I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US008268848B2
`
`c12) United States Patent
`Terauchi et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,268,848 B2
`Sep.18,2012
`
`(54) CYCLOPROPANE COMPOUND
`
`(75)
`
`Inventors: Taro Terauchi, Tsukuba (JP); Ayumi
`Takemura, Tsukuba (JP); Takashi
`Doko, Tokyo (JP); Yu Yoshida, Tsukuba
`(JP); Toshiaki Tanaka, Tsukuba (JP);
`Keiichi Sorimachi, Tsukuba (JP);
`Yoshimitsu Naoe, Tsukuba (JP);
`Carsten Beuckmann, Tsukuba (JP);
`Yuji Kazuta, Tsukuba (JP)
`(73) Assignee: Eisai R&D Management Co., Ltd.,
`Tokyo (JP)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`( *) Notice:
`
`(21) Appl. No.: 13/237,205
`
`(22) Filed:
`
`Sep.20,2011
`
`(65)
`
`Prior Publication Data
`
`US 2012/0095031 Al
`
`Apr. 19, 2012
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/385,342, filed on Sep.
`22, 2010.
`
`(30)
`
`Foreign Application Priority Data
`
`Sep. 22, 2010
`
`(JP) ................................. 2010-211629
`
`(51)
`
`Int. Cl.
`AOJN 43/54
`(2006.01)
`A61K 31/505
`(2006.01)
`(52) U.S. Cl. ........................................ 514/269; 544/298
`(58) Field of Classification Search .................. 514/269;
`544/298
`See application file for complete search history.
`
`514/245
`
`514/252.03
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,935,814 A
`8/ 1999 Bergsma et al.
`6,001,963 A
`12/1999 Bergsma et al.
`6,020,157 A
`2/2000 Bergsma et al.
`6,166,193 A
`12/2000 Yanagisawa
`6,309,854 Bl
`10/2001 Bergsma et al.
`2008/0076771 Al*
`3/2008 Reiter et al.
`2010/0261644 Al
`10/2010 DeFossa et al.
`2012/0165339 Al*
`6/2012 Terauchi et al.
`
`FOREIGN PATENT DOCUMENTS
`9/1998
`10-229887
`12/1998
`10-327888
`12/1998
`10-327889
`7 /1999
`11-178588
`12/2006
`06-328057
`11/1996
`WO 96/34877
`12/2005
`WO 2005/118548
`9/2007
`W02007/105177
`11/2007
`WO 2007/129188
`3/2008
`WO 2008/031772
`4/2008
`WO 2008/038251
`6/2008
`WO 2008/069997
`WO 2008/081399
`7/2008
`WO 2009/039942
`4/2009
`
`JP
`JP
`JP
`JP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`WO
`
`4/2009
`WO 2009/047723
`OTHER PUBLICATIONS
`
`E. Mignot et al., 5 Nature Neuroscience Supplement 1071-1075
`(2002).*
`D.A. Prober et al., 26 The Journal of Neuroscience 13400-13410
`(2006).*
`Richey et al., "Pharmacological Advances in the Treatment oflnsom(cid:173)
`nia," Curr Pharm Des. 17(15):1471-75 (2011).
`Borgland et al., "Orexin A in the VTA is critical for the induction of
`synaptic plasticity and behavioral sensitization to cocaine," Neuron.,
`49:589-601 (2006).
`Brisbare-Roch et al., "Promotion of sleep by targeting the orexin
`system in rats, dogs and humans," Nat. Med., 13: 150-155 (2007).
`Chemelli et al., "Narcolepsy in orexin knockout mice: molecular
`genetics of sleep regulation," Cell, 98:437-451 (1999).
`Dorffner et al., "Effect of almorexant treatment on sleep variables in
`patients with primary insonmia compared with healthy controls,"
`European Neuropsychopharmacology, 20(Suppl 3):S252-S253
`(2007).
`Ida et al., "Possible involvement of orexin in the stress reaction in
`rats," Biochem. Biophys. Res. Commun., 270:318-323 (2000).
`Sakurai et al., "Orexins and orexin receptors: a family of hypotha(cid:173)
`lamic neuropeptides and G protein-coupled receptors that regulate
`feeding behavior," Cell, 92:573-585 (1998).
`Shoblock et al., "Selective blockade of the orexin-2 receptor attenu(cid:173)
`ates ethanol self-administration, place preference, and reinstate(cid:173)
`ment," Psychopharmacology, 215: 191-203 (2011 ).
`Winrow et al., "Orexin receptor antagonism prevents transcriptional
`and behavioral plasticity resulting from stimulant exposure,"
`Neuropharmacology, 58: 185-194 (2010).
`
`(Continued)
`James O Wilson
`Primary Examiner -
`Assistant Examiner - Alexander R Pagano
`(74) Attorney, Agent, or Firm - Fish & Richardson P.C.
