable additives.
The compounds of the present invention may be used in combination with one or more other eutic agents, namely, s antipsychotics, antidepressants, for example, 5HT3 antagonists, 5HT2 nists, serotonin agonists, NK-l antagonists, selective nin reuptake inhibitors (S SRIS), serotonin enaline reuptake inhibitors (SNRIs), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, SHTlA antagonists, SHTlB antagonists, SHTlD antagonists, D1 agonists, M1 agonists, anticonvulsants, ive enhancement drugs, and other psychoactive drugs. [003 8] Examples of other therapeutic agents that may be used in combination with the compounds of the present invention include ondansetron, granisetron, metoclopramide, sumatriptan, rauwolscine, yohimbine, fluoxetine, citalopram, escitalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline tered trademark), zimeldine, venlafaxine, reboxetine, Milnacipran, duloxetine, imipramine, amitriptiline, chlomipramine, nortriptiline, bupropion, amineptine, divalproex, carbamazepine, diazepam, risperidone, olanzapine, idone, aripiprazole, quetiapine, perospirone, clozapine, haloperidol, pimozide, droperidol, chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, acetophenazine, thiothixene, chlorprothixene, igine, loxapine, molindone, and the like. Such combinations may be administered simultaneously (in the same pharmaceutical formulation or in different pharmaceutical formulations), separately, or sequentially.
Particular advantages associated with the use of, and s for treatment with, combinations of the compounds of the present invention include comparable or improved effects ed by using individual ingredients at lower doses than their usual doses. Such use and treatment methods are also expected to further enhance the therapeutic effects on ve and/or negative symptoms of psychiatric ers and/or cognitive impairment.
The use of and methods for treatment with combinations of the compounds of the present invention also may provide benefits in the treatment of patients who do not ently respond to, or who are resistant to, treatment with some type of neuroleptic.
The compounds according to the present invention may be administered in doses which, in the case of treating adults, range from 1 to 2000 mg per day, either once daily or in divided portions. The dose may be increased or sed as appropriate, depending on the age, body weight and symptom of a t.
The compounds of formula [I] may be produced by various s of synthesis.
The methods described below are only illustrative of the process for producing the inventive compounds and should not be taken as limiting.
In the general tion processes, the term “inert solvent” refers to, for example, an alcohol such as ol, l, isopropanol, nol, or ethylene glycol; an ether such as diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, or 1,2—dimethoxyethane; a hydrocarbon such as pentane, hexane, heptane, toluene, benzene, or xylene; an ester such as ethyl acetate or ethyl formate; a ketone such as acetone or methyl ethyl ketone; a halogenated carbon-based solvent such as chloroform or dichloromethane; an amide such as dimethylformamide or N-methylpyrrolidone; acetonitrile; dimethyl sulfoxide; water; or a mixed t thereof.
The term “base” refers to, for example, an alkali metal or alkaline earth metal hydride such as lithium hydride, sodium hydride, potassium hydride, or calcium hydride; an alkali metal or alkaline earth metal amide such as lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide; an alkali metal or alkaline earth metal lower alkoxide such as sodium methoxide, sodium ethoxide, or potassium tert- butoxide; an alkyl lithium such as butyl m, sec-butyl m, tert-butyl lithium, or methyl m; an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or barium hydroxide; an alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, or cesium carbonate; an alkali metal or alkaline earth metal hydrogencarbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate; an amine such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, l,8—diazabicyclo[5.4.0]undecene (DBU), 1,5- icyclo[4.3.0]n0n—5-ene (DBN), or N,N-dimethylaniline; or a basic cyclic compound such as pyridine, imidazole, or 2,6—lutidine. These bases are selected as appropriate, according to various reaction conditions known to skilled artisans.
The term “acid” refers to, for e, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or an c acid such as p- toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, or oxalic acid. These acids are selected as appropriate, according to various reaction conditions known to skilled artisans.
In the l production processes, X1 represents a n atom or a hydroxyl group; X2 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group; P1 represents an ester-protective group such as a methyl group or a benzyl group (refer to Theodora W. Green, Peter G. M. Wuts, “Green’s Protective Groups in Organic Synthesis, Fourth Edition”, Wiley Interscience); P2 represents a nitrogen atom—protective group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group (refer to the same reference as mentioned above); Rla represents a C1-6 alkyl group, a C3-6 cycloalkyl group, a haloC1.6 alkyl group, or a heteroaryl group; R1b represents a CM alkylamino group or a heteroaryl group; and the other symbols are as defined above.
General tion process 1 w1g.
[Formula 3] 2 P1\ x1 0 P1 A1 A/R1 0 \ o N/Kpfi X4}?a 1- R5 R6 0 0 1A2 A R1 HN JL 7/)‘R1 § / (2) R5 N N/KAP [(4 R6 5 l Step 1 R4 Step 2 (4) I | ] Step 1: Compound (1) and compound (2) where X1 is a halogen atom may be reacted in an inert solvent in the presence or absence of a base, to obtain compound (3).
Alternatively, a Mitsunobu reaction between compound (1) and compound (2) where X1 is a hydroxyl group may be performed using either an organophosphorus compound and an azo compound or a phosphorus ylide reagent, in an inert solvent in the ce or absence of a base, to obtain compound (3). Examples ofthe organophosphorus compound include triphenylphosphine, tributylphosphine, and the like. es of the azo nd include azodicarboxylic acid diethyl, azodicarboxylic acid diisopropyl, azodicarboxylic acid di—tert- butyl, and the like. Examples ofthe phosphorus ylide reagent e cyanomethylene tributylphosphorane and the like.
Step 2: A deprotection reaction described in Theodora W. Green, Peter G. M. Wuts, “Green’s Protective Groups in Organic sis, Fourth Edition” may be performed to obtain compound (4).
Step 3: An amidation reaction of nd (4) with compound (5) may be performed in an inert solvent in the presence or absence of a base, to obtain the inventive compound [1]. Such an amidation reaction may be performed in accordance with many standard procedures known to skilled artisans, and includes, for example, amidation via a mixed acid anhydride using ethyl chlorocarbonate, isobutyl carbonate, pivaloyl chloride or the like; amidation Via an acid chloride using oxalyl chloride, thionyl chloride or the like; and amidation using a condensing agent such as 1—ethyl(3~ dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCI), 1,3- dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), diethyl orocyanidate, yldiimidazole (CD1), O—(7—azabenzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (HATU), or benzotriazol-l- yloxytris(dirnethylamino)phosphonium hexafluorophosphate (BOP reagent). To perform the amidation reaction using a condensing agent, an additive such as l—hydroxybenzotriazole (HOBt) or hydroxysuccinimide (HOSu) may be used as needed.
General production process 2 [Formula 4] 2 R2\ x1 j: Ai‘AKR: ”4&6 \ O a’N A“A2 R1 NANA"WR' R R R R {1' \ 3 HN R5 iN/K l ' R >4 —. R6)_/ Step 4: Compound (1) and compound (6) may be reacted in the same manner as shown in Step 1 of General tion process 1, to obtain the inventive compound [1].
Compound (I) mentioned above may be produced in accordance with the process bed below.
General production process 3 -20..
[Formula 5] A1“A2 R1 / V 2 R H QR‘ /\ 1 H ASZA4 N P H A ER\ P2’ Y\0H 2'N\(§o (9i P2 3 A , R4 {\N R4 R Step 5 Step 6 (7) (10) R1 0 2 R1 A1 AZ/\ :AK Step 7 Step 8 (1 t) (1) Step 5: A general oxidation reaction of an alcohol into an de may be performed using an oxidizing agent in an inert solvent to obtain nd (8). Examples ofthe oxidation reaction include processes using an oxidizing agent such as IBX, TEMPO, PCC, or PDC; Swern oxidation; and the like.
Step 6: Compound (8) and compound (9) may be subjected to a reductive amination reaction using a reducing agent in an inert solvent in the presence or absence of an acid, to obtain compound (10). Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium dride, and the like.
Step 7: A deprotection reaction described in Theodora W. Green, Peter G. M. Wuts, “Green’s Protective Groups in Organic Synthesis, Fourth Edition” may be performed to obtain compound (11).
Step 8: Compound (1 1) may be cyclized using a reagent such as sgene, phosgene, or carbonyldiimidazole, in an inert solvent in the presence or absence of a base, to obtain compound (1 ).
Compound (I) mentioned above may also be produced in accordance with the s described below.
General production process 4 [Formula 6] (14) Step 9: A urea formation reaction may be med by reacting compound (12) with, for example, compound (13) or isocyanate in an inert solvent in the presence or absence of a base, to obtain compound (14).
Step 10: nd (14) may be subjected to an intramolecular cyclization reaction to obtain compound (1). Examples of the intramolecular cyclization reaction that occurs in this case include Mitsunobu ons using either an organophosphorus compound and an azo compound or a phosphorus ylide reagent. The intramolecular cyclization reaction may also be performed after conversion of the hydroxyl group of compound (14) to a leaving group by mesylation, tion, halogenation or the like in the presence of a base.
Compound (I) mentioned above may also be produced in accordance with the process described below.
General production process 5 [Formula 7} HNJLNH A1-AZR /flOHN\>J—J\/ x2_</ \\/)R1\R1 A3=A4 i AtAg/wR HNZ R4>___§NH 2 Step 11 Step 12 (16) (19) HN NA \I1 R1.
Step 15 R4 (1 5) (Di-{WNHZR4>—// (17) (1) Step 13 Step 14 (18) Step 11: Compound (15) may be cyclized using a reagent such as sgene, ne, carbonyldiimidazole, or 4-nitrophenyl chloroformate, in an inert solvent in the presence or e of a base, to obtain compound (16).
Step 12: Compound (16) may be reacted with a reducing agent in an inert solvent to obtain compound (17). Examples of the reducing agent include lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and the like. Further, heating and stirring or use of aluminum trichloride, as needed, is red.
Step 13: The same s as shown in Step 12 may be performed to obtain compound (18) from compound (15).
Step 14: The same process as shown in Step 11 may be performed to obtain compound (17) from compound (18).
Step 15: Compound (17) and compound (19) may be reacted using a palladium catalyst or a copper catalyst and, if , a ligand of such a metal catalyst, in an inert solvent in the presence or absence of a base, to obtain compound (1). Examples of the palladium catalyst include Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4 and the like, and examples of the copper catalyst e Cul, CuBr and the like. Examples ofthe ligand of the ium catalyst include triphenylphosphine, Xantphos, BlNAP and the like, and examples of the ligand of the copper catalyst e N,N’-dimethylethylenediamine, 1,2- cyclohexanediamine, phenanthroline, proline and the like.
General production process 6 [Formula 8] N 0 1-A2 ' R13 R3 1 )L A ‘ 7 \w ' I\(/|21)R_1a RR65 N) xN/kAa'A\ “4R1 R2 R4 \ O St9" 16 N 0 A1 A? x2 [ [2 R3 A Q l l 1 RRG N N/kAs-A’fR R2 > it 0 0 1A2 R1b R4 V Step 17 V23.
Step 16: Compound (20) may be reacted with compound (21) using a metal catalyst such as palladium, copper, iron or nickel and, if needed, a ligand, in an inert solvent in the presence or e of a base, to obtain the inventive compound [12]. Compound (21) represents an organometallic reagent and includes, for e, Grignard reagents (e.g., RlaMgCI), zinc reagents (e.g., RlaZnCl), boron reagents (e.g., those where RIa is attached to boric acid or a boric acid ester), and tin reagents (e.g., RlaSnBu3). Examples of the iron reagent include tris(2,4-pentanedionato)iron(III), and examples of the nickel reagent include l,2~bis(diphenylphosphino)ethane nickelClI) chloride and the like.
Step 17: Compound (20) may be reacted with, for example, a C]_6 alkylamine or a heteroaryl group having an NH group in the ring, using a metal st such as palladium or copper and, if needed, a ligand, in an inert solvent in the ce or absence of a base, to obtain the inventive compound [13].
General production process 7 [Formula 9] 2 Al-A‘z/ 2 R X2_</ \} R 3h 0 fix. \ o R1. O A3:A4 3N 0 A1 A?/R1 R 1m R (19) R6 R NJLMW )..J )_/ R4 Step 18 R4 (22) t I l Step 18: The same process as shown in Step 15 may be performed to obtain the inventive compound [I] from compound (22).
Next, the present invention will be described in more detail by means of Production Examples, Working Examples and Test Example, but these Examples are in no way ed to limit the scope of the t invention.
The microwave reaction apparatus used in the Production Examples and Working Examples described below was Initiator from Biotage.
In the Production Examples and g Examples below, the “NH silica gel dge” and “silica gel cartridge” used for purification by column chromatography were Biotage SNAP Cartridge KP-NI-I and Biotage SNAP Cartridge KP-Sil or HP—Sil, respectively.
In the Production Examples and Working Examples below, the “NH silica gel” and “silica gel” used for purification by preparative thin-layer chromatography (PTLC) were NH2 Silica Gel 60F254 Plate Wako (20 cm X 20 cm) from Wako Pure Chemical Industries, Ltd. and Silica Gel 6OF254 (20 cm X 20 cm) from Merck, respectively.
In the Production Examples and Working Examples below, the purification by ative erformance liquid chromatography (HPLC) was performed under the ions shown below. It should be noted that when trifluoroacetic acid was used in the main procedure for producing compounds having a basic functional group, neutralization operation or the like was conducted as appropriate for obtaining the nds in free form.
Apparatus: Preparative HPLC System from Gilson, Inc.
Column: Capcelpak C18 MGII 5 um 20 X 150 mm from Shiseido, Co., Ltd, or Waters e Prep C18 OBD 5 pm 30 X 50 mm Solvent: A—liquid (0.1 % trifluoroacetic acid—containing water), B~liquid (0.1% trifluoroacetic acid-containing acetonitrile) Gradient Condition 1: 0 min (A—liquid/B—liquid = 90/10), 22 min (A-liquid/B-liquid = 20/80), 25 min (A—liquid/B-liquid = 10/90); flow rate, 20 mL/min Gradient Condition 2: 0 min uid/B—liquid = 80/20), 20 min (A—liquid/B-liquid = 5/95), 25 min (A-liquid/B—liquid = 1/99); flow rate, 20 mL/min Gradient Condition 3: 0 min uid/B—liquid = , 11 min (A-liquid/B-liquid = 20/80), 12 min (A—liquid/B-liquid = 5/95); flow rate, 40 mL/min Gradient Condition 4: 0 min (A-liquid/B-liquid = 80/20), 10 min (A-liquid/B-liquid = 5/95), 11 min (Aaliquid/B-liquid = 1/99); flow rate, 40 mL/min Detection method: UV 254 nm In the Production Examples and Working Examples below, mass spectra (MS) were measured under the following conditions: -25r MS spectra: Shimadzu LCMS—ZOIOEV, Micromass Platform LC, or Shimadzu LCMS—lT—TOF In the Production Examples and Working Examples below, nuclear magnetic resonance spectra (NMR) were used for structure confirmation. The nuclear magnetic resonance spectra (NMR) were measured under the ing conditions: NMR spectra: [lH—NMR] 600 MHZ, JNM-ECA600 (JEOL Ltd); 500 MHz, JNM- ECASOO (JEOL Ltd); 300 MHz, UNITYNOVA300 (Varian Inc); 200 MHZ, 2000/200 (Varian Inc.) The RT (retention time) shown in Tables 1—9 to 1-26 are values measured with a high-performance liquid chromatography mass ometer (LCMS) under any one of the conditions shown below.
Condition A: Instrument: Agilent 1290 Infinity and t 6150 Column: Waters Acquity CSH C18, 1.7 um, $2.1 X 50 mm Solvent: A-liquid (0.1 % formic acid-containing water), B-liquid (0.1 % formic acid- oontaining acetonitrile) Gradient: 0 min (A-liquid/B-liquid = 80/20), 1.2-1.4 min (A-liquid/B—liquid = l/99) Flow rate: 0.8 mL/min, Detection method: 254 nm ion B: Instrument: zu LCMS~2010EV Column: Shimpack XR—ODS, 2.2 um, (1)2.0 X 30 mm Solvent: A~liquid (0.1 % formic acid~containing water), B-liquid (0.1 % formic acid— containing acetonitrile) Gradient: 0 min (A—liquid/B-liquid = 90/10), 3 min (A—liquid/B-liquid = 0/ 100) Flow rate: 0.6 , Detection : 254 nm Condition C: Instrument: Agilent 1100 and Micromass Platform LC Column: Waters SunFire C18, 2.5 pm, ¢4.6 X 50 mm ~26- Solvent: A-liquid (0.1 % trifluoroacetic acid-containing water), B-liquid (0.1 % trifluoroacetic acid-containing acetonitrile) Gradient: 0 min (A-liquid/B—liquid = 90/10), 0.5 min (A-liquid/B-liquid = 90/10), .5 min (A—liquid/B-liquid = 20/80), 6.0 min (A-liquid/B-liquid = 1/99), 6.3 min (A-liquid/B- liquid = 1/99) Flow rate: 1 mL/min, Detection method: 254 nm In the Production Examples and Working Examples below, compounds were named in accordance with ACD/Name (ACD/Labs 12.01, Advanced Chemistry pment Inc.) Production Example 1 4-(2-Methylpropyl)[6-(trifluoromethyl)pyridinyl]imidazolidinone [Formula 10] (l) Di—tert-butyl dicarbonate (4.1 g) was added to a solution of 2-amino—4— methylpentan-l-ol (2.0 g) in THF (40 mL), and the e was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was washed with a mixed solvent of hexane/ethyl acetate (= 5:1) to afford tert-butyl (l— y-4—methylpentanyl)carbamate (3.7 g).
(ESI pos.) m/z : +Na]+) (2) To a solution of utyl (1—hydr0xy—4~methylpentan—2-yl)carbamate (2.7 g) in DMSO (60 mL) was added 2-i0doxybenzoic acid (3.5 g), and the e was stirred at room temperature for 3 hr. Water was added thereto, the resulting insoluble matter was filtered off, and the e was extracted with ethyl acetate. The organic layer was washed with _27_ water and brine, and dried over anhydrous magnesium sulfate. After the dessicant was filtered off, the filtrate was concentrated under reduced pressure to afford a crude t of utyl (4-methy1—l~oxopentanyl)carbamate. 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.96 - 1.00 (In, 6 H), 1.61 — 1.84 (m, 3 H), 3.42 - 4.98 (m, 2 H), 9.60 (s, 1 H) (3) The crude product of tert—butyl(4—methyl-l-0xopentan-2—yl)carbamate was dissolved in form, 2~trifluor0methyl—5—aminopyridine (1.35 g) and sodium triacetoxyborohydride (3 .52 g) were added thereto, and the mixture was stirred at room temperature overnight.
Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The dissicant was filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified by column tography (silica gel cartridge, hexane/ethyl acetate) to afford tert-butyl hyl{[6-(trifluoromethyl)pyridin—3-yl]amino}pentan~2—yl)carbamate (2.58 g).
