Heteroaryl-Substituted Hexahydropyrano [3, 4-d][1, 3] Thiazin-2-Amine Compounds

73 Pages·2015·5.29 MB·English

US 201403 64426A1
(19) United States
(12) Patent Application Publication (10) Pub. No.: US 2014/0364426 A1
Brodney et al. (43) Pub. Date: Dec. 11, 2014
(54) HETEROARYL-SUBSTITUTED (52) US. Cl.
HEXAHYDROPYRANO[3,4-D][1,3] CPC .................................. .. C07D 513/04 (2013.01)
THIAZIN-Z-AMINE COMPOUNDS USPC ........................................ .. 514/2242; 544/48
(71) Applicant: P?zer Inc., New York, NY (US) (57) ABSTRACT
(72) Inventors: Michael Aaron Brodney, Newton, MA The present invention is directed to compounds, tautomers
(US); Christopher Ryan Butler, and pharmaceutically acceptable salts of the compounds
Canton, MA (US); Elizabeth Mary Which are disclosed, Wherein the compounds have the struc
Beck, Cambridge, MA (US); Jennifer ture of Formula 1,
Elizabeth Davoren, Cambridge, MA
(US); Erik Alphie LaChapelle,
Johnston, RI (US); Brian Thomas I
O’Neill, Haddam, CT (US)
(21) Appl.No.: 14/464,935
(22) Filed: Aug. 21, 2014
HZN
Related US. Application Data
(63) Continuation of application No. 14/178,470, ?led on
Feb. 12, 2014, noW Pat. No. 8,865,706.
(60) Provisional application No. 61/764,185, ?led on Feb.
13, 2013.
Publication Classi?cation and the variables R1 and R2 are as de?ned in the speci?cation.
Corresponding pharmaceutical compositions, methods of
(51) Int. Cl. treatment, methods of synthesis, and intermediates are also
C07D 513/04 (2006.01) disclosed.
US 2014/0364426 A1 Dec. 11, 2014
HETEROARYL-SUBSTITUTED erate regeneration and recovery after peripheral nerve dam
HEXAHYDROPYRANO[3,4-D][1,3] age. (See Farah et al., J. Neurosci., 2011, 31(15): 5744-5754).
THIAZIN-Z-AMINE COMPOUNDS [0005] Insulin resistance and impaired glucose homoeosta
sis are important indicators of Type 2 diabetes and are early
FIELD OF THE INVENTION risk factors of AD. In particular, there is a higher risk of
sporadic AD in patients with Type 2 diabetes and AD patients
[0001] The present invention relates to small molecule are more prone to Type 2 diabetes (Butler, Diabetes, 53:474
compounds and pharmaceutically acceptable salts thereof 481, 2004.). Recently, it has also been proposed that AD
that are inhibitors of [3-site amyloid precursor protein (APP) should be reconsidered as Type 3 diabetes (de la Monte, J.
Cleaving Enzyme 1 (BACE1) and inhibitors of BACE2. This Diabetes Sci. Technol., 2008; 2(6): 1 101-1 1 13). Of special
invention relates to inhibiting the production of A-beta pep interest is the fact that AD and Type 2 diabetes share common
tides that can contribute to the formation of neurological pathogenic mechanisms and possibly treatments (Park S. A.,
deposits of amyloid protein. The present invention also J. Clin. Neurol., 2011; 7: 10-1 8; Raffa, Br. J. Clin. Pharmacol
relates to the treatment of Alzheimer’s Disease (AD) and 2011, 71 (3):365-376). Elevated plasma levels of AB, the
other neurodegenerative and/or neurological disorders, as product of BACE activities, were recently associated with
well as the treatment of diabetes in mammals, including hyperglycemia and obesity in humans (see Meakin et al.,
humans. More particularly, this invention relates to thioami Biochem 1., 2012, 441 (1):285-96.; Martins, Journal ofAlzhe
dine compounds and pharmaceutically acceptable salts imer’s Disease, 8 (2005) 269-282). Moreover, increased AB
thereof useful for the treatment of neurodegenerative and/or production prompts the onset of glucose intolerance and insu
neurological disorders, such as AD and Down’s Syndrome, lin resistance in mice (Cozar-Castellano, Am. J. Physiol.
related to A-beta peptide production. Endocrinol. Metab., 302:E1373-E1380, 2012; Delibegovic,
Diabetologia (2011) 54:2143-2151). Finally, it is also sug
BACKGROUND OF THE INVENTION gested that circulating AB could participate in the develop
ment of atherosclerosis in both humans and mice (De Meyer,
[0002] Dementia results from a wide variety of distinctive Atherosclerosis 216 (2011) 54-58; Catapano,Atherosclerosis
pathological processes. The most common pathological pro 210 (2010) 78-87; Roher, Biochimica et Biophysica Acta
cesses causing dementia are Alzheimer’s disease (“AD”), 1812 (2011) 1508-1514).
cerebral amyloid angiopathy (“CM”) and prion-mediated dis
[0006] Therefore, it is believed that BACE1 levels may play
eases (see, e.g., Haan et al., Clin. Neurol. Neurosurg., 1990, a critical role in glucose and lipid homoeostasis in conditions
92(4):305-310; Glenner et al., J. Neurol. Sci., 1989, 94: 1-28). of chronic nutrient excess. Speci?cally, BACE1 inhibitors
AD is a progressive, neurodegenerative disorder character may be potentially useful for increasing insulin sensitivity in
ized by memory impairment and cognitive dysfunction. AD
skeletal muscle and liver as illustrated by the fact that reduc
affects nearly half of all people past the age of 85, the most tion in BACE1 decreases body weight, protects against diet
rapidly growing portion of the United States population. As
induced obesity and enhances insulin sensitivity in mice (see
such, the number of AD patients in the United States is
Meakin et al., Biochem. J. 2012, 441(1):285-96). Of equal
expected to increase from about 4 million to about 14 million
interest is the identi?cation of LRPl as a BACE1 substrate
by 2050.
and the potential link to atherosclerosis (Strickland, Physiol.
[0003] The accumulation of amyloid-[3 (AB peptides) is Rev., 88: 887-918, 2008; Hyman, J. Biol. Chem., Vol. 280,
believed to be one of the underlying causes of Alzheimer’s No. 18, 17777-17785, 2005).
Disease (AD), which is the most common cause of cognitive [0007] Likewise, inhibition of BACE2 is proposed as a
decline in the elderly (Hardy & Allsop, Trends Pharmacol treatment of Type 2 diabetes with the potential to preserve and
Sci., 1991; 12(10):383-8; Selkoe, Behav. Brain Res., 2008; restore [3-cell mass and stimulate insulin secretion in pre
192(1): 1 06- 1 3). AB, the major protein constituent of amyloid diabetic and diabetic patients (WO201 1/ 020806). BACE2 is a
plaques, is derived from sequential cleavage of the type I [3-cell enriched protease that regulates pancreatic [3 cell func
integral membrane protein, amyloid precursor protein (APP)
tion and mass and is a close homologue of BACE1. Pharma
by two proteases, [3- and y-secretase. Proteolytic cleavage of cological inhibition of BACE2 increases [3-cell mass and
APP by the [3-site APP cleaving enzymes (BACE1 and function, leading to the stabilization of Tmem27. (See Ester
BACE2) generates a soluble N-terminal ectodomain of APP hazy et al., Cell Metabolism 2011, 14(3): 365-377). It is
(sAPP3) and the C-terminal fragment 099. Subsequent cleav suggested that BACE2 inhibitors are useful in the treatment
age of the membrane-bound C99 fragment by the y-secretase and/or prevention of diseases associated with the inhibition of
liberates the various AB peptide species, of which A640 and BACE2 (e.g., Type 2 diabetes, with the potential to preserve
A642 are the most predominant forms (Vassar et al., J. Neu and restore [3-cell mass and stimulate insulin secretion in
rosci., 2009; 29(41):12787-94; Marks & Berg, Neurochem. pre-diabetic and diabetic patients) (WO2011/020806).
