Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• This disclosure pertains to compounds, compositions and methods for using orexin antagonists to treat or ameliorate human and animal diseases as therapeutic agents.
• CNS central nervous system
• neurological diseases that involve or are modulated by orexin receptors including but not limited to disorders that are responsive to orexin receptor antagonists, e.g., substance addiction and dependence, cognitive impairment, Alzheimer's disease (AD), posttraumatic stress disorder (PTSD), schizophrenia, panic, anxiety, autism, and depression.
• the orexins are comprised of two excitatory hypothalamic neuropeptides: orexin A (OX-A; a 33 amino acid peptide) and orexin B (OX-B; a 28 amino acid peptide). They were simultaneously discovered in 1998 by two research groups searching for new signaling molecules, (1) Sakurai and co-workers (who named them orexin-A and -B) (Sakurai, T. et al, Cell 1998, 92, 573) and (2) de Lecea and co-workers (who named them hypocretin 1 and 2, respectively) (de Lecea, L. et al, Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 322).
• neuropeptides are endogenous ligands for two G protein-coupled receptors (GPCR) named OX 1 R and OX 2 R (also referred to as Hcrt1 and Hcrt2, respectively) and are derived proteolytically from the same precursor peptide called pre-pro-orexin polypeptide (Sakurai T., et al. The Journal of biological chemistry. 1999; 274, 17771-17776). Though structurally related, the binding affinities of these endogenous ligands for the two GPCRs differ.
• Orexin A binds to OX 1 R with about 100-fold higher affinity than Orexin B, whilst both Orexin A and Orexin B bind to OX2R with the same affinity (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375).
• modulation of the orexin signaling was originally considered for potential novel treatments of narcoleptic or insomniac patients since the role of orexins in regulation of sleep and wakefulness was well-studied and understood, and the discovery of small-molecule modulators of orexin signaling facilitated the development of this class of compounds.
• Narcoleptic patients show a diminished activity in hypothalamic orexin neurons thereby lowering the amounts of circulating orexins in the cerebrospinal fluid. In contrast, activation of orexin neurons maintains wakefulness and arousal.
• the effects of orexin signaling on feeding and energy homeostasis were also established earlier and found to be coordinated to the sleep-wake cycle (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). More recent studies have established the role of orexin signaling in other key physiological pathways such as neuroendocrine functions (Inutsuka, A.; Yamanaka, A. Front. Endocrinol. 2013, 4:18.
• Small molecule orexin antagonists have been broadly categorized into three classes based on their overall receptor selectivity profiles: (1) DORA (dual-acting, or non-selective OX 1 R/OX 2 R antagonists), (2) SORA-1 (selective OX 1 R antagonists), and (3) SORA-2 (selective OX 2 R antagonists). It has been shown that while OX 2 R knockout mice and OX 1 R/OX 2 R double knockout mice both show a narcoleptic phenotype, the effect is very muted in OX 1 R knockouts (Wang C., et al. Neurosci., 2018, 11, 220. doi: 10.3389/fnmol.2018.00220).
• variables are as defined herein, including any pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers thereof, as well as compositions comprising the same.
• compounds of formula I and compositions comprising the same can be used to treat conditions such as those described herein, such as through activity as Orexin receptor antagonists.
• Orexin receptor antagonists the compounds and/or compositions of the same can be referred to herein as “Orexin receptor antagonists”.
• this disclosure also provides compositions that comprise the above compounds and/or a pharmaceutically acceptable salt thereof.
• this disclosure provides methods for treating CNS disorders such as, among others, substance addiction and dependence, posttraumatic stress disorder (PTSD), schizophrenia, panic, anxiety and depression, cognitive impairment and Alzheimer's disease (AD) in a subject in need or at risk thereof, the methods comprising the step of administering to said subject a therapeutically effective amount of Orexin receptor antagonists or a pharmaceutically acceptable salt thereof.
• the Orexin receptor antagonists or a pharmaceutically acceptable salt thereof could be formulated to be administered periodically, for example and without limitation, every 3, 6 to 24 hours as deemed clinically beneficial.
• Other aspects and embodiments are contemplated herein as would be understood by those of ordinary skill in the art.