(ESI pos.) m/z : 362([M+H]+) (4) A solution of4M hydrochloric acid in 1,4-dioxane was added to a solution of tert—butyl 4- methyl{ [6-(trifluorornethyl)pyridin~3 ~yl]amino}pentanyl)carbamate (2.3 g) in ethanol (30 mL), and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced re. The residue was dissolved in THF (20 mL) and cooled in ice, triethylamine (2.0 mL) and sgene (0.41 g) were then added thereto, and the resulting mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After the desiccant was filterred off, the filtrate was concentrated under reduced re, and the residue was washed with /ethyl e (= 2:1) to affore the title compound (0.58 g). -28— (ESI pos.) m/z : 288([M+H]+) 1H NMR (600 MHZ, FORM-d) d ppm 0.97 - 1.03 (m, 6 H), 1.48 - 1.55 (In, 1 H), 1.61 - 1.66 (m, 1 H), 1.69 - 1.79 (m, I H), 3.56 (dd, J=8.7, 6.4 Hz, 1 H), 3.94 - 4.01 (m, 1 H), 4.06 - 4.11 (m, 1 H), 5.28 (br. s., 1 H), 7.64 (d, J=8.7 Hz, 1 H), 8.37 (dd, J=8.7, 2.3 Hz, 1 H), 8.67 (d, J=2.8 Hz, 1 H) The following compounds were synthesized according to the similar procedure. panyl)-1—[6-(trifluoromethyl)pyridinyl]imidazolidin—2-0ne (ESI pos.) m/z : 274([M+H]+) 1 ~(6-Methoxypyridin—3 -y1)propy1imidazolidinone (ESI pos.) m/z : 23 6([M+H]+) Production Example 2 (4S)(Propanyl)[6~(trifluoromethyl)pyridinyl]imidazolidin-Z-one [Formula 11] o /N CF3 (2) JL ' N\ CFa (1) <1 CF3 \ le HN N H NU oJLNLJ0 figH 2 H OH 0 N HN/lLN / CF3 H3 \/ (1) Pyridine (2.9 mL) was added to a solution of uoromethyl—5—aminopyridine (1.95 g) in chloroform (15 mL), the mixture was cooled in ice, and phenyl formate (1-8 mL) was added thereto. The resulting mixture was stirred at room temperature overnight, and the reaction mixture was concentrated under reduced pressure. The residue was washed with isopropyl ether to afford phenyl [6-(trifluoromethyl)pyridinyl]carbamate (2.16 g).
(ESI pos.) m/z : 283([M+H}+) (2) Triethylamine (0.54 mL) and phenyl [6—(trifluoromethyl)pyridinyl]carbamate (600 mg) were added to a solution of L~Valinol (200 mg) in chloroform, and the mixture was stirred at 80°C for 1 hr. The reaction mixture was trated under reduced pressure, and the residue was purified by column tography (silica gel cartridge, hexane/ethyl acetate) to afford 1-[(2S)-1—hydroxymethylbutan—2-yl][6-(trifluoromethy1)pyridin-3~y1]urea (640 mg).
(ESI pos.) m/z : 292([M+H]+) (3) Triphenylphosphine (770 mg) and diethyl azodicarboxylate (2.2 M solution in toluene, 1.3 mL) were added to a solution of 1{(28)-l-hydroxy-3~methylbutan—2—yl]—3—[6— (trifluoromethyl)pyridin~3 —y1]urea (640 mg) in THF (10 mL), and the e was d at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was d by column chromatography (silica gel cartridge and NH silica gel cartridge, hexane/ethyl acetate), and the resulting solid was washed with isopropyl ether to afford the title compound (500 mg). This product contained byproducts ating in reaction reagents.
(ESI pos.) m/z : 274([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.96 — 1.05 (m, 6 H), 1.76 - 1.86 (m, 1 H), 3.59 - 3.66 (m, 2 H), 3.99 - 4.08 (m, 1 H), 7.64 (d, J=8.7 Hz, 1 H), 8.41 (dd, J=8.7, 2.5 Hz, 1 H), 8.67 (d, J=2.5 Hz, 1 H) The following compounds were synthesized according to the similar procedure. (4R)(Propan—2~y1)[6-(trifluoromethy1)pyridinyl]imidazolidin-2—one (4S)(2—Methylpropy1)-1—[6—(trifluoromethyl)pyridin—3-y1]imidazolidin-Z-one (ESI pos.) m/z : 288([M+H]+) (4S)-4~(Cyclohexy1methy1)~l-[6~(trifluoromethy1)pyridinyl]imidazolidin—2-one (ESI pos.) m/z : 328([M+H]+) -(Butanyl)[6—(trifluoromethyl)pyridin-3«y1]imidazolidin—2—one (ESI pos.) m/z : 288([M+H]+) (4S)—4-Phenyi—1-[6—(trifluoromethy1)pyridin-3—y1]imidazolidin-Z-one (ESI pos.) m/z : 308([M+H]+) -30.. (4S)tert-Butyl-1~[6—(trifluoromethy1)pyridin—3 -yl]imidazolidin—2—one (ESI pos.) m/z : 288([M+H]+) (4S)Ethy1[6-(trifluoromethyl)pyridin—3 -y1]imidazoiidin—Z—one (ESI pos.) m/z : 260([M+H]+) (4S)~1—(5-F1uoropyridin—2—yl)—4-(propan—2-yl)imidazolidin~2~one (ESI pos.) m/z : 224([M+H]+) (4S)(6—Br0m0pyridin—3-y1)—4-(pr0pan—2-yl)imidazo1idin~2~0ne (ESI pos.) m/z : 284([M+H]+) ~Benzyl[6-(trifluoromethyl)pyridinyl]imidazolidin—2—one (ESI pos.) m/z : 322([M+H]+) -Propy1[6-(trifluoromethyl)pyridinyI]imidazoh'din0ne (ES! pos.) m/z : 274([M+H]+) (4S)(6-Bromopyridin—3-y1)tert-butylimidazolidin-2—one (ESI pos.) m/z : 298([M+H]+) (4S)(Cyclopropylmethyl)—1-[6-(trifluoromethyl)pyridin—3-yl]imidazolidinone (ESI pos.) m/z : 286([M+H]+) (4S)—4-Propyl[6-(trifluoromethyl)pyridin-3 -y1] irnidazolidin-Z-one 1H NMR (200 MHz, DMSO-d6) (1 ppm 0.82 - 0.98 (m, 3 H), 1.23 — 1.64 (m, 4 H), 3.48 — 3.62 (m, 1 H), 3.66 - 3.84 (m, 1 H), 3.98 - 4.14 (m, 1 H), 7.68 (s, 1 H), 7.81 (d, J=8.79 Hz, 1 H), 8.17 - 8.28 (m, 1 H), 8.86 - 8.93 (m, 1 H) (4R)—4—(2—F1uoropropan~2~yl)~1-[6~(trifluoromethyl)pyridin—3-yl]imidazolidin—2—0ne (1381 p03.) m/z : 292([M+H]+) (4R)—4~(2-Methoxypropanyl)~1-[6—(triflu0romethy1)pyridin—3—y1]imidazolidin—2—0ne (ESI pos.) m/z : 304([M+H]+) (4R)~4-[(1S)F1uoropropyl][6-(trifluoromethyl)pyridin-3—y1]imidazolidinone 1H NMR (600 MHZ, CHLOROFORM—d) d ppm 1.06 - 1.16 (m, 3 H), 1.64 - 1.79 (m, 2 H), 3.91 (dd, 1:929, 5.16 Hz, 1 H), 3.96 - 4.04 (m, 1 H), 4.06 — 4.16 (m, 1 H), 4.34 - 4.50 (m, 1 H), 5.45 (br. 3., 1 H), 7.66 (d, J=8.67 Hz, 1 H), 8.30 - 8.38 (m, 1 H), 8.70 - 8.76 (m, 1 H) (4S)Cyclopropyl-l-[6~(trifluor0methyl)pyridin—3-yl]imidazolidin—2-one (ESI pos.) m/z : 272([M+H]+) (4S)(2-Fluoromethylpropyl)—1-[6-(trifluoromethyl)pyridin~3~y1]imidazolidin-2~one (ESI pos.) m/z : 306([M+H]+) (4S)-4—[2-(Benzyloxy)ethyl]—1-[6-(trifluoromethyl)pyridin—3-yl]imidazolidin-2—one Production e 3 {(5S)~2—Oxo(propan—2—y1)[6-(trifluoromethyl)pyridinyl]imidazolidinyl}acetic acid [Formula 12] fix/60F“ 0 /N ”N (1) if CF: (2) Hof i CF3 HN N \' / ———> NAN/Q] —> N NU :\__l \ )_/ (1) Sodium hydride (0.53 g) was added to a solution of (4S)(propan—2-yl)—1-[6- (trifluoromethyl)pyridinyl]imidazolidinone (5.6 g) in DMF (20 mL), and the e was stirred at room temperature for 10 min. Thereafter, tert-butyl cetate (2.0 mL) was added portionwise thereto, and the mixture was stirred at room temperature for 2 hr.
Water and saturated aqueous sodium hydrogen ate solution were added thereto, and the mixture was extracted with chloroform. The organic layer was separated out by phase- separation cartridge (Biotage, Isolute Phase Separator) and concentrated under reduced pressure. The e was purified by column tography (silica gel cartridge, hexane/ethyl e) to afford tert-butyl {(5 S)-2—oxo—5-(propan—2-yl)~3-[6- (trifluoromethy1)pyridin—3~yl]imidazolidiny1}acetate (802 mg).
(ESI p03.) m/z : 388([M+H]+) (2) Trifluoroacetic acid (30 mL) was added to a solution of tert-butyl {(SS)—2-ox0-5—(propan~ 2-yl)-3—[6-(trifluoromethyl)pyridinyl]imidazolidiny1}acetate (4.44 g) in chloroform (20 mL), and the mixture was stirred at room temperature for 64 hr. Additional trifluoroacetic acid (9 mL) was added thereto, the resulting mixture was further stirred for 1 hr, and the reaction mixture was then concentrated under reduced re. A portion (6.5 g) of the residue was dissolved in diethyl ether, followed by extraction with 6M aqueous sodium hydroxide solution and water. The water layer was washed with l ether and then made acidic using 1M hydrochloric acid. After extraction with chloroform, the organic layer was separated out by phase-separation cartridge, and the solvent was led off under reduced pressure to afford the title compound (2.3 g).
(ESI pos.) m/z 2 332([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.90 (d, J=6.6 Hz, 3 H), 1.01 (d, J=7.0 Hz, 3 H), 2.06 - 2.16 (m, 1 H), 3.59 (dd, J=8.9, 6.4 Hz, 1 H), 3.78 (d, J=18.2 Hz, 1 H), 3.86 - 3.92 (m, 1 H), 3.92 - 3.99 (m, 1 H), 4.48 (d, J=18.2 Hz, 1 H), 7.64 (d, J=9.1 Hz, 1 H), 8.30 - 8.37 (m, 1 H), 8.75 (d, J=2.5 Hz, 1 H) The following compounds were synthesized according to the similar procedure. [3-(6-Methoxypyridin—3-yl)~2~oxo—5~pr0pylimidazolidin—1 -yl]acetic acid (ESI pos.) m/z : 294([M+H]+) {(5S)Oxo(propanyl)[5-(trifluoromethyl)pyrimidiny1]imidazolidin-l-y1}acetic acid (ESI neg.) m/z : 331([M-H]-) [(5 S)(5~Chloropyrimidinyl)oxo(propan~2~yl)imidazolidin-l -yl]aCetic acid (ESI pos.) m/z : 299([M+H]+) 2- { (5S)Ox0(pr0panyl)—3 —[6~(trifluoromethyl)pyridin—3 -yl] imidazolidin~ l — panoic acid (mixture of diastereomers) (ESI pos.) rn/z : 346([M+H]+) [(5S)—3-(5-Fluoropyrimidin—2-yl)oxo-5—(propan~2~yl)imidazolidin—1—yl]acetic acid (ESI pos.) m/Z : 283([M+H]+) [(5 S)-3~(6—Bromopyridin~3wyl)~5~tert-butyl0xoimidazolidin-1 -y1] acetic acid (ESI pos.) m/z 2 356([M+H]+) {(5S)(Cyclopr0pylmethyl)—2-oxo—3—[6—(trifluoromethyl)pyridin-3 idazolidin— 1 - yl}acetic acid (ESI pos.) m/z : 344([M+H]+) {(5 S)Oxo—5~pr0pyl[6-(trifluoromethy1)pyridin~3~yl]imidazolidinyl}acetic acid (ESI pos.) rn/Z : 332([M+H]+) [(5 S)-3~ [3 -Fluoro—5 -(trifluoromethyl)pyridin~2-yl]~2—ox0-5 -(propan—Z—yl)imidazolidin—1 - yl] acetic acid (ESI pos.) m/z : 350([M+H]+) {(5S)OX0(propan—2—y1)—3—[2—(trifluoromethyl)pyrimidin—5~yl]imidazolidin—l -yl } acetic acid (ESI pos.) m/z : 333([M+H]+) [(5 S)~3 «(5~Methoxypyrimidin—2-y1)ox0(propan—2—yi)imidazolidin—1-yl]acetic acid (ESI pos.) m/z : 295([M+H]+) [(5 5-Ethylpyrimidin—2-yl)~2~0x0-5—(propanyl)imidazolidin-1‘y1]acetic acid (ESI pos.) m/z : 293([M+H]+) {(5S)(2-Methy1propyI)oxo[6-(trifluoromethyl)pyridiny1]imidazolidin—1-y1}acetic acid (ESI pos.) m/z : 346([M+H]+) {(5 S)tert-Butyloxo[6-(trifluoromethyl)pyridiny1]imidazolidiny1}acetic acid [(5 S)—3 — [3 ~F1uor0~5~(trifluoromethyl)pyridin-2—y1]-S—(2-methylpropy1)~2-oxoimidazolidin yl]acetic acid (ESI pos.) m/z : 364([M+H]+) {(5S)Cyclopropyl-2—0x0[6-(trifluoromethyl)pyridin-3 -y1]imidazolidin-1 -yl}acetic acid (ESI pos.) m/z : 330([M+H]+) 3—[3—Fluoro-5—(trifluoromethyl)pyridin-Z-yl]-2—oxo~5—propy1imidazolidiny1}acetic acid (ESI pos.) m/z 2 372([M+Na]+) {(SR)—5—[(1S)—1—Fluor0propyl]-3—[3—fluor0-5«(trifluoromethyl)pyridin-2—yl] oxoimidazolidiny1} acetic acid (ESI pos.) m/z : 390([M+Na]+) [(SS)-3 -(5~Chloropyrimidin—2-yl)-2—oxopropy1imidazolidin—1 -y1] acetic acid (ESI pos.) m/z : 321([M+Na]+) {(5S) Butanyl] -3 —[3 —fluoro—5-(trifluoromethyl)pyridin—2-y1]oxoimidazolidin-1 ~ y1}acetic acid (ESI pos.) m/z : 364([M+H]+) [(5 S)—5- [(2S)-Butanyl] ~3—(5 —ch10ropyrimidin—2—y1)~2-oxoimidazolidin— 1 ~yl]acetic acid (ESI pos.) m/z : 313([M+H]+) [(5 S)—5-[(ZS)-Butanyl]-3—(5~flu0r0pyrimidin—2—yl)~2—oxoimidazolidin»1 —y1]acetic acid (ESI pos.) m/z : 297([M+H]+) {(58)»5-[(28)~Butan—2—yl]-2—oxo—3-[5~(trifluoromethyl)pyrimidin-Z-yl]imidazolidin yl}acctic acid (ESIpos.)n1/z : 247([M+H]+) [(5S)[(ZS)-Butanyl]—3-(5-chloroflu0ropyridin~2-y1)oxoimidazolidiny1]acetic acid (ESI pos.) m/z : 330([M+H]+) {(5S)(Z-Fluoromethy1pr0pyl)oxo-3~[6~(trifluoromethyl)pyridin—3 —y1]imidazolidin-1 - y1}acetic acid (ESI pos.) m/z : +H]+) Production Example 4 (4S)—4-(Pr0pany1)—1 rifluoromethy1)pyrimidin—2—y1]imidazolidin—Z-one [Formula 13] EL 0 H2N5%NH2 (1) HN NH (2) HN/mNH \\ 0 N’ CF3 H3 HNJLN \Q/ (1) To a suspension of L—Valinamide hydrochloride (1.0 g) and sodium hydrogen ate (3.03 g) in acetonitrile (100 mL) was added p—nitrophenyl chloroformate (1.32 g), and the mixture was stirred at room ature for 3 hr. Water was added thereto, the resulting mixture was d at room temperature overnight, and then acetonitrile was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol) to afford (SS)(propan—2—y1)imidazolidine-2,4- dione (540 mg).
(ESI pos.) m/z : 143([M+H]+) (2) To a suspension of lithium aluminum hydride (290 mg) in diethyl ether (20 mL) was added (SS)(propanyl)imidazolidine-2,4—dione (540 mg) while cooling in ice, and the mixture was stirred at room temperature overnight. After cooling in ice, water (1 mL), 4M aqueous sodium hydroxide solution (1 mL), THF (15 mL) and ethanol (2 mL) were added o, and the resulting mixture was stirred at room temperature for 10 min. After filtration through Celite (registered trademark), the filtrate was concentrated under reduced pressure to afford (4S)(propan—Z-yl)imidazolidin-Z-one (160 mg). (1381 pos.) m/z : 129([M+H]+) (3) A solution of (4S)(propan—2—yl)imidazolidinone (100 mg), 2—chloro romethylpyrimidine (142 mg), Pd2(dba)3 (40 mg), Xantphos (45 mg) and sodium tert— butoxide (70 mg) in toluene (2 mL) was stirred at 100°C for 1 hr. The reaction e was purified by column chromatography (NH silica gel cartridge and silica gel cartridge, hexane/ethyl acetate) to afford the title compound (47 mg). 1H NMR (600 MHz, FORM-d) d ppm 0.95 - 1.02 (m, 6 H), 1.75 — 1.85 (m, l H), 3.50 - 3.61 (m, 1 H), 3.87 (dd, , 6.6 Hz, 1 H), 4.18 - 4.26 (m, 1 H), 5.17 (br. s., l H), 8.84 (s, 2 H) The following compounds were synthesized according to the similar procedure. (4S)-1u(5uChloropyrimidin-2~yl)—4—(propan—2-yl)imidazoiidin~2-one (ESI pos.) m/z : 241([M+H]+) 6—[(4S)—2-Oxo(propany1)imidazolidinyl]pyridine-3—carbonitrile (ESI pos.) m/z : 231([M+H]+) (4S)—4-(Propan—2—y1)—1-[5-(trifluoromethyl)pyrazin~2~y1]imidazolidin—Q-one (ESI pos.) m/z : 275([M+H]+) (4S)—1—(5—F1uoropyrimidin—2-yl)(propan—2—yl)imidazolidin—2—one (ESI pos.) m/z : 225([M+H]+) (4S)—1~[3~F1uoro(trifluoromethyl)pyridin-2—y1](propan—2—yl)imidazolidin-Z-one (ESI pos.) m/z : 292([M+H]+) (4S)-4—(Propan—2—yl)[2-(trifluoromethy1)pyrimidin—5-yi]imidazolidin—2~one (ESI pos.) m/z : 275([M+H]+) (4S)—1 -(5-Ch10ropyridin-2—y1)~4—(propan-Z-yl)imidazolidinone (ESI pos.) m/z : 240([M+H]+) (4S)(5-Methoxypyrirnidinyl)-4—(pr0pany1)imidazolidin—2-one (ESI pos.) m/z : 237([M+H]+) (4S)(5-Ethy1pyrimidin~2—y1)(propanyl)imidazolic1in—2—one (ESI pos.) m/z : +H]+) (4S)-1—[3~F1uoro~5~(trifluoromethyl)pyridiny1]~4-(2-methylpropyl)imidazolidinone 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.95 ~ 1.01 (m, 6 H), 1.47 - 1.56 (m, 1 H), 1.61 - 1.77 (In, 2 H), 3.76 - 3.85 (m, 1 H), 3.93 - 4.03 (m, 1 H), 4.07 — 4.19 (m, 1 H), 5.12 (br. .,1 H), 7.63 - 7.71 (m, 1 H), 8.45 (s, 1 H) (4S)[3 ~F1uoro-5 ~(trifluoromethyl)pyridin-2~y1] py1imidazoIidin-Z—one (ESI pos.) m/z : 314([M+Na]+) (4S)-1~(5—Ch10r0—3-flu0ropyridinyl)propy1imidazolidin~2~0ne (ESI pos.) m/z : 258([M+H]+) (4S)—4-(Cyclopropylmethy1)—l-[3~flu0ro(trifluoromethy1)pyridin-Z-yl]imidazolidin—2~one (ESI pos.) m/z : 304([M+H]+) tion Example 5 2- {(5 S)—2—Oxo—5 ~propy1imidazolidin— 1-yl]-N-[4-(trifluoromethy1)pyridin—Z-yl]acetamide [Formula 14] FC \ FC \ (3) 3C“: _, HNKNO)LLINUX) _.......... HNK 5 (1) A solution of(ZS)arninopentan~1~ol (500 mg) in THF (6 mL) was cooled in a dry etone bath under nitrogen atmosphere, and a solution of 4-methoxyphenyl isocyanate (657 mg) in THF (4 mL) was added dropwise thereto. After the mixture was stirred for 17 hr while gradually warming to room temperature, methanol was added thereto, and the solvent was distilled off under reduced pressure to afford )hydroxypentan yl](4-methoxyphenyl)urea (1.17 g).