`ABSTRACT
`(57)
`A cyclopropane compound represented by the following for(cid:173)
`mula (A) or a pharmaceutically acceptable salt thereof has
`orexin receptor antagonism, and therefore has a potencial of
`usefulness for the treatment of sleep disorder for which orexin
`receptor antagonism is effective, for example, insomnia:
`
`(A)
`
`wherein Q represents --CH- or a nitrogen atom, Ria and
`Ri 6 each independently represent a Ci_ 6 alkyl group and the
`like, Ric represents a hydrogen atom and the like, R2a, R26 ,
`R2c and R2d each independently represent a hydrogen atom, a
`halogen atom, a Ci_ 6 alkyl group and the like, R3a, R36 and R3c
`each independently represent a hydrogen atom, a halogen
`atom and the like, and R3 d represents a hydrogen atom and the
`like.
`
`27 Claims, 1 Drawing Sheet
`
`Page 1 of 166
`
`EISAI EXHIBIT 1005
`
`

`

`US 8,268,848 B2
`Page 2
`
`OTHER PUBLICATIONS
`English translation of the allowed claims in JP 2012-500752 dated
`Feb. 28, 2012.
`Request for Expedited Examination of JP 2012-500752 dated Jan.
`18, 2012 (in Japanese).
`Request for Expedited Examination of JP 2012-500752 dated Jan.
`18, 2012 (English translation).
`International Search Report and Written opinion of PCT /JP2011/
`071325 dated Oct. 18, 2011 (in Japanese).
`
`International Search Report and Written opinion of PCT/JP2011/
`071325 dated Oct. 18, 2011 (English Translation).
`Decision to Grant JP 2012-500752 dated Feb. 28, 2012 (in Japanese).
`Decision to Grant JP 2012-500752 dated Feb. 28, 2012 (English
`translation).
`
`* cited by examiner
`
`Page 2 of 166
`
`

`

`d
`
`1 ·
`
`•
`
`*
`
`j I l
`
`*
`
`*
`
`130
`
`M
`......
`
`120 rr
`-.c 110
`C i 100 -Ill
`.§ 90
`I-
`C. t 80
`
`Ill
`
`~ 11.. i ~f I ~ I i I ~ ~:3::~
`
`l!lll mg/kg
`
`13 mg/kg
`
`010 mg/kg
`
`W30 mg/leg
`
`llOOmg/kg
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`.
`
`~
`'?
`~
`~ ....
`
`~
`
`N
`
`d r.,;_
`00
`'N
`O',
`00
`00
`~
`
`00 = N
`
`70
`
`60
`
`1
`
`51
`
`82
`
`95
`
`129
`
`240
`
`* : indicating significance compared to vehicle group (P <= 0.05).
`
`Page 3 of 166
`
`

`

`US 8,268,848 B2
`
`1
`CYCLOPROPANECOMPOUND
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application claims priority from U.S. Provi(cid:173)
`sional Application No. 61/385,342 filed Sep. 22, 2010 and
`Japanese Patent Applicaton No. 2010-211629 filed Sep. 22,
`2010, all of the contents of which are incorporated herein by
`reference.
`
`BACKGROUND OF THE INVENTION
`
`(1) Field of the Invention
`The present invention relates to a cyclopropane compound
`having orexin receptor antagonism or a pharmaceutically
`acceptable salt thereof, and a medicinal use thereof. The
`present invention also relates to a pharmaceutical composi(cid:173)
`tion comprising the above-mentioned compound as an active
`ingredient.
`(2) Description of Related Art
`Orexin-A (OX-A, consisting of 33 amino acid peptides)
`and orexin-B (OX-B, consisting of 28 amino acid peptides),
`two types ofintracerebral neuropeptides, which are expressed
`by neurons localized at the hypothalamus in the brain, have
`been discovered (Patent Document 5 and Non-Patent Docu(cid:173)
`ment 1) as endogenous ligands of G protein-coupled recep(cid:173)
`tors mainly existing in the brain, namely, orexin receptors
`(Patent Documents 14). It has been known that such orexin
`receptors include two subtypes, namely, an OX 1 receptor
`(OX!) as a type 1 subtype and an OX2 receptor (OX2) as a
`type 2 subtype. OX! binds OX-A more selectively than
`OX-B, andOX2 is able to bind OX-Aas well as OX-B. Orexin
`has been found to stimulate the food consumption of rats, and
`thus, it has been suggested that orexin would play a physi(cid:173)
`ological role as a mediator in a central feedback mechanism
`for controlling feeding behavior (Non-Patent Document 1).
`On the other hand, it has been observed that orexins control
`sleep-wake conditions. Thus, it is considered that orexins will
`potentially lead to new therapies for narcolepsy, as well as for
`insomnia and other sleep disorders (Non-Patent Document
`2). In addition, it has been suggested that orexin signals in the
`ventral tegmental area regarding neural plasticity associated
`with opioid dependence and nicotine dependence play an
`important role in vivo (Non Patent Document 3 and Non
`Patent Document 4 ). It has been also reported that OX2 recep(cid:173)
`tor was selectively inhibited to alleviate ethanol dependence
`in experiment using rats (Non Patent Document 5). Moreover,
`it has been reported that corticotropin-releasing factor (CRF),
`whichinvolved in depression and anxiety disorder, is involved
`in orexin-induced behaviors in rats, and that orexin may play
`an important role in some stress reactions (Non Patent Docu(cid:173)
`ment 6).