• This disclosure pertains to a fused six (6) and five (5) membered ring system derivatives of formula (I) wherein the fused 6 & 5 membered rings are as described herein with enabling structural descriptions, to pharmaceutically acceptable salts thereof, to the preparation of the same, to pharmaceutical compositions containing one or more compounds of formula (I), and to the use of the same as pharmaceuticals and/or therapeutic agents, particularly (i.e., in preferred embodiments) to the use of the same as orexin receptor antagonists (“Orexin receptor antagonists”).
• novel agents as described by formula (I) which are non-peptide antagonists of human orexin receptors and are potentially useful in the treatment of disorders relating to orexinergic dysfunctions; including but not limited for such disorders like substance addiction, anxiety, panic, cognitive dysfunctions, mood, or appetite, sleep, Alzheimer (AD), metabolic syndrome, and hypertension; and especially these compounds could be of great therapeutic value in the treatment of anxiety disorders, addiction disorders, and sleep disorders.
• this disclosure provides compounds of formula (I):
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); when R 1 is heteroaryl, it is preferred as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluor
• this disclosure provides a compounds of formula II, wherein the ring system (illustrated by A-B-J-D-E variables in formula (I) fused to the six (6)-membered ring is preferably an imidazolo ring system as represented by formula (II):
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )cycloalkyl; R 2
• this disclosure provides compounds wherein the imidazole fused six-membered ring is as shown in formula II-a:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3
• this disclosure provides compounds wherein the imidazole fused six-membered ring is as shown in formula II-b:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 alkyl, (C 1-4 alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )
• this disclosure provides compounds wherein the imidazole fused six-membered ring is as shown in formula II-c:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C
• this disclosure provides compounds wherein the pyrazole fused six-membered ring is preferred as shown in formula III-a:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl
• this disclosure provides compounds wherein the pyrazole fused six-membered ring is preferred as shown herein according to embodiment formula III-b:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 alkyl, (C 1-4 alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )
• this disclosure provides compounds wherein the pyrazole fused six-membered ring is preferred as shown herein according to embodiment formula III-c:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C
• this disclosure provides compounds wherein the pyrazole fused six-membered ring is preferred as shown herein according to embodiment formula III-d:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (
• this disclosure provides compounds wherein the stereogenic centers and main scaffold rings are preferred as shown in the exemplification formula as shown herein according to embodiment formula II-aa-ac, II-ba-bc, and II-ca-cc:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C
• this disclosure provides compounds wherein the stereogenic centers and main scaffold rings are preferred as shown in the exemplification formula as shown herein according to embodiment formula III-aa-ac, III-ba-bc, and III-ca-cc:
• R 1 aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferred as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 alkyl, (C 1-4 )alkoxy, halogen (such as F, Cl, Br or I), (C 1-3 )fluoroalkyl, (C 1 _ 3)fluoroalkoxy and (C 3
• this disclosure provides compounds of formula I, II, III, II-a, II-b, II-c, III-a, III-b and III-c shown below:
• alkyl as used herein means a linear or branched carbon chain (e.g., having the general formula C (n) H (2n+1) ) including but not limited to any of C 1 -C 100 (e.g., methyl, ethyl, propyl, and the like).
• fluroalkyl as used herein means an alkyl substituted by at least one flourine atom.
• alkoxy as used herein means an alkyl bonded to oxygen (i.e., R—O).
• fluoroalkoxy as used herein means an alkoxy substituted by at least one fluorine atom.
• heterocycloalkyl as used herein means a cycloalkyl comprising at least one heteroatom (e.g., N and/or O) within the cyclic ring thereof.
• aryl as used herein means a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is an example of a monocyclic aromatic or aryl ring system.
• heteroaryl as used herein means a monocyclic or bicyclic aromatic or aryl ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement.
• both rings may be aromatic or aryl; and one or both rings may contain said heteroatom or heteroatom groups.
• heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetra
• cycloalkyl or “cycloalkenyl” refers to a monocyclic or fused or (C 1-3 )alkyl bridged bicyclic carbocyclic ring system that is not aromatic or aryl. Cycloalkenyl rings have one or more units of unsaturation.