Res., 2010; 35:181-210). Therefore, limiting the generation
[0008] Aminodihydrothiazine or thioamidine compounds
of AB directly through inhibition of BACE1 is one of the most
are described in US2009/0082560, WO 2009/091016 and
attractive approaches for the treatment of AD, as BACE1
WO 2010/038686 as useful inhibitors of the [3-secretase
inhibitors could effectively inhibit the formation of all pre enzyme. Co-pending PCT application, PCT/IB2012/054198,
dominant A[3 peptides.
?led by P?zer Inc on Aug. 17, 2012, also describes aminodi
[0004] In addition, it has been determined that BACE1 hydrothiazine compounds that are useful inhibitors of the
knock-out mice had markedly enhanced clearance of axonal [3-secretase enzyme. The present invention is directed to
and myelin debris from degenerated ?bers, accelerated novel thioamidine compounds and their use in the treatment
axonal regeneration, and earlier reinnervation of neuromus of neurodegenerative diseases, including AD, as well as the
cular junctions compared with littermate controls. These data treatment of metabolic diseases and conditions such as dia
suggest BACE1 inhibition as a therapeutic approach to accel betes and obesity.
US 2014/0364426 A1 Dec. 11, 2014
SUMMARY OF THE INVENTION for the therapeutic and/ or prophylactic treatment of diseases
and disorders characterized by elevated [3-amyloid levels,
[0009] A ?rst embodiment of a ?rst aspect of the present
including diabetes or Type 2 diabetes; for increasing insulin
invention is a compound of Formula I:
sensitivity in skeletal muscle and liver in a mammal, includ
ing humans; and for treating and/ or preventing obesity.
[0018] The present invention is also directed to methods of
treatment employing the compounds of Formula I such as:
[0019] (1) Methods of inhibiting BACE enzyme activity, by
administering a therapeutically effective amount of a thioa
midine compound of any of the embodiments of Formula I or
a pharmaceutically acceptable salt thereof, and a pharmaceu
tically acceptable carrier, to a mammal or a patient in need
thereof.
[0020] (2) Methods for treating conditions or diseases of
the central nervous system and neurological disorders in
Which the [3-secretase enzyme is involved (such as migraine;
epilepsy; Alzheimer’s disease; Parkinson’s disease; brain
injury; stroke; cerebrovascular diseases (including cerebral
arteriosclerosis, cerebral amyloid angiopathy, hereditary
Wherein
cerebral hemorrhage, and brain hypoxia-ischemia); cognitive
[0010] R1 is hydrogen or methyl, Wherein said methyl is
disorders (including amnesia, senile dementia, HIV-associ
optionally substituted With one to three ?uoro;
ated dementia, Alzheimer’s disease, Huntington’s disease,
[0011] R2 is a 5- to lO-membered heteroaryl, having one to Lewy body dementia, vascular dementia, drug-related
four heteroatoms independently selected from N, O or S,
dementia, tardive dyskinesia, myoclonus, dystonia, delirium,
Wherein at least one of the heteroatoms is N and Wherein said
Pick’s disease, Creutzfeldt-Jacob disease, HIV disease,
N is optionally substituted With R4; and Wherein said 5- to
Gilles de la Tourette’s syndrome, epilepsy, muscular spasms
lO-membered heteroaryl is optionally substituted on carbon
and disorders associated With muscular spasticity or weak
With one to three R3;
ness including tremors, and mild cognitive impairment
[0012] R3 at each occurrence is independently selected (“MCI”); mental de?ciency (including spasticity, Down syn
from the group consisting of halogen, hydroxy, cyano, drome and fragile X syndrome); sleep disorders (including
Cl_6alkyl, Cl_6alkoxy, Cl_6alkoxy-Cl_6alkyl, C3_6cy
hypersomnia, circadian rhythm sleep disorder, insomnia,
cloalkoxy, C3_6cycloalkoxy-(CR5“R5b)mi, C3_6cycloalkyl
parasomnia, and sleep deprivation) and psychiatric disorders
(CRSGRSZ’L‘Oi, i(CR5“R5b)m4C3_6cycloalkyl or
such as anxiety (including acute stress disorder, generalized
i(CR5“R5b)m-(4- to 6-membered heterocycloalkyl);
anxiety disorder, social anxiety disorder, panic disorder, post
Wherein said Cl_6alkyl, C1_6alkoxy or Cl_6alkoxy-Cl_6alkyl
traumatic stress disorder, agoraphobia, and obsessive-com
are each optionally substituted With one to three ?uoro and pulsive disorder); factitious disorder (including acute hallu
Wherein said C3_6cycloalkyl, C3_6cycloalkoxy and (4- to cinatory mania); impulse control disorders (including
6-membered heterocycloalkyl) moieties are optionally sub compulsive gambling and intermittent explosive disorder);
stituted With one to three sub stituents independently selected mood disorders (including bipolar I disorder, bipolar II dis
from the group consisting of ?uoro, methyl, ?uoromethyl,
order, mania, mixed affective state, major depression, chronic
di?uoromethyl or tri?uoromethyl;
depression, seasonal depression, psychotic depression, sea
[0013] R4 is hydrogen, C1_6alkyl, i(CR5“R5b)m%3_6cy
sonal depression, premenstrual syndrome (PMS), premen
cloalkyl or i(CR5“R5b)m-(4- to 6-membered heterocy strual dysphoric disorder (PDD), and postpartum depres
cloalkyl); Wherein said C1_6alkyl, C3_6cycloalkyl and -(4- to sion); psychomotor disorder; psychotic disorders (including
6-membered heterocycloalkyl) moieties are each optionally schizophrenia, schizoaffective disorder, schizophreniform,
substituted With one to three substituents independently and delusional disorder); drug dependence (including nar
selected from ?uoro, methyl, tri?uoromethyl, methoxy or cotic dependence, alcoholism, amphetamine dependence,
tri?uoromethoxy;
cocaine addiction, nicotine dependence, and drug Withdrawal
[0014] R5“ and RSZ’ are independently hydrogen, methyl, syndrome); eating disorders (including anorexia, bulimia,
?uoromethyl, di?uoromethyl, tri?uoromethyl or methoxy; binge eating disorder, hyperphagia, obesity, compulsive eat
[0015] m at each occurrence is independently 0, l or 2; and ing disorders and pagophagia); sexual dysfunction disorders;
[0016] n is l, 2 or 3; urinary incontinence; neuronal damage disorders (including
or a tautomer thereof or a pharmaceutically acceptable salt of ocular damage, retinopathy or macular degeneration of the
said compound or tautomer. eye, tinnitus, hearing impairment and loss, and brain edema),
[0017] Another embodiment of the present invention is a nerve injury treatment (including accelerating regeneration
pharmaceutical composition comprising compounds of For and recovery after peripheral nerve damage) and pediatric
mula I, or a tautomer thereof or a pharmaceutically acceptable psychiatric disorders (including attention de?cit disorder,
salt of said compound or tautomer, and a pharmaceutically attention de?cit/hyperactive disorder, conduct disorder, and
acceptable vehicle, diluent or carrier. The pharmaceutical autism) in a mammal, preferably a human, comprising
compositions described herein can be used for inhibiting administering to said mammal a therapeutically effective
production of amyloid-[3 protein and for inhibiting beta-site amount of a compound of Formula I or pharmaceutically
amyloid precursor protein cleaving enzyme 1 (BACEl); for acceptable salt thereof. The compounds of Formula I may
treating a neurodegenerative disease and, in particular, Alzhe also be useful for improving memory (both short-term and
imer’s Disease; for inhibiting BACEl and/or BACE2 activity long-term) and learning ability. The text revision of the fourth
US 2014/0364426 A1 Dec. 11, 2014
edition of the Diagnostic and Statistical Manual of Mental not limited to speci?c methods of synthesis, which may of
Disorders (DSM-IV-TR) (2000, American Psychiatric Asso course vary. It is also to be understood that the terminology
ciation, Washington, DC.) provides a diagnostic tool for used herein is for the purpose of describing particular
identifying many of the disorders described herein. The embodiments only and is not intended to be limiting.