`Orexin receptors are found in the mammalian brain and
`may have numerous implications in pathologies such as
`depression; dysphoria; anxiety; addictions, obsessive com(cid:173)
`pulsive disorder; affective neurosis; depressive neurosis;
`anxiety neurosis; dysthymic disorder; mood disorder; sexual
`dysfunction; psychosexual dysfunction; sex disorder; schizo(cid:173)
`phrenia; manic depression; delirium; dementia; severe men- 60
`ta! retardation and dyskinesias such as Huntington's disease
`and Tourette syndrome; eating disorders; sleep disorders;
`cardiovascular diseases, diabetes; appetite/taste disorders;
`vomiting/nausea; asthma; Parkinson's disease; Cushing's
`syndrome/disease; basophil adenoma; prolactinoma; hyper- 65
`prolactinemia; hypopituitarism; hypophysis
`tumour/ad(cid:173)
`enoma; hypothalamic diseases; inflammatory bowel disease;
`
`2
`gastric dyskinesia; gastric ulcers; Froehlich's syndrome;
`hypophysis diseases, hypothalamic hypogonadism; Kall(cid:173)
`man's syndrome (anosmia, hyposmia); functional or psy(cid:173)
`chogenic
`amenorrhea; hypopituitarism; hypothalamic
`5 hypothyroidism; hypothalamic-adrenal dysfunction; idio(cid:173)
`pathic hyperprolactinemia; hypothalamic disorders of growth
`hormone deficiency; idiopathic growth deficiency; dwarfism;
`gigantism; acromegaly; disturbed biological and circadian
`rhythms; sleep disturbances associated with diseases such as
`10 neurological disorders, neuropathic pain and restless leg syn(cid:173)
`drome; heart and lung diseases, acute and congestive heart
`failure; hypotension; hypertension; urinary
`retention;
`osteoporosis; angina pectoris; myocardial
`infarction;
`ischemic or haemorrhagic stroke; subarachnoid haemor-
`15 rhage; ulcers; allergies; benign prostatic hypertrophy;
`chronic renal failure; renal disease; impaired glucose toler(cid:173)
`ance; migraine; hyperalgesia; pain; enhanced or exaggerated
`sensitivity to pain such as hyperalgesia, causalgia, and allo(cid:173)
`dynia; acute pain; bum pain; atypical facial pain; neuropathic
`20 pain; back pain; complex regional pain syndrome I and II;
`arthritic pain; sports injury pain; pain related to infection e.g.
`HIV, post-chemotherapy pain; post-stroke pain; post-opera(cid:173)
`tive pain; neuralgia; conditions associated with visceral pain
`such as irritable bowel syndrome, migraine and angina; uri-
`25 nary bladder incontinence e.g. urge incontinence; tolerance to
`narcotics or withdrawal from narcotics; sleep apnea; narco(cid:173)
`lepsy; insomnia; parasonmia; and neurodegenerative disor(cid:173)
`ders including nosological entities such as disinhibition-de(cid:173)
`mentia-parkinsonism-amyotrophy complex; pallido-ponto-
`30 nigral degeneration epilepsy; seizure disorders and other
`diseases related to general orexin system dysfunction.
`(2R)-2-{ (1 S)-6, 7-dimethoxy-1-[2-( 4-trifluoromethyl(cid:173)
`phenyl)ethyl]-3,4-dihydro- l H-isoquinolin-2-yl }-N-methyl-
`2-phenylacetamide (ACT-078573; almorexant), a compound
`35 that functions as an orexin receptor antagonist, had been
`clinically developed as a therapeutic agent for insonmia
`(Patent Document 6). This compound causes a decrease in
`wakefulness in rats, which is characterized by decreased
`functions of awakening and spontaneous locomotor activity,
`40 and it dose-dependently increases both rapid eye movement
`(REM) sleep time and non-REM sleep time, and this com(cid:173)
`pound, when administered to normal humans, exhibits dose(cid:173)
`dependently a reduction of sleep latency, sleep efficacy and
`extension of total sleep time (Non Patent Document 7).
`45 Thereis is also an article reporting that the compound, when
`administered to patients with insonmia, exhibits improve(cid:173)
`ment of sleep efficacy, shortness of sleep latency, increase of
`REM sleep and improvement of REM sleep ratio (Non Patent
`Document 8). Furthermore, it has also been described that
`50 this compound improves the memory function of model rats
`(Patent Document 7), and that the compound is effective for
`posttraumatic stress disorder (Patent Document 8). On the
`other hand, 5-chloro-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-
`1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl }-l ,3-benzox-
`55 azole (MK-4305; suvorexant, Patent Document 9) and
`MK-6096, which have dual orexin antagonisms against OX!
`and OX2, have been clinically developed as a medicine for
`msonmia.
`
`RELATED ART DOCUMENTS
`
`Patent Documents
`Patent Document 1:
`W01996/34877
`Patent Document 2: JP 10-327888 A
`Patent Document 3: JP 10-327889 A
`Patent Document 4: JP 11-178588 A
`
`International Publication No.
`
`Page 4 of 166
`
`

`

`US 8,268,848 B2
`
`International Publication No.
`
`International Publication No.
`
`International Publication No.
`
`3
`Patent Document 5: JP 10-229887 A
`International Publication No.