• Preferred cycloalkylor cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantly and decalinyl.
• halogen can be F, Cl, Br or I
• preferred embodiments are those in which halogen is F, CI or Br.
• substituted means, for a particular group (e.g., alkyl, aryl, heteroaryl, aromatic), the replacement of one functional group by another (e.g., the substitution of an alkyl hydrogen by fluorine to provide fluoroalkyl).
• any embodiment given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, unless otherwise indicated.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 36 Cl, 125 I, respectively.
• the disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C, are present.
• isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F or labeled compound may be particularly preferred for PET or SPECT studies.
• Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• stereogenic center in their structure.
• This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
• the disclosure also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726 (see also US 2017/0022208 A1, US 2017/0253603 A2).
• compositions are used herein to refer to an agent or a compound according to the invention that is a therapeutically active, non-toxic base and acid salt form of the compounds.
• the acid addition salt form of a compound that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and the like. See, e.g., WO 01/062726 (see also US
• Compounds containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt form, e. g., metal or amine salts, by treatment with appropriate organic and inorganic bases.
• Appropriate base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, e. g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, and salts with amino acids such as, for example, arginine, lysine and the like.
• said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
• Compounds and their salts can be in the form of a solvate, which is included within the scope of the present disclosure. Such solvates include for example hydrates, alcoholates and the like.
• the compounds of the present invention also include prodrugs, analogs or derivatives.
• prodrug is a recognized art in the field and is intended to encompass compounds or agents which, under physiological conditions, are converted into orexin antagonists.
• a common method for making a prodrug is to select moieties which are hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent.
• the prodrug is converted by an enzymatic activity of the host animal to an orexin antagonist.
• This disclosure also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of all formulas, which compounds are identical to the compounds of all formulas described herein except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
• isotopically labelled, especially 2 H (deuterium) labelled compounds of all formulas and salts thereof are within the scope of this disclosure. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability resulting e.g., in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g., in an improved safety profile.
• the compounds of all formulas are not isotopically labelled.
• isotopically labelled compounds of all formula could be prepared by anyone skilled in the art in analogy to the methods described hereinafter but using the appropriate isotopic variation of suitable reagents or starting materials.
• this disclosure provides methods for preparing the compounds disclosed herein.
• the compounds of this disclosure are prepared using the methods described in the Examples below, or suitable variants thereof as would be understood by those of ordinary skill in the art.
• the methods can comprise the use of intermediate compounds such as those disclosed herein, with specific uses of such intermediates being described in more detail in the Examples section.
• this disclosure provides intermediates (e.g., Intermediates A through J shown in the Examples section below) that can be used to produce the compounds of the formulas disclosed herein, such as but not limited to Examples 1 through 21.
• this disclosure also provides intermediates used to produce intermediates A through J.
• such intermediates can include Intermediate A, Intermediate A1, Intermediate A2, Intermediate A3, and/or Intermediate A4; Intermediate B and/or Intermediate B1; Intermediate C and/or Intermediate C 1 ; Intermediate D and/or Intermediate D1; Intermediate E and/or Intermediate E1; Intermediate F, Intermediate F1 and/or Intermediate F2; Intermediate G and/or Intermediate G1; Intermediate H and/or Intermediate H1; Intermediate I, Intermediate I1, and/or Intermediate I2; Intermediate J and/or Intermediate J1.
• Intermediate A and Intermediate F can be used to produce a compound of Example 1.
• Intermediate A and Intermediate B can be used to produce a compound of Example 2.
• Intermediate A and Intermediate C can be used to produce a compound of Example 3.
• Intermediate J and Intermediate D can be used to produce a compound of Example 4. In some embodiments, Intermediate A and Intermediate D can be used to produce a compound of Example 5. In some embodiments, Intermediate J and Intermediate E can be used to produce a compound of Example 6. In some embodiments, Intermediate A and Intermediate E can be used to produce a compound of Example 7. In some embodiments, Intermediate I and Intermediate E can be used to produce a compound of Example 8. In some embodiments, Intermediate I and Intermediate D can be used to produce a compound of Example 9. In some embodiments, Intermediate J and Intermediate B can be used to produce a compound of Example 10. In some embodiments, Intermediate I and Intermediate B can be used to produce a compound of Example 11. In some embodiments, Intermediate I and Intermediate F can be used to produce a compound of Example 12.