(ESI pos.) m/z : 253([M+H]+) (2) A on of l-[(ZS)hydroxypentanyl](4-rnethoxyphenyl)urea (550 mg) and potasium tert-butoxide (593 mg) in THF (25 mL) was cooled in ice under nitrogen phere, and a solution of p—toluenesulfonylchrolide (672 mg) in THF (10 mL) was added dropwise thereto. After the mixture was stirred for 1 hr while g in ice, water was added thereto, and the resulting e was extracted with chloroform. The organic layer was separated out by phase-separation cartridge, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate = 88:12 - 0:100), and further recrystalized from chloroform/hexane.
The solid was collected by filtration to afford (4S)(4~methoxyphenyl) propylimidazolidin-Z-one (34 mg). In addition, the filtrate was concentrated under reduced pressure to afford (4S)(4-meth0xyphenyl)propylimidazolidin~2~one (254 mg).
(ESI pos.) m/z : 235([M+H}+) ~38- (3) Sodium hydride (60%, 27 mg) was added to a solution of (4S)—1-(4~methoxyphenyl)-4— propylimidazolidin~2—one (32 mg) in DMF (1.5 mL), and the mixture was stirred at room temperature for 15 min. To the e was added 2-chloro-N—[4—(trifluoromethyl)pyridin- cetamide (39 mg), and the resulting mixture was stirred for 15 hr. Thereafter, the reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC, and further the resulting solid was washed with isopropyl ether to afford 2-[(5S)(4-methoxyphenyl)oxo propylimidazolidin—1-yl]-N-[4—(trifluoromethyl)pyridin—2~yl]acetamide ( l 9 mg).
(ESI pos.) m/z : 437([M+H]+) (4) A suspension of 2-[(5S)(4-methoxyphenyl)—2-oxopropylimidazolidinyl]-N—[4— (trifluoromethyl)pyridin—2~yl]acetamide (137 mg) in acetonitrile (3 mL) was cooled in ice, and a solution of ammonium cerium nitrate (340 mg) in water (3 mL) was added dropwise thereto. After stirring the mixture at room ature for 2 hr, an onal solution of ammonium cerium nitrate (100 mg) in water (0.5 mL) was added thereto, and the mixture was stirred at room temperature for 10 min. ted aqueous sodium hydrogen carbonate solution was added thereto, the resulting mixture was extracted with ethyl acetate, and then the c layer was washed with brine, followed by drying over anhydrous magnesium sulfate. After the dissicant was filterred off, the t was distilled off under d pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform/methanol = 98:2 - 80:20) to afford the title compound (76 mg). (1381 pos.) m/z : 331([M+H]+) The fol1owing compounds were obtained according to the similar procedure.
N—(4-Chloropyridin~2~yl)—2— { (5R)[(1 S)fluoropropyl]—2—oxoimidazolidin—1— yl}acetamide (ESI pos.) m/z : +H]+) N—(4-Cyclopropylpyridin-Z-yl) { (5R)—5-[(1 S)—1-fluoropropy1]-2—oxoimidazolidin-1 - yl}acetamide (ESI p05.) m/z : 321([M+H]+) _39- 2-{(5R)[(1S)—1-F1uoropr0pyl]oxoimidazolidin—1-yl}-N—[4-(trifluoromethyi)pyridin~2- yl]acetamide (ESI pos.) m/z : 371 ([M+Na]+) N-(S-Chlor0pyridin—2-y1)[(5S)oxo-5~propylimidazolidin—1-y1]acetamide (ESI pos.) m/z : 297([M+H]+) N—(S~Chloro~6—methylpyridinyl)~2~[(5S)oxopr0py1imidazolidin~1-y1]acetamide (ESI pos.) m/z : 311([M+H]+) 2~[(5S)~2~OX0—5~(pr0pany1)imidazolidin—1-yl]-N—[4-(trifluoromethyl)pyridin—2- y1]acetamide (ESI pos.) m/z : 331([M+H]+) N—(4-Cyclopropylpyridin-2~y1)[(5S)oxo(propan~2~y1)imidazolidin-l-yl}acetamide (ESI pos.) m/z : +H]+) N—(4-Ch10ropyridin—2—y1)[(5S)oxo~5-(propanyl)imidazolidin-1~y1]acetamide (ESI pos.) m/z : 297([M+H]+) 2~ { (5 S)-5 - [(2 S)-Butan-2~y1]-2—0xoimidazolidin—1-y1}-N—(4-chloropyridin-fz-yl)acetamide (ESI pos.) m/z : 333([M+Na]+) 2- { (SS)-5 - [(2 any1]oxoimidazolidin—1~y1}~N-(4-cyclopropylpyridin-2— y1)acetamide (ESI pos.) m/z : 317([M+H]+) 2- { (5 S)-5 — [(2 S)-Butany1]0xoimidazolidin~1-y1}-N—[4-(trifluoromethyl)pyridin y1]acetamide (ESI pos.) m/z : 345([M+H]+) Production Example 6 2-[(SS)Oxo—5—(pr0pan~2~y1)imidazoIidiny1]-N-[6-(trifluoromethyl)pyridin—3 - yl] acetamide [Formula 15] 0 @We H2N 0 (1) >LNH i (2) HN N M. HN o _. _\ 0M6 : (9“‘40 HCI fl 0MB ‘\ OMe o o HNJLN EtOC OMB 2 0MB <3) t)4 NAN ()5 \ OMe T OMe / \ / 0 (6) HN ‘( o JL OMe ——-* HNKO JOL "L1” NUNH j OMe j“ (1) To a solution of L-valine methyl ester hydrochloride (2.6 g) and triethylamine (1.6 g) in chloroform (30 mL) was added 2,4—dimethoxybenzyl isocyanate (3.0 g), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford methyl N-[(2,4—dimethoxybenzyl)carbamoy1]~L-va1inate (4.2 g).
(ESI pos.) m/z : 325([M+H]+) (2) A solution of methyl N—[(2,4-dimethoxybenzyl)carbamoyl]-L-valinate (4.2 g) and ylamine (1.3 g) in methanol was stirred while heating to reflux for 5 hr. After the solvent was distilled off under reduced re, the residue was d by column chromatography (NH silica gel cartridge, hexane/ethyl acetate) to afford (SS)(2,4- dimethoxybenzyl)(pr0pany1)imidazolidine-2,4—dione (4.3 g). (1381 pos.) m/z : 293([M+H]+) (3) Bis(2—methoxyethoxy)alurninum sodium hydride (65%, on in toluene) was added to a solution of (SS)~3~(2,4-dimethoxybenzyl)—5~(propan—2~y1)imidazolidine-2,4-dione (4.3 g) in THF (300 mL), and the mixture was stirred while g to reflux for 3 hr. After cooling in ice, sodium sulfate decahydrate was added thereto, followed by stirring. After filtration, the solvent was distilled off under d pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford (4S)(2,4— dimethoxybenzyl)—4~(propanyl)imidazolidinone (2.4 g). (4) Sodium hydride (60%, 380 mg) was added to a solution of (4S)(2,4-dimethoxybenzyl)~ 4-(propan—2—yl)imidazolidin-Z-one (2.4 g) in DMF (35 mL), and the mixture was stirred for min. Ethyl bromoacetate (1.14 mL) was added thereto, and the mixture was stirred at 90°C for 1 hr. Additional ethyl bromoacetate (1 . 14 g) and sodium hydride (60%, 380 mg) were added o, and the resulting mixture was further stirred at 90°C for 1 hr. After the solvent was distilled off under reduced re, the residue was purified by column chromatography (silica gel cartridge, /ethyl acetate) to afford ethyl [(5S)~3-(2,4- dimethoxybenzyl)—2~oxo—5—(propan—2-yl)imidazolidin-1~yl]acetate (1.5 g).
(ESI pos.) m/z : 365([M+H]+) (5) An aqueous solution of2M sodium hydroxide (2.6 mL) was added to a solution of ethyl [(5S)-3~(2,4—dimethoxybenzyl)~2-oxo(propan~2—yl)imidazolidin-l-yl]acetate (850 mg) in methanol (10 mL), and the mixture was stirred at room temperature ght. To the reaction mixture was added 2M hydrochloric acid (2.6 mL), and the reaction mixture was concentrated under reduced pressure. DMF (10 mL), 5-aminotrifluoromethylpyridine (380 mg), HATU (890 mg), and ropylethylamine (300 mg) were added thereto, and the resulting mixture was stirred at 80°C for 3 hr. The solvent was distilled off under d pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl e) to afford )(2,4-dimethoxybenzyl)oxo(propan~2— yl)imidazolidin-1 —yl]—N-[6-(trifluoromethyl)pyridiny1]acetamide (900 mg).
(ESI pos.) m/z : 481([M+H]+) (6) Trifluoroacetic acid (20 mL) was added to 2-[(5 S)(2,4-dimethoxybenzyl)-2—0xo (propan—Z~yl)imidazolidinyl]-N-[6-(trifluoromethyl)pyridin-3—yl]acetamide (900 mg), and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under d re, and saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford the title compound (310 mg).
(ESI pos.) m/z : 331([M+H]+) Production Example 7 (2R,3S)Amino-3—fluoropentan-l-ol hydrochloride [Formula 16] Boce X (1) BOC‘NYO (2) BOC‘NXO (3) HzNé OH N O W_._> ‘—’ ‘\—/ OHCg \ fl /‘(—/ Fae:F OH F (l) A solution of tert—butyl (4R)—4—formyl-2,2-dimethyl—l,3—oxazolidine carboxylate (14.0 g) in THF (250 mL) was cooled in a dry ice/acetone bath under nitrogen atmosphere, and ethyl magnesium bromide (24 mL, 3M solution in diethyl ether) was added dropwise o. The resulting mixture was stirred for 3 hr while elevating the temperature gradually to 0°C, and saturated s um chloride on was added thereto.
The mixture was separated into phases, the aqueous layer was then extracted with ethyl e, and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the e was concentrated under reduced re. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate = 92:8 - 37:63) to afford tert-butyl (4R)(1-hydroxypropyl)- 2,2-dimethyl-1,3-oxazolidine~3~carboxylate (11.14 g). (1381 pos.) m/z : 282([M+Na]+) (2) A solution of tert—butyl (4R)(1-hydroxypropy1)—2,2-dimethy1—1,3~oxazolidine carboxylate (10.0 g) in chloroform (200 mL) was cooled in ice under nitrogen atomosphere, diethylaminosulfur trifluoride (6.1 mL) was added se thereto, and the mixutere was stirred under cooling in ice for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the resulting mixture was extracted with chloroform, followed by drying over anhydrous magnesium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and then the e was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate : 95:5 - 60:40) to afford tert-butyl ((4R)[(1S)fluoropropyl]-2,2—dimethyl—1,3~0xazolidine-3«carboxylate (4.74 g). 1H NMR (600 MHz, CHLOROFORM-d) (1 ppm 0.91 (t, J=7.22 Hz, 3 H), 1.28 - 1.62 (m, 17 H), 3.72 - 4.01 (m, 3 H), 4.30 — 4.63 (In, 1 H) (3) A 5-10% HCl/methanol on (70 mL) was added to tert-butyl ((4R)[(IS)-1— fluoropropyI]-2,2~dimethyl-1,3-oxazolidinecarboxylate (4.9 g), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to afford the title compound (2.96 g).
(ESI pos.) m/z : +H]+) Production Example 8 (4R)[(1 S)Fluoropropy1]-1—[3-fluoro~5-(trifluoromethyl)pyridin—2—yl]imidazolidinone [Formula17] H2N OH CszNz, OH CszN (2) NH2 /—(—/ HCl4%. (1) ”*2 F H—/ F F (3) CbZHNa. HN‘$\:/>—CF3 (4) HN=JLN \ / (1) A solution of (2R,3S)aminofluoropentan—1~01 hydrochloride (2.0 g) in THF (60 mL) was cooled in ice, a solution of ium carbonate (4.4 g) in water (6 mL) and a solution of benzyl chloroformate (2.4 g) in THF (6 mL) were added thereto, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was led off under reduced pressure, and the residue was purified by column chromatography (silica gel dge, hexane/ethyl acetate = 88:12 ~ 0:100) to afford benzyl S)—3-fluoro-l- hydroxypentan-Z-yl]carbamate (2.5 g). 1H NMR (600 MHz, DMSO-d6) d ppm 0.88 (t, J=7.43 Hz, 3 H), 1.45 - 1.65 (m, 2 H), 3.36 - 3.50 (m, 2 H), 3.59 - 3.70 (In, 1 H), 4.30 — 4.44 (m, I H), 4.65 - 4.71 (m, 1 H), 4.95 — 5.04 (m, 2 H), 7.12 - 7.36 (m, 5 H) (2) A solution of benzyl {(2R,3S)fluoro~l~hydroxypentan—2~yl]carbamate (2.4 g) in form (40 mL) was cooled in ice, triethylamine (2 mL) and esulfonyl de (0.8 mL) were added thereto, and the mixture was stirred for 30 min. Saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. After the desiccant was ed off, the solvent was distilled off under reduced pressure, and the residue was dissolved in DMF (40 mL).
Sodium azide (3.06 g) was added thereto, and the e was stirred at 60°C for 2 hr.
Water was added thereto, the resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the t was distilled off under reduced pressure. The residue was dissolved in THF (50 mL), nylphosphine (3.59 g) and water (10 mL) were added thereto, and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform/methanol = 98:2 - 80:20) to afford benzyl [(2R,3S)—1-aminofluoropentan~2uyl]carbamate (2.34 g).
(ESI pos.) m/z : 255([M+H]+) (3) Potassium carbonate was added to a solution of benzyl [(2R,3S)-1—arnino-3—fluoropentan- 2-yl]carbamate (2.2 g) and 2,3-difluorotrifluoromethy1pyridine (1.74 g) in acetonitrile (45 mL), and the e was stirred at 80°C for 5 hr. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel dge, hexane/ethyl acetate = 95:5 - 20:80) to afford benzyl [[(2R,3 S)-3~fluoro—1-{[3- fluoro~5-(trifluoromethyl)pyridin—2-yl]amino}pentan~2—yl]carbarnate (2.95 g). (1381 pos.) m/z : +H]+) (4) Sodium hydride (about 60%, 546 mg) was added to a solution of benzyl [(2R,3S)—3- fluoro-1—{[3~fluoro—5—(trifluoromethyl)pyridin—2—yl]amino}pentan—2~yl]carbamate (2.85 g) in THF (35 mL), and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, the ing mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate = 80:20 - 40:60) to afford the title compound (2.07 g).
(ESI pos.) m/z : 310([M+H]+) The following compounds were obtained according to the similar ure. (4S)[(ZS)-Butan—2~yl]—l ~[3 —fluoro(trifluoromethyl)pyridinyl]imidazolidin~2—one (ESI pos.) m/z : 306([M+H]+) (4S)[(ZS)-Butanyl]-l -(5-chloropyrimidin—Z-yl)irnidazolidin-Z-one (ESI pos.) m/z : +H]+) ~[(2S)~Butan~2-yl](5-fluoropyrimidin—2-y1)imidazolidinone (ESI pos.) m/z : 239([M+H]+) (4S)[(ZS)-Butan-2—yl]~l—[5—(trifluor0methyl)pyrimidin-2—y1]imidazolidin—2-one (ESI pos.) m/z : 289([M+H]+) (4S)[(2S)-Butanyl](5-chloro—3~fluoropyridinyl)imidazolidinone (ESI pos.) m/z : 277([M+H]+) Production Example 9 (4S)—4-(2-Fluoroethyl)—l -[6-(trifluoromethyl)pyridinyl]imidazolidin-2—one la 18] o N ’ O CF3 O N ’N A U , CFa HN N \l JLN \ / HN (2) HN (1) 5U _> ——-—-—> BnO > ) HO F (1) Palladium hydroxide (120 mg) was added to a solution of (4S)—4-[2~ (benzyloxy)ethyl]-l-[6-(trifluoromethyl)pyridin—3~yl]imidazolidin0ne (1.12 g) in methanol (25 mL), the system was purged with en gas, and the mixture was stirred at room temperature for 3 hr. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to afford (4S)— 4-(2-hydroxyethyl)- l -[6-(trifluoromethyl)pyridin—3-yl]imidazolidin-Z-one (235 mg). (2) A suspension of -(2—hydroxyethy1)—1—[6~(trifluoromethyl)pyridin~3—yl]imidazolidin— 2—0ne (0.10 g) in form (10 mL) was cooled in ice, diethylaminosulfur trifluoride (0144 mL) was added thereto, and the mixture was stirred at room temperature for 3 hr.
Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the organic layer was washed with water and brine, followed by drying over anhydrous sodium sulfate.
After the desiccant was d off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel dge, hexane/ethyl e = 4:1 ~ 0:100) to afford the title compound (0.05 g). 1H NMR (600 MHZ, CHLOROFORM—d) (1 ppm 1.86 - 2.01 (m, 2 H), 3.65 (dd, J=7.9, .2 Hz, 1 H), 3.89 ~ 3.941 (m, l H), 4.10 (d, J=7.9 Hz, 1 H), 4.60 (dd, J=39.2, 4.5 Hz, 2 H), 7.73 (s, 1 H), 7.82 (d, J=7.2 Hz, 1 H), 8.21 (d, J=7.2 Hz, 1 H), 8.90 (s, 1 H).
Production Example 10 (2S)-2—Aminofluoropentan—1-ol hydrochloride [Formula 19] B°°HN OH \__/ <1) BachX <2) HZN on o . Boc\N>< (3) \‘ .u —’ 34° _‘"’ .—- HO—/— F_/_\ HCI Hofi Ff‘ (1) A solution of tert-butyl [(ZS)-1,5—dihydroxypentanyl]carbamate (9.45 g), 2,2~ dimethoxypropane (48 mL) and p-toluenesulfonic acid monohydrate (0.41 g) in chloroform (100 mL) was stirred at room temperature for 3 hr. ted aqueous sodium hydrogen carbonate solution was added thereto, and the solvent was distilled off under reduced pressure. Ethyl acetate was added thereto, and the resulting mixture was washed with water and brine, followed by drying over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel cartridge, hexane/ethyl acetate = 10:1 — 0:100) to afford tert~butyl (4S)—4~(3—hydroxypropy1)-2,2-dimethy1—1,3-0xazolidinecarboxylate (3 .05 g).
