Quinoline derivatives acting as kappa-opioid receptor antagonists

Abstract

Disclosed herein are kappa-opioid receptor (KOR) antagonist compounds of Formula (I), Formula (II) and their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds are useful in methods of treating a variety of diseases and disorders adapted to KOR antagonism, including substance abuse disorders, depression, anxiety, and other psychiatric conditions.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 485,712, filed February 17, 2023, and U.S. Provisional Patent Application No. 63 / 520,478, filed August 18, 2023, which are incorporated herein by reference in their entirety as fully set forth herein. Background Technology

[0002] The kappa-opioid receptor (KOR) is a member of the opioid receptor family that binds dynorphin, an opioid peptide that is the primary endogenous ligand. KOR has a broad and distinctive distribution in the brain, spinal cord, and peripheral tissues, particularly in brain regions involved in reward, cognitive function, and stress response. Evidence suggests that dynorphin levels rise under pain and stress conditions, and that disruption of KOR produces anti-stress effects. Such discoveries have led to the development of KOR antagonists for the treatment of depression, anxiety, addiction disorders, and other stress-related mental illnesses [M.Urbano et al., Bioorganic & Medicinal Chemistry Letters, 24:2021-2032, 2014 ("Urbano 2014"); Jacobson et al., Annu. Rev. Pharmacol. Toxicol., 60:615-636 (2020); see also: Handbook in Experimental Pharmacology, 271: Eds. Lee-Yuan Liu-Chen Saadet Inan (2022)].

[0003] Pharmacological studies of prototypical KOR antagonists (i.e., morphine-derived ligands nor-BNI and GNTI, and non-morphine-derived JDTI) have established the therapeutic potential of the KOR / dynorphin system [Urbano 2014]. However, such prototypical KOR antagonists exhibit delayed onset of action ranging from hours to days, followed by antagonistic effects lasting for weeks at the minimum effective dose. Furthermore, such compounds show poor blood-brain barrier penetration. For these reasons, recent research has focused on developing (shorter)-acting KOR antagonists with improved pharmacokinetics.

[0004] The mechanism by which KOR antagonists provide therapeutic effects is generally understood. Both direct regulation of KOR and regulation of downstream signaling pathways regulated by dynorphin-KOR signaling contribute to therapeutic efficacy. Indeed, KOR antagonists have been extensively studied precisely because they are known to block significant stress-induced neuroadaptation, namely, increased dynorphin expression in the nucleus accumbens (NAc). The NAc is a component of the mesolimbic system, which plays a role in the pathology and triggers of mental illness. In addition to repeated exposure to substance abuse, stress triggers a complex series of intracellular events involving the transcription factor CREB (cAMP response element-binding protein) in the NAc. KOR antagonists alleviate depressive-like signs resulting from increased dynorphin expression mediated by CREB [WACarlezon et al., Depression and Anxiety, 33:895-906, 2016]. According to the model proposed by Carlezone et al., stress activates CREB in the NAc, leading to increased dynorphin expression. This increased dynorphin then promotes the activation of KOR. KOR is expressed at the terminals and cell bodies of mesocorticolimbic dopamine (DA) neurons, and KOR activation inhibits DA release. Therefore, treatment with KOR antagonists blocks the action of dynorphin, restores DA function, and thus provides antidepressant-like and anti-anxiety-like effects.

[0005] The neuropeptides oxytocin and vasopressin also play roles in pathways operating in neuropsychiatric disorders including depression, anxiety, autism, schizophrenia, PTSD, addiction, and ADHD [Cid-Jofre et al., Int. J. Mol. Sci., 22:12077, (2021)]. These are amplified neuropeptide pathways, downstream of dynorphin responses, and they can be modulated by KOR antagonists, which allow for multi-step modulation of adaptive psychopathology. In fact, multi-step interdiction in amplified pathways is a recognized principle in disease-modifying therapeutics.

[0006] μ and κ opioid binding sites have been found in the pituitary gland, which are important for the release of oxytocin and vasopressin [Jordan et al., J. Neuroendocrinol., 8:883-887, (1996); Shuster et al., Neuroscience, 96(2), 373-383, (2000); Morris et al., J Clin. Pharmacol., 50:1112-1117, (2010)]. Oxytocin secretion is centrally inhibited by both μ and κ agonists, and is directly inhibited by κ agonists through κ receptor activation [Lutz-Bucher & Koch, Euro J Pharmacol., 66:375-378, (1980)]. Therefore, both κ and μ opioid antagonists cause an increase in oxytocin levels; however, when administered intracerebroventricularly (ICV), only the κ antagonist enhances both oxytocin and vasopressin levels [Van de Heijning et al., Eur J Pharmacol., 197:175-180, (1991), ibid., 209:199-206, (1991)]. Additionally, the endogenous κ opioid receptor agonist dynorphin regulates serotonin (5-HT) release and, for example, affects social deficits in rodents during substance withdrawal: as demonstrated in humans, these effects can lead to relapse [Pomrenze et al., Neuron 110:4125-4143, (2022)].

[0007] Physiologically, dynorphin / KOR signaling promotes REM sleep. Furthermore, while KOR antagonists do not promote drowsiness in the absence of pain, they do normalize interrupted sleep in chronic pain, revealing a pathophysiological role for KOR signaling, which is selectively recruited to promote alertness and improve survival. Notably, while this mechanism may be beneficial in the short term, disruption of sleep homeostasis over longer periods can become maladaptive, leading to persistent chronic pain. Therefore, novel approaches to treating chronic pain could arise from normalizing pain-related sleep disruptions via KOR antagonism [Ito, et al., Brain:00; 1–14 (2022)]. Furthermore, sleep disturbances are not only caused by chronic pain, but they are also common symptoms of major depressive disorder (MDD), and they are a significant adverse effect of most existing classes of antidepressants, most notably selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) [EC Settle, J. Clin. Psychiatry 59:25-30 (1998)]. Therefore, KOR antagonism can normalize sleep disturbances without somnolence, which is a broad advantage in therapeutic interventions for MDD and in clinical settings characterized by sleep disturbances as an adverse effect of drug therapy.

[0008] To date, the mechanisms of action of KOR antagonists, along with considerable development and testing, including recent clinical findings (e.g., aticaprant and ALKS-5461), provide strong evidence that KOR antagonists offer therapeutic effects in people with a wide range of conditions, including mood disorders, anxiety disorders, and substance abuse disorders, as defined, for example, in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The Research Domain Criteria (RDC) project provides an additional framework for classifying psychopathological disorders: the RDC aims to classify such disorders based on both observable behavioral and neurobiological dimensions. In this context, KOR antagonists have therapeutic effects on at least two types within the domains defined by the RDC; namely, those related to reward and those related to adverse effects of stress. Within these domains, the use of KOR antagonists for treating anhedonia (“positive valence systems”) and for blocking adverse effects of stress (“negative valence systems”) has been recognized.

[0009] KOR antagonists offer benefits from advances in the field, with their utility recognized in treating major depressive disorder and substance abuse-related disorders, particularly in the context of rapid-acting treatments that avoid the drawbacks associated with typical KOR antagonists. Further advances have shown that KOR antagonists can be used specifically to treat stress-mediated symptoms, as well as social anxiety disorder and phobias. Prophylactic treatments have also been suggested to prevent adverse conditions caused by stress, and in this regard, KOR antagonists have been proposed as a preventative treatment for PTSD in individuals at risk of PTSD. Other therapeutic applications of KOR antagonists include treating impairments in reward-related functioning, as this frequently occurs in patients with mood and anxiety spectrum disorders and may also present with other types of conditions such as schizophrenia or schizoaffective disorder.

[0010] KOR antagonism is an established treatment approach for a wide range of disorders and conditions. Despite advances in this field, new and improved KOR antagonists are still needed to treat a variety of conditions, including substance abuse disorder, major depressive disorder, anhedonia, and stress-related symptoms. Summary of the Invention

[0011] In several embodiments, this disclosure addresses this and other needs by providing a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0012]

[0013] In equation (I), according to one embodiment, X is CH and Y is NH. In another embodiment, X is N and Y is -C (=N-CN)NR. 9 In yet another implementation, X is NH and -YR 2 Empty, meaning it does not exist.

[0014] In one implementation, R 1 and R 1a Independently selected from H, C1-C6 alkyl groups, and halogens. In another embodiment, R 1 and R 1a Together with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl or 3 to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O and S).

[0015] R 2 It is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, and 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S).

[0016] R 9 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0017] R 3 In each case, it is a C1-C6 alkyl group.

[0018] The subscript n is 0, 1, or 2.

[0019] Substituent R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10 Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)).

[0020] R and R' are independently selected from H and C1-C6 alkyl groups.

[0021] In equation (I), R 1 R 1a R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN, and C1-C6 haloalkyl groups.

[0022] In some other embodiments, this disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0023]

[0024] In equation (II), Ar is the object of (R) 3 ) n The substituted 5 to 6 heteroaryl groups (of which 1 to 4 heteroaryl members are independently selected from N, O and S).

[0025] In some embodiments, X is CH and Y is NH. In other embodiments, X is N and Y is selected from bond, C(O), and -C (=N-CN)NR. 9 In some other implementations, X is NH and -YR 2 It is empty (i.e., it does not exist).

[0026] In some implementation schemes, R 1 and R 1a It is independently selected from H, C1-C6 alkyl groups and halogens.

[0027] In other implementations, R 1 and R 1aTogether with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl groups or optionally substituted 3- to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O and S).

[0028] In equation (II), when X is CH, then:

[0029] (i)R 1 and R 1a At least one of them is not H and Ar is not Diazole, thiadiazole, or triazole; or

[0030] (ii) Optionally, R 1 or R 1a Together with Y and the carbon atoms they are bonded to, they form fused 5- to 6-membered heterocyclic alkyl groups;

[0031] R 2 Selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), and -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S)).

[0032] R 9 It is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0033] R 3 In each case, it is independently a C1-C6 alkyl or a C1-C6 haloalkyl.

[0034] The subscript n is 0, 1, or 2.

[0035] R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10 Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)).

[0036] R and R' are independently selected from H and C1-C6 alkyl groups.

[0037] In equation (II), R 1 R 1a R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NRR', NO2, OR, CN, and C1-C6 haloalkyl groups.

[0038] Despite the inclusion of formula (II), it should be understood that formula (II) does not include the following compounds:

[0039]

[0040] In some other embodiments, this disclosure provides pharmaceutical compositions comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0041] In some other embodiments, this disclosure provides a method for treating a disorder in a subject, wherein the disorder is therapeutically adapted to κ-opioid receptor (KOR) antagonism. The method includes administering to the subject a compound as disclosed herein or a pharmaceutically acceptable salt thereof.

[0042] In other embodiments, this disclosure provides methods for treating a disorder in a subject suffering from a disorder, wherein the disorder is selected from those disclosed herein, such as substance abuse or addiction, mental disorders, obesity and eating disorders, migraines, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, and seizures. The methods include administering to the subject a compound as disclosed herein or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disorder as disclosed herein in a subject. In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for preparing a medicament for treating a disorder as disclosed herein. Detailed Implementation

[0044] This disclosure relates in part to compounds that antagonize the κ-opioid receptor (KOR). One advantage of these compounds is their high potency, particularly their selective combination with KOR relative to the μ-opioid receptor (MOR).

[0045] definition

[0046] "Alkyl" refers to a straight-chain or branched hydrocarbon group containing 1 to 20 carbon atoms. For example, an alkyl group may have 1 to 10 carbon atoms or 1 to 6 carbon atoms. Some exemplary alkyl groups include straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc.; and also include branched isomers of straight-chain alkyl groups, such as, but not limited to, those that are branched.

[0047] Therefore, alkyl groups include primary alkyl, secondary alkyl, and tertiary alkyl groups. Alkyl groups may be unsubstituted or optionally substituted with one or more substituents as described herein (e.g., halogens).

[0048] Each of the terms "halogen", "halide" and "halo" refers to -F or fluorine, -Cl or chlorine, -Br or bromine, or -I or iodine.

[0049] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 20 carbon atoms and having 1 to 3, 1 to 2, or at least one carbon-carbon double bond. Alkenyl groups may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0050] "Alkyne" or "alkynyl group" refers to a straight-chain or branched unsaturated hydrocarbon having a specified number of carbon atoms and at least one triple bond. Examples of (C2-C8) alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, and 4-octyne. The alkynyl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0051] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic, or polycyclic 3- to 14-membered ring system, such as C3-C8 cycloalkyl. Cycloalkyl groups can be linked by any of the atoms. Some representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0052] When used alone or as part of another term, "aryl" means a carbocyclic aromatic group, whether fused or not, having a specified number of carbon atoms, or, if not specified, a maximum of 14 carbon atoms, such as C6-C6. 10 Aryl or C6-C 14 Aryl. Some examples of aryl include phenyl, naphthyl, biphenyl, phenanthrene, and naphthacenyl (see, for example, Lang's Handbook of Chemistry (Dean, JA, ed.), 13th edition, Table 7-2

[1985] ). "Aryl" also refers to an aryl ring as part of a fused polycyclic system, such as an aryl ring fused with a cycloalkyl group as defined herein. An exemplary aryl group is phenyl. Aryl groups may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0053] The term "heteroatom" refers to N, O, and S. Compounds of this disclosure containing N or S atoms may optionally be oxidized to the corresponding N-oxide, sulfoxide, or sulfone compound.