• Intermediate J and Intermediate F can be used to produce a compound of Example 13.
• Intermediate I and Intermediate C can be used to produce a compound of Example 14.
• Intermediate J and Intermediate C can be used to produce a compound of Example 15.
• Intermediate A and Intermediate G can be used to produce a compound of Example 16.
• Intermediate A and Intermediate H can be used to produce a compound of Example 17.
• Intermediate I and Intermediate H can be used to produce a compound of Example 18.
• Intermediate I and Intermediate G can be used to produce a compound of Example 19.
• Intermediate J and Intermediate H can be used to produce a compound of Example 20.
• Intermediate J and Intermediate G can be used to produce a compound of Example 21.
• the phrase “can be used” is equivalent to “can be reacted with” (e.g., as shown in the Examples section below). While such methods for preparing the compounds of Examples 1-21 can be used, those of ordinary skill in the art would understand other methods can also be used.
• the compounds of this disclosure can be used for various in vivo methods of treatment, the compounds can also be used in vitro to inhibit Orexin receptors type 1 and/or 2 (i.e., Orexin receptors type 1 and/or 2 antagonists).
• Orexin receptors type 1 and/or 2 i.e., Orexin receptors type 1 and/or 2 antagonists.
• Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and/or the human orexin-2 receptors can be incubated with one or more antagonists or potential antagonists (e.g., compounds of Examples 1-21) and one or more indicator compounds (e.g., fluorescent calcium indicator such as fluo-4 AM) along with one or more agonists, and antagonist activity measured using a Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices).
• Antagonistic activity can be recorded as the 50% inhibitory concentration (IC 50 ) values.
• Other suitable methods for identifying antagonistic compounds are also known to those of ordinary skill in the art.
• his disclosure provides compounds that can be used for in vivo treatments of various disease states, and/or in vitro (e.g., as Orexin receptors type 1 and/or 2 antagonists).
• this disclosure provides compounds of formulas I, II, III, IIa, IIb, IIc, IIIa, IIIb, IIIc, IIaa, IIab, IIac, IIba, IIbb, IIbc, IIca, IIcb, IIcc, IIIaa, IIIab, IIIac, IIIba, IIIbb, IIIbc, IIIca, IIIcb, and/or IIIcc, or as may be otherwise disclosed and/or contemplated herein:
• R 5 and R 6 connected as alkyl to form a (C 1-3 )alkyl bridge cyclic structure
• A-B-J-D-E is a five-member heteroaryl
• A is N; and/or,
• B is C or N; and/or,
• J is C or N; and/or,
• D is C; and/or,
• E is C; and/or,
• M is selected from the group consisting of C, CH, CR 2 R 3 , CR 2 , CR 3 , O; and/or,
• G is selected from the group consisting of C, CH, CR 2 R 3 , CR 2 , CR 3 , and O; and/or,
• K is selected from the group consisting of C, CH, CR 2 R 3 , CR 2 , CR 3 , and O; and/or,
• L is selected from the group consisting of C, CH, CR 2 R 3 , CR 2 , CR 3 , and O.
• this disclosure provides the preferred compounds shown below:
• this disclosure provides a composition comprising any one or more of such a compound, and/or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
• this disclosure provides a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.
• this disclosure provides a therapeutically effective amount of such a compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
• this disclosure provides such a pharmaceutical composition further comprises at least one second therapeutic agent.
• this disclosure provides methods of preventing or treating a condition selected from the group consisting of a central nervous system (CNS) disorder, substance addiction, dependence, panic, anxiety, depression, posttraumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer disease (AD) in a subject in need thereof, by administering to the subject any of such one or more compounds and/or composition comprising one or more of such compounds, or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
• the methods can include administering a composition comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
• the composition comprises a pharmaceutically acceptable salt or isotope of such a compound.