`Patent Document 6:
`W02005/118548
`Patent Document 7:
`W02007 /105177
`Patent Document 8:
`W02009/04 7723
`Patent Document 9:
`W02008/069997
`Non Patent Documents
`Non Patent Document 1: Sakurai T. et al., Cell, 1998, 92,
`573-585
`Non Patent Document 2: Chemelli R. M. eta!., Cell, 1999,
`98, 43 7-451.
`Non Patent Document 3: S. L. Borgland et al., Neuron,
`2006, 49, 589-601
`Non Patent Document 4: C. J. Winrow et al., Neurophar(cid:173)
`macology, 2010, 58, 185-194
`Non Patent Document 5: J. R. Shoblock et al., Psychop- 20
`harmacology, 2011, 215, 191-203
`Non Patent Document 6: T. Ida et al., Biochemical and
`Biophysical Research Communications, 2000, 270, 318-323
`Non Patent Document 7: F. Jenck et al., Nature Medicine
`2007, 13, 150-155
`Non Patent Document 8: G Dorffner et al., European Neu(cid:173)
`ropsychopharmacology, Vol. 20, Supplement, 3, 2007, S252-
`S253
`
`4
`Substituent Group a: a cyano group, a halogen atom, a
`hydroxyl group, an oxo group, a formula -NR5R6 wherein
`R5 and R6 each independently represent a hydrogen atom or a
`C 1_6 alkyl group, a C 1_6 alkyl group which may optionally
`5 have 1 to 3 substituents selected from Substituent Group ~' a
`C 1_6 alkoxy group which may optionally have 1 to 3 substitu(cid:173)
`ents selected from Substituent Group ~' a C 1_6 alkylcarbonyl
`group which may optionally have 1 to 3 substituents selected
`from Substituent Group ~' a C 1_6 alkylsulfonyl group which
`10 may optionally have 1 to 3 substituents selected from Sub(cid:173)
`stituent Group ~' an aryl group selected from Group 1, which
`may optionally have 1 to 3 substituents selected from Sub(cid:173)
`stituent Group ~' and a heteroaryl group selected from Group
`2, which may optionally have 1 to 3 substituents selected from
`15 Substituent Group ~;
`Substituent Group ~: a cyano group, a halogen atom, a
`hydroxyl group, a C3 _8 cycloalkyl group, and a C 1_6 alkoxy
`group;
`Group 1: a phenyl group, a naphthyl group, an azulenyl
`group, an anthryl group, and a phenanthryl group;
`Group 2: a fury! group, a thienyl group, a pyrrolyl group, an
`imidazolyl group, a triazolyl group, a tetrazolyl group, a
`thiazolyl group, a pyrazolyl group, an oxazolyl group, an
`isoxazolyl group, an isothiazolyl group, a furazanyl group, a
`25 thiadiazolyl group, an oxadiazolyl group, a pyridyl group, a
`pyrazinyl group, a pyridazinyl group, a triazinyl group, an
`indolyl group, an isoindolyl group, an indazolyl group, a
`benzoxazolyl group, a benzisoxadiazolyl group, a benzothia(cid:173)
`zolyl group, a benzisothiazolyl group, a quinolyl group, and
`30 an isoquinolyl group; and
`Group 3: a fury! group, a thienyl group, a pyrrolyl group, an
`imidazolyl group, a triazolyl group, a tetrazolyl group, a
`thiazolyl group, a pyrazolyl group, an oxazolyl group, an
`isoxazolyl group, an isothiazolyl group, a furazanyl group, a
`35 thiadiazolyl group, an oxadiazolyl group, a pyridyl group, a
`pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a
`triazinyl group, a 2-pyridonyl group, a 4-pyridonyl group, a
`pyridazidonyl group, a pyrimididonyl group, a purinyl group,
`a pteridinyl group, a quinolyl group, an isoquinolyl group, a
`40 naphthylidyl group, a quinoxalyl group, a cinnolyl group, a
`quinazolyl group, a phthalazyl group, an imidazopyridyl
`group, an imidazothiazolyl group, an imidazoxazolyl group,
`a benzimidazolyl group, an indolyl group, an isoindolyl
`group, an indazolyl group, a pyrrolopyridyl group, a
`45 thienopyridyl group, a fluoropyridyl group, a benzoxazolyl
`group, a benzisoxadiazolyl group, a benzothiazolyl group, a
`benzisothiazolyl group, a pyridopyrimidinyl group, anoxodi(cid:173)
`hydropyridopyrimidinyl group, a benzofuryl group, a ben(cid:173)
`zothienyl group, a benzothiadiazolyl group, a benzo[l,3]di-
`50 oxolyl group, a thienofuryl group, a dihydrousobenzofuranyl
`group, a chromanyl group, an isochromanyl group, a 1,3-
`dioxaindanyl group, a 1,4-dioxatetralinyl group, and a dihy(cid:173)
`drobenzo[l,4]oxazinyl group.
`[2] The compound according to [1] above, which is repre(cid:173)
`sented by the following formula (II), or a pharmaceutically
`acceptable
`salt
`thereof:
`
`BRIEF SUMMARY OF THE INVENTION
`
`It is an object of the present invention to provide a cyclo(cid:173)
`propane compound or a pharmaceutically acceptable salt
`thereofhaving orexin receptor antagonism, and a pharmaceu(cid:173)
`tical composition comprising the same.