(E81 1305.) m/z : 282([M+Na]+) (2) A on of utyl (4S)(3-hydroxypropyl)~2,2—dimethy1-1,3-0xazolidine carboxylate (3.05 g) in chloroform (40 mL) was cooled in a dry ice—acetone bath, bis(2- methoxyethyl)aminosulfur trifluoride (2.77 mL) was added thereto, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium en carbonate solution was added thereto, and the organic layer was washed with water and brine, followed by drying with anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the e was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate = 10:1 - 2:1) to afford tert-butyl (4S)(3-fluoropropyl)-2,2-dimethyl—l,3-oxazolidine—3~carboxylate (900 mg). (3) According to the r procedure as in Production Example 7 (3), the title compound (580 mg) was ed from tert—butyl (4S)(3-fluoropropyl)—2,2-dimethyl-1,3-0xazolidine— 3—carboxylate (900 mg) as a crude product.
Working Example 1 N-(3 ,5~Difluorophenyl) [3-(6-methoxypyridin~3~y1)~2~oxopropylimidazolidin yl] acetamide [Formula 20] ”01.0lU FQNfliNU“ N,N—diisopropylethylamine (0.06 mL), HATU (142 mg), and 3,5-difluoroani1ine (48 mg) were added to a solution of [3-(6—methoxypyridin—3-yl)oxo—5-propy1imidazolidin- l-yl]acetic acid (100 mg) in chloroform (2 mL), and the mixture was stirred at room ature overnight. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. After the ant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography a gel cartridge, hexane/ethyl acetate) to afford the title compound (114 mg).
Working Example 2 2—{2-Oxo(propan—2-y1)[6-(trifluoromethyl)pyridinyl]imidazolidin—l—yl}~N-[3- (trifluoromethyl)phenyl]acetarnide ula21] ii 0 851 W CF—~5”© (MELU Sodium hydride (60%, 22 mg) was added to a solution of 4~(propanyl)-l-[6— (trifluoromethyl)pyridiny1]imidazolidir1—2—one (50 mg) in DMF (1.5 mL), and the mixture was stirred at room temperature for 15 min. After 2-chloro-N—[3— (trifluoromethyl)phenyl]acetarnide (52 mg) was added thereto, the resulting mixture was stirred at room temperature for 21 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added to the on mixture, followed by extraction with chloroform. The organic layer was separated out by phase separation cartridge and concentrated under reduced pressure. The residue was purified by column chromatography (NH cartridge, and silica gel cartridge, hexane/ethyl acetate) and ative HPLC to afford the title compound (79 mg).
Working Example 3 2- {(5S)Oxo(propan—2-yl)[6-(trifluoromethyl)pyridin-3 -yl]imidazolidin-1—y1}-N-[4- (trifluoromethyl)pyridinyl]acetamide [Formula 22] o H HO\i o N 0 fix U033 F30 \ Nf JUL U013 N N \ N N \ \___/ m U \ l \‘ ‘q x \ \\ ‘i Oxalyl chloride (57uL) and DMF (0.05 mL) were added to a solution of {(SS) oxo-S-(propan—2—yl)~3 — [6~(trifluoromethyl)pyridin—3-y1]imidazolidin— l —y1} acetic acid (200 mg) in chloroform (2.5 mL), and the mixture was d at room temperature for 1 hr.
The reaction e was concentrated under reduced pressure to afford the residue (236 mg). Half of this residue was dissolved in chloroform (0.5 mL), and triethylamine (158 uL) was added thereto. A solution of 2~aminotrifluoromethy1pyridine (40 mg) in chloroform (1 mL) was added thereto while cooling in ice, and the resulting mixture was stirred at room ature for 3 hr. After the reaction mixture was concentrated under reduced pressure, the residue was purified by preparative HPLC and PTLC (hexane/ethyl acetate = 1 :1) to afford the title compound (20 mg).
Working e 4 )(6-Cyanopyridin~3~yl)—2-0xo(propan—2-y1)imidazolidin—1-y1]-N—[3- (trifluoromethyl)phenyl]acetamide [Formula 23] FSCQ F30\© HN 0o /N HN 0o Br (NJKN/U//N NJLN CN l _> ‘i ‘i A on of 2-[(5 S)(6-bromopyridin-3—y1)oxo(propan—2-y1)imidazolidin—1- yl]~N—[3-(trifluoromethyl)phenyl]acetamide (150 mg), zinc cyanide (91 mg), Pd2(dba)3 (8.5 mg), Xantphos (11 mg), and N,N,N’,N’-tetramethylethylenediamine (14 uL) in DMF (2 mL) was stirred under irradiation with microwave at 180°C for 30 min. Additional zinc cyanide (91 mg) was added thereto, and the ing mixture was stirred under the same condition for 30 min. NH silica gel was added thereto, the mixture was stirred, followed by filtration, and the e was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (47 mg).
Working Example 5 2— {(5 S)—2—Oxo(propanyl)—3-[6—( 1 H—pyrazol— 1 ~y1)pyridin—3-yl]imidazolidin- 1 ~y1}—N—[3~ (trifluoromethyl)phenyl]acetamide [Formula 24] F3C\© F30© HN Oil: ,N HN Br /N \ / 03L N? N N N NU W T A solution of 2-[(5S)—3~(6—b1‘omopyridinyl)oxo(propan-2~yl)imidazolidin-l— yl]~N-[3—(trifluoromethyl)phenyl]acetamide (150 mg), pyrazole (105 mg), trans—1,2- bis(methylamino)cyclohexane (18 mg), copper(I) iodide (12 mg), and cesium carbonate (3 02 mg) in 1,4~dioxane (2 mL) was stirred at 120°C for 2 hr. After filtration through Celite, the e was concentrated under reduced re. The residue was purified by preparative HPLC and PTLC e/ethyl acetate = 1:1) to afford the title compound (74 mg).
Working Example 6 2—[(SS)—3~[6—(Dimethylamino)pyridin—3-yl]-2—oxo(propan—2-yl)imidazolidin-l-yl]—N—[3~ (trifluoromethyl)phenyl]acetamide [Formula 25] o ”or? O HN / i /N HN Br JOL /N N\ N N \ I N N \ I T \\ A solution of 2-[(5 6-bromopyridinyl)oxo-S-(pr0panyl)imidazolidin-1— yl]-N-[3-(trifluoromethyl)phenyl]acetamide (250 mg) and dimethyl amine (2M solution in THF, 1.3 mL), Pd2(dba)3 (24 mg), BINAP (32 mg), and potassium tert—butoxide (87 mg) in toluene (5 mL) was stirred at 120°C for 2 hr. Water was added o, the mixture was extracted with chloroform, and the organic layer was concentrated under reduced pressure.
The residue was purified by preparative HPLC and PTLC (hexane/ethyl acetate = 1:1) to afford the title compound (34 mg).
Working Example 7 2-[(5S)Ox0(propan~2—yl)—3-(6-propylpyridin—3—yl)imidazolidinyl]-N-[3- (trifluoromethyl)phenyl]acetamide [Formula 26] ECO O F3C© HN o /N Br \ HN\/<3 NJLN / NAN/UV,N \\ \\ To a suspension of 2—[(5 6-bromopyridinyl)—2—oxo—5-(pr0pan—2- y1)imidazolidinyl]-N-[3~(trifluoromethyl)phenyl]acetamide (50 mg) and ,4- pentanedionato)iron(III) (55 mg) in THF (1 mL) and NM? (0.1 mL) was added n- propylmagnesium bromide (2M on in THF, 0.31 mL), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added thereto, the resulting mixture was extracted with acetic acid, and the organic layer was washed with water and brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced re. The residue was purified by column chromatography (hexane/ethyl acetate) to afford the title compound (24 mg).
Working Example 8 N,N-Dimethy1~5—[(4S)—2~0X0(2-0x0{[3—(trifluoromethyl)phenyl]amino}ethy1)~4— (propan—2~yl)imidazolidin—1~y1]pyridine-Z-carboxamide [Formula 27] F3C© F3C© HNKNEEN \/ O ,N (1) HN Br (NLNMO WV ‘\ (2) FGCO F3C\© HN\<O O O o (3) Mag/W/N /N we» HN\<O wafto ‘C n (1) A suspension of 2-[(5S)(6-bromopyridin—3-yl)oxo~5-(propan yl)imidazolidin—1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (100 mg), potassium carbonate (43 mg), and Pd(PPh3)4 (24 mg) in DMF/ethanol (2:1, 2.1 mL) was stirred under atmosphere of carbon monoxide gas at 80°C for 1.5 hr. Saturated aqueous sodium en carbonate solution was added thereto, the mixture was washed with ethyl acetate, and the organic layer was washed with water and brine. After concentration under d pressure, the residue was purified by preparative HPLC to afford methyl 5—[(4S)oxo(2-oxo{ [3- (trifluoromethyl)phenyl]amino}ethyl)(propany1)imidazolidin— l ~yl]pyridine ylate (50 mg). (1331 pos.) m/z : 465([M+H]+) (2) To a solution of methyl 5-[(4S)oxo(2-oxo-2—{[3- (trifluoromethyl)phenyl]amino } ethyl)-4—(propanyl)imidazolidin— 1 —yl]pyridine carboxylate (50 mg) in methanol/water (2:1, 1.5 mL) was added 6M s sodium hydroxide solution (27 uL), and the mixture was stirred at room ature for 1 hr, followed by at 60°C for 1 hr. Afier 2M hydrochloric acid was added thereto to make the mixture acidic, the resulting mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure to afford 5—[(4S)oxo—3—(2—oxo~2—{[3— (trifluoromethyl)phenyl]amino}ethyl)(propanyl)imidazolidin-l -y1]pyridine carboxylic acid (43 mg). (1331 pos.) m/z : +H]+) (3) According to the similar procedure as in Working Example 1, the title compound (33 mg) was obtained from 5-[(4S)ox0(2-oxo—2-{[3~(trifluor0methyl)phenyl]amino}ethyl)~4- (propan—Z-yl)imidazolidin—1-yl]pyridine—2—carboxylic acid (43 mg) and ylamine (solution in THF).
Working Example 9 2-[(5 S)-3 -(5 -Fluoropyrimidin—2-yl)oxo~5~propylimidazolidin—l -yl]—N— [4— (trifluor0methyl)pyridinyl]acetamide [Formula 28] Fscfi F30 / N \\,N HM o 0 (NANH HN{NAN/RI)o N , F ..\—’ N ..\—/ > > A solution of 2-[(5S)oxopropylimidazolidin~l-y1]-N-[4- (trifluoromethyl)pyridinyl]acetamide (70 mg), 2-chlorofluoropyrimidine (33 mg), Pd2(dba)3 (22 mg), Xantphos (24 mg), and sodium tert-butoxide (30 mg) in toluene was stirred at 80°C for 2 hr. Saturated aqueous sodium en carbonate solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The ant was filtered off, the solvent was distilled off under reduced pressure, and the e was purified by preparative HPLC to afford the title compound (27 mg).
Working Example 10 N—[6—(Difluoromethyl)pyridinyl]—2-{(5S)(2-methylpropyl)~2-oxo—3—[6— (trifluoromethyl)pyridinyl]imidazolidin—1-yl}acetamide [Formula 29] MeO F HO F \/ \ / \ / HNff);JLUNUCFa (1) 0 , ”Nefio:JLN \Nl CF3 _. EMU/ca (1) Lithium borohydride (27 mg) was added to a solution of methyl 5-[({(SS)-5~(2- methylpropyl)~2-oxo[6-(trifluoromethyl)pyridin~3-yl]imidazolidin—1- yl}acethyl)amino]pyridine~2—carboxy1ate (160 mg) in THF (2 mL), and the mixture was d at room temperature for 18 hr. Saturated aqueous ammonium de solution was added thereto, followed by extraction with chloroform. The solvent was distilled off under d pressure, and the residue was purified by preparative HPLC to afford N-[6- (hydroxymethyl)pyridin—3-y1]{(5S)(2-methylpropyl)-2~oxo[6- orornethyl)pyridinyl]imidazolidin-1 -y1} acetamide (43 mg).
(EST pos.) m/z : 452([M+H]+) (2) To a solution ofN-[6-(hydroxymethyl)pyridinyl]{(5S)(2-methylpr0pyi)—2—oxo [6-(trifluoromethyl)pyridin—3-yl]imidazolidin-l-yl}acetamide (35 mg) in DMSO (1 mL) was added 2~iodoxybenzoic acid (26 mg), and the e was stirred at room temperature for 2 hr. Water and ethyl acetate were added thereto, the resulting mixture was subjected to filtration, and then the e was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform (1 mL) and cooled in ice, and then diethylaminosulfur trifluoride (0.08 mL) was added thereto. After the resulting mixture was stirred at room temperature for 3 days, water was added thereto, followed by extraction with chloroform. After the solvent was distilled off under d pressure, the e was purified by PTLC (silica gel, hexane/ethyl acetate = 1:1, and NH silica gel, hexane/ethyl acetate = 1:1), and the solid was washed with isopropyl ether to afford the title compound (3.8 mg). -55..
Working Example 11 N-(6-Acety1pyridin—3-yl){(5S)(2-methy1propyl)oxo[6-(trifluoromethy1)pyridin~3— yl]imidazolidin—l -yl } ide [Formula 3 0] ‘N \ \ \N “N‘CONOJLUNUCB . ”NfNE/N \N/ CF3 : r A suspension ofN—(6-brom0pyridin—3-yl){(5 S)~5~(2»methylpr0pyl)~2-oxo[6- (trifluoromethy1)pyridin—3-y1]imidazolidiny1}acetamide (78 mg), tributy1(1- ethoxyviny1)tin (145 mg), bis(triphenylphosphine)palladium(ll) dichloride (22 mg), and copper(I) iodide (6.3 mg) in acetonitrile (1.5 mL) was stirred under irradiation with microwave at 150°C for 2 hr. Saturated aqueous sodium en carbonate solution was added thereto, followed by tion with chloroform. The organic layer was separated by phase separation cartridge, and the solvent was distilled off under reduced pressure. The residue was purified by ative HPLC, 1M HCl (1.5 mL) was added to the resulting product, and the mixture was stirred at room ature for 10 min. The mixture was made basic with saturated sodium hydrogen carbonate, followed by extraction with chloroform, and the solvent was distilled off under d pressure to afford the title compound (60 mg) Working Example 12 N—(6-Cyclopropy1pyridin~3—yl)—2—{(5S)—5—(2-rnethy1propyl)oxo[6- (trifluoromethyl)pyridinyl]imidazolidin—1-yl}acetamide [Formula 31] ~56- A solution ofN—(6—bromopyridin—3-y1){(5 S)(2—methylpropyl)—2-ox0-3—[6— (trifluoromethyl)pyridinyl]imidazolidin—1~yl}acetamide (50 mg), cyclopropyl boronic acid (17 mg), palladium acetate (1.1 mg), triphenylphosphine (2.6 mg), and potassium carbonate (41 mg) in toluene/water (= 20: 1, 1.5 mL) was stirred at 110°C for 9 hr. Additional cyclopropyl c acid (35 mg) was added thereto, and the mixture was further stirred at 110°C for 6 hr, followed by at 80°C for 2 hr. The solvent was distilled offunder reduced pressure, and the residue was d by preparative HPLC. After further purification by PTLC (NH silica gel, hexane/ethyl acetate = 1:1), the resulting solid was washed with isopropyl ether to afford the title compound (25 mg).
Tables 1—1 to 1-26 show the structural formulae and instrumental data of the compounds shown in Working Examples 1 to 12 and compounds synthesized in s r to those of the exemplified compounds. Each number shown in the column of “Example” in the tables indicates which one of the above Working es 1 to 12 the synthesis of each intended compound was based on. The column of “Configuration” shows the configuration of the carbon atom to which R4 is attached in the inventive compound as represented by a [I], and the term “racemate” refers to a racemic mixture.
[Table 1-1] > (531 pos.) m/z F I 1H NMR (600 MHZ. CHLOROFORM—d) d ppm 0.98 o (t. J=7.3 Hz. 3 H). 1.33 " 1.42 (m. 2 H). 1.51 - 1.57 (m. 1 H). 1.81 — 1.89 (m, 1 H). 3.52 (dd, J=8.7. 7.3 Hz. 1 H). 3.77 - 3.86 (m. 2 H). 3.92 (s. 3 H). 3.96 (t. 1 1 te 405([M+H]+) =89 Hz. 1 H). 4.1301 J=15.6 Hz. 1 H). 6.53 (tt.
J=8.7. 2.3 Hz, 1 H). 6.77 (d. J=9.2 Hz. 1 H). 7.09 - 7.15 (m, 2 H). 3.03 (dd. J=9.2. 2.8 Hz, 1 H). 8.10 (d.
J=2.8 Hz. 1 H). 8.94 (br. s., I H) 489([M+H]+)- “Sun/Hm”- 443([M+H]+)- 457([M+H]+)- IMammy)- 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 1.03 (d. 3:7.0 Hz, 3 H). 1.21 — 1.35 (m. 2 H), 2.22 - 2.32 (m. 1 H). 3.60 - 3.71 (m, 1 s 475([M+H]+) H). 3.90 — 3.97 (m. 2 H). 3.99 — 4.06 (m. 1 H). 4.08 — 4.15 (m. 1 H). 7.34 — 7.99 (m. 1 H). 7.40 - 7.47 (m. 1 H). 7.68 — 7.70 (m. 2 H). 7.85 (s. 1 H). 8.28 - 8.37 (m. 1 H). 8.71 (br. 5.. 1 H). 8.80 (d. 0122.9 Hz. I H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.93 - 1.89 (m. 13 H). 3.59 ~ 3.63021. 1 H). 3.94 — 4.04 (m. 2 H). 4.07 - 4.16 (m. 2 H). 7.33 - 7.38 (m. 1 s 529([M+H]+) H), 7.38 - 7.44 (m. 1 H). 7.63 - 7.69 (m. 2 H). 7.83 (s. 1 H). 8.27 (dd. J=8.7. 2.5 Hz. 1 H), 8.57 (s. 1 H). 8.81 (d. J=2.5 Hz, 1 H) 1H NMR (600 MHz. CHLORUFORM~d) d ppm 0.86 (d. 1116.5 Hz. 3 H). 1.03 (1-. J=7.4 Hz. 3 H). 1.23 ‘ 1.35 (m. 1 H). 1.37 — 1.47 (m, 1 H). 1.97 — 2.06 (m, I H). 3.65 (dd. J=9.5. 6.6 Hz. 1 H). 3.91 (t. J=9.5 Hz. 1 489([M+H]+) H). 4.01 - 4.06 (m. 2 H). 4.07 — 4.12 (m. 1 H), 7.35 - 7.40 (m. 1 H). 7.41 ~ 7.47 (m. 1 H). 7.64 - 7.72 (m. 2 H). 7.86 (s. 1 H). 8.29 - 8.37 (m, 1 H). 8.70 (br. 5.. 1 H). 8.79 (d. J=25 HZ. 1 H) [Table 1 2] Structure “4913"”~ (ESI p05.) m/z 1H NMR (600 MHz, FORM—d) 6 ppm 1.01 (d. J=6.2 Hz. 3 H). 1.03 (d. .1=6.2 Hz. a H). 1.46 ~ 1.88 (m. 3 H). 3.61 (dd. J=8.9. 7.15 Hz. 1 H). 3.93 -' 8 489([M+H]+) 4.02 (m. 2 H). 4.08 - 4.13 (m. 1 H). 4.16 (d. J=15.7 H2. 1 H). 7.35 - 7.40 (m. 1 H). 7.41 ~ 7.47 (m. 1 H). 7,64 ~ 7.71 (m. 2 H). 7.84 (s. 1 H). 8.26 - 8.34 (m. 1 H). 8.53 (br. s.. 1 H). 8.78 (d. J=2.9 Hz. 1 H) 1H NMR (500 MHZ. CHLORDFORM*d) d ppm 0.87 (d. J=7.0 HZ. 3 H). 1.01 (d. J=7.0 Hz, 3 H). 2.14 " _L 447([M+Na]+) 2.25011. 1 H). 3.79 - 3.92 (m. 2 H). 3.99 " 4.74 (m. 3 H). 7.28 - 7.49 (m. 3 H), 7.58 ‘7 7.69 (m. 1 H). 7.83 (br. 8.. 1 H). 8.15 (d. J=2.9 H2. 1 H). 8.22 - 8.35 (m. 1 H). 9.05 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 3.53 (d. J=16.1 Hz. 1 H). 3.77 (dd. J=9.3. 7.6 Hz, 1 H). 4.16 (d. J=16.5 Hz. 1 H). 4.26 (t. J=9.3 Hz. 1 H). ..s N 509([M+H]+) 4.96 (dd. J=9.3. 7.6 Hz. 1 H). 7.22 - 7.40 (m. 7 H). 7.46 '- 7.52011. 1 H). 7.59 (d. J=9.1 Hz, 1 H). 7.70 (s. 1 H). 7.98 (br. 5., 1 H). 8.27 (dd. J=8.7. 2.5 Hz. 1 H). 8.68 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) 1:) ppm 1.05 (s. 9 H). 3.63 (dd. J=9.5. 5.4 Hz. 1 H). 3.72 (dd.