• the composition can comprise an unlabeled form of the compound or an isotopically labeled form of the compound in which the compound has a structure depicted by the formula wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• this disclosure provides for the use of a compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, disclosed herein in the preparation of a medicament for preventing and/or treating a condition selected from the group consisting of a central nervous system (CNS) disorder, substance addiction, dependence, panic, anxiety, depression, posttraumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer disease (AD) in a subject in need thereof.
• the use can include a composition comprises a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
• such use can comprise a composition a pharmaceutically acceptable salt or isotope of the compound.
• such use can comprise a composition comprises an unlabeled form of the compound or an isotopically labeled form of the compound in which the compound has a structure depicted by the formula wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• This disclosure also provides intermediates of the compounds disclosed herein as well as methods for preparing the same. In some embodiments, such methods for preparing can include using any of the intermediates disclosed herein (e.g., any one or more of Intermediates A-J). Other embodiments are also contemplated here as would be understood by those of ordinary skill in the art.
• compositions comprising one or more compounds of this disclosure (or the like, such as a pharmaceutically acceptable salt thereof) (i.e., as an active agent, as a therapeutic agent), and one or more pharmaceutically acceptable carriers or excipients.
• a pharmaceutical composition contains a therapeutically effective amount of one ore more of such compounds or the like (i.e., active agent(s)), or an appropriate fraction thereof.
• a composition can optionally contain an additional active agent.
• a peptide product is at least about 90%, 95% or 98% pure.
• Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials and vehicles.
• Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials.
• the use of such excipients in pharmaceutical formulations is known in the art.
• conventional vehicles and carriers include without limitation oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents (e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer's solution) ⁇ , and organic solvents (e.g., dimethyl sulfoxide and alcohols [e.g., ethanol, glycerol and propylene glycol]).
• oils e.g., vegetable oils such as olive oil and sesame oil
• aqueous solvents e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]
• isotonic solutions e.g., Ringer's solution
• organic solvents e.g., dimethyl sulfoxide and alcohols [e.g., ethanol, glycerol
• Potential routes of administration of a pharmaceutical composition comprising the compounds or the like disclosed herein can include, without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasal inhalation), buccal, sublingual, rectal (e.g., by suppository), vaginal (e.g., by suppository), and/or other suitable route.
• parenteral including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical
• topical including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.
• terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression of or cause regression of the medical condition being treated, or to alleviate to some extent the medical condition or one or more symptoms or complications of that condition, at least in some fraction of the subjects taking that compound.
• therapeutically effective amount also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, organ or human which is sought by a medical doctor or clinician.
• treat include alleviating, ameliorating, inhibiting the progress of, reversing or abrogating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating or eradicating one or more causes of the condition.
• Reference to “treatment” of a medical condition includes prevention of the condition.
• prevent include precluding, reducing the risk of developing and delaying the onset of a medical condition or one or more symptoms or complications associated with the condition.
• medical conditions (or “conditions” for brevity) includes diseases and disorders.
• diseases and “disorders” are used interchangeably herein.
• Agents include, for example, agents that are known with respect to structure, and their orexin antagonist activities of such agents may render them suitable as “therapeutic agents” in the methods and compositions disclosed herein.
• therapeutic agents include, for example, agents that are known with respect to structure, and their orexin antagonist activities of such agents may render them suitable as “therapeutic agents” in the methods and compositions disclosed herein.
• abbreviations which may have been used herein and are defined as follows:
• Method A Agilent 1100 series with mass spectrometry detection (MS: Agilent single quadrupole). Column: Zorbax SB (3.5 ⁇ m, 4.6 ⁇ 150 mm). Conditions: MeCN (0.1% FA) [gradient eluent A]; water (0.1% FA) [gradient eluent B]. Gradient: 95% B+5% B over 5 min (flow: 0.8 ml/min). Detection: UV 280/254 nm+MS.
• Method B Agilent 1100 series with mass spectrometry detection (MS: Agilent single quadrupole). Column: X-Bridge C18 (3.5 ⁇ m, 4.6 ⁇ 150 mm).