`The present invention relates to the following [1] to [20]:
`[ 1] A compound represented by the following formula (I) or a
`pharmaceutically acceptable salt thereof:
`
`[Formula 1]
`
`(I)
`
`wherein
`A 1 represents a pyrimidinyl group or a N-oxide pyrimidi(cid:173)
`nyl group, each of which may optionally have substituents
`selected from Substituent Group a,
`A2 and A3 each independently represent an aryl group
`selected from Group 1, which may optionally have 1 to 3 55
`substituents selected from Substituent Group a, or a hetero(cid:173)
`cyclic group selected from group 3, which may optionally
`have 1 to 3 substituents selected from Substituent Group ~'
`R1 , R2 and R3 each independently represent a hydrogen
`atom, a halogen atom, a C 1_6 alkyl group which may option- 60
`ally have 1 to 3 substituents selected from Substituent Group
`~' or a C3 _8 cycloalkyl group which may optionally have 1 to
`3 substituents selected from Substituent Group ~'
`X represents an oxygen atom, a C 1_6 alkylene group, a
`formula -NR4 - wherein R4 represents a hydrogen atom or 65
`a cl-6 alkyl group,
`L represents a bond or a formula -CONH-, wherein
`
`[Formula 2]
`
`(II)
`
`Page 5 of 166
`
`

`

`US 8,268,848 B2
`
`5
`wherein Ai, A 2 , A 3 , Ri, R2 , R3 , X and L have the same
`definitions as those according to [1] above.
`[3] The compound according to [1] or [2] above, which is
`represented by the following formula (III), or a pharma(cid:173)
`ceutically acceptable salt thereof:
`
`[Formula 3]
`
`6
`Ria and Ri 6 each independently represent a Ci_6 alkyl
`group, a halo-Ci_ 6 alkyl group, a hydroxy-Ci_ 6 alkyl group or
`a Ci_ 6 alkoxy-Ci_ 6 alkyl group,
`Ric represents a hydrogen atom or a hydroxyl group,
`R2 a, R26 , R2c and R2d each independently represent a
`hydrogen atom, a halogen atom, a hydroxyl group, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group, a halo-Ci_ 6 alkyl group or a
`cyano group, and
`R3 a, R36, R3c and R3 d each independently represent a
`hydrogen atom, a halogen atom, a hydroxyl group, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group, a halo-Ci_ 6 alkyl group, a
`Ci_ 6 alkoxy-Ci_ 6 alkyl group, a cyano group or a cyano-Ci_ 6
`alkyl group.
`15 [7] A compound represented by the following formula (A) or
`a pharmaceutically acceptable salt thereof:
`
`(III) 10
`
`[Formula 5]
`
`(A)
`
`20
`
`wherein
`Ai represents a pyrimidinyl group or a N-oxide pyrimidi(cid:173)
`nyl group, each of which is substituted with Ria, Ri 6 and Ric)
`A 2 represents an aryl group selected from Group 1 or a
`heteroaryl group selected from Group 2, each of which is
`substituted with R2a, R26 , R2c and R2d,
`A 3 represents an aryl group selected from Group 1 or a
`heterocyclic group selected from Group 3, each of which is
`substituted with R3 a, R36, R3c and R3 d, wherein
`Ria, Ri 6 and Ric each independently represent a hydrogen
`atom, a hydroxyl group, a Ci_ 6 alkyl group, a halo-Ci_ 6 alkyl
`group, a hydroxy-Ci_ 6 alkyl group or a Ci_ 6 alkoxy-Ci_ 6 alkyl
`group, wherein
`R2 a, R26 , R2 c and R2d each independently represent a 30
`hydrogen atom, a halogen atom, a hydroxyl group, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group or a halo-Ci_ 6 alkyl group,
`R3 a, R36, R3 c and R3 d each independently represent a
`hydrogen atom, a halogen atom, a hydroxyl group, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group, a halo-Ci_ 6 alkyl group, a 35
`Ci_ 6 alkoxy-Ci_ 6 alkyl group, a cyano group or a cyano-Ci_ 6
`alkyl group, and
`X, L, Group 1, Group 2 and Group 3 have the same defi(cid:173)
`nitions as those according to [1] above.
`[ 4] The compound according to [3] above, or a pharmaceuti- 40
`cally acceptable salt thereof, wherein L represents a for(cid:173)
`mula ----CONH-.
`[5] The compound according to [ 4] above, or a pharmaceuti(cid:173)
`cally acceptable salt thereof, wherein X represents an oxy(cid:173)
`gen atom.