[0054] A “heteroaryl” (alone or in combination with any other part described herein) is a monocyclic aromatic ring structure containing 5 to 10 (e.g., 5 or 6) ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, comprising one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) heteroatoms independently selected from O, S, and N. Heteroaryls are also intended to contain oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary nitrogen. A carbon or heteroatom is the connecting point of the heteroaryl ring structure, resulting in a stable compound. Some examples of heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, quinoxalinyl, indoleazinyl, benzo[b]thiopheneyl, quinazolinyl, purine, indole, quinolinyl, pyrimidinyl, pyrroleyl, pyrazolyl, and pyrazolyl. azole group, thiazolyl group, thiophene group, iso azole group, Thiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuranyl, and indolyl. The heteroaryl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0055] "Heterocyclic alkyl" is a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic, or polycyclic ring system having 3 to 14 (e.g., 3 to 6) atoms, wherein 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S, or N. The cyclic heteroatoms also contain oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary nitrogen rings. Heterocyclic alkyl can be fused with another ring system, for example, with an aryl or heteroaryl ring of 5 to 6 ring members. The connecting point of the heterocyclic alkyl ring is on a carbon or heteroatom, thereby maintaining a stable ring. Some examples of heterocyclic alkyl include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuranyl, and dihydroindolyl. Heterocyclic alkyl can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0056] The terms “nitrile” or “cyano” are used interchangeably and refer to the -CN group.

[0057] Unless the context clearly specifies otherwise, nouns without quantifiers as used herein and in the appended claims mean one / something and more / somethings. When a range is used herein to refer to physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), all combinations and sub-combinations of the range and specific embodiments are intended to be included. When referring to a number or numerical range, the term “about / approximately” means that the number or numerical range mentioned is an approximation within experimental variability (or within statistical experimental error), and therefore in some cases the number or numerical range will vary from 1% to 15% of said number or numerical range. The term “comprising” (and related terms such as variations thereof or “having” or “including”) is not intended to exclude certain other embodiments described herein (e.g., embodiments of any composition, composition, method, or process, etc.) from being “consisting of” or “substantially composed of” said features.

[0058] The compounds described herein can exist in a variety of isomers, including configurational, geometrical, and conformational isomers, including, for example, cis or trans conformations. The compounds can also exist in one or more tautomers, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to cover all isomers of the compounds of this disclosure, including tautomers. The compounds of this disclosure can also exist in open-chain or cyclized forms. In some cases, one or more cyclized forms may be produced by dehydration. The specific composition of the open-chain and cyclized forms may depend on how the compound is isolated, stored, or administered. For example, the compound may exist primarily in its open-chain form under acidic conditions but cyclized under neutral conditions. All forms are included in this disclosure.

[0059] Some of the compounds described herein may have asymmetric centers and thus exist in different enantiomers and diastereomers. Compounds as described herein may be in the form of optical isomers or diastereomers. Therefore, this disclosure covers compounds as described herein in the form of optical isomers, diastereomers, and mixtures thereof (including racemic mixtures), and their uses. Optical isomers of the compounds of this disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed techniques, or by chemical separation of stereoisomers using an optically active resolving agent.

[0060] Unless otherwise stated, the term "stereoisomer" means a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Therefore, a stereoisomerically pure compound having one chiral center will be substantially free of its opposite enantiomers. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of other stereoisomers of the compound. The stereoisomers described above can be considered as a composition comprising two stereoisomers present in their respective weight percentages as described herein.

[0061] If there is a difference between the structure shown and its given name, the structure shown shall prevail. Furthermore, if the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, then the structure or part thereof should be interpreted as encompassing all its stereoisomers. However, in some cases where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relevant stereochemistry. Those skilled in the art of organic synthesis will know whether a compound is prepared as a single enantiomer by the method used to prepare it.

[0062] As used herein, the term "isotope" refers to an isotopically enriched compound. As used herein, and unless otherwise stated, the term "isotopically enriched" means an atom having an isotopic composition different from that of its natural abundance. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition different from that of its natural abundance. In isotope, "isotopic enrichment" refers to the percentage of a given atom in a molecule where a particular isotope replaces the natural isotopic composition of that atom. For example, a 1% enrichment of deuterium at a given location means that 1% of the molecules in a given sample contain deuterium at that specific location. Since the natural distribution of deuterium is about 0.0156%, the enrichment of deuterium at any location in a compound synthesized using a non-enriched starting material is about 0.0156%.

[0063] Therefore, as used herein, and unless otherwise stated, the term "isotope enrichment factor" refers to the ratio between the isotopic composition of a particular isotope and its natural isotopic composition.

[0064] Regarding the compounds presented in this article, when the position of a specific atom is specified as having deuterium or "D", it should be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. In some specific implementations, the sites designated as having deuterium typically have a minimum isotopic enrichment factor of at least 1000 (15% deuterium inclusion), at least 2000 (30% deuterium inclusion), at least 3000 (45% deuterium inclusion), at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion) at each designated deuterium atom. The isotope enrichment and isotope enrichment factors of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0065] As used herein, and unless otherwise stated to the contrary, the term "compound" is inclusive because it encompasses a compound or its pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers. Thus, for example, a compound includes pharmaceutically acceptable salts of the tautomers of that compound. Similarly, a compound includes pharmaceutically acceptable salts of the isotopes of that compound.

[0066] In this disclosure, "medicinal salt" means a medicinal organic or inorganic acid or base salt of the compound described herein. Representative pharmaceutically usable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetates, amsonates (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium, calcium edetate, camphorsulfonates, carbonates, chlorides, citrates, clavulariates, dihydrochlorides, edetates, ethanedisulfonates, estolates, esylates, fiunarates, gluconates, glutamates, glycolyllarsanilates, hexafluorophosphates, hexylresorcinol salts, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, and iodine. Compounds, isothiocyanates, lactates, lactobionates, laurates, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucates, naphthalenesulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, 1,1-methylene-bis-2-hydroxy-3-naphthoate (einbonate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonic acids, propionates, p-toluenesulfonates, salicylates, stearates, hypoacetates, succinates, sulfates, sulfosalicates, suramates, tannins, tartrates, teoclates, toluenesulfonates, triethiodide, and valerates. Medicinal salts may have more than one charged atom in their structure. In this case, the medicinal salt may have multiple counterions. Therefore, a medicinal salt may have one or more charged atoms and / or one or more counterions.

[0067] The term "treatment" and its variations refer to improving or eradicating a disease or disease-related symptoms. In several embodiments, the term refers to minimizing or slowing the spread, progression, or worsening of a disease by administering one or more of the preventive or therapeutic compounds described herein to a patient suffering from the disease.

[0068] The term “prevention”, and its variations, refers to the prevention in patients of the onset, recurrence or spread of disease by means of the application of the compounds described herein.

[0069] The term "effective amount" refers to an amount of a compound or other active ingredient as described herein that is sufficient to provide a therapeutic or preventive benefit in the treatment or prevention of a disease, or sufficient to delay or minimize symptoms associated with the disease. Furthermore, a therapeutically effective amount of a compound as described herein means an amount by which a single therapeutic agent, or a therapeutic agent in combination with other therapeutic agents, provides a therapeutic benefit in the treatment or prevention of a disease. When used in combination with a compound as described herein, the term may cover amounts that improve overall treatment, alleviate or prevent symptoms or causes of the disease, or enhance the therapeutic efficacy of another therapeutic agent or synergize with another therapeutic agent.

[0070] The term "patient" or "object" includes animals such as humans, cattle, horses, sheep, lambs, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, the animal is a mammal, such as a non-primate or primate (e.g., monkeys and humans). In one embodiment, the patient is a person, such as a human infant, child, adolescent, or adult. In this disclosure, the terms "patient" and "object" are used interchangeably.

[0071] compound

[0072] In several embodiments, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0073]

[0074] In equation (I), according to one embodiment, X is CH and Y is NH. In another embodiment, X is N and Y is -C (=N-CN)NR. 9 In yet another implementation, X is NH and -YR 2 Empty, meaning it does not exist.

[0075] In one implementation, R 1 and R 1a Independently selected from H, C1-C6 alkyl groups, and halogens. In another embodiment, R 1 and R 1a Together with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl or 3 to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O and S);

[0076] R 2 It is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl and 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S).

[0077] R 9Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0078] R 3 In each case, it is a C1-C6 alkyl group.

[0079] The subscript n is 0, 1, or 2.

[0080] Substituent R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10 Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10 Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)).

[0081] R and R' are independently selected from H and C1-C6 alkyl groups.

[0082] In equation (I), R 1 R 1a R 2 R 3 R 4 R 5 R 6 R 7 and R 8Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN, and C1-C6 haloalkyl groups.

[0083] In some other embodiments, this disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0084]

[0085] In equation (II), Ar is the object of (R) 3 ) n Substituted 5- or 6-membered heteroaryl groups (where 1 to 4 heteroaryl members are independently selected from N, O and S).

[0086] In some embodiments, X is CH and Y is NH. In other embodiments, X is N and Y is selected from bond, C(O), and -C (=N-CN)NR. 9 In some other implementations, X is NH and -YR 2 It is empty (i.e., it does not exist).

[0087] In some implementation schemes, R 1 and R 1a It is independently selected from H, C1-C6 alkyl groups and halogens.

[0088] In other implementations, R 1 and R 1a Together with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl groups or optionally substituted 3- to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O and S).

[0089] In equation (II), when X is CH, then:

[0090] (i)R 1 and R 1a At least one of them is not H and Ar is not Diazole, thiadiazole, or triazole; or

[0091] (ii) Optionally, R 1 or R 1a Together with Y and the carbon atoms they bind to, they form fused 5- to 6-membered heterocyclic alkyl groups.

[0092] R 2Selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), and -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S)).

[0093] R 9 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0094] R 3 In each case, it is independently a C1-C6 alkyl or a C1-C6 haloalkyl.

[0095] The subscript n is 0, 1, or 2.

[0096] R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10 Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10 Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)).

[0097] R and R' are independently selected from H and C1-C6 alkyl groups.

[0098] In equation (II), R 1 R 1a R2 R 3 R 4 R 5 R 6 R 7 and R 8 Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NRR', NO2, OR, CN, and C1-C6 haloalkyl groups.

[0099] Despite the inclusion of formula (II), it should be understood that formula (II) does not include the following compounds:

[0100]

[0101] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has formula (IIA), wherein each substituent is defined as disclosed herein in formula (II):

[0102]

[0103] In several embodiments, Ar is a 5-membered heteroaryl group (where 1 to 4 heteroaryl members are independently selected from N, O, and S). In some illustrative embodiments, Ar is selected from pyrazolyl, imidazolyl, ... azole group, iso azole group, diazole group, iso Diazole, thiazolyl, isothiazolyl, and thiadiazoleyl groups. In some specific embodiments, Ar is selected from pyrazolyl, ... azole and isopropyl Azolium group.

[0104] In some other implementations, X is N and Y is a key.

[0105] In one implementation, X is CH and Y is NH. In another implementation, X is N and Y is -C (= N-CN)NR. 9 In one exemplary implementation, R 9 It is H.

[0106] In some implementation schemes, R 2 It is an optionally substituted 3- to 6-membered heterocyclic alkyl group (where one ring member is O). For example, in several embodiments, R 2 Selected from the alternatives:

[0107] In one illustrative implementation, R 2 yes

[0108] In some other implementations, R 2 It is substituted with 1 to 3 substituents selected from halogens and OH and combinations thereof. In some embodiments, R 2 It is replaced only by halogens, such as one, two, or three halogens. For example, in one embodiment, the halogen is F. In other embodiments, R... 2 It is replaced only by OH, such as 1, 2 or 3 OH.

[0109] In one implementation, the subscript n is 0. In another implementation, n is 1.

[0110] In some implementation schemes, R 1 and R 1a One of them is H and the other is a halogen. For example, R 1 It is H and R 1a It is halogen, or R 1 It is halogen and R 1a It is H. In some other implementations, R 1 and R 1a One of them is H and the other is F. In some illustrative embodiments, R 1 It is H and R 1a Is it F, or R? 1 and R 1a Each of them is H. R is considered. 1 and R 1a All of these combinations.