J=9.5. 5.0 Hz. 1 H). 4.00 (d. J=16.1 Hz. 1 H). 4.06 (t. _\ t.) 489([M+H]+) J=9.5 Hz. 1 H). 4.34 (d. J=16.1 Hz. 1 H). 7.35 - 7.40 (m. 1 H). 7.41 - 7.46 (m. 1 H). 7.66 - 7.71 (m. 2 H). 7.85 (s. 1 H). 8.33 (dd, J=8.7. 2.5 Hz. 1 H). 8.76 ~ 8.82 (m. 2 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.00 (t. J=7.4 Hz. 3 H). 1.64 - 1.73 (m. 1 H). 1.92 - 2.00 (m. 1 H). 3.59 - 3.64 (m. 1 H). 3.90 - 3.96 (m. I H). .4 b 461([M+H]+) 4.01 (d. J=15.7 Hz. 1 H). 4.06 - 4.16 (m. 2 H). 7.33 - 7.38 (m. 1 H). 7.40 - 7.46 (m. 1 H). 7.63 - 7.70 (m. 2 H). 7.85 (s. 1 H). 8.32 (dd. J=8.7. 2.5 Hz. 1 H). 8.56 (br. 3.. 1 H). 8.79 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.88 (d. J=6.6 Hz. 3 H). 1.01 (d. J=6.6 Hz. 3 H). 2.19 - 2.30 (m. 1 H). 3.58 (dd. J=8.9. 6.4 Hz. 1 H). 3.83 - _L 01 485(£M+H1+) 3.89 (m. 1 H). 3.90 - 3.95 (m. 1 H). 4.00 - 4.11 (m. 2 H). 7.31 - 7.48 (m. 3 H). 7.64 (d. J=8.3 Hz. 1 H). 7.85 (s. 1 H). 8.06 ~ 8.15 (m. 1 H). 8.40 (d. J=2.9 Hz. 1 H). 8.84 (br. s.. 1 H) 1H NMR(601J MHz. CHLOROFORM-d) (1 ppm 0.88 (8. 0:7.0 Hz. 3 H). 1.03 (d. 0:13.13 Hz. 3 H). 2.20 — 2.31 (m.1 H), 3.66 (dd. J=7.8. 5.0 Hz. 1 H). 3.86 ~ _; O) 443([M+H]+) 3.99 (m. 3 H). 4.13 (d. J=15.7 Hz. 1 H). 6.52 — 6.60 (m. 1 H). 7.10 — 7.16011. 2 H). 7.69 (d. J=8.7 Hz. 1 H). 8.33 (dd. J=8.7. 2.5 Hz. 1 H). 8.75 — 8.83 (m. 2 1H NMR (600 MHz. CHLOROFORM-d) d ppm 090 (d.d=70Hz.8H).1.0.3(d Hz 3H). 2.20- 2.29(m. 1 H) 3.66(dd. J=8.5. 5..6Hz 1 H) 3.87- 17 475([M+H]+) 4.05 (m. 3 H). 4.28 (d. d=16.1 Hz, 1 H). 7.26 * 7.30 (m. 1 H). 7.55 - 7.59 (m. 1 H). 7.61 - 7.64 (m, 1 H). 7.68 (d, J=8.7 Hz. 1 H). 8.12 - 8.21 (m. 1 H). 8.36 - 8.45 (m. 2 H). 8.76 (d. d=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) (:1 ppm 0.92 (d. J=6.6 Hz. 3 H). 1.04 (d. J=6.6 Hz. 3 H). 2.20 (t.
J=1.0 Hz. 1 H). 3.61 - 3.70 (m. 1 H). 3.91 - 4.03 (m. 18 476([M+H]+) 3 H). 4.32 (d. J=16.5 Hz. 1 H). 7.44 (d. J=7.8 Hz. 1 H). 7.67 (d, d=9.1 Hz. 1 H). 7.88 (t. J=8.1 Hz. 1 H). 8.37 (d. J=8.7 Hz. 1 H). 8.40 - 8.46 (m. 1 H). 8.55 (br. 5.. 1 H). 8.74 (d, J=2.5 Hz. 1 H) [Table 13] ““19”“—“- (ES! pos.) m/z F 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.91 (1:1. 0:70 Hz. 3 H). 1.04 (0. 3:7.0 Hz. 3 H). 2.19 — 2.25 (m. 1 H). 3.61 — 3.68 (m. 1 H). 3.92 — 3.98 (m, 2 S +H]+) H). 4.06 (d. J=16.5 Hz, 1 H). 4.23 (d. J=16.5 Hz, 1 H). 7.26 — 7.30 (m. 1 H). 7.66 (d. J=8.7 Hz, 1 H). 8.40 - 8.43 (m, 1 H). 8.44 — 8.48 (m, 2 H), 8.74 (d. 3:29 Hz, 1 H). 3.35 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFURM-d) d ppm 0.89 (d. J=7.0 Hz. 3 H). 1.04 (d, 0=7.0 Hz. 3 H). 2.23 — 2.31 (m. 1 H). 3.60 — 3.69 (m, 1 H). 3.39 — 4.01 (m. 2 432([M+H]+) H). 4.04 — 4.14 (m. 2 H). 7.34 ~ 7.41 (m, 1 H). 7.41 — 7.47 (m.1 H). 7.52 - 7.73 (m, 2 H). 7.85 (s. 1 H). 8.30 (dd. 11:13.7. 2.5 Hz. 1 H). 8.59 (br. s.. 1 H). 8.81 (d. 0:25 Hz. 1 H) 1H NMR (600 MHz. FORM-d) d ppm 0.91 (d. J=6.6 Hz. 3 H). 1.03 (d. d=6.6 112.3 H). 2.26 (td.
J=6.9. 3.1 Hz.1 H). 3.66 (dd. J=7.6, 5.2 Hz. 1 H). 3.87 — 3.94 (m. 2 H). 3.97 (d. 0:157 Hz. 1 H). 4.16 473({M+H1+) (d. 3:153 Hz. 1 H). 6.45 ~ 6.49 (m. 1 H). 7.33 — 7.47 (m. 2 H). 7.65 - 7.70 (m. 1 H). 7.71 - 7.75 (m, 1 H). 7.33 (s. 1 H). 7.99 (41. 0:91 Hz, 1 H). 8.19 - 8.25 (m. 1 H). 8.52 (0. 3:25 Hz, 1 H). 8.55 (d. J=2.5 Hz. 1 H). 8.91 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFORM—d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 0.97 (d. J=7.0 Hz. 3 H). 2.14 - 2.25 (m.1 H). 3.07 (s. 6 H). 3.55 (dd. J=B.5. 6.0 Hz. 450([M+H]+) 1 H). 3.72 - 3.83 (m, 3 H). 4.15 (d. 3:153 Hz. 1 H). 6.55 (d. 0:9.5 Hz. 1 H). 7.30 - 7.45 (m. 2 H). 7.54 — 7.72 (m.1 H), 7.90 ~ 7.88 (m. 2 H). 8.12 (d. J=2.5 Hz, 1 H). 9.19 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) 01 ppm 0.35 (d. J=6.6 Hz. 3 H). 0.86 (t. J=7.2 Hz, 3 H). 1.00 (d.
J=7.0 Hz. 3 H), 1.65 - 1.81 (m, 2 H). 2.15 - 2.28 (m. 1 H). 2.69 - 2.80 (m, 2 H). 3.55 — 3.65 (m, 1 H). 3.83 449(EM+11] 1.) - 3.93 (m. 2 H). 3.96 - 4.14 (m. 2 H). 7.05 ~ 7.18 (m. 1 H), 7.28 - 7.42 (m, 2 H). 7.57 - 7.67 (m, 1 H). 7.85 (s. 1 H). 8.01 - 8.09 (m. 1 H). 8.57 (d. J=2.5 Hz. 1 H). 9.10 (br. s.. 1 H) 1H NMR (600 MHZ. CHLOROFORM'd) d ppm 0.88 (d. J’-‘7.0 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H), 2.22 - 2.30 (m, 1 H). 3.56 (dd, J=7.4, 4.5 Hz. 1 H). 3.89 — 432([M+H]+) 4.00 (m. 3 H). 4.16 (d. J=15.7 Hz. 1 H). 7.38 - 7.45 (m. 2 H). 7.62 " 7.66 (m. 1 H). 7.69 (d. J=8.7 HZ, 1 H). 7.99 (S. 1 H). 8.32 (dd. J=8.7. 2.5 Hz, 1 H), 8.81 (d, J=2.5 Hz. 1 H). 8.87 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) 01 ppm 0.89 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.22 - 2.31 (m. 1 H), 3.62 -‘ 3.68011. 1 H), 3.90 - 3.97 (m. 2 491 ( [M+H}+) H). 3.99 - 4.04 (m. 1 H). 4.08 - 4.14 (m. 1 H). 6.96 - 7.01 (m. 1 H), 7.31 - 7.36 (m. 2 H). 7.59 (s. 1 H). 7.68 (d. J=8.7 Hz. 1 H). 8.33 (dd. J=8.7. 2.5 Hz. 1 H). 8.63 (br. 5.1 H). 9.80 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. OHLOROFORM-d) 0 ppm 0.89 (d. J=6.6 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.23 — 2.31 (m. 1 H). 3.63 — 3.69 (m. 1 H), 3.91 — 3.97 (m. 2 507([M+H]+) H). 4.00 — 4.05 (m. 1 H). 4.10 — 4.14 (m, 1 H). 7.36 — 7.43 (m. 2 H). 7.52 — 7.66 (m. 1 H). 7.68 (d. .1=8.7 Hz, 1 H). 7.87 (s. 1 H). 8.34 (dd, 3:3.7. 2.5 Hz. 1 H). 8.62 (br. s..1 H). 8.80 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. GHLOROFORM-d) 3 ppm 0.38 (d. J=6.6 Hz, 3 H). 1.03 (d, J=7.0 Hz. 3 H). 2.21 ~ 2.31 (m. 1 H). 3.60 - 3.69011. 1 H). 3.89 ~ 3.95 (m. 2 441 ([M+H]+) H). 3.98 - 4.05 (m. 1 H). 4.07 - 4.14 (m. 1 H). 7.06 - 7.14 (m. 1 H). 7.24 (t. J=8.3 Hz. 1 H). 7.31 - 7.36 (m. 1 H). 7.61 - 7.73 (m. 2 H). 8.33 (dd. J=8.7. 2.5 Hz. 1 H), 8.57 (br. s.. 1 H). 8.80 (d. J=2.5 Hz. 1 H) [Tab1_e1—4] 1H NMR (sou MHz, CHLOROFORM-d) d ppm 0.90 (d. J=6.6 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.23 (s. 3 H). 2.27 — 2.31 (m. 1 H). 2.31 (s. 3 H). 3.63 (dd. 435(£M+H]+) J=6.8. 4.3 Hz. 1 H). 3.86 ~ 3.97 (:11. 2 H). 4.01 - 4.14 (m. 2 H). 6.88 (d, J=7.8 Hz. 1 H). 7.05 (d. J=7.4 Hz. 1 H), 7.66 (d. d=8.7 Hz. 1 H). 7.76 (s. 1 H). 8.24 (br. .1 H). 8.27 — 2.34 (m. 1 H). 8.82 (d. J=2.5 Hz. 1 H) I467([M+H}+) 1H NMR (600 MHz. FORM-d) 6 ppm 0.90 (d, J=6.6 Hz. 3 H). 1.02 (d. J=7.0 Hz. 3 H). 2.19 - 2.27 (m. 1 H). 3.63 (dd. d=9.1. 6.2 Hz, 1 H). 3.78 (s, 3 H). 3.82 (s. 3 H). 3.87 - 4.03 (m, 3 H). 4.31 (d.
J:16.1 Hz. 1 H), 6.59 (dd. J=8.9. 3.1 Hz. 1 H). 8.79 (d, J=9.1 Hz. 1 H). 7.66 (d. J=9.1 Hz. 1 H). 8.04 (d.
J=3.3 Hz. 1 H). 8.36 (dd. J=8.7. 2.5 Hz, 1 H). 8.45 (br. 5.. 1 H). 8.81 (d. J=2.5 Hz, 1 H) I475([M+H]+) 1H NMR (500 MHZ. CHLOROFORM‘d) (:1 ppm 0.88 (d. J=7.0 Hz. 3 H). 1.03 (d, J=7.0 H2. 3 H). 2.22 " 2.31 (m. 1 H). 3.60 “ 3.71 (m. 1 H). 3.89 — 3.98 (m. 2 H). 3.99 — 4.06 (m. 1 H). 4.10 — 4.18 (111.1 H). 7.53 “ 7.60 (m. 2 H). 7.63 (d. J=8.3 HZ. 2 H). 7.63 ((1. J=8.7 Hz. 1 H). 8.30 (dd. J=8.7. 2.5 H2. 1 H). 3.77 - 3.85 (m. 2 H) 1H NMR (600 MHz. CHLOROFORM-d) (1 ppm 0.89 (d. J=6.6 Hz. 3 H). 1.02 (d. J=7.0 Hz. 3 H), 2.23 - 232 (m. 1 H). 2.95 (s. 6 H). 3.63 (dd. J=8.7. 5.8 Hz. 1 H). 3.88 -' 3.98 (m. 2 H). 3.98 - 4.05 (n1. 1 H). 4.07 - 4.13 (m. 1 H). 6.46 - 6.52 (m. 1 H). 6.73 - 6.78 (m. 1 H). 7.03 (s. 1 H). 7.16 (t. J=B.3 Hz. 1 H). 7.66 (d.
J=8.7 Hz. 1 H). 8.16 (br. 5., 1 H). 8.34 (dd. J=8.7. 2.5 Hz. 1 H). 8.80 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.22 '- 2.31 (m. 1 H). 3.06 (s. 3 H). 3.63 - 3.71 (m. 1 H). 3.89 - 3.98 (m. 2 H). 4.00 - 4.07 (m. 1 H). 4.10 - 4.18 (m. 1 H). 7.52 (t. J=B.1 Hz. 1 H). 7.65 - 7.73 (m. 2 H), 7.83 - 7.90 (m, 1 H). 8.05 - 8.10 (111.1 H). 8.31 - 8.37 (m. 1 H). 8.78 - 8.82 (m, 1 H). 8.84 (s. 1 1H NMR (600 MHz. CHLOROFORM-d) d ppm 2.84 (dd, J=13.6. 8.7 Hz. 1 H). 3.29 (dd. J=13.6. 5.0 Hz, 1 H). 3.65 (dd. J=9.3. 6.4 Hz. 1 H). 3.93 (t. J=9.1 Hz, 1 H). 4.04 - 4.09 (m. 1 H). 4.15 ~ 4.19 (m. 1 H). 4.23 - 4.31 (m. 1 H). 7.18 - 7.24 (m. 2 H). 7.27 - 7.39 (m. 4 H). 7.41 - 7.48 (m. 1 H). 7.59 - 7.70 (m, 2 H). 7.84 (s. 1 H). 8.15 - 8.23 (m. 1 H). 8.36 (br. s.. 1 H). 8.74 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM~d) d ppm 1.02 (t. J=7.2 Hz. 3 H). 1.36 - 1.48 (m. 2 H). 1.58 - 1.68 (m. 1 H). 1.86 - 1.96 (m. 1 H). 3.62 (dd. J=9.1. 7.0 Hz. 1 H). 3.92 - 3.98 (m. 1 H). 4.01 (d. J=16.1 Hz. 1 H). 4.06 - 4.18 (m. 2 H). 7.34 - 7.40 (m. 1 H). 7.40 - 7.47 (m. 1 H). 7.63 ~ 7.71 (m. 2 H). 7.85 (s. 1 H). 8.31 (dd, J=8.7. 2.5 Hz. 1 H). 8.57 (br. 5.. 1 H). 8.78 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM—d) (1 ppm 0.91 (d. J=6.6 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.24 - 230 (m. 1 H), 3.62 ~ 3.69 (m. 1 H). 3.89 - 3.96 (m. 2 H). 4.01 (d. J=15.7 Hz. 1 H). 4.14 (d. J=15.7 H2. 1 H). 7.21 (s. 1 H). 7.34 - 7.40 (m. 2 H). 7.42 - 7.47 (m. 1 H). 7.60 - 7.63 (m. 1 H). 7.68 - 7.78 (m. 1 H). 786 (s. 1 H). 8.29 (s. 1 H). 8.35 - 8.40 (m. 1 H). 8.49 (d. J=2.5 Hz. 1 H). 8.86 (br. 5.. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.84 (d. J=6.6 Hz. 8 H). 0.98 (d. J=7.0 Hz. 3 H). 2.17 - 227 (m. 1 H). 3.57 - 3.63 (m. 1 H). 3.75 (s. 3 H). 437 ( [M+H]+) 3.83 - 3.92 (m. 2 H). 3.96 - 4.05 (m. 2 H). 6.61 - 6.65 (m. 1 H), 6.91 - 6.96 (m. 1 H). 7.17 (t, J=8.3 Hz. 1 H). 7.20 - 7.23 (m, 1 H). 7.62 (d. J=B.7 Hz. 1 H). 8.25 - 8.32011. 2 H). 8.74 (d, J=2.5 Hz. 1 H) ~61- [Table 1-5] (ESI pos.) m/Z C d Configurahon 1H-NMR (E81 2.) m/z I499([M+H]+)--l= 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.87(d. J=6.6 Hz. 3 H), 1.01 (d. J=7.0 Hz. 3 H). 2.17 - 2.30 (m, 1 H). 3.59 - 3.67 (m. 1 H). 3.86 - 3.95 (m, 2 37 S H). 3.99 — 4.11 (m. 2 H). 6.71 - 6.78 (m. 1 H). 7.00 (d. J=7.8 Hz. 2 H). 7.07 - 7.14 (m. 1 H). 7.17 - 7.37 (m. 5 H). 7.66 (d. J=8.7 Hz. 1 H). 8.33 (dd. J=8.7, 2.5 Hz. 1 H). 8.39 (br. 5.. 1 H). 8.72 - 9.80 (m. 1 H) I499([M+H]+) 1H NMR (600 MHz. CHLOROFORM—d) (1 ppm 0.90 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.23 - 2.34 (m. 1 H). 2.79 (s. 3 H). 3.62 ~ 3.67 (m. 1 H). 3.90 - 3.99 (n1. 2 H). 4.10 (s, 2 H). 7.43 - 7.53 (m. 2 38 S H). 7.64 - 7.73 (m. 2 H). 7.81 (d. J=7.4 Hz. 1 H). 8.19 - 8.25 (m. 1 H). 8.34 (dd. J=8.7. 2.5 Hz. 1 H). 8.53 (s. 1 H). 8.67 (d. J=5.0 Hz. 1 H). . 3:2.5 Hz. 1 H) I. I 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.90 (6. 3:7.0 Hz. 3 H). 1.03 (d. d=7.0 Hz. 3 H), 2.24 - 2.34 (m. 1 H). 3.65 (dd. J=8.1. 5.2 Hz. 1 H). 3.89 — 39 S 483([M+H}+) 3.99 (m. 2 H). 4.04 - 4.14 (m. 2 H). 7.32 - 7.47 (m. 5 H). 7.52 (s. 1 H). 7.56 - 7.60 (m. 2 H). 7.67 (d. J=8.7 Hz. 1 H). 7.75 (s. 1 H). 8.35 (dd. J=8.7. 2.5 Hz. 1 H). 3.46 (br. 5.. 1 H). 8.77 - 8.84 (m. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.88 (d. J=7.0 Hz. a H), 1.04 (d. J=7.0 Hz. 3 H). 2.20 — 2.29 (m. 1 H). 3.57 (dd. 0:3.7. 5.8 Hz. 1 H). 3.87 — S 426([M+H]+) 4.00 (m. 3 H). 4.17 (d. 0:157 Hz, 1 H). 7.10 (d.