skilled artisan will recognize that there are alternative nomen [0029] In this speci?cation and in the claims that follow,
clatures, nosologies, and classi?cation systems for disorders reference will be made to a number of terms that shall be
described herein, including those as described in the DMS de?ned to have the following meanings:
IV-TR, and that terminology and classi?cation systems [0030] As used herein, “eating disorders” refer to illnesses
evolve with medical scienti?c progress; in which the patient suffers disturbances in his/her eating
[0021] (3) Methods for treating a neurological disorder behaviors and related thoughts and emotions. Representative
(such as migraine; epilepsy; Alzheimer’s disease; Parkin examples of obesity-related eating disorders include overeat
son’s disease; Niemann-Pick type C; brain injury; stroke; ing, bulimia, binge-eating disorder, compulsive dieting, noc
cerebrovascular disease; cognitive disorder; sleep disorder) turnal sleep-related eating disorder, pica, Prader-Willi syn
or a psychiatric disorder (such as anxiety; factitious disorder; drome, and night-eating syndrome.
impulse control disorder; mood disorder; psychomotor dis [0031] “Patient” refers to warm-blooded animals such as,
order; psychotic disorder; drug dependence; eating disorder; for example, guinea pigs, mice, rats, gerbils, cats, rabbits,
and pediatric psychiatric disorder) in a mammal, preferably a dogs, cattle, goats, sheep, horses, monkeys, chimpanzees, and
human, comprising administering to said mammal a thera humans.
peutically effective amount of a compound of Formula I or [0032] The term “pharmaceutically acceptable” means the
pharmaceutically acceptable salt thereof; substance or composition must be compatible, chemically
[0022] (4) Methods for the treatment (e.g., delaying the and/or toxicologically, with the other ingredients comprising
progression or onset) of diabetes or diabetes-related disorders a formulation, and/ or the mammal being treated therewith.
including Type 1 and Type 2 diabetes, impaired glucose tol
[0033] The term “therapeutically effective amount” means
erance, insulin resistance, hyperglycemia, and diabetic com an amount of a compound of the present invention that (i)
plications such as atherosclerosis, coronary heart disease, treats or prevents the particular disease, condition, or disor
stroke, peripheral vascular disease, nephropathy, hyperten
der, (ii) attenuates, ameliorates, or eliminates one or more
sion, neuropathy, and retinopathy;
symptoms of the particular disease, condition, or disorder, or
[0023] (5) Methods for the treatment of obesity co-mor
(iii) prevents or delays the onset of one or more symptoms of
bidities, such as metabolic syndrome. Metabolic syndrome the particular disease, condition, or disorder described herein.
includes diseases, conditions or disorders such as dyslipi [0034] The term “treating”, as used herein, unless other
demia, hypertension, insulin resistance, diabetes (e.g., Type 2
wise indicated, means reversing, alleviating, inhibiting the
diabetes), coronary artery disease and heart failure. For more progress of, delaying the progression of, delaying the onset
detailed information on metabolic syndrome, see, e.g., Zim of, or preventing the disorder or condition to which such term
met, P. Z. et al., “The Metabolic Syndrome: Perhaps an Etio
applies, or one or more symptoms of such disorder or condi
logic Mystery but Far From a MythiWhere Does the Inter
tion. The term “treatment”, as used herein, unless otherwise
national Diabetes Federation Stand?,” Medscape Diabetes &
indicated, refers to the act of treating as “treating” is de?ned
Endocrinology, 7(2), (2005); and Alberti, K. G. et al., “The immediately above. The term “treating” also includes adju
Metabolic SyndromeiA New Worldwide De?nition,” Lan
vant and neo-adjuvant treatment of a subject. For the avoid
cet, 366, 1059-62 (2005); and
ance of doubt, reference herein to “treatment” includes ref
[0024] (6) Methods for the treatment of nonalcoholic fatty
erence to curative, palliative and prophylactic treatment, and
liver disease (NAFLD) and hepatic insulin resistance;
to the administration of a medicament for use in such treat
[0025] The present invention is also directed to combina
ment.
tion therapies wherein the compounds of this invention may
[0035] The term “alkyl” refers to a linear or branched-chain
also be used in conjunction with other pharmaceutical agents
saturated hydrocarbyl substituent (i.e., a substituent obtained
for the treatment of the diseases, conditions and/or disorders
from a hydrocarbon by removal of a hydrogen); in one
described herein. Therefore, methods of treatment that
embodiment containing from one to six carbon atoms. Non
include administering compounds of the present invention in
limiting examples of such substituents include methyl, ethyl,
combination with other pharmaceutical agents are also pro propyl (including n-propyl and isopropyl), butyl (including
vided; n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isoamyl,
[0026] All patents, patent applications and references
hexyl and the like.
referred to herein are hereby incorporated by reference in
[0036] The term “alkoxy” refers to a linear or branched
their entirety.
chain saturated hydrocarbyl sub stituent attached to an oxygen
[0027] Other features and advantages of this invention will
radical (i.e., a substituent obtained from a hydrocarbon alco
be apparent from this speci?cation and the appendent claims
hol by removal of the hydrogen from the OH); in one embodi
which describe the invention. It is to be understood that both
ment containing from one to six carbon atoms. Non-limiting
the foregoing and the following detailed description are
examples of such substituents include methoxy, ethoxy, pro
exemplary only and are not restrictive of the invention as
poxy (including n-propoxy and isopropoxy), butoxy (includ
claimed. ing n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pen
toxy, hexoxy and the like.