[0111] In some implementation schemes, R 1 and R 1a Together with the carbon atoms they are bonded to, they form optionally substituted fused C3-C8 cycloalkyl groups or optionally substituted 3- to 6-membered heterocyclic alkyl groups (wherein 1 to 4 ring members are independently selected from N, O, and S). In one embodiment, R 1 and R 1a Together with the carbon atoms they are bonded to, they form optionally substituted fused 3- to 6-membered heterocyclic alkyl groups. In another embodiment, R 1 and R 1a Together with the carbon atoms they are bonded to, they form optionally substituted C3-C8 cycloalkyl groups. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0112] In several implementation schemes, R 1 or R 1a Together with Y and the carbon atoms they are bonded to, they form fused 5- to 6-membered heterocyclic alkyl groups. An illustrative heterocyclic alkyl group is a pyrrolealkyl group.

[0113] In some other embodiments, this disclosure provides compounds of formula (I) or formula (II), wherein R 4 Selected from H, CN, halogens, and C1-C6 alkyl groups. In one embodiment, R... 4 It is a C1-C6 alkyl group.

[0114] In some other implementation schemes, R 5 and R 7 It is independently selected from H, halogens, and CN. For example, in one embodiment, R 5 and R 7 At least one of them is H. In another implementation, R 5 and R 7 Each of them is H.

[0115] Some other embodiments provide a compound of formula (I), wherein R 6 Selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl. In one exemplary embodiment, R 6 It is a C1-C6 alkyl group.

[0116] In several implementation schemes, R 8 Selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 5 to 10 heteroaryl (of which 1 to 4 heteroaryl members are independently selected from N, O, and S), and -CONRR'. In some embodiments, R 8 It is a halogen or a 5- to 10-membered heteroaryl group (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S). An illustrative embodiment provides a compound of formula (I), wherein R 8 It is a halogen, such as F.

[0117] In several embodiments, this disclosure provides compounds of formula (I), wherein:

[0118] X is CH and Y is NH;

[0119] R 1 and R 1a One of them is H and the other is F;

[0120] R 2 It is an optional substituted 3- to 6-membered heterocyclic alkyl group (one of which is O);

[0121] n is 0 or 1;

[0122] R 4 Selected from H, CN, halogens, and C1-C6 alkyl groups;

[0123] R5 and R 7 Independently selected from H, halogens, and CN, wherein R 5 and R 7 At least one of them is H;

[0124] R 6 Selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl; and

[0125] R 8 Selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 5 to 10 heteroaryl (of which 1 to 4 heteroaryl members are independently selected from N, O and S), and -CONRR'.

[0126] Illustrative embodiments of the compounds of formula (I) and (II) and their pharmaceutically acceptable salts are present in Table 1 below and throughout the examples.

[0127] Table 1. Representative compounds with formula (I).

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] Pharmaceutical Composition

[0160] This disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds disclosed herein, or their pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers, miscible with a pharmaceutically acceptable carrier. In some embodiments, in accordance with recognized pharmaceutical compounding practices, the composition further comprises one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, excipients, stabilizers, emulsifiers, preservatives, colorants, buffers, and flavoring agents.

[0161] In one embodiment, the pharmaceutical composition comprises a compound selected from the compounds shown in Table 1 or its pharmaceutically acceptable salts, stereoisomers, isotopes and / or tautomers, and a pharmaceutically acceptable carrier.

[0162] The pharmaceutical compositions disclosed herein are formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific condition being treated, the specific patient being treated, the patient's clinical condition, the cause of the condition, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to the medical practitioner.

[0163] The "therapeutic effective amount" of the applied compound, or its pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers, is governed by considerations that it is the minimum amount required to exhibit antagonism against κ-opioid receptors. Such an amount may be below the level toxic to normal cells or the object as a whole. Generally, the initial therapeutic effective amount of the applied compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers) is about 0.01 to about 200 mg / kg or about 0.1 to about 20 mg / kg patient body weight / day, with a typical initial range of about 0.3 to about 15 mg / kg / day. Oral unit dosage forms (e.g., tablets and capsules) may contain about 0.1 mg to about 1000 mg of the compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers). In another embodiment, such a dosage form contains about 50 mg to about 500 mg of the compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers). In yet another embodiment, such a dosage form comprises about 25 mg to about 200 mg of the compound of this disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such a dosage form comprises about 10 mg to about 100 mg of the compound of this disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such a dosage form comprises about 5 mg to about 50 mg of the compound of this disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage form may be administered once daily or twice daily.

[0164] In some embodiments, the compound, or its pharmaceutically acceptable salt or solvate, as described herein, is substantially pure because it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated, for example, in one or more steps of a synthetic method.

[0165] The compositions disclosed herein can be administered orally, topically, parenterally, by inhalation or spraying, or rectally in dosage units. As used herein, the term parenterally includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques.

[0166] Suitable oral compositions as described herein include, but are not limited to, tablets, sugar tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0167] In another embodiment, a pharmaceutical composition suitable for a single unit dose is also covered, the pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable stereoisomer, salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0168] The compositions of this disclosure suitable for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions. For example, liquid formulations of the compounds of this disclosure contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically palatable formulation of the compounds of this disclosure.

[0169] For tablet compositions, the compounds disclosed herein are mixed with non-toxic, pharmaceutically acceptable excipients for the preparation of tablets. Examples of such excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated using known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained therapeutic effect over the desired time period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used.

[0170] Formulations intended for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0171] For aqueous suspensions, the compounds of this disclosure are mixed with excipients suitable for maintaining a stable suspension. Some examples of such excipients include, but are not limited to, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragali, and gum arabic.

[0172] Oral suspensions may also contain dispersants or wetting agents, such as naturally occurring phospholipids, such as lecithin, or condensation products of alkyl esters and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecanol, or condensation products of ethylene oxide and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides, such as polyethylene dehydrated sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0173] Oily suspensions can be formulated by suspending the compounds of this disclosure in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in mineral oils (e.g., liquid paraffin). The oily suspension may contain a thickener such as beeswax, anhydride, or cetyl alcohol.

[0174] Sweeteners (such as those shown above) and flavoring agents can be added to provide palatable oral formulations. These compositions can be preserved by adding antioxidants (such as ascorbic acid).

[0175] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water are provided in the form of compounds of this disclosure that can be mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0176] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers may be naturally occurring gums (e.g., gum arabic or tragacanth), naturally occurring phospholipids (e.g., soybean, lecithin), and esters or metaesters derived from fatty acids and hexitan anhydrides (e.g., sorbitan monooleate and the condensation product of said metaester with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate)). The emulsion may also contain sweeteners and flavoring agents.

[0177] Syrups and elixirs can be formulated with sweeteners (e.g., glycerol, propylene glycol, sorbitol, or sucrose). Such formulations may also contain demulcents, preservatives, flavoring agents, and coloring agents. Pharmaceutical compositions can be in the form of sterile injectables, aqueous suspensions, or oil suspensions. The suspension can be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Water, Ringer's solution, and isotonic sodium chloride solution can be used as acceptable carriers and solvents. Additionally, sterile non-volatile oils are commonly used as solvents or suspending media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (e.g., oleic acid) can be used to prepare injectables.

[0178] The compounds disclosed herein can be administered in suppository form for rectal administration of a drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycol.

[0179] Compositions intended for parenteral administration are administered in a sterile medium. Depending on the carrier and concentration (the concentration of the drug in the formulation) used, parenteral formulations can be suspensions or solutions containing dissolved drug. Excipients (such as local anesthetics, preservatives, and buffers) may also be added to the parenteral composition.

[0180] How to use

[0181] In another embodiment, this disclosure provides a method for antagonizing KOR. The method includes contacting the receptor with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. According to various embodiments, the contact may occur, for example, in vivo or in vitro.

[0182] In some embodiments, this disclosure also provides methods for treating a disorder in a subject suffering from a disorder that is therapeutically adapted to κ-opioid receptor (KOR) antagonism.

[0183] As described in the overview above, KOR is a member of the opioid receptor family, binding to the opioid peptide dynorphin as its primary endogenous ligand. The term "antagonist" generally refers to a molecule that interacts with a receptor by binding to its natural ligand binding site or at a location other than the binding site, thereby acting as an antagonist. Therefore, expressions such as "KOR antagonism" refer to antagonistic interactions with KOR by binding to a site belonging to dynorphin or at a location other than the binding site (i.e., allosteric binding).

[0184] In another embodiment, this disclosure provides a method for treating a disorder in a subject suffering from such a disorder, comprising administering to the subject a compound as described herein or a pharmaceutically acceptable salt thereof. The disorder is selected from one or more of the following: substance abuse or addiction, mental disorders, obesity and eating disorders, migraines, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, and seizures.

[0185] In some embodiments, the disturbance is sleep interruption caused by or accompanying pain, a mental disorder as described herein, or pharmacological treatment of a mental disorder. The pain can be chronic pain or neuropathic pain. In several embodiments, sleep interruption can be characterized as a sleep disorder, such as a sleep disorder caused by a disorder of initiating and maintaining sleep (DIMS, insomnia), excessive sleepiness, a sleep-wake schedule disorder, or partial wakefulness (parasomnia) [Cormier RE. Sleep Disturbances. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990. Chapter 77]. In other embodiments, sleep interruption is sleep deprivation, such as sleep deprivation caused by abnormal frequency and / or duration of wakefulness. In some embodiments, the interrupted sleep is characterized by an interrupted sleep phase, such as rapid eye movement (REM) sleep. According to the methods described herein, treatment in this context can lead to sleep normalization, i.e., reduction or elimination of sleep disturbances. In several embodiments, sleep normalization includes the restoration of REM sleep, the prolongation of REM sleep duration, the reduction of REM sleep interruption frequency, and combinations thereof.

[0186] In some implementations, the disorder is one of substance abuse or addiction. For example, the disorder may be selected from gambling, drug addiction, drug abuse, alcohol dependence, alcohol abuse, and substance-induced depression or mood disorder.

[0187] In other implementations, the disorder is a mental disorder. Some examples of mental disorders suitable for treatment by the methods described herein include anxiety disorders, depressive disorders, mood disorders, schizophrenia spectrum disorders, stress-related disorders, obsessive-compulsive disorders, social phobia, generalized anxiety disorder (GAD), social anxiety disorder, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorder (ASD).

[0188] As understood in the art, the term "anxiety disorder" generally refers to a variety of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders, including generalized anxiety disorder, panic disorder, stress-related disorders, obsessive-compulsive disorder, phobias, social anxiety disorder, separation anxiety disorder, and post-traumatic stress disorder (PTSD). In one implementation, the anxiety disorder is a social anxiety disorder. In another implementation, the anxiety disorder is a phobia.

[0189] Generalized anxiety disorder is characterized by chronic and persistent anxiety that is not focused on any particular object or situation. People with generalized anxiety disorder may experience nonspecific, persistent fear and worry, and / or exhibit exaggerated attention to routine events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0190] People with panic disorder may experience unexpected, brief episodes of intense fear and anxiety. Accompanying symptoms include trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. The APA defines such an episode as a sudden onset of fear or discomfort that peaks within 10 minutes, can last for hours, and can be triggered by stress, fear, or even movement; the specific cause is not always apparent. The diagnosis of panic disorder is further supplemented by the chronic consequences of aggression: these include worry about the potential impact of the aggression, a persistent fear of future aggression, or significant behavioral changes resulting from the aggression. Therefore, those with panic disorder may experience symptoms beyond a specific panic attack. For example, a panic disorder sufferer may notice normal changes in their heartbeat, which forms the basis for a false focus on cardiac health or the onset of another panic attack. In some cases, a person may experience heightened awareness of bodily functions (hypervigilance) during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness—a form of extreme hypochondria.

[0191] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by repetitive obsessive thoughts (distressing, persistent, and intrusive thoughts or images) and compulsive behaviors (impulses to perform specific actions or rituals). OCD thought patterns reside in beliefs that evoke causal relationships that do not actually exist. Compulsive behaviors can be completely illogical, such as walking in a certain pattern to alleviate obsessive thoughts of impending harm. Compulsive behaviors can be completely unexplained and often arise from stress-triggered impulses to complete rituals. A small percentage of OCD patients may experience only obsessive thoughts without overt compulsive behaviors; even fewer experience only compulsive behaviors.

[0192] Phobias are the single largest category of anxiety disorders, encompassing all conditions in which a specific stimulus or situation triggers fear or anxiety. Those suffering from phobias typically anticipate dire consequences from encountering the object they fear: some examples include social phobia, specific phobias, agoraphobia, and phobias of animals, places, or bodily fluids.