J=5.4 Hz. 1 H). 7.29 — 7.34 (m, 1 H), 7.69 (d. 4:9.1 Hz. 1 H). 8.10 (1:1. 1:51: Hz. 1 H). 8.26 - 8.32 (m. 1 H). 8.82 (d. J=2.9 Hz. 1 H). 9.17 (br. s..1 H) - 1H NMR (600 MHz. CHLOROFORM‘d) d ppm 0.89 (d. J=7.0 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.22 - 2.31 (m. 1 H). 3.67 (dd. J=7.6. 4.3 Hz, 1 H). 3.91 - 3.97 (m. 2 H). 4.00 (d. J=15.7 Hz, 1 H). 4.16 (d. 426([M+H]+) J=15.7 Hz. 1 H). 6.92 (dd. J=8.7. 3.3 Hz. 1 H). 7.68 (d. J=8.7 Hz. 1 H). 8.09 -' 8.16 (m. 1 H). 8.23 - 8.28 (m. 1 H). 8.30 - 8.35 (m. 1 H). 8.74 (br. 5.. 1 H). 8.80 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) :1 ppm 0.94 (d. J=7.0 112.3 H). 1.02 (d. J=7.0 Hz. a H), 2.06 — 2.22 (m. 1 H), 3.62 (dd, 1:219, 6.4 Hz. 1 H). 3.91 — 3.98 (m. 1 H). 4.00 - 4.06 (m. 1 H). 4.34 (d. J=17.8 42 477([M+H]+) Hz. 1 H). 4.86 (d. J=17.8 Hz, 1 H). 7.36 (d. J=5.0 Hz. 1 H). 7.64 (d. J=9.1 Hz. 1 H). 8.33 — 8.41 (m. 1 H). 8.51 (hr. 9.. 1 H). 8.76 (d. J=2.9 Hz. 1 H). 8.86 (d.
J=5.0 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.83 (d. J=6.6 Hz. 3 H). 1.03 (d. J=6.6 Hz. 3 H). 2.13 - 2.26 (m. 1 H). 3.66 (dd. J=9.1. 5.8 Hz. 1 H). 3.84 — 43 482([M+H]+) 4.01 (m. 2 H). 4.11 - 4.24 (m. 2 H). 7.37 - 7.46 (m. 1 H). 7.68 (d. J=8.7 Hz. 1 H). 8.37 - 8.47 (m, 1 H). 8.71 (d. J=2.5 Hz. 1 H). 9.95 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) 6 ppm 0.91 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.23 " 2.28 (m. 1 H). 2.31 (s. 3 H). 3.59 - 3.70 (m, 1 H), 3.85 " 3.95 (m. 2 H). 4.02 (d. J=15.7 Hz. 1 H). 4.09 44 +H]+) -' 4.18 (m, 1 H). 7.29 '- 7.33 (m. 2 H). 7.34 - 7.40 (m. 1 H). 7.40 - 7.46 (m. 1 H), 7.66 - 7.75 (m. 1 H). 7.86 (s. 1 H). 8.20 (s. 1 H). 6.34 (dd. J=9.1. 2.9 Hz. 1 H), 8.46 (d. J=2.9 Hz. 1 H). 8.92 (br. s.. 1 H) 1H NMR (600 MHZ. CHLOROFORM-d) d ppm 0.91 (d. J=7.0 Hz. 3 H). 1.04 (d. J=6.6 Hz. 3 H). 2.23 - 2.31 (m. 1 H). 2.36 (s. 3 H). 3.62 - 3.71 (m. 1 H). 3.90 - 3.97 (m. 2 H). 4.01 (d, J=15.7 Hz. 1 H). 4.14 45 487([M+H]+> (d. J=15.7 Hz. 1 H). 6.90 (s. 1 H). 7.31 - 7.40 (m. 2 H). 7.41 - 7.47 (m. 1 H). 7.66 - 7.73 (171. 1 H), 7.81 - 7.89 (m. 2 H). 8.39 (dd. J=B.7. 2.9 Hz. 1 H). 8.59 (d.
J=2.9 Hz. 1 H). 8.81 (br. 5.. 1 H) [Table 1-6] 22222::n F F 1H NMR (600 MHz. CHLOROFORM-d) (3 ppm 0.89 (d. J=7.0 Hz. 3 H), 1.01 (d. J37.0 Hz. 3 H). 1.30 (t, J=7.5 Hz. 3 H). 2.19 " 2.30 (m. 1 H), 2.82 (q. J=7.4 Hz. 2 H). 3.62 (dd. J=8.5. 6.0 HZ. 1 H). 3.81 -' 3.96 46 7 )I’Nkm 435([M+H]+) 0 L_/ (m. 3 H). 4.1601. J=15.3 Hz. 1 H). 7.18 (d. J=3.3 Hz, 1 H). 7.32 - 7.39 (m, 1 H). 7.40 - 7.46 (111. 1 H). 7.65 - 7.71 (111.1 H). 7.86 (s. 1 H). 8.04 — 8.12 (m. 1 H). 8.56 (d. J=2.5 Hz. 1 H). 8.99 (br. s.. 1 H) 1H NMR (600 MHZ. CHLOROFORM'd) (:1 ppm 0.88 (d. J=7.0 H2. 3 H). 1.01 (d. J=7.0 Hz. 3 H). 2.13 “ 2.27 (m. 1 H). 2.54 (S. 3 H), 3.51 (dd. J=3.3. 5.8 H2. 1 H). 3.80 — 3.96 (m. 3 H). 4.15 (d, J=15.7 Hz. 1 H). 421 ([M+H]+) 7.16 (d. J=B.7 HZ. 1 H). 7.33 — 7.38 (m. 1 H). 7.39 — 7.46 (m. 1 H). 7.54 — 7.71 (m. 1 H). 7.35 (s. 1 H). 8.02 “ 8.09 (m. 1 H). 3.52 (d. J=2.5 Hz. 1 H). 8.95 (br. s.. 1 H) 1H NMR (600 MHz. FORM1-d)d ppm 0.89 (d. J=7.0 HZ. 3 H). 1.02 (d. J=7.0 HZ. 3 H). 2.21 - 2.29011, 1 H). 3.14 (S. 3 H). 3.15 (s. 3 H). 3.61 - 3.67 (m. 1 H). 3.86 - 3.95 (m. 2 H). 3.98 (d. J=15.7 478([M+H1+) H2. 1 H). 4.140). J=15.7 Hz, 1 H). 7.34 - 7.39 (m. 1 H). 7.40 - 7.46 (m. 1 H). 7.64 - 7.69071. 1 H). 7.73 (d. J=8.7 Hz. 1 H). 7.85 (s. 1 H). 8.09 - 8.17 (m. 1 H). 8.75 (d. J=2.5 Hz. 1 H). 3.33 (br. s.. 1 H) 1H NMR (600 MHz. OHLOROFORM-d) d ppm 0.90 (d. J=6.6 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.17 - 477([M+H]+) 2.28 (m. 1 H). 3.85 - 3.94 (m, 2 H). 4.03 - 4.17 (m, 2 H). 4.27 (d. J=16.1 Hz. 1 H), 8.40 - 8.47 (m. 2 H). 8.82 - 3.87 (m. 3 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.83 (d. J=7.0 Hz, 3 H). 1.02 (d. J=6.6 Hz. 3 H). 2.20 - 2.32 (m. 1 H). 3.56 ~ 3.67 (m. 1 H). 3.87 - 3.95 (m. 2 425([M+H}+) H). 3.97 - 4.04 (m. 1 H). 4.05 - 4.12 (m. 1 H). 6.96 1* 7.06 (m. 2 H). 7.42 - 7.54 (m. 2 H). 7.66 (d. J=8.7 Hz. 1 H), 8.31 (dd. J=B.7. 2.5 Hz. 1 H), 8.44 (br. s.. 1 H). 8.80 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.88 (d. J=7.0 Hz. 3 H). 1.03 (d. 0:7.0 Hz. a H). 2.19 - 2,33 (m. 1 H). 3.60 - 3.69 (m. 1 H). 3.39 — 3.96 (m, 2 441([M+H]+) H), 3.97 - 4.04 (m. 1 H). 4.05 — 4.14 (m, 1 H). 7.28 (d. J=9.1 Hz. 2 H). 7.47 (1:1. 0:01 Hz. 2 H). 7.57 (d.
J=8.7 Hz. 1 H). 8.32 (dd. 0:07. 2.5 Hz. 1 H). 8.53 (br. s.,1 H). 8.81 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.88 (d, .0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.21 - 2.31 (m. 1 H). 3.66 (dd. J=7.8. 5.0 Hz. 1 H). 3.86 '- S 432(1M+H]+) 4.02 (m. 3 H). 4.16 (d. d=15.7 Hz. 1 H). 7.56 ~ 7.72 (m. 5 H). 8.26 - 8.33 (m. 1 H). 8.83 (d. J=2.5 Hz. 1 H), 8.99 (br. s.. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.21 - 2.34 (m. 1 H). 3.61 1* 3.69 (m. 1 H). 3.89 -' 3.97 (m. 2 S 491 ([M+H]+) H). 4.02 (s. 1 H). 4.08 - 4.15 (m, 1 H). 7.18 (d. J=8.7 Hz. 2 H). 7.55 (d. J=9.1 Hz, 2 H). 7.68 (d. J=8.7 Hz. 1 H). 8.31 (dd. J=8.7. 2.5 Hz. 1 H). 3.62 (br. s.. 1 H). 8.81 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) (1 ppm 0.91 (d, J=6.6 Hz. 3 H). 1.04 (d. J=7.0 Hz. 8 H). 2.12 - 2.24 (tn. 1 H). 3.69 (dd. J=8.9. 5.0 Hz. 1 H). 3.88 - S 483([M+H]+) 4.03 (m. 2 H). 4.27 - 4.39 (m. 2 H). 7.68 (d. J=9.1 Hz. 1 H). 8.37 - 8.45 (m. 1 H). 8.73 (d. J=2.5 Hz. 1 [Table 1-7] (E81 pas.) m/z .1.1.1..—“1 /0 F 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.87 H O N /N (d. J=6.6 Hz. 3 H). 1.02 (d. J=7.0 Hz. a H). 2.20 — 2.29 (m. 1 H). 3.65 (dd, 0:3.1. 5.2 Hz. 1 H). 8.87 — 55 S 438({M+H]+) 4.01 (211.6 H). 4.12 (0. 0:15.? Hz. 1 H). 6.84 — 6.99 (m. 1 H). 7.00 — 7.05 (m. 1 H). 7.53 (d. J=8.7 Hz, 1 H). 8.06 (d. J=5.8 Hz, 1 H). 8.30 — 8.37 (m. 1 H). 8.71 (br. s.. 1 H). 8.79 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHZ. FORM-d) :1 ppm 0.90 (d. J=7.0 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.14 - 2.28 (m. 1 H). 3.67 (dd. J=8.3. 5.8 Hz. 1 H). 3.87 - U1 O'J S 433([M+H]+) 4.00 (m. 2 H). 4.07 ‘1 4.21 (m. 2 H). 7.67 (d. J=9.1 Hz. 1 H). 7.95 (dd. J=8.7. 2.5 Hz. 1 H). 8.30 (d.
J=8.7 Hz. 1 H). 8.37 - 8.45 (m. 1 H). 8.55 - 8.61 (m, 1 H). 8.75 (d. J=2.9 Hz. 1 H). 9.03 (s. 1 H) 1H NMR (600 MHZ, CHLOROFORM-d) 6 ppm 0.90 (d. J=7.0 Hz. 3 H). 1.02 (d. J=6.6 Hz. 3 H). 2.18 - 2.27 (m. 1 H). 3.63 (dd. J=8.5. 5.6 Hz. 1 H). 3.85 (s.
U1 —.1 438([M+H]+) 3 H). 3.89 - 4.03 (m. 3 H). 4.20 - 4.31 (m. 1 H). 6.50 (d, J=8.3 Hz. 1 H). 7.54 - 7.60 (m. 1 H). 7.62 -' 7.73 (m. 2 H). 8.24 (br. s.. 1 H). 8.37 (dd. J=8.7. 2.5 Hz. 1 H). 8.78 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.89 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.22 - 2.32 (m. 1 H). 3.60 - 3.69 (m. 1 H). 3.88 - 3.97 (m. 5 438([M+H1+) H). 3.99 - 4.06 (m. 1 H). 4.08 - 4.15 (m. 1 H). 6.73 (d. J=8.7 Hz. I H). 7.67 (d. J=9.1 Hz. 1 H). 7.84 (dd.
J=8.9. 2.7 Hz. 1 H), 8.22 (d. J=2.5 Hz. 1 H). 8.31 ~ 8.39 (m. 2 H). 8.79 (d. J=2.5 Hz, 1 H) 1H NMR (600 MHz. OHLOROFORM-d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.21 - 2.33 (m. 1 H). 3.68 (dd. J=7.8. 5.0 Hz. 1 H). 3.88 - 01 (D S 476 ( [M+H]+> 4.05 (m. 3 H). 4.20 (d. J=15.7 Hz. 1 H). 7.64 (ti. 41:87 Hz. 1 H). 7.69 (d. d=8.7 Hz. 1 H). 8.25 - 8.35 (m. 2 H). 8.70 (d. .J=2.5 Hz. 1 H), 8.80 (d. J=2.5 Hz. 1 H). 9.10 (s. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.22 -' 2.31 (m. 1 H). 3.61 - 3.69 (m. 1 H). 3.86 (s. 3 H). 3.90 - 8.98 (m. 2 H). 4.00 - 4.06 (m. 1 H). 4.10 - 438([M+H]+) 4.16 (m, 1 H). 7.68 (d. J=8.7 Hz. 1 H). 7.77 - 7.84 (m, 1 H). 8.08 (d. J=2.5 Hz. 1 H). 8.15 (d. J=2.1 Hz. 1 H). 8.32 - 8.39 (m, 1 H), 8.68 (s. 1 H). 8.78 (d.
J=2.9 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) :1 ppm 0.90 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.14 - 2.24 (m. 1 H). 3.60 " 3.69 (m, 1 H). 3.89 - 3.99 (m. 2 O) _. 442([M+H]+) H). 4.04 (d. J=16.5 Hz. 1 H). 4.21 (d. J=16.5 Hz. 1 H). 7.04 ‘- 7.10 (rn, 1 H). 7.66 (d. J=8.7 Hz, 1 H). 8.18 (d. J=5.4 Hz. 1 H). 8.24 (s. 1 H). 8.39 - 8.45 (m. 1 H). 8.67 (br. s.. 1 H). 8.73 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.90 (d. J=7.0 Hz. 3 H). 1.0201. J=7.0 Hz. 3 H). 2.13 — O) N 443([M+H1+) 2.26 (m. 1 H). 3.80 ~ 3.91 (m. 2 H). 4.00 - 4.14 (m. 2 H). 4.18 - 4.28 (m. 1 H). 7.24 - 7.26 (m. 1 H). 8.40 - 8.46 (m. 2 H). 8.58 (s. 2 H). 8.97 (br. s.. 1 H) 1H NMR (600 MHz, CHLOROFORM—d) 1! ppm 0.90 (d. J=7.0 Hz, 3 H). 1.02 (d. J=7.0 1 H). 2,15 — 2.26011. 1 H). 2.36 (s. a H). 3.59 — 3.67 (m, 1 H). 63 422([M+H]+) 3.89 — 4.03 (m. a H). 4.25 ~ 4.32 (m. 1 H). 6.86 — 6.91 (m. 1 H). 7.65 (d. J=8.7 Hz. 1 H). 8.00 (br. s.. 1 H). 8.13 (d. J=5.0 Hz. 1 H). 8.40 — 8.49 (m, 2 H). 8.72 (d, 0:29 Hz. 1 H) ~64- [Table 18] Structure Configuration 1H NMR (600 MHz. GHLOROFORM-d) d ppm 0.so (a .1:6..6Hz 3H).1..03(d Hz 3H). 2.17— 227 (m. 1 H). 3.59 ~ 3.53011. 1 H). 3.89 — 3.98 (m. 2 64 3 426([M+H]+) H). 4.03 (d. J=16.5 Hz. 1 H). 4.22 (d. J=16.1 Hz. 1 H). 7.37 — 7.49 (m. 1 H). 7.66 (d. 1:9.1 Hz. 1 H). 8.11 — 8.22 (m. 2 H). 8.43 (dd. J=8.7. 2.5 Hz. 1 H). 8.63 (hr. 3.. 1 H). 9.74 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.91 (d. J=6.6 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.14 - 2.25 (m. 1 H). 3.61 — 3.69 (m. 1 1-0.3.89 — 3.99011. 2 O) 01 442([M+H]+) H). 4.04 (d. J=16.5 Hz. 1 H). 4.22 (d. J=16.5 Hz, 1 H). 7,02 — 7.10 (m. 1 H). 7.66 (d. J=B.7 Hz.1 H). 8.19 (d. J=5.4 Hz. 1 H). 8.25 (s, 1 H). 8.40 — 3.45 (m, 1 H). 8.69 (br. s.. 1 H). 8.74 (d. J=2.5 Hz. 1 H) 489([M+H]+) 1H NMR (600 MHZ, FORM'd) d ppm 0.83 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.21 - 2.32 (m. 1 H), 3.61 ' 3.58 (m. 1 H), 3.89 - 3.96 (m. 2 H). 3.93 " 4.04011. 1 H). 4.07 " 4.14 (m. 1 H). 5.77 ~ O) 425([M+H]+) .85011. 1 H). 7.10 - 7.15 (m. 1 H). 7.21 - 7.30 (m. 1 H). 7.46 - 7.53 (In, 1 H). 7.68 (d. J=8.7 Hz. 1 H). 8.27 “ 8.35 (m. 1 H). 8.60 (br. 3.. 1 H). 8.80021. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.89 (d. J=6.6 Hz. 3 H). 1.02 (d. J=7.0 Hz. 3 H). 2.22 ’ 2.30 (m. 1 H). 2.34 (s. 3 H). 3.64 (dd. J=7.6. 4.7 Hz. 421 ([M+H]+) 1 H). 3.87 - 3.98 (m. 2 H). 4.06 (s. 2 H). 6.91 - 6.97 (m, 1 H). 7.20 (t. J=7.8 Hz. 1 H). 7.27 - 7.32 (m. 1 H), 7.35 (s. 1 H). 7.67 (d. d=8.7 H2. 1 H). 8.25 - 8.38 (m. 2 H). 8.80 (d. J=2.5 Hz. 1 H) 1H NMR (600 MHz. CHLOROFORM-d) 6 ppm 0.89 (d. J=7.0 Hz. 3 H). 1.03 (d. J=6.6 Hz, 3 H), 2.19 - 2.29 (m. 1 H). 3.64 (dd. J=8.7. 5.8 Hz. 1 H). 3.94 - 486([M+H]+) 1. 3 H). 4.18 (d. d=16.1 H2. 1 H). 5.04 (s. 2 H). 7.34 (t. J=7.8 Hz. 1 H). 7.54 - 7.60 (m. 1 H). 7.66 (d.