DETAILED DESCRIPTION OF THE INVENTION
[0037] In some instances, the number of carbon atoms in a
[0028] The present invention may be understood more hydrocarbyl substituent (i.e., alkyl, cycloalkyl, etc.) is indi
readily by reference to the following detailed description of cated by the pre?x “CK-Cf” or “Cx_y”, wherein x is the mini
exemplary embodiments of the invention and the examples mum and y is the maximum number of carbon atoms in the
included therein. It is to be understood that this invention is substituent. Thus, for example, “C 1-C6-alkyl” or “C l_6 alkyl”
US 2014/0364426 A1 Dec. 11, 2014
refers to an alkyl substituent containing from 1 to 6 carbon 5-membered heteroaryl substituents such as triazolyl, imida
atoms. Illustrating further, C3-C6cycloalkyl or C3_6-cy Zolyl, furanyl, thiophenyl, pyrazolyl, pyrrolyl, oxazolyl, isox
cloalkyl refers to saturated cycloalkyl group containing from azolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl
3 to 6 carbon ring atoms. and isothiazolyl. The heteroaryl group can also be a bicyclic
[0038] The term “cycloalkyl” refers to a carbocyclic sub heteroaromatic group such as indolyl, benzofuranyl, ben
stituent obtained by removing a hydrogen from a saturated zothienyl, benZimidazolyl, benzothiazolyl, benzoxazolyl,
carbocyclic molecule, for example one having three to six benzoisoxazolyl, oxazolopyridinyl, imidazopyridinyl, imida
carbon atoms. The term “C3_6cycloalkyl” means a radical of Zopyrimidinyl and the like. In a group that has a heteroaryl
a three to six membered ring Which includes the groups cyclo sub stituent, the ring atom of the heteroaryl substituent that is
propyl, cyclobutyl, cyclopentyl and cyclohexyl. The term
bound to the group may be one of the heteroatoms, or it may
“C3_6cycloalkoxy” refers to a three to six membered
be a ring carbon atom. Similarly, if the heteroaryl substituent
cycloalkyl group attached to an oxygen radical. Examples
is in turn substituted With a group or substituent, the group or
include cyclopropoxy, cyclobutoxy, cyclopentoxy and cyclo
hexoxy. sub stituent may be bound to one of the heteroatoms, or it may
be bound to a ring carbon atom. The term “heteroaryl” also
[0039] In some instances, the number of atoms in a cyclic
includes pyridyl N-oxides and groups containing a pyridine
substituent containing one or more heteroatoms (i.e., het
N-oxide ring. In addition, the heteroaryl group may contain
eroaryl or heterocycloalkyl) is indicated by the pre?x “x- to
an oxo group such as the one present in a pyridone group.
y-membered”, Wherein x is the minimum and y is the maxi Further examples include furyl, thienyl, oxazolyl, thiazolyl,
mum number of atoms forming the cyclic moiety of the imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,
substituent. Thus, for example, “4- to 6-membered heterocy isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridaZi
cloalkyl” refers to a heterocycloalkyl containing from 4 to 6 nyl, pyrimidinyl, pyraZinyl, pyridin-2(lH)-onyl, pyridaZin-2
atoms, including one to three heteroatoms, in the cyclic moi (lH)-onyl, pyrimidin-2(lH)-onyl, pyraZin-2(1H)-onyl, imi
ety of the heterocycloalkyl. Likewise the phrase “5- to
dazo[l ,2-a]pyridinyl, and pyrazolo[l,5-a]pyridinyl. The
6-membered heteroaryl” refers to a heteroaryl containing
heteroaryl can be further substituted as de?ned herein.
from 5 to 6 atoms, and “5- to lO-membered heteroaryl” refers
to a heteroaryl containing from 5 to 10 atoms, each including [0044] Examples of single-ring heteroaryls and heterocy
cloalkyls include furanyl, dihydrofuranyl, tetrahydrofuranyl,
one or more heteroatoms, in the cyclic moiety of the het
eroaryl. Furthermore the phases “5-membered heteroaryl” thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrro
and “6-membered heteroaryl” refer to a ?ve membered het lyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimi
dazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,
eroaromatic ring system and a six membered heteroaromatic
ring system, respectively. The heteroatoms present in these pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl,
ring systems are selected from N, O and S. oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,
isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiaoxadiaZ
[0040] The term “hydroxy” or “hydroxyl” refers to iOH.
olyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl, 1,2,4
When used in combination With another term(s), the pre?x
“hydroxy” indicates that the sub stituent to Which the pre?x is oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl), pyra
nyl (including 1,2-pyranyl or l,4-pyranyl), dihydropyranyl,
attached is substituted With one or more hydroxy substituents.
pyridinyl, piperidinyl, diaZinyl (including pyridaZinyl, pyri
Compounds bearing a carbon to Which one or more hydroxy
midinyl, piperaZinyl, triaZinyl (including s-triaZinyl, as-tri
sub stituents include, for example, alcohols, enols and phenol.
aZinyl and v-triaZinyl), ovainyl (including 2H-l ,2-ovainyl,
[0041] The term “halo” or “halogen” refers to ?uorine
6H-l ,3-ovainyl, or 2H-l ,4-ovainyl), isovainyl (including
(Which may be depicted as iF), chlorine (Which may be
o-isovainyl or p-isovainyl), oxazolidinyl, isoxazolidinyl,
depicted as 4C1), bromine (Which may be depicted as iBr),
oxathiaZinyl (including 1,2,5-oxathiaZinyl or 1,2,6-oxathi
or iodine (Which may be depicted as fl).
aZinyl), oxadiaZinyl (including 2H-l,2,4-oxadiaZinyl or
[0042] The term “heterocycloalkyl” refers to a substituent
2H-l ,2,5-oxadiaZinyl), morpholinyl.
obtained by removing a hydrogen from a saturated or partially
saturated ring structure containing a total of the speci?ed [0045] The term “heteroaryl” can also include, When speci
number of atoms, such as 4 to 6 ring atoms, Wherein at least ?ed, ring systems having two rings Wherein such rings may be
one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, fused and Wherein one ring is aromatic and the other ring is
or sulfur), With the remaining ring atoms being independently not fully part of the conjugated aromatic system (i.e., the
selected from the group consisting of carbon, oxygen, nitro heteroaromatic ring can be fused to a cycloalkyl or heterocy
gen, and sulfur. In a group that has a heterocycloalkyl sub cloalkyl ring). Non-limiting examples of such ring systems
stituent, the ring atom of the heterocycloalkyl substituent that include 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro
is bound to the group may be a nitrogen heteroatom, or it may quinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-di
be a ring carbon atom. Similarly, if the heterocycloalkyl sub hydro-5H-cyclopenta[c]pyridinyl, l,4,5,6-tetrahydrocyclo
stituent is in turn substituted With a group or substituent, the penta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]
group or substituent may be bound to a nitrogen heteroatom, pyrazolyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, 6,7
or it may be bound to a ring carbon atom. dihydro-5H-pyrrolo[l,2-b][l,2,4]triazolyl, 5,6,7,8
[0043] The term “heteroaryl” refers to an aromatic ring tetrahydro-[l,2,4]triazolo[l,5-a]pyridinyl, 4,5,6,7
structure containing the speci?ed number of ring atoms in tetrahydropyrazolo [ l , 5-a]pyridinyl, 4, 5, 6,7-tetrahydro- l H
Which at least one of the ring atoms is a heteroatom (i.e., indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl. It is to be
oxygen, nitrogen, or sulfur), With the remaining ring atoms understood that if a carbocyclic or heterocyclic moiety may
being independently selected from the group consisting of be bonded or otherWise attached to a designated substrate
carbon, oxygen, nitrogen, and sulfur. Examples of heteroaryl through differing ring atoms Without denoting a speci?c point
substituents include 6-membered heteroaryl substituents of attachment, then all possible points are intended, Whether
such as pyridyl, pyrazyl, pyrimidinyl, and pyridaZinyl; and through a carbon atom or, for example, a trivalent nitrogen
US 2014/0364426 A1 Dec. 11, 2014
atom. For example, the term “pyridyl” means 2-, 3- or 4-py tion, including compounds exhibiting more than one type of
ridyl, the term “thienyl” means 2- or 3-thienyl, and so forth. isomerism; and mixtures thereof (such as racemates and dias
[0046] If substituents are described as “independently” tereomeric pairs). Also included are acid addition or base
having more than one variable, each instance of a substituent addition salts wherein the counterion is optically active, for
is selected independent of the other(s) from the list of vari example, D-lactate or L-lysine, or racemic, for example, DL
ables available. Each substituent therefore may be identical to tartrate or DL-arginine.