[0193] Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by a traumatic experience. PTSD can occur after extreme events such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged exposure to severe stressors; for example, a soldier may tolerate fighting alone but suffer from the stress of prolonged combat. Common PTSD symptoms include flashbacks, avoidance behavior, and depression.

[0194] The methods described in this article can be used to treat depressive disorders, depression, or depressive illnesses. Some examples include major depressive disorder, medication-resistant depression, dysphoric mood, and bipolar disorder.

[0195] In some implementations, the methods described herein can be used to treat mood disorders or affective disorders. Some examples include major depressive disorder (MDD), bipolar disorder, anhedonia, dysphoric mood, major depression, psychotic major depression (PMD), psychotic depression, postpartum depression, seasonal affective disorder (SAD), and catatonic depression, which is a rare but severe form of major depression that includes motor behavioral disorders and other symptoms.

[0196] The terms “anhedonia” and “anhedonia symptoms” used herein are interchangeable and are defined as the inability to experience pleasure from activities that are normally found to be pleasurable (e.g., exercise, hobbies, music, sexual activity, or social interaction). Anhedonia is similar to the criteria for “depressive disorder with melancholic features” as defined in the DSM-5, characterized by loss of pleasure in most or all activities, failure to respond to pleasurable stimuli, a quality of depressed mood that is more pronounced than the quality of sadness or loss, worsening of symptoms in the early morning hours, early awakening, psychomotor retardation, excessive weight loss, or excessive guilt. It should be understood that, in several implementations, treatment of a depressive disorder with melancholic features includes treatment of both the depressive disorder and the associated melancholic features. In one implementation, the mood disorder is anhedonia. In another implementation, the mood disorder is major depressive disorder. In yet another implementation, the mood disorder is seasonal affective disorder (SAD).

[0197] In other embodiments, the methods described herein can be used to treat schizophrenia or schizoaffective disorder, or obesity or eating disorders such as bulimia, anorexia nervosa, etc.

[0198] In other embodiments, the method is used to treat migraines. Preventative treatment, in which the KOR antagonist compound described herein is administered to prevent migraines in individuals at risk of or prone to migraine recurrence.

[0199] In another implementation, the methods described herein can be used to treat postnatal depression (PND). A significant drop in progesterone levels immediately after birth can lead to the onset of PND. Symptoms of PND range from mild depression to more severe psychosis requiring hospitalization. PND may also be accompanied by or manifest as severe anxiety and irritability. Typical treatment regimens are frustrating, PND is not well-suited to treatment with classic antidepressants, and women with PND show a higher incidence of premenstrual syndrome (PMS).

[0200] In several embodiments, the methods described herein can be used to treat neurodegenerative diseases or disorders, including mood and behavioral disorders associated with neurodegenerative diseases. The scope of neurodegenerative diseases considered herein includes diseases and disorders associated with progressive loss of neuronal structure or function, or neuronal death. Neurodegenerative diseases and disorders include, but are not limited to: Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); hypoxic and ischemic injury; ataxia and seizures; seizures caused by schizoaffective disorder or by medications administered to treat schizophrenia; benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusions, such as spinal cord injury and head injury; dementia, including multi-infarct dementia and Alzheimer's disease; altered consciousness; Down syndrome. Parkinsonism induced by drugs, such as acute akathisia induced by nerve blocks, acute dystonia, Parkinson's syndrome, tardive dyskinesia, nerve block malignant syndrome, and drug-induced postural tremor; epilepsy; Fragile X syndrome; Tourette syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced motor disorders; intellectual disability; motor disorders, including akinesia and akinetic (rigid) syndromes, including basal ganglia calcification, corticobasal ganglia degeneration, multiple system atrophy, Parkinson's syndrome-ALS dementia complex, Parkinson's disease, post-encephalitis Parkinson's syndrome, and progressive supranuclear palsy;Muscle spasms and disorders associated with muscle spasms or weakness, including chorea (e.g., benign hereditary chorea, drug-induced chorea, unilateral throwing disorder, Huntington's disease, neuroacanthosis, Sydenham's chorea, and symptomatic chorea), movement disorders (e.g., tics, including complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus), tremor (e.g., resting tremor, postural tremor, and intention tremor), and dystonia (including axial dystonia, dystonic writer's cramp). Writer's scramp), hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spastic dysarthria and torticollis; neuronal damage, including eye injury, retinopathy, or macular degeneration; neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, perinatal asphyxia, and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; renal tubular sclerosis; and neurodegenerative changes induced by viral infections such as acquired immunodeficiency syndrome (AIDS) and encephalopathy. The methods also consider the treatment or prevention of loss of neuronal functional characteristics in neurodegenerative disorders.

[0201] In some implementations, the methods described herein can be used to treat epilepsy. Epilepsy is a brain disorder characterized by recurrent seizures over time. Various types of epilepsy intended for treatment include generalized epilepsy, childhood absence epilepsy, juvenile myoclonic epilepsy, grand mal seizures during wakefulness, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0202] In some implementations, the methods described herein can be used to treat status epilepticus. Status epilepticus (SE) can include convulsive status epilepticus, early status epilepticus, definitive status epilepticus, refractory status epilepticus, extremely refractory status epilepticus; nonconvulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges.

[0203] Seizure-related status epilepticus is characterized by the presence of seizures and can include early status epilepticus, definitive status epilepticus, refractory status epilepticus, or ultra-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Definitive status epilepticus is characterized by the persistence of seizures despite first-line therapy; therefore, second-line therapy is administered. Refractory status epilepticus is characterized by the persistence of seizures despite first-line and second-line therapy; general anesthetics are typically used. Ultra-refractory status epilepticus is characterized by the persistence of seizures despite first-line and second-line therapy and general anesthetic treatment for 24 hours or longer.

[0204] Nonconvulsive status epilepticus includes focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, and mild nonconvulsive status epilepticus; as well as generalized nonconvulsive status epilepticus, such as late onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0205] In some implementations, the methods described herein can be used to treat epileptic seizures. As used herein, the term "epileptic seizure" refers to changes in physical manifestations or behavior that occur following an episode of abnormal electrical activity in the brain. Additionally, the term "epileptic seizure" is often used interchangeably with "convulsion," which refers to rapid and uncontrolled shaking of the body. During a convulsion, a person's muscles repeatedly contract and relax. The type of behavior and brain activity defines two categories of epileptic seizures: generalized and partial (also known as focal or regional). The classification of epileptic seizures provides information for the diagnosis of epilepsy.

[0206] Electrical impulses generated throughout the brain cause generalized seizures, while impulses localized to a specific part of the brain cause partial seizures. The part of the brain that produces a seizure is sometimes referred to as a lesion.

[0207] Generalized tonic-clonic seizures are classified into six types. The most common and severe, and therefore the most well-known, is the generalized tonic-clonic seizure: also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls to the ground. Following the loss of consciousness, there is a generalized rigidity lasting 30 to 60 seconds – the “tonic” phase – followed by violent convulsions lasting 30 to 60 seconds – the “clonic” phase – after which the patient enters a deep state – the “postictal” or post-ictal phase. During a grand mal seizure, a person can suffer injuries and accidents such as biting their tongue and urinary incontinence.

[0208] Second, absence seizures cause brief loss of consciousness, usually lasting a few seconds, and are rarely or never accompanied by symptoms. They are most common in children, who typically experience a halt in activity accompanied by a blank stare. These seizures begin and end abruptly and can occur several times a day. Aside from possibly noticing a "loss of time," patients are usually unaware of the seizure. Third, myoclonic seizures consist of sporadic twitching, usually occurring on both sides of the body. Patients sometimes describe the twitching as a brief electric shock. When severe, these seizures can cause dropping or involuntary throwing of objects. Fourth, clonic seizures consist of repetitive, rhythmic twitching involving both sides of the body simultaneously. Fifth, tonic seizures are characterized by muscle rigidity. Finally, atonic seizures consist of a sudden and generalized loss of muscle tone, particularly in the arms and legs, often leading to falls.

[0209] In various embodiments, the seizures described herein include: epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; prolonged seizures; recurrent seizures; status epileptic seizures, such as refractory convulsive status epileptic seizures and nonconvulsive status epileptic seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized tonic-clonic seizures; infantile spasms; Jacksonian seizures; and massive bilateral myoclonic seizures. Myoclonus seizure; multifocal seizures; neonatal paroxysmal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; minor seizures; Sylvan seizures; visual reflex seizures; and withdrawal seizures.

[0210] Example

[0211] The present disclosure is further illustrated by the following examples. These examples are non-limiting and constitute other embodiments of the present disclosure.

[0212] General methods. Commercially available reagents and solvents were used without purification unless otherwise specified. Extraction solvent: ACS grade. Reaction solvent: Reagent grade. Reagents: Unless otherwise specified, the highest quality reagents available from Alfa Aesar, Fisher, Combi-Blocks, and Aldrich were used. TLC: Silica gel 60F254 aluminum plates (whatman, Al Sil G / UV type, 250 μm layer); visualization by UV absorption. Rapid chromatography was performed on silica gel 60 (0.40 to 0.63 mm, 230 to 440 mesh, EM Science). A Biotage Flash+ system was used for medium-pressure column chromatography. NMR: Obtained on a Bruker AV NEO 500 MHz spectrometer and a Bruker AVIII 400 MHz spectrometer. 1 H and 13 C spectrum. 1 H and 13 C10 NMR data are reported as chemical shifts (δ) relative to the residual signal in the deuterated solvent, in parts per million (ppm): chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m = multiplet, br = broad peak), and coupling constant in Hz. Reactions were monitored by an Agilent 1260 Infinity with an Agilent 6120 quadrupole LC / MS detector. Purity was determined by LC-MS using an Agilent SB-C18 column (1.8 μm, 2.1 × 50 mm) and detected using UV at wavelengths of 254 and 230 nm. Elution was performed at 25 °C with CH3CN in water containing 0.1% HCO2H at a flow rate of 1.0 mL / min over 5 minutes, from 10% to 90%. The purity of all tested compounds was greater than 95%. High-resolution mass spectra were obtained using positive ion mode electrospray ionization (ESI) on an Agilent 6230TOF LC / MS system.

[0213] Compound Synthesis

[0214] The following exemplary procedures are provided to illustrate the synthesis of specific compounds described in this disclosure. Those skilled in the art can readily adapt the procedures, starting materials, and reagents to synthesize all the compounds described herein.

[0215] Example 1: (3R,4S)-1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-3-fluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (1)

[0216]

[0217] Step 1. 2-Chloro-6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline (int-5)

[0218]

[0219] A mixture of (1-methyl-1H-pyrazol-3-yl)acetic acid (int-2; 121 mg, 0.86 mmol) and int-1 (250 mg, 0.86 mmol) in POCl3 (3 mL) was stirred at 90 °C for 1 hour. POCl3 was removed under reduced pressure. The residue was quenched with ice / water and alkalized to approximately pH 7 with a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give 2-chloroquinoline int-3.

[0220]

[0221] A mixture of int-3 (50 mg, 0.12 mmol), int-4 (25 mg, 0.11 mmol), Pd(dppf)Cl2 (8 mg, 0.012 mmol), and K2CO3 (33 mg, 0.24 mmol) in dioxane / H2O (0.8 / 0.2 mL) was purged with nitrogen. The mixture was heated at 120 °C for 2 hours. After cooling to room temperature, the mixture was partitioned between brine (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-5.

[0222]

[0223] Step 2. (3R,4S)-3-fluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

[0224]

[0225] A mixture of ketone int-7 (275 mg, 2.75 mmol), chiral amine int-6 (400 mg, 1.83 mmol), NaBH(OAc)3 (776 mg, 3.66 mmol), and AcOH (209 μL, 3.66 mmol) in 1,2-dichloroethane (6 mL) was stirred at room temperature for 24 hours. The mixture was quenched with water, and the product was extracted with EtOAc (3×). The organic phase was concentrated under reduced pressure, and the product was purified by column chromatography using CH2Cl2:MeOH to give compound int-8. LCMS (M+H) m / z = 303.

[0226] At room temperature, HCl (4M dioxane) (2.9 mL, 11.5 mmol) was slowly added to a solution of int-8 (470 mg, 1.15 mmol) in CH₂Cl₂ (1 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The mixture was redissolved in MeOH and quenched with PL-HCO₃ MPSPE resin (Agilent) and stirred for 2 minutes. The mixture was filtered and the resin was washed with MeOH. The organic phase was concentrated under reduced pressure, and the product int-9 was ready for use without further purification. LCMS (M+H) m / z = 203.