• Step 1 Synthesis of Compound A1: Ethyl-3-Phenyl-1H-pyrazole-5-carboxylate (0.5 g, 2.31 mmol) was dissolved in Acetone (10.0 mL). The K 2 CO 3 (0.96 g, 6.9 mmol) was added, followed by 1-Bromo-2-Chloro-ethane (0.1 mL, 11.6 mmol). The reaction mixture was heated at 55° C. for 16 h. LCMS data shows desired product formation m/z 279.0 and minor amount of side product formation. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude product.
• Step 3 Synthesis of Compound A3: Compound A2 (0.47 g, 1.97 mmol) was dissolved in dry DMF (12.0 mL). The NaH (0.12 g, 2.96 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m/z 201.1. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product.
• the dry CO 2 gas was bubbled through the reaction mixture at ⁇ 65° C. and the reaction mixture was gradually warmed at room temperature.
• the LCMS data shows desired product formation m/z 245, debrominated side product (m/z 201) and some unknown product formation.
• the reaction mixture was quenched by water and extracted with ethyl acetate. The ethyl acetate layer was separated and debrominated product was recovered. The aq. Layer was acidified with 1 M HCl solution and evaporated to dryness to obtain 0.022 g of solid product.
• Step 1 Synthesis of Compound B1: 2-Chloro-5-trifluoromethyl-pyridine (0.33 g, 1.82 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.36 g, 1.81 mmol) were dissolved in dry DMSO (5.0 mL). The DIPEA (1.6 mL, 9.1 mmol) was added and reaction mixture was stirred at 100° C. temperature for 4 h. TLC shows product formation. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate.
• Step 2 Synthesis of Intermediate B: Compound B1 (0.24 g, 0.71 mmol) were dissolved in dry Dioxane (3.0 mL). The 4.0 M HCl solution in dioxane (1.77 mL, 7.08 mmol) was added and reaction mixture was stirred at 50° C. temperature for 4 h. LCMS shows product formation m/z 246. The reaction mixture was concentrated under reduced pressure to obtain solid product (0.19 g, Yield 78.4%). MS (ESI) mass calcd.
• Step 1 Synthesis of Compound Cl: 2-Chloro-5-ethyl-pyrimidine (0.2 g, 1.37 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.28 g, 1.37 mmol) were dissolved in dry DMF (5.0 mL). The Cs 2 CO 3 (0.89 g, 2.75 mmol) was added and reaction mixture was stirred at 120° C. temperature for 24 h. TLC shows product formation. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate.
• Step 1 Synthesis of Compound D1: [(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidine-2-yl]methanamine (0.35 g, 1.4 mmol) and 2-chloro-5-ethyl-pyrimidine (0.2 g, 1.4 mmol) were dissolved in dry DMF (4.0 mL). The K 2 CO 3 (0.39 g, 2.82 mmol) was added and reaction mixture was stirred at 120° C. temperature for 6 h. TLC shows product formation. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine.
• Step 2 Synthesis of Intermediate D: Compound 01 (0.1 g, 0.3 mmol) was dissolved in MeOH (3.0 mL). The 20.0% Pd—OH/C (30.0 mg) was added and reaction mixture was stirred at ambient temperature for 24 h. The TLC shows little amount of starting material and product formation. The 20.0% Pd—OH/C (30.0 mg) was further added and reaction mixture was stirred at ambient temperature for another 24 h. The TLC shows completion of reaction. The LCMS data shows m/z 235 of product formation. The reaction mixture was filtered over celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 66.0 mg of crude product. The crude product is used in next step without purification. MS (ESI) mass calcd. for C 13 H 22 N 4 , 234.3; m/z found 235.2 [M+H] + .
• Step 1 Synthesis of Compound E1: [(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidine-2-yl]methanamine (0.32 g, 1.29 mmol) and 2-chloro-5-trifluoromethyl-pyridine (0.23 g, 1.29 mmol) were dissolved in dry DMF (5.0 mL). The K 2 CO 3 (0.36 g, 2.58 mmol) was added and reaction mixture was stirred at 120° C. temperature for 4 h. TLC shows product formation and LCMS shows m/z 394 of product formation. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate.