or different from the other substituent(s). [0052] When any racemate crystallizes, crystals of two dif
[0047] If substituents are described as being “indepen ferent types are possible. The ?rst type is the racemic com
dently selected” from a group, each instance of a substituent pound (true racemate) referred to above wherein one homo
is selected independent of the other(s). Each substituent geneous form of crystal is produced containing both
therefore may be identical to or different from the other enantiomers in equimolar amounts. The second type is the
substituent(s). racemic mixture or conglomerate wherein two forms of crys
[0048] As used herein, the term “Formula I” may be here tal are produced in equimolar amounts each comprising a
single enantiomer.
inafter referred to as a “compound(s) of the invention,” “the
present invention,” and “compound of Formula I.” Such terms [0053] The compounds of Formula I may exhibit the phe
are also de?ned to include all forms of the compound of nomenon oftautomeri sm; such tautomers are also regarded as
Formula I, including hydrates, solvates, isomers, crystalline compounds of the invention. For example, the compounds of
and non-crystalline forms, isomorphs, polymorphs, and Formula I may exist in several tautomeric forms, including
metabolites thereof. For example, the compounds of the the 2-aminodihydrothiazine form, Ia, and the 2-imino-tet
invention, or pharmaceutically acceptable salts thereof, may rahydrothiazine form, Ib. All such tautomeric forms, and
exist in unsolvated and solvated forms. When the solvent or mixtures thereof, are included within the scope of compounds
water is tightly bound, the complex will have a well-de?ned of Formula I. Tautomers exist as mixtures of a tautomeric set
stoichiometry independent of humidity. When, however, the in solution. In solid form, usually one tautomer predominates.
solvent or water is weakly bound, as in channel solvates and Even though one tautomer may be described, the present
hygroscopic compounds, the water/solvent content will be invention includes all tautomers of the compounds of For
dependent on humidity and drying conditions. In such cases, mula I and salts thereof. Examples of tautomers are described
non-stoichiometry will be the norm. by the compounds of Formula Ia and lb and, collectively and
[0049] The compounds of the invention may exist as clath generically, are referred to as compounds of Formula I.
rates or other complexes. Included within the scope of the
invention are complexes such as clathrates, drug-host inclu
sion complexes wherein the drug and host are present in
stoichiometric or non-stoichiometric amounts. Also included
are complexes of the compounds of the invention containing
two or more organic and/or inorganic components, which
may be in stoichiometric or non-stoichiometric amounts. The
resulting complexes may be ionized, partially ionized, or
non-ionized. For a review of such complexes, see J. Pharm.
Sci., 64 (8), 1269-1288 by Haleblian (August 1975).
[0050] The compounds of the invention have asymmetric
carbon atoms. The carbon-carbon bonds of the compounds of
the invention may be depicted herein using a solid line (-), a
solid wedge (_ ), or a dotted wedge ( """""|| ). The use of
a solid line to depict bonds to asymmetric carbon atoms is
meant to indicate that all possible stereoisomers (e. g., speci?c
enantiomers, racemic mixtures, etc.) at that carbon atom are
included. The use of either a solid or dotted wedge to depict I g
bonds to asymmetric carbon atoms is meant to indicate that
only the stereoisomer shown is meant to be included. It is
possible that compounds of Formula I may contain more than
one asymmetric carbon atom. In those compounds, the use of
a solid line to depict bonds to asymmetric carbon atoms is
meant to indicate that all possible stereoisomers are meant to
be included. For example, unless stated otherwise, it is
intended that the compounds of Formula I can exist as enan
tiomers and diastereomers or as racemates and mixtures
thereof. The use of a solid line to depict bonds to one or more [0054] The compounds of this invention may be used in the
asymmetric carbon atoms in a compound of Formula I and the form of salts derived from inorganic or organic acids.
use of a solid or dotted wedge to depict bonds to other asym Depending on the particular compound, a salt of the com
metric carbon atoms in the same compound is meant to indi pound may be advantageous due to one or more of the salt’s
cate that a mixture of diastereomers is present. physical properties, such as enhanced pharmaceutical stabil
[0051] Stereoisomers of Formula I include cis and trans ity in differing temperatures and humidities, or a desirable
isomers, optical isomers such as R and S enantiomers, dias solubility in water or oil. In some instances, a salt of a com
tereomers, geometric isomers, rotational isomers, conforma pound also may be used as an aid in the isolation, puri?cation,
tional isomers, and tautomers of the compounds of the inven and/or resolution of the compound.
US 2014/0364426 A1 Dec. 11, 2014
[0055] Where a salt is intended to be administered to a decyl, lauryl, myristyl, and stearyl chlorides, bromides, and
patient (as opposed to, for example, being used in an in vitro iodides), arylalkyl halides (e.g., benzyl and phenethyl bro
context), the salt preferably is pharmaceutically acceptable. mides), and others.
The term “pharmaceutically acceptable salt” refers to a salt [0060] In one embodiment, hemisalts of acids and bases
prepared by combining a compound of Formula I with an acid may also be formed, for example, hemisulfate and hemical
whose anion, or a base whose cation, is generally considered cium salts.
suitable for human consumption. Pharmaceutically accept
[0061] Also within the scope of the present invention are
able salts are particularly useful as products of the methods of so-called “prodrugs” of the compound of the invention. Thus,
the present invention because of their greater aqueous solu certain derivatives of the compound of the invention which
bility relative to the parent compound. For use in medicine,
may have little or no pharmacological activity themselves
the salts of the compounds of this invention are non-toxic
can, when administered into or onto the body, be converted
“pharmaceutically acceptable salts.” Salts encompassed
into the compound of the invention having the desired activ
within the term “pharmaceutically acceptable salts” refer to ity, for example, by hydrolytic cleavage. Such derivatives are
non-toxic salts of the compounds of this invention which are
referred to as “prodrugs.” Further information on the use of
generally prepared by reacting the free base with a suitable
prodrugs may be found in “Pro-drugs as Novel Delivery
organic or inorganic acid. Systems, Vol. 14, ACS Symposium Series (T. Higuchi andV.
[0056] Suitable pharmaceutically acceptable acid addition Stella) and “Bioreversible Carriers in Drug Design,” Perga
salts of the compounds of the present invention, when pos mon Press, 1987 (ed. E. B. Roche, American Pharmaceutical
sible, include those derived from inorganic acids, such as Association). Prodrugs in accordance with the invention can,
hydrochloric, hydrobromic, hydro?uoric, boric, ?uoroboric, for example, be produced by replacing appropriate function
phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and alities present in the compounds of any of Formula I with
sulfuric acids, and organic acids such as acetic, benzene certain moieties known to those skilled in the art as “pro
sulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, moieties” as described, for example, in “Design of Prodrugs”
glycolic, isothionic, lactic, lactobionic, maleic, malic, meth by H. Bundgaard (Elsevier, 1985).
anesulfonic, tri?uoromethanesulfonic, succinic, toluene [0062] The present invention also includes isotopically
sulfonic, tartaric, and tri?uoroacetic acids. Suitable organic
labeled compounds, which are identical to those recited in
acids generally include, for example, aliphatic,
Formula I, but for the fact that one or more atoms are replaced
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxy
by an atom having an atomic mass or mass number different
lic, and sulfonic classes of organic acids.