[0227] Step 3. (3R,4S)-1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-3-fluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (1)

[0228]

[0229] A suspension of int-5 (10 mg, 0.027 mmol), int-9 (8.3 mg, 0.04 mmol), and DIPEA (9.5 μL, 0.054 mmol) in 1-BuOH (0.5 mL) was heated at 155 °C for 6 hours under microwave irradiation. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by preparative TLC using CH2Cl2 / MeOH to obtain 1.

[0230]

[0231] HRMS (ESI-TOF): C 30 H 38 FN7O[M+H] + Calculated value: 532.3195, measured value: 532.3169.

[0232] Example 2: (R)-6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline (2)

[0233]

[0234] A mixture of (1-methyl-1H-pyrazol-3-yl)acetic acid (int-2; 350 mg, 2.5 mmol) and int-10 (480 mg, 2.08 mmol) in POCl3 (5 mL) was stirred at 100 °C for 1 hour. POCl3 was removed under reduced pressure. The residue was quenched with ice / water and alkalized to approximately pH 7 with saturated NaHCO3 (aqueous solution), and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give 2-chloroquinoline int-11.

[0235]

[0236] A mixture of int-11 (180 mg, 0.507 mmol), int-12 (203 mg, 1.01 mmol), and KF (71 mg, 1.22 mmol) in DMSO was heated at 130 °C for 7 hours under microwave irradiation. The mixture was cooled to room temperature, diluted with EtOAc (60 mL), and washed with brine (3×). The organic phase was dried over Na2SO4, concentrated under reduced pressure, and the product was purified by column chromatography using CH2Cl2 / EtOAc. Int-13 was obtained. LCMS: (M+1)m / z = 518,520.

[0237] Et3B (1M in THF) (868 μL, 0.87 mmol) was added to a suspension of int-13 (150 mg, 0.29 mmol), Cs₂CO₃ (283 mg, 0.87 mmol), and Pd(dppf)Cl₂ (21 mg, 0.029 mmol) in THF (3 mL). The reaction was heated at 45 °C for 10 min. The mixture was diluted with EtOAc and washed with brine (2×). The organic phase was dried over Na₂SO₄, concentrated under reduced pressure, and the product was purified by column chromatography using CH₂Cl₂ / EtOAc to give product int-14.

[0238]

[0239] HCl (4M dioxane) (0.5 mL, 2.0 mmol) was slowly added to a solution of int-14 (95 mg, 0.2 mmol) in CH₂Cl₂ (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the product int-15 was ready for use without further purification. LCMS (M+H) m / z = 368.

[0240] A mixture of int-15 (11 mg, 0.027 mmol), int-16 (3.7 mg, 0.032 mmol), NaBH(OAc)3 (11.4 mg, 0.054 mmol), DIPEA (4.7 μL, 0.027 mmol), and AcOH (3.1 μL, 0.054 mmol) in 0.4 mL of 1,2-dichloroethane was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 2.

[0241] HRMS (ESI-TOF): C 27 H 36 FN5O[M+H] + Calculated value: 466.2977, measured value: 466.2959.

[0242] Example 3: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidine-4-amine

[0243]

[0244] A mixture of int-17 (250 mg, 1.38 mmol), int-18 (175 μL, 1.38 mmol), and CeCl3 (68 mg, 0.28 mmol) was heated in a microwave-safe vial at 160 °C for 6 minutes under microwave irradiation. The mixture was then stirred with 1 mL of water for 5 minutes. The solid was filtered and washed with water (3×) and hexane (2×). The quinolone product was...

[0245]

[0246] The mixture of the above quinolone product (160 mg, 0.65 mmol) in POCl3 (3 mL) was stirred at 90 °C for 1 hour. POCl3 was removed under reduced pressure. The residue was quenched with ice / water and the product was extracted with EtOAc (3×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give 2-chloroquinoline int-19.

[0247]

[0248] A suspension of int-19 (840 mg, 3.16 mmol), int-20 (811 μL, 6.32 mmol), and DIPEA (1.1 mL, 6.32 mmol) in 1-BuOH (10 mL) was heated at 140 °C for 3.5 h under microwave irradiation. The mixture was concentrated under reduced pressure and purified by column chromatography using hexane / EtOAc to obtain int-21.

[0249]

[0250] A mixture of int-21 (370 mg, 1.0 mmol), N,N-dimethylacetamide dimethyl acetal (1.02 mL, 7.0 equivalents), and DIPEA (523 μL, 3.0 mmol) was heated at 125 °C for 20 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was washed with hexane (3×), and the resulting solid was ready for use in the next step without further purification.

[0251] The mixture of the above intermediate (880 mg, 2.0 mmol) and N-methylhydrazine in EtOH (6 mL) was heated at 70 °C for 2 hours. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Imidazole int-22 was obtained.

[0252]

[0253] The mixture of int-22 (180 mg, 0.42 mmol) in 10% H₂SO₄ was stirred at 45 °C for 2 hours. The mixture was alkalized to pH 7 with a saturated aqueous NaHCO₃ solution, and the product was extracted with EtOAc (2×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Product int-23 was obtained and could be used without further purification.

[0254]

[0255] A mixture of int-23 (40 mg, 0.105 mmol), int-24 (20 mg, 0.126 mmol), NaBH(OAc)3 (46 mg, 0.21 mmol), DIPEA (16 μL, 0.126 mmol), and AcOH (12 μL, 0.21 mmol) in 0.6 mL of 1,2-dichloroethane was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 3.

[0256]

[0257] HRMS (ESI-TOF): C 27 H 35 F2N5O[M+H] + Calculated value: 484.2883, measured value: 484.2859.

[0258] Example 4: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (4)

[0259]

[0260] Compound 4 was obtained using the procedure of Example 3 with a suitable amine and int-23. HRMS (ESI-TOF): C 27 H 35 F2N5O[M+H] + Calculated value: 484.2883, measured value: 484.2874.

[0261] Example 5: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)-N-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (5)

[0262]

[0263] Compound 5 was obtained using the procedure of Example 3 with a suitable amine and int-23. HRMS (ESI-TOF): C 27 H 35 F2N5O[M+H] + Calculated value: 484.2883, measured value: 484.2866.

[0264] Example 6: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (6)

[0265]

[0266] Compound 6 was obtained using the procedure of Example 3 with a suitable amine and int-23. HRMS (ESI-TOF): C 27 H 36 FN5O[M+H] + Calculated value: 466.2977, measured value: 466.2954.

[0267] Example 7: 1-(6-ethyl-4-methyl-3,8-bis(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (7)

[0268]

[0269] A mixture of int-3 (80 mg, 0.194 mmol), int-20 (50 μL, 0.39 mmol), and DIPEA (68 μL, 0.39 mmol) was heated at 125 °C for 8 hours under microwave irradiation. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc to give product int-25.

[0270]

[0271] A mixture of int-25 (60 mg, 0.116 mmol), int-26 (36 mg, 0.174 mmol), Pd(dppf)Cl2 (8.5 mg, 0.012 mmol), and K2CO3 (32 mg, 0.23 mmol) in dioxane / H2O (0.8 / 0.2 mL) was purged with nitrogen. The mixture was heated at 120 °C for 2 hours. After cooling to room temperature, the mixture was partitioned between brine (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-27.

[0272]

[0273] The mixture of int-27 (29 mg, 0.061 mmol) in 10% H₂SO₄ was stirred at 45 °C for 1 hour. The mixture was alkalized to pH 7 with a saturated aqueous NaHCO₃ solution, and the product was extracted with EtOAc (2×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Int-28 was obtained and could be used without further purification.

[0274]

[0275] A mixture of int-28 (24 mg, 0.056 mmol), int-24 (10.6 mg, 0.067 mmol), NaBH(OAc)3 (24 mg, 0.112 mmol), DIPEA (11.7 μL, 0.067 mmol), and AcOH (6.5 μL, 0.112 mmol) in 1,2-dichloroethane (0.6 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 7.

[0276] HRMS (ESI-TOF): C 30 H 38 FN7O[M+H] + Calculated value: 532.3195, measured value: 532.3171.

[0277] Example 8: (R)-6-ethyl-4-methyl-3,8-bis(1-methyl-1H-pyrazol-3-yl)-2-(2-methylpiperazin-1-yl)quinoline (8)

[0278]

[0279] A mixture of int-3 (150 mg, 0.36 mmol), int-12 (144 mg, 0.72 mmol), and KF (50 mg, 0.86 mmol) in DMSO (1.0 mL) was heated at 130 °C for 7 hours under microwave (mw) irradiation. The mixture was cooled to room temperature, diluted with EtOAc (60 mL), and washed with brine (3×). The organic phase was dried over Na2SO4, concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-35 was obtained.

[0280]

[0281] A mixture of int-35 (Example 8; 45 mg, 0.078 mmol), int-26 (24 mg, 0.117 mmol), Pd(dppf)Cl2 (5.7 mg, 0.0078 mmol), and K2CO3 (23 mg, 0.164 mmol) in dioxane / H2O (0.8 / 0.2 mL) was purged with nitrogen. The mixture was heated at 120 °C for 1.5 hours. After cooling to room temperature, the mixture was partitioned between brine (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-36.

[0282]

[0283] A mixture of int-36 (30 mg, 0.057 mmol) and TFA (87 μL, 1.13 mmol) in CH2Cl2 (500 μL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH2Cl2 / MeOH to give 8. LCMS: (M+1)m / z = 430.

[0284] Example 9: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline-2-yl)-N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (9)

[0285]

[0286] A mixture of int-25 (100 mg, 0.19 mmol), int-4 (44 mg, 0.21 mmol), Pd(dppf)Cl2 (14 mg, 0.019 mmol), and K2CO3 (53 mg, 0.38 mmol) in dioxane / H2O (0.8 / 0.2 mL) was purged with nitrogen. The mixture was heated at 120 °C for 1.5 h. After cooling to room temperature, the mixture was partitioned between brine (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using CH2Cl2 / MeOH to give int-37.

[0287]

[0288] A mixture of int-37 (78 mg, 0.165 mmol) and 10% H₂SO₄ (4 mL) was stirred at 45 °C for 2 hours. The mixture was alkalized to pH 7 with a saturated aqueous solution of NaHCO₃, and the product was extracted with EtOAc (2×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-38.

[0289]

[0290] A mixture of int-38 (11 mg, 0.025 mmol), int-24 (5.0 mg, 0.031 mmol), NaBH(OAc)3 (11 mg, 0.05 mmol), DIPEA (5.4 μL, 0.031 mmol), and AcOH (3 μL, 0.05 mmol) in 0.4 mL of 1,2-dichloroethane was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 9. LCMS: (M+1)m / z = 532.

[0291] Example 10: (R,E)-N'-cyano-N-ethyl-4-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-3-methylpiperazine-1-carboximidamide (10)

[0292]

[0293] A mixture of int-15 (Example 2; 11 mg, 0.027 mmol), int-39 (7.7 mg, 0.054 mmol), and DIPEA (4.7 μL, 0.027 mmol) in EtOH (0.3 mL) was heated at 130 °C for 29 hours. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH2Cl2 / MeOH to give 10.

[0294]

[0295] Example 11: (R,E)-N'-cyano-4-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)piperazine-1-formamidin

[0296]

[0297] A mixture of int-15 (Example 2; 10 mg, 0.027 mmol), int-40 (10 mg, 0.041 mmol), and DIPEA (4.7 μL, 0.027 mmol) in iPrOH (0.3 mL) was heated at 120 °C for 2 hours. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH2Cl2 / MeOH to give 11. LCMS: (M+1)m / z = 519.

[0298] Example 12: (R)-6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-2-(2-methylpiperazin-1-yl)-8-(1H-pyrazol-3-yl)quinoline

[0299]

[0300] A mixture of int-35 (Example 8; 30 mg, 0.052 mmol), int-41 (15 mg, 0.078 mmol), Pd(dppf)Cl2 (4 mg, 0.005 mmol), and K2CO3 (15 mg, 0.109 mmol) in dioxane / H2O (0.8 / 0.2 mL) was purged with nitrogen. The mixture was heated at 110 °C for 1.5 h. After cooling to room temperature, the mixture was partitioned between brine (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-42 in 89% (24 mg).

[0301]

[0302] A mixture of int-42 (20 mg, 0.038 mmol) and 4.0 M HCl in dioxane (194 μL, 0.78 mmol) in CH2Cl2 (200 μL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH2Cl2 / MeOH to give 12. LCMS: (M+1)m / z = 416.

[0303] Example 13: (R)-6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-2-(2-methylpiperazin-1-yl)quinoline (13)

[0304]

[0305] Compound 13 was prepared using the procedure of Example 2, and it is identical to int-15 shown in the scheme therein. HRMS (ESI-TOF): C 21 H 26 FN5[M+H] + Calculated value: 368.2245, measured value: 368.2231.