J=8.7 Hz. 2 H). 7.93 (s. 1 H), 8.15 - 8.21 (m. 1 H). 8.86 - 8.91 (m. 1 H). 8.98 (s. 1 H) 1H NMR (600 MHZ. CHLOROFORM-d) d ppm 0.90 (d. J=7.0 Hz. 3 H). 1.04 (d. J=7.0 Hz. 3 H). 2.17 - 2.26 (rn. 1 H), 3.51 ~ 3.70 (m. 1 H). 3.88 - 3.98 (m. 2 433([M+H]+) H). 4.07 - 4.13 (m. 1 H). 4.14 ~ 4.21 (m. 1 H), 7.26 - 7.28 (m. 1 H). 7.66 (d. J=8.7 Hz. 1 H). 8.39 (dd.
J=8.9. 2.7 Hz. 1 H). 8.43 - 8.49 (m. 2 H). 8.76 (d.
J=2.5 Hz. 1 H), 9.00 (br. s., 1 H) - 1H NMR (600 MHZ. CHLOROFORM—d) 01 ppm 0.90 (d. J=7.0 Hz. 3 H). 1.03 (d. J=7.0 Hz. 3 H). 2.15 - 2.26 (m. 1 H). 3.58 — 3.69 (m. 1 H). 3.85 " 3.99 (m, 2 H). 4.08 (d, J=16.5 HZ. 1 H). 4.17 — 4.25 (m. 1 H), \l _n. 476([M+H}+) 7.66 (d. J=9.1 Hz. 1 H). 7.92 (dd. vJ=B.7, 2.1 Hz. 1 H). 8.25 — 8.33 (m. 1 H). 3.41 (dd, J=8.7, 2.5 HZ. 1 H). 8.51 "‘ 8.57 (m. 1 H). 3.74 (d. J=2.5 HZ. 1 H). 8.90 (br. 5.. 1 H) 1H NMR (500 MHz. CHLOROFORM~d) d ppm 0.90 (d. J—66 Hz 3H) 1..03(d J=7.0Hz.3H). 2.14- 2.27 (m. 1H). 358- 3.68(m. 1 H). 388- 3.299(m. “-1 442([M+H]+) H). 4.04 (d. J=16.1 Hz. 1 H). 4.21 (d. J=16.5 Hz, 1 H). 7.64 ~ 7.71 (m. 2 H). 8.10 -— 8.19 (m. 1 H). 8.24 (d. J=2.5 Hz. 1 H). 8.43 (dd. J=8.7. 2.5 Hz. 1 H). 8.64 (br. 5.. 1 H). 8.74 (d. J=2.9 Hz. 1 H) [Table 1-9] Compound Example Structure Configuration (ES! pas.>m/z RT‘T’E‘") condlbon 1.1 M 494 ( ) condition A 1.079 +H1+> condition A 1.155 499(EM+H1+) condition A 1.126 500([M+H]+) condition A i/n\\_,N\F/\ 5L} [.066 3 477([M+H3+) I condition A 2.63 3 432([M+H1+) condition C I“sun/WM 2.80 condition C 1.081 446([M+H]+) condition A I449([M+H3*) 0.750 condition A I425([M+H]+) 1.001 condition A [Table 1-10] RT (min) condition 0,740 438([M+H]+) ion A I4“ “NIH-”4.) 1.221 condition A (1935 00 U1 condition A I ,052 446 ( [M+H] +3 condition A 1.146 m \I condition A 0.933 condition A 1.044 condition A 1.037 condition A L098 condition A -67..
[Table 1~1 1] Structure Configuration condition F F/ 2W“ F \ 1“ 0,9 22 0 ~.\_/ 439([M+H]+) condition A I437([M+H]+) 0.977 condition A 0.702 450([M+H]+) condition A 0.994 436([M+H]+) condition A 0.947 458([M+H)+) condition A .454([M+H]+) 1.109 ion A I456([M+H]+) 1.135 condition A I456(£M+H]+) 1 .061 condition A l .061 +H)+) condition A '427([M+H]+) 1.87 condition C ~68- [Table 1-12] . RT (min) LOSS 454 ) condition A 0.918 437 ( [M+H]+) condition A 1.076 500([M+H]+) condition A 1.90 s 456([M+H]+) condition 8 1.48 450 ( [Mi-H3...) condition B 1.84 464([M+H]+) condition 8 1.96 470 ( [M+H]+) condition 5 2.05 470([M+H3+) condition B 1.95 486 ( {M+H]“‘) condition B 1.88 472 ( [M+H] +) conditinn B [Table 1-13] . RT (min) / 1'92 ”3 2 L] 479([M+H]+) condition B 1 ‘4 ld62([M+H]+) 0.813 condition A 1.081 condition A 1.037 456([M+H]+) condition A I456({M+H]+) 1.121 E 1 7 8 condition A 1.083 “8 474([M+H]+) condition A 1.113 condition A 1.195 ion A I .078 condition A conliifign 3 -70..
[Table 114] RT (min) 1.74 443([M+H]+) condition 8 conid-iz'in 8 COLE; A cognflfil A iZn B l494([M+H]+) Gong; B consign B conga): A coniégisogn A I.corléicfisoan A [Table 1-15] RT (min) i .084 442([M+H]+> condition A 1.003 442 ( [M+H] +) condition A 1.152 508 ( [M+H] +) condition A 1 .1 BB 474([M+H]+) condition A 1 .01 6 494({M+H]+) condition A 1.230 490(EM+H]+) ion A 1.021 condition A 1.193 condition A I .025 condition A can‘éilf. A [Table 1-16] 1.1 14 483([M+H3+) condition A H1.131 460 ( [MW]+> condition A 1.100 508( [M+H3+) condition A 1.009 +H1*) condition A 0.965 466( [M+H]+) condition A E1.075 506([M+H1+) condition A 12.16 494([M+H1+) condition A 1.068 49‘“ [MM-fl” condition A 1.168 506 ( [M+H]+) condft‘ion A 1.133 472([M+H]+) condition A [Table 1—17] - RT (min) 1.123 51 HUME-11+) condition A 2.27 460 ([M+H]+) condition B I.1.075 condition A I472([M+H]+) 0.969 condition A I.0.924 condition A I.1.015 condition A 0.958 condition A 0.738 403 ( [M+H] +) condition A I.0.943 ion A I.1.! 14 condition A [Table 1~18] . RT (min) 1.029 443([M+H]+> c on dition A 0.986 condition A 0.906 condition A 0.943 ion A cofc'listfosn A 0.890 c on dition A 00:153. A 1.194 condition A .341?an IIcorlétiiien A [Table 1-19] RT (min) F 0 1.107 452([M+H]+) condition A 1.109 450([M+H]+) condition A 0.927 +H]+) condition A 0.861 condition A 0.861 condition A 0.648 condition A c0383; A 0.812 condition A 0.637 condition A I.0.707 c o ndition A [Table 1-20] Example Structure RT (min) Configurifim (ESI pos.) m/z 2.39 sown/”HM 2,18 457([M+H]+) 1.162 408([M+H]+) ion A 1.059 185 418([M+H]+) condition A 1.053 187 426([M+H] +) ion A 0.864 188 393 ( [M+H]+) condition A 0.937 409 ( [M+H]+) condition A 0.995 _. (D O 443([M+H] +) condition A 0.852 405 ( Wm“) condition A 0.907 403 ( [M+H]+) condition A -77* [Table 1-21] condition I.0.991 condition A 7 cond'rt'lon A I.waif; A I configifin 3 I.00:81:: A ~78- [Table 1-22] condition WI.0.903 427 ( [M+H]+) condition A 0.914 condition A 0.802 ion A 9033335., A 207 coiiltizogn A 1.082 condition A 1 .087 condition A 1 .089 condition A 0.360 condition A coriciiisosn A —79- [Table 1-23] 1.028 414([M+H1+) condition A =0.857 420( EM+HW condition A 1.024 495([M+H]+) condition A 0.968 451([M+H]+) ion A 0.893 457([M+H1*) condition A 0.9 03 445 ( {MN-i“) condition A 0.971 467( [M+H3+) condition A 0.955 471 ([M+H]+) condition A 0.7 04 443([M+H]+) condition A 0.897 437(EM+H1*) condition A [Table 1-24] RT (min) (ESI Dos.) m/z L095 466([M+H]+) condition A cnfé'sltiaozn A confifign 8 conzfign B m conIdgfiin 3 congién B - coféféfn A coriégtfoon A conig‘fign B [Table 1-25] . RT (min) 1.92 233 3 5 463 ( [M+H]+) condition 8 condition B 235 3 coniifign B 236 9 I.cuféiiisozn A 237 9 coféigtizfn A 233 9 50:81:31 A 239 3 coni'ittjiin B 240 9 éi'Jt‘itosn A 241 I.OWL???“ A 1 .008 443([M+H]+) condition A [Table 1—26] RT (min) N \ | «an”K W,\—/ 0.951 s 409([M+H]+) condition A | 1.073 457([M+H]+) condition A 1 .025 423([M+H]+) condition A 1.159 condition A 1.039 ion A c0331? A 1.008 condition A cofoiififn A I.0.822 c on dition A The 1H—NMR data of the following compounds listed below among those shown in Tables 1-9 to 1-26 are shown below: Compound 73 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.96 (d, J=7.02 Hz, 3 H), 1.02 (d, J=6.61Hz, 3 H), 2.12 — 2.30 (m, 1 H), 3.84 - 3.97 (m, 2 H), 4.02 — 4.15 (m, 2 H), 4.17 - 4.28 (m, 1 H), 7.20 — 7.27 (m, 1 H), 7.64 — 7.74 (m, 1 H), 8.41 - 8.50 (m, 3 H), 8.97 (br. s., 1 H) nd 74 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.92 (d, J=6.61 Hz, 3 H), 1.05 (d, =7.02 Hz, 3 H), 2.19 - 2.28 (m, 1 H), 3.63 (dd, J=9.08, 6.19 Hz, 1 H), 3.90 - 4.07 (m, 3 H), 4.32 ((1, 1:16.51 Hz, 1 H), 7.28 - 7.31 (m, 1 H), 8.41 — 8.48 (m, 2 H), 8.68 (br. s., 1 H), 9.18 (s, 2 H) Compound 93 1H NMR (600 MHz, CHLOROFORM—d) (1 ppm 0.90 (d, J=7.02 Hz, 3 H), 1.01 (d, J=7.02 Hz, 3 H), 2.12 - 2.23 (m, 1 H), 3.78 — 3.83 (m, 1 H), 3.84 ~ 3.88 (m, 1 H), 3.90 (s, 3 H), 4.03 - 4.08 (m, 1 H), 4.10 - 4.18 (m, 2 H), 7.24 - 7.26 (m, 1 H), 8.34 (s, 2 H), 8.41 - 8.47 (m, 2 H), 9.09 (br. s., 1 H) Compound 94 1H NMR (600 MHz, CHLOROFORM-d) (:1 ppm 0.90 (d, J=6.61 Hz, 3 H), 1.01 (d, J=7.02 Hz, 3 H), 1.25 (t, J=7.64 Hz, 3 H), 2.15 - 2.24 (m, 1 H), 2.61 (q, J=7.84 Hz, 2 H), 3.77 - 3.84 (m, 1 H), 3.87 (dd, J=10.94, 6.40 Hz, 1 H), 4.07 (dd, J=10.73, 9.50 Hz, 1 H), 4.10 ~ 4.17 (m, 2 H), 7.23 - 7.25 (m, 1 H), 8.41 - 8.45 (m, 2 H), 8.48 (s, 2 H), 9.05 (br. s., 1 H) Compound 103 1H NMR (600 MHZ, CHLOROFORM-d) (:1 ppm 0.89 (d, J=7.0 Hz, 3 H), 1.03 (d, J=7.0 Hz, 3 H), 1.32 (s, 9 H), 2.13 - 2.26 (m, 1 H), 3.66 (dd, J=8.9, 6.0 Hz, 1 H), 3.83 — 4.01 (In, 2 H), 4.05 - 4.17 (m, 2 H), 6.27 (s, 1 H), 7.68 (d, J=8.7 Hz, 1 H), 8.40 (dd, J=8.7, 2.5 Hz, 1 H), 8.72 (d, J=2.5 Hz, 1 H), 9.32 (br. s., 1 H) Compound 107 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.98 — 1.04 (m, 2 H), 1.29 (t, J=7.6 Hz, 1 H), 1.72 - 1.85 (m, 1 H), 2.76 ~ 2.86 (m, 1 H), 3.57 — 3.65 (m, 1 H), 3.91 - 4.04 (m, 1 H), 4.11 (t, J=8.9 Hz, 1 H), 4.18 (d, J=16.1Hz,1 H), 7.15 - 7.29 (m, 2 H), 7.64 - 7.71 (m, 1 H), 8.32 - 8.38 (In, 1 H), 8.52 — 8.59 (m, 1 H), 8.73 - 8.77 (m, 1 H) nd 108 1H NMR (600 MHz, CHLOROFORM-d) (1 ppm 1.02 (s, 6 H), 1.57 - 1.67 (m, 2 H), 1.75 - 1.84 (m, 1 H), 2.69 (s, 3 H), 3.58 - 3.68 (m, 1 H), 3.91— 4.00 (m, 2 H), 4.08 ~ 4.16 (m, 1 H), 4.21 (d, J=16.1 Hz, 1 H), 7.69 (d, J=9.1Hz,1 H), 8.05 (d, J=8.7 Hz, 1 H), 8.15 — 8.22 (m, 1 H), 8.29 ~ 8.35 (m, 1 H), 8.68 — 8.72 (m, 1 H), 8.76 — 8.80 (m, 1H), 8.83 - 8.87 (m, 1 H) Compound 112 1H NMR (600 MHZ, CHLOROFORM-d) (1 ppm 0.85 — 0.98 (m, 6 H), 1.41 — 1.48 (In, 2 H), 1.62 - 1.76 (m, 1 H), 3.49 — 3.58 (m, 1 H), 3.80 - 3.91 (m, 2 H), 3.98 - 4.05 (m, 1 H), 4.11 (d, J=15.7 Hz, 1 H), 6.36 - 6.64 (m, 1 H), 7.52 (d, J=8.3 Hz, 1 H), 7.59 (d, J=9.1 Hz, 1 H), 8.09 - 8.24 (m, 2 H), 8.53 - 8.58 (In, 1 H), 8.61 (s, 1 H), 8.65 — 8.69 (m, 1 H) Compound 114 1H NMR (600 MHZ, CHLOROFORM-d) d ppm 0.94 - 0.97 (m, 4 H), 0.97 ~ 1.03 (m, 6 H), 1.46 - 1.53 (m, 1 H), 1.69 - 1.83 (m, 2 H), 1.96 - 2.03 (m, 1 H), 3.54 - 3.61 (m, 1 H), 3.90 - 4.00 (m, 2 H), 4.04 - 4.18 (m, 2 H), 7.08 (d, J=8.3 Hz, 1 H), 7.66 (d, J=8.7 Hz, 1 H), 7.86 - 7.93 (m, 1 H), 8.21 (br. s., 1 H), 8.29 - 8.36 (m, 1 H), 8.39 ~ 8.43 (m, 1 H), 8.71 - 8.76 (m, 1 H) Compound 148 1H NMR (600 MHz, CHLOROFORM-d) (1 ppm 1.22 (s, 3 H), 1.24 (s, 3 H), 3.24 (s, 3 H), 3.60 (dd, J=9.1, 6.2 Hz, 1 H), 3.96 (dd, J=9.9, 6.2 Hz, 1 H), 4.02 — 4.10 (m, 1 H), 4.26 (d, J=16.5 Hz, 1 H), 4.45 (d, J=16.5 Hz, 1 H), 7.66 (d, J=9.1 Hz, 1 H), 8.41 - 8.47 (m, 2 H), 8.50 (s, 1 H), 8.69 (br. s., 1 H), 8.70 — 8.73 (m, 1 H) Compound 152 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.11 — 0.24 (m, 2 H), 0.49 - 0.61 (In, 2 H), 0.65 - 0.76 (m, 1H), 1.63 - 1.75 (m, 2 H), 3.94 — 4.04 (m, 2 H), 4.04 ~ 4.10 (m, 1H), 4.14 - 4.20 (m, 1 H), 4.21 - 4.29 (m, 1 H), 7.06 (dd, J=5.4, 1.7 Hz, 1 H), 7.71 (dd, J=9.5, 1.7 Hz, 1 H), 8.17 (d, J=5.4 Hz, 1 H), 8.27 (s, 1 H), 8.48 (s, 1 H), 8.74 (br. s., 1 H) Compound 155 1H NMR (600 MHZ, CHLOROFORM-d) d ppm 1.12 (t, J=7.4 Hz, 3 H), 1.59 - 1.72 (m, 1 H), 1.74 - 1.88 (m, 1 H), 3.90 (dd, J=8.5, 6.8 HZ, 1H), 4.01 - 4.17 (111,2 H), 4.18 — 4.24 (m, 1 H), 4.25 — 4.32 (m, 1 H), 4.62 - 4.78 (m, 1 H), 7.28 (d, J=5.8 HZ, 1 H), 7.67 (d, J=8.7 HZ, 1 H), 8.36 - 8.42 (m, 1 H), 8.44 - 8.50 (m, 2 H), 8.72 - 8.80 (m, 2 H) Compound 161 1H NMR (600 MHZ, CHLOROFORM—d) d ppm 0.98 (t, J=7.4 HZ, 3 H), 1.32 ~ 1.48 (m, 2 H), 1.54 - 1.63 (m, 1 H), 1.80 - 1.89 (m, 1 H), 3.73 - 3.84 (m, 2 H), 4.04 (d, J=16.5 Hz, 1 H), 4.20 - 4.28 (m, 2 H), 7.23 - 7.25 (m, 1 H), 8.40 - 8.44 (m, 1 H), 8.46 (s, 1 H), 8.51 (s, 2 H), 8.86 (br. s., 1 H) Compound 193 1H NMR (600 MHZ, CHLOROFORM—d) d ppm 0.68 - 0.72 (m, 2 H), 0.88 (d, J=6.6 Hz, 3 H), 1.00 (d, J=7.0 Hz, 3 H), 1.01 - 1.05 (m, 2 H), 1.79 ~ 1.86 (m, 1 H), 2.14 - 2.22 (m, 1 H), 3.61 - 3.67 (m, 1 H), 3.77 - 3.88 (m, 2 H), 4.05 (dd, J=10.7, 9.5 HZ, 1H), 4.13 (s, 2 H), 7.22 - 7.25 (m, 1 H), 8.38 (s, 2 H), 8.40 - 8.45 (m, 2 H), 9.10 (br. s., l H) Compound 195 1H NMR (600 MHZ, CHLOROFORM—d) d ppm 0.66 - 0.74 (m, 2 H), 0.88 (d, J=7.0 HZ, 3 H), 0.95 - 1.08 (In, 5 H), 1.76 - 1.88 (m, 1 H), 2.10 - 2.23 (m, 1 H), 3.74 - 3.92 (m, 2 H), 3.99 - 4.19 (m, 3 H), 6.98 — 7.06 (m, 1 H), 8.15 (d, J=5.4 HZ, 1 H), 8.21 ~ 8.28 (m, 1 H), 8.38 (s, 2 H), 8.94 (br. s., 1 H) nd 248 1H NMR (600 MHZ, CHLOROFORM-d) d ppm 0.87 (d, J=6.6 Hz, 3 H), 0.99 (t, J=7.4 HZ, 3 H), 1.25 - 1.32 (m, 1 H), 1.36 - 1.42 (m, 1 H), 1.45 (t, J=7.0 HZ, 3 H), 1.90 - 1.96 (m, 1 H), 3.81 — 3.86 (m, 1 H), 3.87 - 3.92 (m, 1H), 4.00 - 4.17 (m, 5 H), 7.05 (dd, J=5.4, 2.1 HZ, 1 H), 8.16 (d, J=5.4 HZ, 1 H), 8.25 - 8.28 (m, 1 H), 8.32 (s, 2 H), 8.95 - 8.99 (m, 1 H) Compound 249 1H NMR (600 MHZ, CHLOROFORM-d) (1 ppm 0.68 - 0.73 (m, 2 H), 0.86 (d, J=6.6 Hz, 3 H), 0.99 (t, J=7.4 Hz, 3 H), 1.01 -1.05(m, 2 H), 1.22 - 1.33 (m, 1 H), 1.35 — 1.45 (m, 1 H), 1.76 » 1.87 (m, 1 H), 1.89 ~ 1.98 (m, 1 H), 3.80 - 3.87 (m, 1 H), 3.88 - 3.93 (m, 1 H), 3.99 - 4.18 (111,3 H), 7.01 — 7.06 (m, 1 H), 8.16 (d, J=5.4 Hz, 1 H), 8.23 - 8.29 (m, 1 H), 8.38 (s, 2 H), 8.95 (br. s., 1 H) Compound 250 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.84 - 0.91 (m, 5 H), 0.98 (t, J=7.4 Hz, 3 H), 1.09 -1.14(m, 2 H), 1.25 - 1.33 (m, 1H), 1.36 - 1.42 (m, 1 H), 1.44 (t, J=7.0 Hz, 3 H), 1.88 - 1.94 (In, 2 H), 3.83 (dd, J=10.5, 6.4 Hz, 1 H), 3.91 ~ 3.96 (m, 1 H), 3.96 — 4.00 (In, 1 H), 4.03 - 4.07 (m, 1 H), 4.10 (q, J=6.7 Hz, 2 H), 4.23 ~ 4.30 (m, 1 H), 6.71 - 6.75 (m, 1 H), 7.93 - 7.98 (m, 1H), 8.03 — 8.06 (m, 1 H), 8.31 (s, 2 H) Compound 251 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.57 - 0.63 (m, 2 H), 0.69 - 0.74 (m, 2 H), 0.76 (d, J=6.6 Hz, 3 H), 0.87 (t, J=7.4 Hz, 3 H), 0.90 — 0.95 (in, 2 H), 0.95 — 1.00 (m, 2 H), 1.14 - 1.23 (m, 1 H), 1.25 - 1.34 (m, 1 H), 1.69 - 1.76 (m, 1 H), 1.76 - 1.85 (m, 2 H), 3.72 (dd, J=10.7, 6.6 Hz, 1 H), 3.79 - 3.85 (m, 1 H), 3.87 (d, J=16.5 Hz,1 H), 3.90 - 3.96 (m, 1H), 4.14 (d, J=16.5 Hz, 1 H), 6.60 (dd, l=5.4, 1.2 Hz, 1 H), 7.74 - 7.80 (m, 1 H), 7.97 (d, J=5.4 Hz, 1 H), 8.28 (s, 2 H), 8.53 (br. s., 1 H) Test e 1 [Glycine Uptake Inhibition Experiment] A glycine uptake experiment was conducted in accordance with the method published in Neuron, 8, 927-935, 1992. In the experiment, T98G cells (glioma cells) expressing human type 1 glycine transporter (GlyTl) were used. The T98G cells were seeded in a 96-well plate at 2.0 X 104 cells/well and cultured overnight in a C02 incubator.