• Step 2 Synthesis of Intermediate E: Compound E1 (0.02 g, 0.5 mmol) was dissolved in MeOH (5.0 mL). The 10.0% Pd/C (60.0 mg) was added and reaction mixture was stirred at ambient temperature for 24 h under H 2 atm. The TLC shows completion of reaction. The LCMS data shows m/z 274 of product formation. The reaction mixture was filtered over celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 0.16 g of crude product. MS (ESI) mass calcd. for C 13 H 18 F 3 N 3 , 273.3; m/z found 274.1 [M+H] + .
• Step 1 Synthesis of Compound F1: The N-Boc-L-Prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) was added followed by DMAP (0.61 g, 4.97 mmol). The reaction mixture was cooled in ice bath and p-TsCl (0.52 g, 2.73 mmol) was added. The reaction mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m/z 256, 300. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na 2 SO 4 . The evaporation of solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd. for C 17 H 25 NO 5 S, 355.5; m/z found 300.1, 256.1 [M+H] + .
• Step 2 Synthesis of Compound F2: Compound F1 (0.88 g, 2.48 mmol) and 3-Phenyl-1H-Pyrazole (0.43 g, 2.98 mmol) were dissolved in dry DMF (5.0 mL). The Cs 2 CO 3 (1.61 g, 4.96 mmol) was added and the reaction mixture was stirred at 70° C. temperature for 4 h. The LCMS shows product formation m/z 328. The reaction mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na 2 SO 4 . The evaporation of solvent gave crude product.
• Step 1 Synthesis of Compound G1: N-Boc-L-Prolinol (0.2 g, 0.99 mmol) was dissolved in dry DMF (4.0 mL). The NaH (0.08 g, 2.0 mmol) was added under ice cooling. The 2-Chloro-5-Ethyl-Pyrimidine (0.2 g, 1.5 mmol) was added under cooling and reaction mixture was gradually warmed at room temperature under stirring for 3 h. The LCMS shows product formation m/z 308.2. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate three times. The EtOAc layers were separated and dried over anhydrous Na 2 SO 4 . The evaporation of solvent gave crude product.
• Step 1 Synthesis of Compound 11: The ethyl benzoylacetate (0.5 g, 2.6 mmol) was dissolved in DMSO (5.0 mL). The NBS (0.51 g, 2.86 mmol) was added and reaction mixture was stirred at ambient temperature for 24 h. LCMS shows product formation m/z 270.9. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na 2 SO 4 . The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.42 g of product was obtained (Yield 59.7%).
• Step 2 Synthesis of Compound 12: Compound 11 (0.42 g, 1.55 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). The 2-amino-pyridine (0.15 g, 1.55 mmol) was added and reaction mixture was stirred at 80° C. for 1 h. LCMS shows product formation m/z 267.1. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.24 g of product was obtained (Yield 58.0%).
• Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure:
• Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 ⁇ g/mL G418, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 10% heat inactivated fetal calf serum (FCS).
• the cells are seeded at 20′000 cells/well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37° C. in 5% CO2.
• Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH:water (1:1), diluted in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO 3 : 0.375 g/L and 20 mM HEPES for use in the assay at a final concentration of 3 nM.
• BSA bovine serum albumin
• NaHCO 3 0.375 g/L
• 20 mM HEPES for use in the assay at a final concentration of 3 nM.
• Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO 3 : 0.375 g/L and 20 mM HEPES.
• BSA bovine serum albumin
• NaHCO 3 0.375 g/L
• 20 mM HEPES 50 ⁇ L of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, NaHCO 3:0.375 g/L, 5 mM probenecid (Sigma) and 3 ⁇ M of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well.
• the 384-well cell-plates are incubated for 50 min at 37° C. in 5% CO 2 followed by equilibration at RT for 30 min before measurement.
• antagonists are added to the plate in a volume of 10 ⁇ L/well, incubated for 120 min and finally 10 ⁇ L/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak-induced by 3 nM orexin-A with vehicle in place of antagonist.
• the IC50 value (the concentration of compound needed to inhibit 50% of the agonistic response) is determined and may be normalized using the obtained IC50 value of an on-plate reference compound. Optimized conditions were achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where IC50 values have been determined several times for the same compound, the geometric mean has been given. Antagonistic activities of example compounds are shown in Tables 1 and 2.

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