[0306] Example 14: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)-N-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (14)

[0307]

[0308] Compound 14 was obtained using the procedure of Example 3 with a suitable amine and int-23. LCMS: (M+1)m / z = 484.

[0309] Example 15: (3S,4R)-1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-3-fluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (15)

[0310]

[0311] Compound 15 was obtained using the procedure of Example 1 with a suitable amine and int-5. LCMS: (M+1)m / z = 532.

[0312] Example 16: (3R,4S)-4-((1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)piperidin-4-yl)amino)tetrahydro-2H-pyran-3-ol (16)

[0313]

[0314] Compound 16 was obtained using the procedure of Example 3 with a suitable amine and int-23. LCMS: (M+1)m / z = 482.

[0315] Example 17: (3S,4R)-4-((1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)piperidin-4-yl)amino)tetrahydro-2H-pyran-3-ol (17)

[0316]

[0317] Compound 17 was obtained using the procedure of Example 3 with a suitable amine and int-23. LCMS: (M+1)m / z = 482.

[0318] Example 18: (S)-1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-(tetrahydrofuran-3-yl)piperidin-4-amine (18)

[0319]

[0320] Compound 18 was obtained using the procedure of Example 3 with a suitable amine and int-23. HRMS (ESI-TOF): C 26 H 34 FN5O[M+H] + Calculated value: 452.2820, measured value: 452.2812.

[0321] Example 19: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinoline-2-yl)-N-((1-fluorocyclopropyl)methyl)piperidin-4-amine (19)

[0322]

[0323] Compound 19 was obtained using the procedure of Example 3 with a suitable amine and int-23. HRMS (ESI-TOF): C 26 H 33 F2N5[M+H] + Calculated value: 454.2777, measured value: 454.2767.

[0324] Example 20: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline-2-yl)-N-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (20)

[0325]

[0326] Compound 20 was obtained using the procedure of Example 9 with a suitable amine and int-38. LCMS: (M+1)m / z = 532.

[0327] Example 21: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline-2-yl)-N-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (21)

[0328]

[0329] Compound 21 was obtained using the procedure of Example 9 with a suitable amine and int-38. LCMS: (M+1)m / z = 532.

[0330] Example 22: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline-2-yl)-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (22)

[0331]

[0332] Compound 22 was obtained using the procedure of Example 9 with a suitable amine and int-38. LCMS: (M+1)m / z = 532.

[0333] Example 23: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline-2-yl)piperidin-4-amine (23)

[0334]

[0335] A mixture of int-5 (10 mg, 0.027 mmol), int-43 (8.2 mg, 0.04 mmol), and DIPEA (9 μL, 0.054 mmol) in n-BuOH (0.5 mL) was heated at 155 °C for 6 hours under microwave irradiation. The mixture was cooled to room temperature, concentrated under reduced pressure, and the product was purified by preparative TLC using hexane / EtOAc. Int-44 was obtained in 77% (11 mg). LCMS: (M+1)m / z = 530.

[0336] A mixture of int-44 (8 mg, 0.015 mmol) and 4.0 M HCl in dioxane (76 μL, 0.3 mmol) in CH₂Cl₂ (100 μL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH₂Cl₂ / MeOH to give compound 23. HRMS (ESI-TOF): C 25 H 31N7[M+H] + Calculated value: 430.2714, measured value: 430.2717.

[0337] Example 24: 2-(2,5-diazabicyclo[4.1.0]heptane-2-yl)-6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline (24)

[0338]

[0339] A mixture of int-5 (15 mg, 0.041 mmol), int-45 (24 mg, 0.123 mmol), and KF (5.7 mg, 0.098 mmol) in DMSO (0.5 mL) was heated at 145 °C for 7 hours under microwave irradiation. The mixture was cooled to room temperature, diluted with EtOAc (40 mL), and washed with brine (3×). The organic phase was dried over Na2SO4, concentrated under reduced pressure, and the product was purified by column chromatography using CH2Cl2 / MeOH. Int-46 was obtained in 41% (9 mg). LCMS: (M+1)m / z = 528.

[0340] A mixture of int-46 (8 mg, 0.015 mmol) and 4.0 M HCl in dioxane (38 μL, 0.152 mmol) in CH₂Cl₂ (150 μL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH₂Cl₂ / MeOH to give compound 24. HRMS (ESI-TOF): C 25 H 29 N7[M+H] + Calculated value: 428.2557, measured value: 428.2551.

[0341] Example 25: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (192)

[0342]

[0343] A mixture of Int-1A (200 mg, 0.66 mmol), Int-2A (172 mg, 0.79 mmol), and DIPEA (345 μL, 1.98 mmol) in iPrOH (345 μL) was heated at 135 °C for 12 hours under microwave irradiation. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-3A was obtained in 71% (230 mg) yield.

[0344]

[0345] A mixture of Int-3A (220 mg, 0.45 mmol) and 4.0 M HCl in dioxane (1.7 mL, 6.79 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, the crude product was dissolved in MeOH, and filtered through a PL-HCO₃ MPa Agilent column, which was then washed with MeOH (3×). The organic phase was concentrated under reduced pressure to give Int-4A in 86% (150 mg) yield, and the product was ready for use without further purification. HRMS (ESI-TOF): C₂₁H₂₅F₂N₅[M+H] + Calculated value: 386.2151, measured value: 386.2164.

[0346] A mixture of Int-4A (50 mg, 0.13 mmol), Int-5A (126 mg, 0.52 mmol), and DIPEA (68 μL, 0.39 mmol) in CH3CN (500 μL) was stirred at 120 °C for 20 h. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 192, in 55% (33 mg) yield. HRMS (ESI-TOF): C25H31F2N5O[M+H] + Calculated value: 456.2570, measured value: 456.2580.

[0347] Example 26: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-fluoro-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (193)

[0348]

[0349] Compound 193 was obtained using the procedure of Example 25 with Int-4A and a suitable toluenesulfonate. HRMS (ESI-TOF): C25H31F2N5O[M+H] + Calculated value: 456.2570, measured value: 456.2580.

[0350] Example 27: (3R,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (194)

[0351]

[0352] A mixture of Int-1A (100 mg, 0.33 mmol), Int-6A (85 mg, 0.39 mmol), and DIPEA (172 μL, 0.99 mmol) in 1-BuOH (345 μL) was heated at 150 °C for 9 hours under microwave irradiation. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-7A was obtained in 70% (112 mg) yield.

[0353]

[0354] A mixture of Int-7A (100 mg, 0.2 mmol) and 4.0 M HCl in dioxane (0.77 mL, 3.08 mmol) in CH₂Cl₂ (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the crude product was dissolved in MeOH and filtered through a PL-HCO₃ MPa Agilent column. The column was washed with MeOH (3×). The organic phase was concentrated under reduced pressure to give Int-8A in 90% (71 mg) yield. The product was ready for use without further purification. HRMS (ESI-TOF): C₂₁H₂₅F₂N₅[M+H] + Calculated value: 386.2151, measured value: 386.2150.

[0355] A mixture of Int-8A (20 mg, 0.052 mmol), Int-5A (25 mg, 0.103 mmol), and DIPEA (27 μL, 0.156 mmol) in CH3CN (500 μL) was stirred at 150 °C for 5 hours. The mixture was filtered through a PL-HCO3 MPagilent column and washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 194, in 50% (12 mg) yield. HRMS (ESI-TOF): C25H31F2N5O[M+H] + Calculated value: 456.2570, measured value: 456.2579.

[0356] Example 28: (3S,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (195)

[0357]

[0358] Compound 195 was obtained using a suitable chiral amine and toluenesulfonate, following the procedure used for the synthesis of 192. HRMS (ESI-TOF): C25H31F2N5O[M+H + Calculated value: 456.2570, measured value: 456.2582.

[0359] Example 29: (3R,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (196)

[0360]

[0361] Compound 196 was obtained using a suitable chiral amine and toluenesulfonate, following the procedure used for the synthesis of 192. HRMS (ESI-TOF): C25H31F2N5O[M+H + Calculated value: 456.2570, measured value: 456.2587.

[0362] Example 30: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisocyanate) (197) azir-5-yl)quinoline-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine

[0363]

[0364] A mixture of Int-9A (1.0 g, 4.58 mmol), Int-5A (2.2 g, 9.16 mmol), and DIPEA (2.4 mL, 13.74 mmol) in CH3CN (10 mL) was stirred at 120 °C for 20 h under microwave irradiation. The mixture was filtered through a PL-HCO3 MPagilent column, and the column was washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography using CH2Cl2 / MeOH to give int-10 in 69% (915 mg).

[0365]

[0366] A mixture of int-10A (940 mg, 3.26 mmol) and 4.0 M HCl in dioxane (12 mL, 48.9 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, the product was dissolved in MeOH and filtered through a PL-HCO₃ MPa Agilent column. The column was washed with MeOH (4×) and the organic phase was concentrated under reduced pressure. Int-11A was given in 94% (580 mg) yield, and the product was ready for use without further purification. HRMS (ESI-TOF): C₁₇FN₂O[M+H] + Calculated value: 189.1398, measured value: 189.1399.

[0367] A mixture of Int-12A (15 mg, 0.05 mmol), Int-11A (19 mg, 0.1 mmol), and DIPEA (9 μL, 0.05 mmol) in iPrOH (500 μL) was heated at 140 °C for 14 h under microwave irradiation. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CH2Cl2 / MeOH. 197 mg was obtained in 52% (11.9 mg) HRMS (ESI-TOF): C25H30F2N4O2[M+H] + Calculated value: 457.2410, measured value: 457.2420.

[0368] Example 31: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisocyanate) (198)-Azol-5-yl)quinoline-2-yl)-3-fluoro-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine

[0369]

[0370] A mixture of Int-9A (500 mg, 2.29 mmol), Int-13A (1.11 g, 4.58 mmol), and DIPEA (1.2 mL, 6.87 mmol) in CH3CN (10 mL) was stirred at 120 °C for 24 hours under microwave irradiation. The mixture was filtered through a PL-HCO3 MPa Gilent column, and the column was washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography using CH2Cl2 / MeOH to give Int-14A in a yield of 74% (490 mg).

[0371]

[0372] A mixture of Int-14A (29 mg, 0.1 mmol) and 4.0 M HCl in dioxane (0.38 mL, 1.5 mmol) in CH₂Cl₂ (300 μL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the salt was ready for use without further purification. HRMS (ESI-TOF): C₁₇FN₂O[M+H] + Calculated value: 189.1398, Measured value: 189.1404. A mixture of Int-12A (15 mg, 0.05 mmol), Int-15A and DIPEA (52 μL, 0.3 mmol) in 1-BuOH (500 μL) was heated at 140 °C for 14 h under microwave irradiation. The mixture was filtered through a PL-HCO3 MPa Gilent column and the column was washed with MeOH (3×). The organic phase was concentrated under reduced pressure and the product was purified by preparative TLC using CH2Cl2 / MeOH. 198 was obtained, with a yield of 26% (two steps, 6.1 mg). HRMS (ESI-TOF): C25H30F2N4O2[M+H] + Calculated value: 457.2410, measured value: 457.2408.

[0373] Example 32: (3S,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisocyanate) (208)-Azol-5-yl)quinoline-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine

[0374]

[0375] A mixture of Int-12A (50 mg, 0.164 mmol), Int-16A (50 mg, 0.23 mmol), and DIPEA (86 μL, 0.492 mmol) in 1-BuOH (500 μL) was heated at 150 °C for 9 hours under microwave irradiation. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-17A was obtained in 43% (21 mg) yield.

[0376] LCMS:HRMS(ESI-TOF):C26H32F2N4O3[M+H] + Calculated value: 487.2515, measured value: 487.2513.

[0377] A mixture of Int-17A (15 mg, 0.03 mmol) and 4.0 M HCl in dioxane (115 μL, 0.46 mmol) in CH₂Cl₂ (200 μL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the product was ready for use without further purification. HRMS (ESI-TOF): C₂₁H₂₄F₂N₄O[M+H] + Calculated value: 387.1991, measured value: 387.1995.

[0378] A mixture of Int-18A (10 mg, 0.023 mmol), Int-5A (11.5 mg, 0.047 mmol), and DIPEA (16 μL, 0.092 mmol) in CH3CN (300 μL) was stirred at 120 °C for 15 h. The mixture was filtered through a PL-HCO3 MPagilent column, and the column was washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 208, in a yield of 20% (2.1 mg). HRMS (ESI-TOF): C25H30F2N4O2[M+H] + Calculated value: 457.2410, measured value: 457.2410.