from the atomic mass or mass number usually found in
[0057] Speci?c examples of suitable organic acids include nature. Examples of isotopes that can be incorporated into
acetate, tri?uoroacetate, formate, propionate, succinate, gly compounds of the present invention include isotopes of
colate, gluconate, digluconate, lactate, malate, tartaric acid, hydrogen, carbon, nitrogen, oxygen, sulfur, ?uorine and chlo
citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, rine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 32P, 35S,
aspartate, glutamate, benzoate, anthranilate, stearate, salicy 18F, and 36Cl, respectively. Compounds of the present inven
late, p-hydroxybenzoate, phenylacetate, mandelate, tion, prodrugs thereof, and pharmaceutically acceptable salts
embonate (pamoate), methanesulfonate, ethanesulfonate, of said compounds or of said prodrugs that contain the afore
benzenesulfonate, pantothenate, toluenesulfonate, 2-hy mentioned isotopes and/or other isotopes of other atoms are
droxyethanesulfonate, sufanilate, cyclohexylaminosul
within the scope of this invention. Certain isotopically labeled
fonate, algenic acid, l-hydroxybutyric acid, galactarate, compounds of the present invention, for example those into
galacturonate, adipate, alginate, butyrate, camphorate, cam which radioactive isotopes such as 3H and 14C are incorpo
phorsulfonate, cyclopentanepropionate, dodecylsulfate, gly
rated, are useful in drug and/or substrate tissue distribution
coheptanoate, glycerophosphate, heptanoate, hexanoate, assays. Tritiated, i.e., 3H, and carbon-l4, i.e., l4C, isotopes
nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pecti are particularly preferred for their ease of preparation and
nate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and detectability. Further, substitution with heavier isotopes such
undecanoate. as deuterium, i.e., 2H, can afford certain therapeutic advan
[0058] Furthermore, where the compounds of the invention tages resulting from greater metabolic stability, for example
carry an acidic moiety, suitable pharmaceutically acceptable increased in vivo half-life or reduced dosage requirements
salts thereof may include the lighter alkali metal salts, i.e., and, hence, may be preferred in some circumstances. Isoto
sodium or potassium salts; alkaline earth metal salts, e.g., pically labeled compounds of Formula I of this invention and
calcium or magnesium salts; and salts formed with suitable prodrugs thereof can generally be prepared by carrying out
organic ligands, e. g., quaternary ammonium salts. In another the procedures disclosed in the Schemes and/or in the
embodiment, base salts are formed from bases which form Examples and Preparations below, by substituting a readily
non-toxic salts, including aluminum, arginine, benzathine, available isotopically labeled reagent for a non-isotopically
choline, diethylamine, diolamine, glycine, lysine, meglu labeled reagent.
mine, olamine, tromethamine and Zinc salts. [0063] A second embodiment of the ?rst aspect of the
[0059] Organic salts may be made from secondary, tertiary present invention is the compound of the ?rst embodiment of
or quaternary amine salts, such as tromethamine, diethy the ?rst aspect wherein R2 is a 5-membered heteroaryl
lamine, N,N'-dibenzylethylenediamine, chloroprocaine, cho selected from the group consisting of pyrazolyl, oxazolyl,
line, diethanolamine, ethylenediamine, meglumine (N-meth isoxazolyl, triazolyl and oxadiazolyl; each optionally substi
ylglucamine), and procaine. Basic nitrogen-containing tuted on carbon with one to two R3; and wherein said pyra
groups may be quatemized with agents such as lower alkyl Zolyl and triazolyl are substituted on N with R4; R3 at each
(Cl-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlo occurrence is independently selected from the group consist
rides, bromides, and iodides), dialkyl sulfates (e. g., dimethyl, ing of halogen, cyano, C1_6alkyl, and C1_6alkoxy; wherein
diethyl, dibutyl, and diamyl sulfates), long chain halides (e. g., said alkyl is optionally substituted with one to three ?uoro;
US 2014/0364426 A1 Dec. 11, 2014
and R4 is hydrogen, methyl or tri?uoroethyl; or a tautomer and
thereof or a pharmaceutically acceptable salt of said com [0069] R3 is methyl; or a tautomer thereof or a pharma
pound or tautomer. ceutically acceptable salt of said compound or tautomer.
[0064] A third embodiment of the ?rst aspect of the present [0070] A seventh embodiment of the ?rst aspect of the
invention is the compound of the second embodiment of the present invention is the compound of the fourth embodiment
?rst aspect Wherein R2 is selected from the group consisting of the present invention selected from the group consisting of:
of (4aR,6R,8aS)-8a- (2,4-Di?uorophenyl)-6-(5 -?uoro-l -me
thyl-lH-pyrazol-3-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4
d][l,3]thiaZin-2-amine; (4aR,6R,8aS)-8a-(2,4-Di?uorophe
nyl)-6-[l-(2,2,2-tri?uoroethyl)-lH-pyrazol-4-yl]-4,4a,5,6,8,
8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2-amine; (4aR,6R,
8aS)-8a-(2,4-Di?uorophenyl)-6-(5-methyl-1,2,4-oxadiazol
3 -yl) -4,4a,5 ,6,8,8a-hexahydropyrano [3 ,4-d] [ l ,3]thiaZin-2
amine; (4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6-(4-?uoro
l-methyl- l H-pyrazol-3 -yl) -4,4a, 5, 6,8,8a-hexahydropyrano
[3,4-d] [l ,3]thiaZin-2-amine; (4aR, 6R, 8aS)-8a-(2,4
Di?uorophenyl)-6-(2-methyl-2H-l ,2,3 -triazol-4-yl)-4,4a,5,
6,8,8a-hexahydropyrano [3 ,4-d] [ l ,3]thiaZin-2-amine; (4aR,
6R,8aS)-6-[4-(Di?uoromethyl)-l,3-oxazol-2-yl]-8a-(2,4
di?uorophenyl)-4,4a,5 ,6, 8, 8a-hexahydropyrano [3,4-d] [l ,3]
thiaZin-2-amine; (4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6
[l -(2H3)methyl-lH-pyrazol-4-yl]-4,4a,5,6,8,8a
hexahydropyrano [3 ,4-d] [l ,3]thiaZin-2-amine; (4aR,6R,
8aS)-8a-(2,4-Di?uorophenyl)-6-(l -methyl-lH- l ,2,3
triazol-4 -yl) -4,4a,5 ,6,8,8a-hexahydropyrano [3 ,4-d] [l ,3]
thiaZin-2-amine; 2-[(4aR,6R,8aS)-2-Amino-8a-(2,4
di?uorophenyl)-4,4a,5 ,6, 8, 8a-hexahydropyrano [3,4-d] [l ,3]
thiaZin-6-yl]-l,3-oxazole-4-carbonitrile; (4aR,6R,8aS)-8a
(2,4-Di?uorophenyl)-6-(5-methylpyraZin-2-yl)-4,4a,5,6,8,
8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2-amine; (4aS,6S,
8aR)-8a-(2,4-Di?uorophenyl)-6-(5 -methylpyraZin-2-yl)-4,
4a, 5, 6, 8, 8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2 -amine;
and (4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6-(5-ethoxy-l
methyl-lH-pyrazol-3-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,
R3 is selected from the group consisting of ?uoro, cyano, 4-d] [ l ,3]thiaZin-2-amine; or a tautomer thereof or a pharma
methyl, ?uoromethyl, di?uoromethyl, tri?uoromethyl, meth ceutically acceptable salt of said compound or tautomer.
oxy and ethoxy; and R4 is methyl or tri?uoroethyl; or a tau [0071] An eighth embodiment of the ?rst aspect of the
tomer thereof or a pharmaceutically acceptable salt of said present invention is the compound of the ?fth embodiment of
compound or tautomer. the ?rst aspect of the present invention selected from the
[0065] A fourth embodiment of the ?rst aspect of the group consisting of: (4R,4aR,6R,8aS)-8a-(2,4-Di?uorophe
nyl)-4-methyl-6-(3-methyl-l,2-oxazol-5-yl)-4,4a,5,6,8,8a
present invention is the compound of the third embodiment of
hexahydropyrano[3,4-d] [l ,3]thiaZin-2-amine; (4S,4aR,6R,
the ?rst aspect wherein R1 is hydrogen; or a tautomer thereof
8aS)-8a-(2,4-Di?uorophenyl)-4-(?uoromethyl)-6-(3
or a pharmaceutically acceptable salt of said compound or
methyl-l ,2-oxazol-5-yl)-4,4a, 5, 6, 8, 8a-hexahydropyrano[3,
tautomer.