The test substance was dissolved in a 100% DMSO solution and then dissolved in a 10 mM HEPES buffer solution (pH 7.4) ning 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose and 0.2% bovine serum n. After removing the cell culture medium, the test nce was ted to a 10-min pretreatment. Subsequently, the test substance and [3H] glycine (final concentration: 250 nM) were added to the cells and reaction was performed at room temperature for 15 s. After the end of the reaction, the extracellular fluid was aspirated with a manifold to remove excess labeled glycine present outside the cells, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide on. The glycine content in the cells was determined by measuring the radioactivity in the cell lysate with a liquid scintillation r. Glycine uptake in the presence of 10 uM ALX5407 was defined as non-specific uptake, and the value calculated by subtracting the amount of the non-specific uptake from the total uptake in the absence of 10 “M ALX5407 was defined as specific uptake. In addition, glycine uptake tory ty (ICso value) was calculated from an inhibition curve at the concentrations of each test substance ranging from 10’9 to 10'5 M.
It should be noted that ALX5407 is an HCl salt ofN-{(3R)([1,1 ’—biphenyl]—4- yloxy)(4-fluorophenyl)propyl]-N—methylglycine.
All the compounds of the Working Examples in the present invention were found to have ICso values of less than 10 uM. Specific examples of their 1050 values are as foliows: Compound 8, 0.66 uM; Compound 11, 0.089 uM; Compound 12, 0.071 uM; Compound 13, 0.074 uM; nd 54, 0.80 nM; Compound 61, 0.053 uM; Compound 62, 0.033 uM; Compound 93, 0.054 uM; nd 98, 0.26 uM; Compound 103, 0.23 uM; Compound 104, 0.24 uM; Compound 148, 0.075 uM; Compound 152, 0.043 uM; Compound 165, 0.15 uM; Compound 186, 0.045 uM; Compound 188, 0.60 uM; nd 193, 0.022 uM; Compound 220, 0.017 uM; Compound 248, 0.016 uM; Compound 249, 0.018 uM; and Compound 250, 0.024 uM.
INDUSTRIAL APPLICABILITY The inventive compounds have glycine orter (GlyTl)—inhibiting activity, and thus, are effective in the prevention or treatment of diseases associated with the glycine orter which are, specifically, schizophrenia, Alzheimer’s disease, cognitive impairment, dementia, anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post—traumatic stress disorder, specific phobias, acute stress disorder), depression, drug dependence, spasm, tremor, pain, son’s disease, attention deficit hyperactivity disorder, bipolar disorder, eating er, sleep disorders or the like.

Claims (14)

1. A compound of formula [I] or a pharmaceutically acceptable salt thereof: [Formula 1] \ o N o A1,A2 R1' 7L R5 R1 NAN/K\A3’[K4 R6 \_/ wherein R1 and R1, are the same or ent and each represent a en atom; a halogen atom; a CH; alkoxy group; a haloC1-6 alkyl group; a cyano group; a heteroaryl group which may be substituted by a C1-6 alkyl group; a Cm alkyl group; a C3-6 cycloalkyl group; a CM alkylamino group; or the formula CONR'IR8 wherein R7 and R8 are the same or different and each represent a hydrogen atom or a CM alkyl group, R2 represents a hydrogen atom or a Cm alkyl group, R3 represents a phenyl group which may be substituted by l to 3 substituents selected from halogen atoms, cyano groups, C1_6 alkyl groups, C1-6 alkoxy groups, Cm alkylarnino groups, C1.6 alkylsulfonyl groups, haloC1_6 alkyl , haloC1_5 alkoxy groups, haloCl_6 alkylsulfanyl groups, phenyl , phenoxy groups, heteroaryl groups which may be tuted by a CM alkyl group, and the formula ~SOgNR9RI° wherein R9 and R10 are the same or different and each represent a hydrogen atom or a Cm alkyl group; or a aryl group or a bicyclic heteroaryl group wherein each heteroaryl group may be substituted by 1 to 3 substituents selected from halogen atoms, CM alkyl groups, C3-6 cycloalkyl groups, C16 alkoxy groups, cyano groups, CH, alkanoyl groups and haloCH; alkyl groups, R4 represents a C1_6 alkyl group which may be tuted by l to 3 halogen atoms, a C1_6 alkoxy group, a C3_6 cycloalkyl group or a phenyl group; a C3-6 cycloalkyl group; or a phenyl group, R5 and R6 are the same or different, and each represent a hydrogen atom or a CM alkyl group, and A', A2, A3, and A4 are the same or different, and each ent the formula CH or a nitrogen atom, provided that one or two of A1, A2, A3, and A4 represent a nitrogen atom.
2. The nd or ceutically acceptable salt thereof according to claim 1, wherein R1 is a hydrogen atom; a halogen atom; a C1_6 alkoxy group; a haloC1.6 alkyl group; a cyano group; a heteroaryl group which may be substituted by a C1_6 alkyl group; a C1-6 alkyl group; a CM alkylamino group; or the formula CONR7R8 wherein R7 and R8 are the same or different and each represent a en atom or a Cm alkyl group, R11 is a hydrogen atom, R3 is a phenyl group which may be substituted by 1 to 3 substituents selected from halogen atoms, cyano groups, C1.6 alkyl groups, C1-6 alkoxy groups, CM alkylamino groups, 01-6 alkylsulfonyl , haloC1_6 alkyl groups, haloCM alkoxy groups, halocm alkylsulfanyl groups, phenyl , phenoxy groups, aryl groups which may be substituted by a C1_6 alkyl group, and the formula -SOzNR9R10 wherein R9 and R10 are the same or ent and each represent a hydrogen atom or a CM alkyl group; or a heteroaryl group which may be substituted by 1 to 3 substituents selected from halogen atoms, C1-6 alkyl , C1-6 alkoxy groups, cyano groups, and haloCM alkyl groups, and R4 is a CM alkyl group which may be tuted by a C3-6 cycloalkyl group or a phenyl group; or a phenyl group.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is a C1_5 alkyl group which may be substituted by 1 to 3 halogen atoms.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1 0r 2, wherein R4 is a CM alkyl group.
5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R2 is a hydrogen atom, and R5 and R6 are both a hydrogen atom.
6. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R1 is a halogen atom; a (31-5 alkoxy group; a haloCm alkyl group; a cyano group; a heteroaryl group which may be substituted by a Cl_6 alkyl group; a 01-6 alkyl group; a C1_5 alkylamino group; or the formula CONR7R8 wherein R7 and R8 are the same or different and each represent a hydrogen atom or a CM alkyl group, and R" is a hydrogen atom.
7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 5, wherein R1 is a halogen atom, a CM alkoxy group, a haloC1-6 alkyl group, a 01-6 alkyl group, or a C3-6 cycloalkyl group, and R1, is a hydrogen atom, a halogen atom, a C1-6 alkoxy group, a haloC1-5 alkyl group, a 01-6 alkyl group, or a C3-6 cycloalkyl group.
8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R1 is ed in the para position.
9. The compound or ceutically acceptable salt f according to any one of claims 1 to 8, wherein any one of A1, A2, A3 and A4 is a nitrogen atom or Al and A3 are both a nitrogen atom.
10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, n Al is a nitrogen atom, A2 and A4 are both the formula CH, and A3 is the formula CH or a nitrogen atom.
11. The compound or pharmaceutically acceptable salt f according to any one of claims 1 and 3 to 10, wherein R3 is a aryl group which may be substituted by 1 to 3 substituents selected from halogen atoms, Cm alkyl groups, C3_6 cycloalkyl groups, CH; alkoxy groups, cyano groups, C1_6 alkanoyl groups and haloC1.6 alkyl groups.
12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 10, wherein R3 is a pyridyl group which may be substituted by 1 to 3 substituents selected from n atoms, C1_6 alkyl groups, C3-6 cycloalkyl groups, 01-6 alkoxy groups, cyano groups, CH, yl groups and haloCM, alkyl groups.
13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 10, wherein R3 is a pyridyl group which may be substituted by 1 to 3 substituents selected firom n atoms, C1_6 alkyl groups, CM cycloalkyl groups and haloC1.6 alkyl groups.
14. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: 2-[(5S)—3—(5~methoxypyri1nidin-2—yl)—2-0x0(pr0pan~2-yl)imidazolidin~1~yl]-N—[4— (trifluoromethy1)pyridin-2—yl]acetamide, 2—[(5S)—3-(5-ethy1pyrimidin~2—y1)0xo(propanyl)imidazolidin—1—yl]-N-[4— romethyl)pyfidin~2-y1}acetamide, 2-[(5 S)—3 -(5-chloropyrimidin-Z—y1)—2-0xo~5~propylimidazolidin~1—yl]-N-[4- (trifluoromethyl)pyridin—2-yl]acetamide, N-(4-ch10ropyridin—2—yl)[(5S)-3—(5-chloropy1i1nidin~2-yl)—2—oxo-S- imidazolidiny1] acetamide, 2-[(SS)(5~chlor0pyrimidin-Z-yl)—2-oxopropylimidazolidiny1]-N—(4— ethylpyridin-Z-yl)acetamide, 2—[(5S)—3—(5~fluoropyrimidin-2—yl)~2-0xopropylimidazolidin—l-yI]-N—[4- (trifluoromethyl)pyridinyl]acetamide, )(5-fluoropyrimidin-Z-yl)0x0-5~(propan—2-y1)imidazolidin—1-y1]-N-[4- (trifluoromethy1)pyridinyl]aceta1nide, N—(4—cyclopropylpyridin—Z—yl) {(5S)oxo(propanyl)-3—[5— (trifluoromethyl)pyrimidin—Z-yl]imidazolidiml-y1}acetamide, 2-[(5S)[(ZS)-butanyl](5-chloropyrimidin—2-yl)—2—oxoimidazolidin~l-yl]—N-[4— (trifluoromethyl)pyrldin~2~y1]acetamide, N-(4-chloropyridin—2—yl)[(5S)(5~chloropyrimidin—2—yl)oxo(propan-2— yl)imidazolidin—1—yl]acetamide, N—(4—chloropyfidin—2~yl){(SS)-2—oxo—5—(propan—2-yl)~3~[5- (trifluoromethyl)pyrimidin—2-y1]imidazolidiml ~yl } acetamide, 2—[(5S)(5-cyclopropylpyrimidin—Z-yl)—2—0xo(propanyl)imidazolidin—l-yl]-N- [4-(tn'fluoromethyl)pyridin—Z—yl]acetamide, N—(4-chloropyridiny1)[(SS)(5-cyclopropylpyrimidinyl)oxo(propan—2~ yl)imidazolidin—1—y1]acetamide, 2-[(5 S)—5—[(ZS)—butany1]-3—(5~chloropyrimidin—Z-yl)oxoimidazolidiny1]—N—(4- cyclopropylpyridin-Z-yl)acetamide, )~5—[(ZS)-butan—2-y1]~3~(5-chloropyrimidinyI)-2—oxoimidazolidin-1~y1]-N—(4- chloropyridin-Z-yl)acetamide, 2—[(5S)—5-[(ZS)-butanyl](5-chloropyrimidin-Z-y1)~2—oxoimidazolidin—1 —y1]-N-(4— ethylpyridin—2~yl)acetamide, h10ropyridin~2-y1){(5R)-5—[(1S)fluoropropy1]0x0-3—[5~ (trifluoromethy1)pyrimidin—2-yl]imidazolidin—1-y1}acetamide, N—(4-chloropyridinyl) {(5R)—3~(5-ch10ropyrimidin—2-y1)-5—{(1 S) fluoropropyl]oxoirnidazolidiny1}acetamide, N-(4-cyclopropylpyn'din-Z-yl){(5R)[(1S)—1-fluoropropy1]0x0[5- (trifluoromethyl)pyrimidiny1]imidazolidin-1~y1}acetamide, 2-{(5R)[(1S)flu0ropropy1]oxo[5-(trifluoromethyl)pyrimidin yl]i1nidazolidin-1~y1}—N-[4-(tn'fluoromethyl)pyridinyl]acetamide, 2- {(5R)—3 -(5-chloropyrimidinyl)-S-[(1 S)-1 -fluoropropy1]oxoimidazolidin— l -y1}- N-[4-(trifluoromethy1)pyridin-2~y1]acetamide, 2-[(5R)-5—[(1 S)—1—fluoropropy1]—3-(5-fluoropyrimidin—2-y1)—2—oxoimidazolidin— 1 -y1]- N—[4-(trifluor0methyl)pyridin-Z-yl]acetamide, 2-{(5R)—3-(5-cyclopropylpyrimidin—2~y1)[(1S)-1~flu0ropropy1]~2—oxoimidazolidin- N-[4—(triflu0romethy1)pyn'din-Z-yl]acetamide, 2-{(5R)(5-ethoxypyri1nidin—2-yl)—5—[(1S)fluoropropy1]—2-oxoimidazolidin—1~ yl } ~N—[4—(t1iflu0r0methy1)pyridiny1}acetamide, N-(4-cyclopropylpyridin—Z-yl)-2— {(5R)—3—(5-ethoxypyrimidin—2-y1)—5-[(1 S)— 1 - fluoropropyl]oxoimidazolidinyl} acetamide, N—(4-chlor0pyridin-2—yl)—2- {(5R)—3 -(5~ethoxypyrimidin~2~yl)—5-[(1 S)—1 - fluoropropyl]oxoimidazolidin—1-y1}acetamide, 2-[(5S)[(ZS)-butan-2~yl]-3—(5-fluoropyrimidin-Z-yl)~2-oxoimidazolidiny1]-N-[4- (trifluoromethyl)pyridin—2~yl]acetamide, 2- {(5 S)[(ZS)-butany1]~2—ox0[5~(trifluoromethyl)pyrimidin—2-y1]imidazoiidiny1} -N—(4~cyclopr0py1pyridinyl)acetamide, 2— {(5 S)—5~[(ZS)-butanyl]ox0-3—[5—(trifluoromethy1)pyrimidin—2-y1]imidazolidin— 1-y1}—N~(4-Ch10r0pyridin-2—yl)acetamide, 2-[(SS)(5-ethoxypyrimidin-Z-yl)—2-oxo-5—(propan-Z-yl)imidazolidinyl]-N-[4- (trifluoromethyl)pyridinyl]acetamide, N-(4-ch10ropyridin—2-yl)—2—[(5S)(5-ethoxypyrimidin—2—y1)—2-oxo~5~(propan—2— y1)imidazolidiny1]acetamide, N-(4-cyclopropylpyridin—2-yl)[(5S)~3~(5-ethoxypyrimidinyl)—2-oxo(propan- 2-y1)imidazolidin- l -y1]acetamide, 2-[(5S)~5-[(ZS)-butan—2~y1](5-ethoxypyrimidin~2~y1)oxoimidazolidin—l ~yl]-N- [4-(trifluoromethyl)pyridin-Z-yl]acetamide, 2-[(SS)[(ZS)—butany1](5—cyclopropylpyrimidin-2—y1)~2—oxoimidazolidin- 1-
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