`[ 6] A compound represented by the following formula (IV) or
`a pharmaceutically acceptable salt thereof:
`
`wherein
`Q represents -CH- or a nitrogen atom, when Q repre(cid:173)
`sents -CH-,
`Ria and Ri 6 each independently represent a Ci_6 alkyl
`group, a halo-Ci_ 6 alkyl group or a Ci_ 6 alkoxy-Ci_ 6 alkyl
`group,
`Ric represents a hydrogen atom,
`R2 a, R26 , R2c, and R2d each independently represent a
`hydrogen atom, a halogen atom, a Ci_ 6 alkyl group, a Ci_ 6
`45 alkoxy group or a halo-Ci_ 6 alkyl group,
`R3 a and R3 c each independently represent a hydrogen
`atom, a halogen atom, a Ci_ 6 alkyl group, a halo-Ci_ 6 alkyl
`group, a Ci_ 6 alkoxy group, a Ci_ 6 alkoxy-Ci_ 6 alkyl group, a
`cyano group or a cyano-Ci_ 6 alkyl group,
`R36 represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl group, a halo-Ci_ 6 alkyl group, a Ci_ 6 alkoxy group or a
`Ci_ 6 alkoxy-Ci_ 6 alkyl group, and
`R3 d represents a hydrogen atom or a fluorine atom,
`or
`55 when Q represents a nitrogen atom,
`Ria and Ri 6 each independently represent a Ci_6 alkyl
`group, a halo-Ci_ 6 alkyl group, a hydroxy-Ci_ 6 alkyl group or
`a Ci_ 6 alkoxy-Ci_ 6 alkyl group,
`Ric represents a hydrogen atom or a hydroxyl group,
`R2 a, R26 , R2c and R2d each independently represent a
`hydrogen atom, a halogen atom, a hydroxyl group, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group or a halo-Ci_ 6 alkyl group,
`R3 a represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group or a Ci_ 6 alkoxy-Ci_ 6 alkyl
`65 group,
`R36 represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl groupor a halo-Ci_ 6 alkyl group,
`
`50
`
`60
`
`[Formula4]
`
`(IV)
`
`wherein
`Q represents -CH- or a nitrogen atom,
`
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`US 8,268,848 B2
`
`7
`R3 c represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl group, a halo-Ci_ 6 alkyl group, a Ci_ 6 alkoxy group or a
`Ci_ 6 alkoxy-Ci_ 6 alkyl group, and
`R3 d represents a hydrogen atom.
`[8] The compound according to [7] above, which is repre-
`sented by the following formula (B), or a pharmaceutically
`acceptable salt thereof:
`
`[Formula 6]
`
`(B)
`
`5
`
`10
`
`20
`
`30
`
`wherein
`Ria and Ri 6 each independently represent a Ci_ 6 alkyl
`group, a halo-Ci_ 6 alkyl group or a Ci_ 6 alkoxy-Ci_ 6 alkyl
`group,
`Ric represents a hydrogen atom,
`R2 a, R26 , R2 c and R2d each independently represent a
`hydrogen atom, a halogen atom, a Ci_ 6 alkyl group, a Ci_ 6
`alkoxy group or a halo-Ci_ 6 alkyl group,
`R3 a and R3 c each independently represent a hydrogen
`atom, a halogen atom, a Ci_ 6 alkyl group, a halo-Ci_ 6 alkyl
`group, a Ci_ 6 alkoxy group, a Ci_ 6 alkoxy-Ci_ 6 alkyl group, a
`cyano group or a cyano-Ci_ 6 alkyl group,
`R36 represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl group, a halo-Ci_ 6 alkyl group, a Ci_ 6 alkoxy group or a 40
`Ci_ 6 alkoxy-Ci_ 6 alkyl group, and
`R3 d represents a hydrogen atom or a fluorine atom.
`[9] The compound according to [7] above, which is repre(cid:173)
`sented by the following formula (C), or a pharmaceutically
`acceptable salt thereof:
`
`8
`Ri 6 represents a Ci_ 6 alkyl group, a halo-Ci_ 6 alkyl group,
`a hydroxy-Ci_ 6 alkyl group or a Ci_ 6 alkoxy-Ci_ 6 alkyl group,
`Ric represents a hydrogen atom or a hydroxyl group,
`R2 a, R26 , R2c and R2d each independently represent a
`hydrogen atom, a halogen atom, a hydroxyl group, a Ci_ 6
`alkyl group, a Ci_ 6 alkoxy group or a halo-Ci_ 6 alkyl group,
`R3 a represents a substituent selected from a hydrogen
`atom, a halogen atom, a Ci_ 6 alkyl group, a Ci_ 6 alkoxy group
`and a Ci_ 6 alkoxy-Ci_ 6 alkyl group,
`R36 represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl group or a halo-Ci_ 6 alkyl group,
`R3 c represents a hydrogen atom, a halogen atom, a Ci_ 6
`alkyl group, a halo-Ci_ 6 alkyl group, a Ci_ 6 alkoxy group or a
`15 Ci_ 6 alkoxy-Ci_ 6 alkyl group, and
`R3 d represents a hydrogen atom.
`[1 OJ The compound according to [9] above, or a pharmaceu(cid:173)
`tically acceptable salt thereof, wherein Ria represents a
`methyl group, Ri 6 represents a methyl group, an ethyl
`group, a hydroxymethyl group, a methoxymethyl group or
`a methoxyethyl group, and Ric represents a hydrogen
`atom.