4-d][l,3]thiaZin-2-amine; (4R,4aR, 6R, 8aS)-8a-(2,4
[0066] A ?fth embodiment of the ?rst aspect of the present
Di?uorophenyl) -4 -methyl-6-(l -methyl- 1 H-pyrazol-4-yl) -4,
invention is the compound of the third embodiment of the ?rst
4a, 5, 6, 8, 8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2 -amine;
aspect wherein R1 is methyl or ?uoromethyl; or a tautomer
(4S,4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-4-(?uorom
thereof or a pharmaceutically acceptable salt of said com
ethyl)-6-(l -methyl- 1 H-pyrazol-4 -yl) -4,4a,5 ,6,8,8a-hexahy
pound or tautomer.
dropyrano[3,4-d] [ l ,3]thiaZin-2-amine; or a tautomer thereof
[0067] A sixth embodiment of the ?rst aspect of the present or a pharmaceutically acceptable salt of said compound or
invention is the compound of the ?fth embodiment of the ?rst
tautomer.
aspect of the present invention Wherein
[0072] A ninth embodiment of a ?rst aspect of the present
[0068] R2 is invention is the compound of the ?rst embodiment of the ?rst
aspect Wherein R2 is a 6-membered heteroaryl selected from
the group consisting of pyridinyl, pyridonyl, pyrimidinyl and
pyraZinyl; each optionally substituted on carbon With one to
two R3 ; and Wherein said pyridonyl is substituted on N With
R4; R3 at each occurrence is independently selected from the
group consisting of halogen, cyano, C l_6alkyl, and
C1_6alkoxy; Wherein said alkyl is optionally substituted With
> one to three ?uoro; and R4 is hydrogen, methyl or tri?uoro
ethyl; or a tautomer thereof or a pharmaceutically acceptable
salt of said compound or tautomer.
US 2014/0364426 A1 Dec. 11, 2014
[0073] A tenth embodiment of the ?rst aspect of the present aZin-2-amine; (4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6-(2
invention is the compound of the ninth embodiment of the methylpyridin-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d]
?rst aspect Wherein R2 is selected from the group consisting [l ,3]thiaZin-2-amine; and (4aR, 6R, 8aS)-8a-(2,4
of di?uorophenyl)-6-(5-?uoropyridin-3-yl)-4,4a,5,6,8,8a
hexahydropyrano[3,4-d][l,3]thiaZin-2-amine or a tautomer
thereof or a pharmaceutically acceptable salt of said com
pound or tautomer.
[0076] A thirteenth embodiment of a ?rst aspect of the
\ \ N
present invention is the compound of the ?rst embodiment of
the ?rst aspect wherein R1 is hydrogen; and R2 is selected
/ R3 /
from the group consisting of oxazolopyridinyl, imidazopy
ridinyl and imidazopyrimidinyl; or a tautomer thereof or a
R3
pharmaceutically acceptable salt of said compound or tau
R3 tomer.
\ N I \
[0077] A fourteenth embodiment of a ?rst aspect of the
present invention is the compound of the thirteenth embodi
/ R3, /N , ment of the ?rst aspect Wherein R2 is selected from the group
consisting of[l,3]oxazolo[4,5-c]pyridinyl, [l,3]oxazolo[5,4
c]pyridinyl, imidazo[ l ,2-a]pyridinyl and imidazo [ l ,2-a]pyri
/R4, N ,
/ N N midinyl; or a tautomer thereof or a pharmaceutically accept
able salt of said compound or tautomer.
\ O / R3 [0078] A ?fteenth embodiment of a ?rst aspect of the
present invention is the compound of the fourteenth embodi
ment of the ?rst aspect selected from the group consisting of
\ N \ N and (4aR,6R,8aS)-8a- (2,4-Di?uorophenyl)-6-(imidazo [l ,2-a]
pyrimidin-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]
thiaZin-2-amine; (4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6
([1,3]oxazolo[4,5-c]pyridin-2-yl)-4,4a,5,6,8,8a
hexahydropyrano [3 ,4-d] [l ,3]thiaZin-2-amine; (4aR,6R,
8aS)-8a-(2,4-Di?uorophenyl)-6-([l,3]oxazolo[5,4-c]
pyridin-2 -yl) -4,4a,5 ,6,8,8a-hexahydropyrano [3 ,4-d] [l ,3]
thiaZin-2-amine; and (4aR, 6R, 8aS)-8a-(2,4
Di?uorophenyl)-6-(imidazo[l,2-a]pyridin-6-yl)-4,4a,5,6,8,
8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2-amine; or a
R3 is selected from ?uoro, methyl, and methoxy; and R4 is tautomer thereof or a pharmaceutically acceptable salt of said
methyl; or a tautomer thereof or pharmaceutically acceptable compound or tautomer.
salt of said compound or tautomer. [0079] A ?rst embodiment of a second aspect of the present
[0074] An eleventh embodiment of the ?rst aspect of the invention is a pharmaceutical composition comprising a
present invention is the compound of the tenth embodiment of therapeutically effective amount of a compound of any one of
the ?rst aspect wherein R1 is hydrogen; or a tautomer thereof the ?rst to ?fteenth embodiments of the ?rst aspect of the
or a pharmaceutically acceptable salt of said compound or present invention, or a tautomer thereof or a pharmaceutically
tautomer. acceptable salt of said compound or tautomer, and a pharma
[0075] A twelfth embodiment of a ?rst aspect of the present ceutically acceptable vehicle, diluent or carrier.
invention is the compound of the eleventh embodiment of the [0080] Further embodiments of the present invention
?rst aspect selected from the group consisting of: (4aR,6R, include methods of treatment employing the compounds of
8aS)-8a-(2,4-Di?uorophenyl)-6-(5 -?uoropyridin-2-yl)-4,
the present invention.