[0379] Example 33: ((R)-4,4-difluoro-1-methylpiperidin-2-yl)((R)-4-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-) (diazol-5-yl)quinoline-2-yl)-3-methylpiperazin-1-yl)methyl ketone (205)

[0380]

[0381] A mixture of Int-19A (25 mg, 0.062 mmol), Int-20A (18 mg, 0.067 mmol), EDCI (24 mg, 0.124 mmol), HOBt (17 mg, 0.124 mmol), and DIPEA (22 μL, 0.124 mmol) in CH₂Cl₂ was stirred overnight at room temperature. The mixture was transferred to a separatory funnel using EtOAc and washed with brine (2×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-21A in 95% (36 mg). HRMS (ESI-TOF): C₃₁H₃₉F₃N₆O₄[M+H] + Calculated value: 617.3058, measured value: 617.3065.

[0382] A mixture of Int-21A (30 mg, 0.048 mmol) and 4 M HCl in dioxane (182 μL, 0.729 mmol) in CH₂Cl₂ (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, the solid was dissolved in MeOH, filtered through a PL-HCO₃ MPa Agilent column, and washed with MeOH (3×). The organic phase was concentrated under reduced pressure, and the product was purified by preparative TLC using CH₂Cl₂ / MeOH to give 200, in a yield of 76% (19 mg). HRMS (ESI-TOF): C₂₆H₃₁F₃N₆O₂[M+H] + Calculated value: 517.2533, measured value: 517.2533.

[0383] A mixture of 200 (15 mg, 0.029 mmol), 37% aqueous formaldehyde solution (7 μL, 0.087 mmol), NaBH(OAc)3 (11.5 mg, 0.054 mmol), and AcOH (3.1 μL, 0.054 mmol) in 0.3 mL of 1,2-dichloroethane was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 205, in 52% (8 mg) yield. HRMS (ESI-TOF): C27H33F3N6O2[M+H] + Calculated value: 531.2690, measured value: 531.2679.

[0384] Example 34: (R)-5-(6-ethyl-8-fluoro-2-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-2-methylpiperazin-1-yl)-4-methylquinoline-3-yl)-3-methyl-1,2,4- diazole (207)

[0385]

[0386] A mixture of Int-19A (26 mg, 0.06 mmol), Int-22A (15 mg, 0.13 mmol), and DIPEA (42 μL, 0.24 mmol) in iPrOH (300 μL) was stirred overnight at 105 °C. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH) to 206, in 82% (24 mg) yield. HRMS (ESI-TOF): C26H34FN5O3[M+H] + Calculated value: 484.2719, measured value: 484.2714.

[0387] A mixture of 206 (10 mg, 0.02 mmol) and DAST (3.7 mg, 0.022 mmol) in CH2Cl2 was stirred at room temperature for 3 hours. The mixture was quenched with 5% sodium bicarbonate aqueous solution, and the product was extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude substance was purified by column chromatography using hexane / EtOAc to give 207 in 32% (3.1 mg) yield. HRMS (ESI-TOF): C26H33F2N5O2[M+H] + Calculated value: 486.2675, measured value: 486.2686.

[0388] Example 35: (2R,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (115)

[0389]

[0390] A mixture of Int-23 (50 mg, 0.14 mmol), Int-24 (60 mg, 2.0 mmol), and KF (20 mg, 0.336 mmol) in DMSO was heated at 130 °C for 10 hours under microwave irradiation. The mixture was diluted with EtOAc (30 mL) and washed with brine (2×). The organic phase was dried over Na2SO4, concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-25 was obtained in a yield of 49% (37 mg).

[0391]

[0392] Et3B (1M in THF) (282 μL, 0.282 mmol) was added to a mixture of Int-25 (50 mg, 0.094 mmol), K2CO3 (25.9 mg, 0.188 mmol), and Pd(PPh3)4 (5.4 mg, 0.005 mmol) in THF (0.5 mL). The reaction was heated at 50 °C for 1 hour. The mixture was diluted with EtOAc and washed with brine (2×). The organic phase was dried over Na2SO4, concentrated under reduced pressure, and the product was purified by column chromatography using CH2Cl2 / EtOAc to give Int-26 in 58% (26 mg). HRMS (ESI-TOF): C 27 H 36 FN5O2[M+H] + Calculated value: 482.2926, measured value: 482.2927.

[0393] HCl (4M dioxane) (1.44 mL, 5.76 mmol) was slowly added to a solution of Int-26 (185 mg, 0.384 mmol) in CH2Cl2 (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure. The crude product was dissolved in MeOH and filtered through a PL-HCO3 MPa Gilent column, and the column was washed with MeOH (3×). The organic phase was concentrated under reduced pressure to give Int-27 in 75% (110 mg) yield. The product was ready for use without further purification. HRMS (ESI-TOF): C 22 H 28 FN5[M+H] + Calculated value: 382.2402, measured value: 382.2403.

[0394] A mixture of Int-27 (110 mg, 0.288 mmol), Int-5 (209.6 mg, 0.865 mmol), and DIPEA (151 μL, 0.865 mmol) in CH3CN (2 mL) was stirred at 110 °C for 12 h under microwave irradiation. The mixture was filtered through a PL-HCO3 MPa Agilent column and washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography using CH2Cl2 / MeOH to give 115 in 58% (75 mg) yield. HRMS (ESI-TOF): C 26 H 34 FN5O[M+H] + Calculated value: 452.2820, measured value: 452.2825.

[0395] Example 36: 1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-N-((3R,4R)-4-fluorotetrahydrofuran-3-yl)piperidin-4-amine (71)

[0396]

[0397] A mixture of (1-methyl-1H-pyrazol-3-yl)acetic acid int-2 (386 mg, 2.76 mmol) and int-17 (500 mg, 2.76 mmol) in POCl3 (5 mL) was stirred at 95 °C for 1 hour. POCl3 was removed under reduced pressure. The residue was quenched with ice / water and alkalized to pH approximately 7 with a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give 2-chloroquinoline int-45a (420 mg, 50% yield) as a pale brown solid.

[0398]

[0399] A mixture of int-45a (80 mg, 0.26 mmol), int-20 (75 mg, 0.527 mmol), and DIPEA (92 μL, 0.12 mmol) in 1-BuOH (2 mL) was heated at 160 °C for 4 hours under microwave irradiation. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-46a was obtained in 66% (71 mg).

[0400]

[0401] A mixture of int-46a (60 mg, 0.146 mmol), 10% H₂SO₄ (1 mL), and THF (1 mL) was stirred at 40 °C for 2 hours. The mixture was alkalized to pH 7.5 with a saturated aqueous NaHCO₃ solution, and the product was extracted with EtOAc (2×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was obtained in 88% (47 mg) yield and was ready for use without further purification.

[0402]

[0403] A mixture of int-47 (10 mg, 0.027 mmol), int-48 (4.7 mg, 0.033 mmol), NaBH(OAc)3 (11.5 mg, 0.05 mmol), DIPEA (5.7 μL, 0.033 mmol), and AcOH (3 μL, 0.05 mmol) in 1,2-dichloroethane (0.4 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 71 in 80% (9.9 mg) yield. HRMS (ESI-TOF): C25H31F2N5O[M+H] + Calculated value: 456.2570, measured value: 456.2557.

[0404] Example 37: 1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)piperidin-4-amine (72)

[0405]

[0406] Compound 72 was obtained using a suitable chiral amine and ketone, int-47, following the procedure used for the synthesis of 71. HRMS (ESI-TOF), C25H31F2N5O[M+H + Calculated value: 456.2570, measured value: 456.2550.

[0407] Example 38: (S)-N-(3,3-difluorocyclohexyl)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)piperidin-4-amine (73)

[0408]

[0409] Compound 73 was obtained using a suitable chiral amine and ketone int-47, following the procedure used for the synthesis of 71. HRMS (ESI-TOF): C27H34F3N5[M+H + Calculated value: 486.2839, measured value: 486.2836.

[0410] Example 39: (R)-1-(4-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-) (diazol-5-yl)quinoline-2-yl)-3-methylpiperazin-1-yl)-2-(pyrrolidone-1-yl)ethane-1-one (47)

[0411]

[0412] A mixture of Int-1b (350 mg, 1.14 mmol), Int-2b (458 mg, 2.29 mmol), and KF (200 mg, 3.42 mmol) in anhydrous DMF was heated overnight at 140 °C. The mixture was transferred to a separatory funnel using EtOAc (100 mL) and washed with brine (3×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-3 in 46% (247 mg) yield.

[0413]

[0414] A mixture of Int-3b (130 mg, 0.28 mmol) and 4 M HCl in dioxane (715 μL, 5.6 mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and Int-4b was ready for use without further purification. HRMS (ESI-TOF): C₂₀H₂₄FN₅O[M+H] + Calculated value: 370.2038, measured value: 370.2042.

[0415] [87-19] A mixture of Int-4b (25 mg, 0.062 mmol), Int-5b (16 mg, 0.124 mmol), EDCI (24 mg, 0.124 mmol), HOBt (17 mg, 0.124 mmol), and DIPEA (22 μL, 0.124 mmol) in CH2Cl2 was stirred at room temperature for 3 hours. The mixture was transferred to a separatory funnel using EtOAc and washed with brine (2×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using CH2Cl2 / MeOH to give 47, in 70% (21 mg) yield.

[0416] HRMS(ESI-TOF):C26H33FN6O2[M+H] + Calculated value: 481.2722, measured value: 481.2721.

[0417] Example 40: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (49)

[0418]

[0419] A mixture of Int-4b (25 mg, 0.062 mmol), Int-6b (9 mg, 0.08 mmol), NaBH(OAc)3 (39 mg, 0.186 mmol), DIPEA (21.6 μL, 0.124 mmol), and AcOH (10.6 μL, 0.186 mmol) in 0.5 mL of 1,2-dichloroethane was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to 49 mg, 89% (26 mg). HRMS (ESI-TOF): C26H36FN5O2[M+H] + Calculated value: 468.2769, measured value: 468.2758.

[0420] Example 41: (R)-5-(2-(4-((3,3-difluorocyclobutyl)methyl)-2-methylpiperazin-1-yl)-6-ethyl-8-fluoro-4-methylquinoline-3-yl)-3-methyl-1,2,4- diazole (59)

[0421]

[0422] A mixture of Int-4b (10 mg, 0.024 mmol), Int-7b (8.2 mg, 0.03 mmol), and DIPEA (12.6 μL, 0.072 mmol) in CH3CN (200 μL) was stirred at 60 °C for 28 hours. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to 59 g, in a yield of 62% (7.1 mg). HRMS (ESI-TOF): C25H30F3N5O[M+H] + Calculated value: 474.2475, measured value: 474.2478.

[0423] Example 42: 5-(6-ethyl-8-fluoro-4-methyl-2-((2R)-2-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (199)

[0424]

[0425] A mixture of Int-4 (12 mg, 0.029 mmol), Int-8 (17 mg, 0.059 mmol), and DIPEA (10.3 μL, 0.072 mmol) in CH3CN (500 μL) was stirred at 110 °C for 7 hours under microwave irradiation. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give CYM-3252 in 28% (4 mg) yield. HRMS (ESI-TOF): C27H36FN5O2[M+H] + Calculated value: 482.2926, measured value: 482.2921.

[0426] Example 43: (R)-5-(6-chloro-8-fluoro-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (50)

[0427]

[0428] A mixture of Int-13b (8 mg, 0.26 mmol), Int-14b (15 mg, 0.77 mmol), and KF (3.7 mg, 0.64 mmol) in anhydrous DMSO was stirred at 125 °C for 6 hours under microwave irradiation. The mixture was transferred to a separatory funnel using EtOAc (30 mL) and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC using CH₂Cl₂ / MeOH to give cpd-5 in 27% (3.2 mg) yield. LCMS: (M+1)m / z = 474.

[0429] Example 44: (R)-5-(8-chloro-4,6-dimethyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (51)

[0430]

[0431] A mixture of Int-15b (8 mg, 0.26 mmol), Int-14b (15 mg, 0.77 mmol), and KF (3.7 mg, 0.64 mmol) in anhydrous DMSO was stirred at 125 °C for 6 hours under microwave irradiation. The mixture was transferred to a separatory funnel using EtOAc (30 mL) and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC using CH₂Cl₂ / MeOH to give 51, in a yield of 23% (2.8 mg). LCMS: (M+1)m / z = 470.

[0432] Example 45: (R)-5-(8-fluoro-6-methoxy-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (37)

[0433]

[0434] A mixture of Int-16b (100 mg, 0.28 mmol), Int-2b (112 mg, 0.56 mmol), and KF (39 mg, 0.67 mmol) in anhydrous DMF was stirred at 140 °C for 4 hours under microwave irradiation. The mixture was transferred to a separatory funnel using EtOAc (50 mL) and washed with brine (3×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-17b in 69% (100 mg) yield.