`[11] A compound, which is selected from the following com(cid:173)
`pounds, or a pharmaceutically acceptable salt thereof:
`25 1)
`(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy ]methyl}(cid:173)
`N-(5-fluoropyridin-2-yl)-2-phenylcyclopropanecarboxa(cid:173)
`mide (Example 1 ),
`2) (1R,2S)-N-(5-chloropyridin-2-yl)-2-{[(2,4-dimethylpyri(cid:173)
`midin-5-y l)oxy ]methy 1 }-2-pheny lcyclopropanecarboxa(cid:173)
`mide (Example 16),
`3) (1 R,2S)-N-[3-( dimethylamino )phenyl]-2-{[(2,4-dimeth(cid:173)
`y lpyrimidin-5-y l)oxy ]methy 1 }-2-pheny lcyclopropanecar(cid:173)
`boxamide (Example 19),
`35 4) (1R,2S)-N-(3-chlorophenyl)-2-{[(2,4-dimethylpyrimidin-
`5-yl )oxy ]methy 1 }-2-pheny lcyclopropanecarboxamide
`(Example 24),
`5)
`(1R,2S)-N-(3-cyano-4-fluorophenyl)-2-{[(2,4-dimeth-
`y lpyrimidin-5-y l)oxy ]methy 1 }-2-pheny lcyclopropanecar(cid:173)
`boxamide (Example 26),
`(1 R,2S )-N-(3-chloro-4-fluorophenyl )-2-{ [ (2,4-dimeth-
`6)
`y lpyrimidin-5-y l)oxy ]methy 1 }-2-pheny lcyclopropanecar(cid:173)
`boxamide (Example 32),
`7)
`(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-(3-methoxyphenyl )-2-pheny lcyclopropanecarboxam(cid:173)
`ide (Example 36),
`8)
`(1R,2S)-N-[3-(cyanomethyl)phenyl]-2-{[(2,4-dimeth-
`y lpyrimidin-5-y l)oxy ]methy 1 }-2-pheny lcyclopropanecar(cid:173)
`boxamide (Example 39),
`9)
`(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-
`2-phenyl-N-[3-( trifluoromethy l)pheny l]cyclopropanecar(cid:173)
`boxamide (Example 43),
`10)
`(1 R,2S)-N-(5-chloro-4-methylpyridin-2-yl)-2-{ [ (2,4-
`dimethylpyrimidin-5-yl)oxy ]methyl }-2-phenylcyclopro(cid:173)
`panecarboxamide (Example 45),
`11) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy ]methyl}(cid:173)
`N-(5-fluoro-4-methylpyridin-2-yl)-2-phenylcyclopropan(cid:173)
`ecarboxamide (Example 51 ),
`12) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-[5-fluoro-4-(methoxymethyl)pyridin-2-yl]-2-phenyl(cid:173)
`cyclopropanecarboxamide (Example 71),
`13) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-(5-fluoro-4-methoxypyridin-2-yl)-2-phenylcyclopro(cid:173)
`panecarboxamide (Example 73),
`65 14) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-(5-fluoro-4-methylpyridin-2-yl)-2-(3-fluorophenyl)cy(cid:173)
`clopropanecarboxamide (Example 82),
`
`45
`
`[Formula 7]
`
`(C) 50
`
`55
`
`60
`
`wherein
`Ria represents a Ci_ 6 alkyl group or a hydroxy-Ci_ 6 alkyl
`group,
`
`Page 7 of 166
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`

`US 8,268,848 B2
`
`15
`
`25
`
`9
`15) (1R,2S)-N-(3,4-difluorophenyl)-2-{[(2,4-dimethylpyri(cid:173)
`midin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropan(cid:173)
`ecarboxamide (Example 84),
`16) (1 R,2S)-N-( 4-chloropyridin-2-yl)-2-{ [ (2,4-dimethylpy(cid:173)
`rimidin-5-y l)oxy ]methy I }-2-(3-fluoropheny l)cyclopro(cid:173)
`panecarboxamide (Example 85),
`17) (1R,2S)-2-{ [ (2,4-dimethylpyrimidin-5-yl)oxy ]methyl}(cid:173)
`N-(5-fluoro-4-methoxymethylpyridin-2-yl)-2-(3-fluo(cid:173)
`rophenyl)cyclopropanecarboxamide (Example 86),
`18) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy ]methyl}- 10
`2-(3-fluoropheny 1)-N-( 4-fluorophenyl )cyclopropanecar(cid:173)
`boxamide (Example 92),
`19) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-
`2-(3-fluoropheny 1)-N-phenylcyclopropanecarboxamide
`(Example 93),
`20) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-(5-fluoro-4-methoxypyridin-2-yl)-2-(3-fluorophenyl)
`cyclopropanecarboxamide (Example 94),
`21) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}- 20
`2-(3-fluoropheny 1)-N-( 5-fluoropyridin-2-yl )cyclopropan(cid:173)