4a, 5, 6,8,8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2-amine;
5-[(4aR,6R,8aS)-2-Amino-8a-(2,4-di?uorophenyl)-4,4a,5, [0081] A ?rst embodiment of a third aspect of the present
invention is a method of inhibiting production of amyloid-[3
6,8,8a-hexahydropyrano [3 ,4-d] [l ,3]thiaZin-6-yl] - l -meth
protein in a patient; the method comprising administering a
ylpyridin-2(lH)-one; rel-(4aR, 6R, 8aS)-8a-(2,4-Di?uo
rophenyl)-6-(6-methylpyridin-3 -yl)-4,4a,5,6,8,8a therapeutically effective amount of a compound according to
any one of the ?rst through ?fteenth embodiments of the ?rst
hexahydropyrano [3 ,4-d] [l ,3]thiaZin-2-amine; (4aR,6R,
8aS)-8a-(2,4-Di?uorophenyl)-6-(5 -methoxypyrimidin-2 aspect of the present invention, or a tautomer thereof or a
pharmaceutically acceptable salt of said compound or tau
yl) -4,4a,5 ,6,8,8a-hexahydropyrano [3 ,4-d] [ l ,3]thiaZin-2
amine; (4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6-(2 tomer to a patient in need of inhibition of production of
amyloid-[3 protein.
methylpyrimidin-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4
d] [ l ,3]thiaZin-2-amine; (4aR,6R,8aS)-8a-(2,4 [0082] A second embodiment of a third aspect of the
Di?uorophenyl)-6-(pyrimidin-5-yl)-4,4a,5,6,8,8a present invention is a method of inhibiting beta-site amyloid
hexahydropyrano [3 ,4-d] [l ,3]thiaZin-2-amine; (4aR,6R, precursor protein cleaving enzyme 1 (BACEl) in a patient,
8aS)-8a-(2,4-Di?uorophenyl)-6-(2-methoxypyridin-4-yl)-4, the method comprising administering a therapeutically effec
4a, 5, 6,8,8a-hexahydropyrano[3 ,4-d] [ l ,3]thiaZin-2-amine; tive amount of a compound according to any one of the ?rst
(4aR,6R,8aS)-8a-(2,4-Di?uorophenyl)-6-(5 -methoxypyri through ?fteenth embodiments of the ?rst aspect of the
din-3 -yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d] [l ,3]thi present invention, or a tautomer thereof or a pharmaceutically
US 2014/0364426 A1 Dec. 11, 2014
acceptable salt of said compound or tautomer to a patient in istered rectally or vaginally. In another embodiment, the com
need of inhibition of beta-site amyloid precursor protein pounds of the invention may also be administered directly to
cleaving enzyme 1 (BACEl). the eye or ear.
[0083] A third embodiment of a third aspect of the present [0092] The dosage regimen for the compounds and/or com
invention is a method for treating a neurodegenerative disease positions containing the compounds is based on a variety of
in a patient, the method comprising administering a therapeu factors, including the type, age, weight, sex and medical
tically effective amount of a compound according to any one condition of the patient; the severity of the condition; the
of the ?rst through ?fteenth embodiments of the ?rst aspect of route of administration; and the activity of the particular
compound employed. Thus the dosage regimen may vary
the present invention, or a tautomer thereof or a pharmaceu
tically acceptable salt of said compound or tautomer to a widely. Dosage levels of the order from about 0.01 mg to
patient in need of treatment thereof. about 100 mg per kilogram of body weight per day are useful
in the treatment of the above-indicated conditions. In one
[0084] A fourth embodiment of a third aspect of the present
embodiment, the total daily dose of a compound of the inven
invention is the method of the third embodiment of the third
tion (administered in single or divided doses) is typically
aspect wherein the neurodegenerative disease is Alzheimer’ s
from about 0.01 to about 100 mg/kg. In another embodiment,
Disease.
total daily dose of the compound of the invention is from
[0085] A ?fth embodiment of a third aspect of the present about 0.1 to about 50 mg/kg, and in another embodiment,
invention is a method of treating or preventing diabetes in a from about 0.5 to about 30 mg/kg (i.e., mg compound of the
patient, the method comprising administering a therapeuti invention per kg body weight). In one embodiment, dosing is
cally effective amount of a compound according to any one of from 0.01 to 10 mg/kg/day. In another embodiment, dosing is
?rst through ?fteenth embodiments of the ?rst aspect of the from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may
present invention, or a tautomer thereof or a pharmaceutically contain such amounts or submultiples thereof to make up the
acceptable salt of said compound or tautomer to a patient in daily dose. In many instances, the administration of the com
need of treatment or prevention thereof. pound will be repeated a plurality of times in a day (typically
[0086] A sixth embodiment of a third aspect of the present no greater than 4 times). Multiple doses per day typically may
invention is the method of the ?fth embodiment of the third be used to increase the total daily dose, if desired.
aspect wherein the diabetes is Type 2 diabetes. [0093] For oral administration, the compositions may be
provided in the form of tablets containing from about 0.01 mg
[0087] Further embodiments of the present invention
to about 500 mg of the active ingredient, or in another
include the use of a compound according to any one of ?rst
through ?fteenth embodiments of the ?rst aspect of the embodiment, from about 1 mg to about 100 mg of active
present invention in the preparation of a medicament useful ingredient. Intravenously, doses may range from about 0.1 to
for treating the conditions, diseases and disorders as about 10 mg/kg/minute during a constant rate infusion.
described herein. [0094] Suitable subjects according to the present invention
include mammalian subjects. Mammals according to the
[0088] Typically, a compound of the invention is adminis
present invention include, but are not limited to, canine,
tered in an amount effective to treat a condition as described feline, bovine, caprine, equine, ovine, porcine, rodents, lago
herein. The compounds of the invention are administered by
morphs, primates, and the like, and encompass mammals in
any suitable route in the form of a pharmaceutical composi
utero. In one embodiment, humans are suitable subjects.
tion adapted to such a route, and in a dose effective for the
Human subjects may be of either gender and at any stage of
treatment intended. Therapeutically effective doses of the development.
compounds required to treat the progress of the medical con
[0095] In another embodiment, the invention comprises the
dition are readily ascertained by one of ordinary skill in the art
using preclinical and clinical approaches familiar to the use of one or more compounds of the invention for the prepa
ration of a medicament for the treatment of the conditions
medicinal arts.
recited herein.
[0089] The compounds of the invention may be adminis
[0096] For the treatment of the conditions referred to
tered orally. Oral administration may involve swallowing, so
above, the compound of the invention can be administered as
that the compound enters the gastrointestinal tract, or buccal
compound per se. Alternatively, pharmaceutically acceptable
or sublingual administration may be employed, by which the
salts are suitable for medical applications because of their
compound enters the blood stream directly from the mouth.
greater aqueous solubility relative to the parent compound.
[0090] In another embodiment, the compounds of the [0097] In another embodiment, the present invention com
invention may also be administered directly into the blood prises pharmaceutical compositions. Such pharmaceutical
stream, into muscle, or into an internal organ. Suitable means compositions comprise a compound of the invention pre
for parenteral administration include intravenous, intraarte sented with a pharmaceutically acceptable carrier. The carrier
rial, intraperitoneal, intrathecal, intraventricular, intraure
can be a solid, a liquid, or both, and may be formulated with
thral, intrasternal, intracranial, intramuscular and subcutane the compound as a unit-dose composition, for example, a
ous. Suitable devices for parenteral administration include tablet, which can contain from 0.05% to 95% by weight of the
needle (including microneedle) injectors, needle-free injec active compounds. A compound of the invention may be
tors and infusion techniques. coupled with suitable polymers as targetable drug carriers.
[0091] In another embodiment, the compounds of the Other pharmacologically active substances can also be
invention may also be administered topically to the skin or present.
mucosa, that is, dermally or transdermally. In another [0098] The compounds of the present invention may be
embodiment, the compounds of the invention can also be administered by any suitable route, preferably in the form of
administered intranasally or by inhalation. In another a pharmaceutical composition adapted to such a route, and in
embodiment, the compounds of the invention may be admin a dose effective for the treatment intended. The active com