`ecarboxamide (Example 95),
`22) (1R,2S)-N-(5-cyanopyridin-2-yl)-2-{[(2,4-dimethylpy(cid:173)
`rimidin-5-y l)oxy ]methy I }-2-(3-fluoropheny l)cyclopro(cid:173)
`panecarboxamide (Example 96),
`23) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-
`2-( 4-fluoropheny 1)-N-( 5-fluoropyridin-2-yl )cyclopropan(cid:173)
`ecarboxamide (Example 100),
`24) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-( 5-fluoro-4-methoxypyridin-2-y 1)-2-( 4-fluoropheny I)
`cyclopropanecarboxamide (Example 104),
`25) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}(cid:173)
`N-(5-fluoro-4-methoxymethylpyridin-2-yl)-2-(4-fluo(cid:173)
`rophenyl)cyclopropanecarboxamide (Example 109),
`26) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy ]methyl}- 35
`N-(5-fluoro-4-methylpyridin-2-yl)-2-(4-fluorophenyl)cy(cid:173)
`clopropanecarboxamide (Example 111 ),
`27)
`(1R,2S)-2-(3-cyanophenyl)-2-{[(2,4-dimethylpyrimi-
`din-5-yl)oxy ]methyl }-N-(5-fluoro-4-methylpyridin-2-yl)
`cyclopropanecarboxamide (Example 117),
`28)
`(1 R,2S)-2-{ [ ( 4-ethyl-2-methylpyrimidin-5-yl)oxy ]me(cid:173)
`thy I }-N-( 5-fluoropyridin-2-y 1)-2-pheny lcyclopropanecar(cid:173)
`boxamide (Example 119),
`29)
`(1 R,2S)-N-(5-cyanopyridin-2-yl)-2-{ [ ( 4-ethyl-2-meth(cid:173)
`ylpyrimidin-5-yl)oxy ]methyl }-2-phenylcyclopropanecar-
`boxamide (Example 120),
`30) (1 R,2S)-N-(5-chloropyridin-2-yl)-2-{ [ ( 4-ethyl-2-meth(cid:173)
`ylpyrimidin-5-yl)oxy ]methyl }-2-phenylcyclopropanecar(cid:173)
`boxamide (Example 121),
`31)
`(1 R,2S)-2-(3,5-difluorophenyl)-2-{[(2,4-dimethylpyri- 50
`midin-5-yl)oxy]methyl}-N-(5-fluoro-4-methylpyridin-2-
`yl)cyclopropanecarboxamide (Example 129),
`32)
`(1R,2S)-2-(3,5-difluorophenyl)-2-{[(2,4-dimethylpyri(cid:173)
`midin-5-yl)oxy ]methyl }-N-( 4-fluorophenyl)cyclopropan(cid:173)
`ecarboxamide (Example 130),
`33)
`(1R,2S)-2-(3,5-difluorophenyl)-2-{[(2,4-dimethylpyri(cid:173)
`midin-5-yl)oxy]methyl}-N-(pyridin-2-yl)cyclopropan(cid:173)
`ecarboxamide (Example 131 ),
`34)
`(1R,2S)-N-(5-chloropyridin-2-yl)-2-(3,5-difluorophe(cid:173)
`nyl)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]
`methyl}cyclopropanecarboxamide (Example 132),
`35)
`(1R,2S)-2-(3,5-difluorophenyl)-2-{[(2,4-dimethylpyri(cid:173)
`midin-5-yl)oxy]methyl}-N-(5-fluoropyridin-2-yl)cyclo(cid:173)
`propanecarboxamide (Example 133),
`36) (1 R,2S)-N-(3,4-difluorophenyl)-2-(3,5-difluorophenyl)- 65
`2-{[(2,4-dimethylpyrimidin-5-yl)oxy]
`methyl}cyclopropanecarboxamide (Example 134),
`
`30
`
`40
`
`45
`
`55
`
`60
`
`10
`3 7) (1 R,2S )-N-(2,4-difluorophenyl )-2-(3 ,5-difluoropheny 1)-
`2-{ [ (2,4-dimethylpyrimidin-5-yl)oxy]
`methyl}cyclopropanecarboxamide (Example 135),
`( 1 R,2S )-N-( 5-cyanopyridin-2-y 1)-2-(3 ,5-difluorophe-
`3 8)
`nyl )-2-{ [ (2,4-dimethylpyrimidin-5-yl )oxy]
`methyl}cyclopropanecarboxamide (Example 137),
`39)
`(1R,2S)-2-(3,5-difluorophenyl)-2-{[(2,4-dimethylpyri(cid:173)
`midin-5-yl)oxy ]methyl }-N-( 5-fluoro-4-methoxypyridin-
`2-yl)cyclopropanecarboxamide (Example 138),
`40)
`(1R,2S)-N-(5-chloropyridin-2-yl)-2-{[(4-(methoxym(cid:173)
`ethy 1)-2-methylpyrimidin-5-yl )oxy ]methyl }-2-pheny lcy(cid:173)
`clopropanecarboxamide (Example 139),
`41)
`(1R,2S)-N-(5-cyanopyridin-2-yl)-2-{[(4-(methoxym-
`ethy 1)-2-methylpyrimidin-5-yl )oxy ]methyl }-2-pheny lcy(cid:173)
`clopropanecarboxamide (Example 140),
`42)
`(1R,2S)-N-(5-fluoropyridin-2-yl)-2-{[(4-(methoxym-
`ethy 1)-2-methylpyrimidin-5-yl )oxy ]methyl }-2-pheny lcy(cid:173)
`clopropanecarboxamide (Example 141 ),
`43)
`(1 R,2S)-N-( 5-fluoro-4-methylpyridin-2-yl)-2-{ [ ( 4-
`methoxymethyl-2-methylpyrimidin-5-yl)oxy ]methyl }-2-