[0435]

[0436] A mixture of Int-17b (100 mg, 0.172 mmol), sodium tetramethoxyborate (91 mg, 0.576 mmol), Pd2(dba)3 (9 mg, 0.009 mmol), and tBuXPhos (8 mg, 0.192 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated at 120 °C for 2 hours. The mixture was transferred to a separatory funnel using EtOAc (50 mL) and washed with brine (3×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-18 in a yield of 16% (15 mg). LCMS: (M+1)m / z = 472.

[0437] A mixture of Int-18b (9 mg, 0.019 mmol) and TFA (29 μL, 0.38 mmol) in CH₂Cl₂ (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the product was ready for use without further purification. LCMS: (M+1)m / z = 372.

[0438] The intermediates Int-6b (4.3 mg, 0.038 mmol), NaBH(OAc)3 (8 mg, 0.038 mmol), DIPEA (2.5 μL, 0.019 mmol), and AcOH (2.1 μL, 0.038 mmol) obtained above were stirred overnight at room temperature in 0.4 mL of 1,2-dichloroethane. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using CH2Cl2 / MeOH to give 37 mg / mL, 32% (2.9 mg) in two steps. LCMS: (M+1)m / z = 470.

[0439] Example 46: (R)-5-(6-ethyl-2-(2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-8-fluoro-4-methylquinoline-3-yl)-3-methyl-1,2,4- diazole (34)

[0440]

[0441] A mixture of Int-1b (100 mg, 0.327 mmol), Int-19b (105 mg, 0.49 mmol), and KF (46 mg, 0.784 mmol) in anhydrous DMF was stirred overnight at 140 °C. The mixture was transferred to a separatory funnel using EtOAc (50 mL) and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-20b in 19% (30 mg) yield. LCMS: (M+1)m / z = 484.

[0442] A mixture of Int-20b (30 mg, 0.062 mmol) and TFA (95 μL, 1.24 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the product was ready for use without further purification. LCMS: (M+1)m / z = 384.

[0443] A mixture of Int-21b (8 mg, 0.016 mmol), Int-6b (3.7 mg, 0.032 mmol), NaBH(OAc)3 (6.8 mg, 0.032 mmol), DIPEA (2.8 μL, 0.016 mmol), and AcOH (1.8 μL, 0.032 mmol) in 1,2-dichloroethane (0.3 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using CH2Cl2 / MeOH to give 34, in 64% (5.0 mg) yield (two steps). LCMS: (M+1)m / z = 482.

[0444] Example 47: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (26) and (S)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (27)

[0445]

[0446] A mixture of Int-1b (15 mg, 0.049 mmol), Int-22b or Int-23b (22 mg, 0.059 mmol), and KF (6 mg, 0.098 mmol) in anhydrous DMF was stirred at 140 °C for 5 hours. The mixture was transferred to a separatory funnel using EtOAc (30 mL) and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC using CH₂Cl₂ / MeOH. Compound 26 was given in 12% (2.7 mg). LCMS: (M+1)m / z = 454. Compound 27 was given in 6% (1.4 mg). LCMS: (M+1)m / z = 454.

[0447] Example 48: (S)-5-(6-ethyl-8-fluoro-4-methyl-2-(3-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (38)

[0448]

[0449] A mixture of Int-1b (75 mg, 0.245 mmol), Int-24b (60 mg, 0.294 mmol), DIPEA (86 μL, 0.49 mmol), and KF (36 mg, 0.613 mmol) in anhydrous DMF was stirred at 140 °C for 8 hours. The mixture was transferred to a separatory funnel using EtOAc (40 mL) and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in 15% (18 mg) yield. LCMS: (M+1)m / z = 470.

[0450] A mixture of Int-25b (18 mg, 0.038 mmol) and TFA (60 μL, 0.76 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the product was ready for use without further purification. LCMS: (M+1)m / z = 370.

[0451] A mixture of Int-26b (21.5 mg, 0.038 mmol), Int-6b (5.2 mg, 0.0456 mmol), NaBH(OAc)3 (24 mg, 0.114 mmol), DIPEA (13 μL, 0.076 mmol), and AcOH (6.5 μL, 0.114 mmol) in 1,2-dichloroethane (0.4 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using CH2Cl2 / MeOH to give 38, in 84% (15 mg) yield. LCMS: (M+1)m / z = 468.

[0452] Example 49: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(3-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyl-1,2,4- diazole (39)

[0453]

[0454] A mixture of Int-1b (75 mg, 0.245 mmol), Int-24b (60 mg, 0.294 mmol), DIPEA (86 μL, 0.49 mmol), and KF (36 mg, 0.613 mmol) in anhydrous DMF was stirred at 140 °C for 8 hours. The mixture was transferred to a separatory funnel using EtOAc (40 mL) and washed with brine (3×). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in 10% (12 mg) yield. LCMS: (M+1)m / z = 470.

[0455] A mixture of Int-28b (12 mg, 0.025 mmol) and TFA (40 μL, 0.511 mmol) in CH2Cl2 (0.4 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the product was ready for use without further purification. LCMS: (M+1)m / z = 370.

[0456] A mixture of Int-29b (12.0 mg, 0.025 mmol), Int-6b (3.4 mg, 0.03 mmol), NaBH(OAc)3 (16 mg, 0.075 mmol), DIPEA (9 μL, 0.05 mmol), and AcOH (4.3 μL, 0.075 mmol) in 1,2-dichloroethane (0.4 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using CH2Cl2 / MeOH to give 39, in 95% (11.1 mg) yield. LCMS: (M+1)m / z = 468.

[0457] Example 50: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinoline-3-yl)-3-methyliso Azole (63)

[0458]

[0459] A mixture of Int-9b (187 mg, 1.32 mmol) and Int-8b (200 mg, 1.1 mmol) in POCl3 (2 mL) was stirred at 100 °C for 1 hour. POCl3 was removed under reduced pressure. The residue was quenched with ice / water and alkalized to approximately pH 7 with a saturated aqueous solution of NaHCO3. The product was extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc to give Int-10b in a yield of 38% (130 mg).

[0460]

[0461] A mixture of Int-10b (65 mg, 0.213 mmol), Int-2b (86 mg, 0.427 mmol), and CsF (78 mg, 0.51 mmol) in anhydrous DMSO was stirred at 130 °C for 3 hours under microwave irradiation. The mixture was transferred to a separatory funnel using EtOAc (100 mL) and washed with brine (4×). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-11b in a yield of 16% (16.2 mg).

[0462]

[0463] A mixture of Int-11b (15 mg, 0.032 mmol) and 4 M HCl in dioxane (40 μL, 0.16 mmol) in CH₂Cl₂ (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and Int-12b was ready for use without further purification. LCMS: (M+1)m / z = 369.

[0464] A mixture of Int-12b (15 mg, 0.037 mmol), Int-6b (5 mg, 0.041 mmol), NaBH(OAc)3 (16 mg, 0.074 mmol), DIPEA (6.5 μL, 0.037 mmol), and AcOH (4.2 μL, 0.074 mmol) in 0.5 mL of 1,2-dichloroethane was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using CH2Cl2 / MeOH to give 50 mg in 81% (14 mg) yield. HRMS (ESI-TOF): C27H35FN4O2[M+H] + Calculated value: 467.2817, measured value: 467.2831.

[0465] Bioactivity

[0466] General methods and materials

[0467] OPRKappa 1 Tango B-Repressor Protein Assay Protocol - Antagonist Mode. The purpose of this assay is to confirm the potency of the compounds of this invention as OPRK1 antagonists. The assay uses Tango OPRK1-bla U2OS cells that express OPRK1 linked to the GAL4-VP16 transcription factor via a TEV protease site. These cells also express a β-repressor / TEV protease fusion protein and a β-lactamase (BLA) reporter gene under the control of the UAS response element. Stimulation of the OPRK1 receptor by an agonist leads to the migration of the β-repressor fusion protein to the GPCR, and the release of GAL4-VP16 from the receptor via proteolysis. The released VP16-GAL4 migrates to the nucleus, where it induces transcription of the BLA gene. BLA expression is monitored by measuring the fluorescence resonance energy transfer (FRET) of cleavable, fluorescent, cell-permeable BLA substrates. As designed, the test compound, acting as an OPRK1 antagonist, inhibits agonist activation and migration of the fusion protein, thereby preventing GAL4-VP16 proteolysis and BLA transcription, resulting in no improvement in pore FRET. The test compound was administered in quadruplicate using a 10-point, 1:3 dilution series starting at a nominal concentration of 10 μmol.

[0468] Tango OPRK1-U20S cell lines were routinely cultured in 150 mm culture dishes at 37°C, 5% CO2, and 95% relative humidity. The growth medium consisted of McCoys 5A medium supplemented with 10% v / v dialyzable fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin and streptomycin).

[0469] On day 1 of the assay, 16,000 cells were seeded in 10 μL of assay medium (DMEM-Glutamax—containing sodium pyruvate, 10% fetal bovine serum deprived by activated charcoal-dextran (CDS), 25 mM HEPES, 0.1 mM non-essential amino acids, and an antibiotic mixture (penicillin-streptomycin)) into each well of a 384 Greiner 788092 black low-profile, clear-bottom, low-volume plate and incubated at 37°C, 5% CO2, and 95% (RH) for 16 to 24 hours.

[0470] On day 2, 50 nL of the test compound in DMSO was added to the appropriate wells, and the plate was incubated at 37 °C, 5% CO2, and 95% (RH) for 30 minutes. Next, 0.65 μL of commercially available U50488 OPRK1 agonist or DMSO in the assay medium was added: this EC80 challenge consisted of 0.6 μL of 111 nM U50488 to produce a final assay concentration of 6 nM. After incubation at 37 °C, 5% CO2, and 95% (RH) for 4 hours, 2.5 μL of LiveBLazer was added. TM A mixture of FRETB / G (CCF4-AM) solutions (solutions A, B, C, and D) was added to each well and incubated in the dark at room temperature for 2 hours. Fluorescence in each well was measured using an excitation filter at 409 nm, 460 nm, and 590 nm, with bottom readout, on a Perkin Elmer Envision.

[0471] The percentage of inhibition is calculated from the median ratio as follows:

[0472]

[0473] in:

[0474] The test compound is defined as a pore containing the test compound;

[0475] Low control was defined as 0% inhibition in pores containing U50488 excitation (6 nM final); and

[0476] High control is defined as well containing DMSO = 100% inhibition.

[0477] Reagent list:

[0478] Tango TM OPRK1-bla U20S cells (Invitrogen K1576)

[0479] McCoy 5A medium (Invitrogen 16600-082)

[0480] Dialysis-grade fetal bovine serum (Invitrogen 26400-036)

[0481] Non-essential amino acids 100× (Invitrogen part 11140-050)

[0482] HEPES (pH 7.3) 1M, (Invitrogen 15630-080)

[0483] Sodium pyruvate 100× (Invitrogen 11360-070)

[0484] Penicillin and streptomycin (Invitrogen 15640)

[0485] Trypsin 0.25% EDTA (Invitrogen 25200056)

[0486] Calcium / magnesium-free DPBS (Invitrogen 14190-136)

[0487] DMEM, high glucose, GlutaMAX (Invitrogen 10569-010)

[0488] Fetal bovine serum, deprived by activated charcoal (Invitrogen 12676-011)

[0489] Anhydrous DMSO (Sigma D2650)

[0490] U50488 OPRK1 agonist MW410.29 (Tocris 67198-19-0)

[0491] GNTI dihydrochloride OPRK1 antagonist MW571.5 (Tocris 1282)

[0492] Nor-Binaltorphimine dihydrochloride MW770.75 (Tocris 0347)

[0493] LiveBLAzer TM -FRET / BG spiking mixture: (Invitrogen K1030 (5 mg)), consisting of solutions A, B, C, and D:

[0494] Solution A (6μL): LiveBLAzer TM -FRET / BG substrate (CCF4-AM)

[0495] Solution B (60 μL)

[0496] Solution C (904 μL)

[0497] Solution C (250 μL of 1N NaOH must be added to 45 mL of Solution C before use)

[0498] A 200 mM stock solution was prepared from solution D (30 μL) [Probinicid] (Sigma P8161) in NaOH-H2O.

[0499] OPRMu1 Discover X-β-Repressor Protein Assay - Antagonist Mode. The purpose of this assay is to determine the potency and specificity of compounds synthesized as OPRK1 antagonists. This assay evaluates the activation of OPRMu1 in the membrane recruitment of β-repressor proteins. Additionally, the assay uses low-affinity fragment complementation of β-galactosidase (β-gal) to evaluate the accessibility of GPCR-β-repressor proteins. The assay uses U20S cells expressing OPRMu1 fused to the complementary β-gal fragment (enzyme receptor). As designed, compounds used as antagonists will prevent receptor activation, resulting in reduced pore luminescence. Test compounds are applied in quadruplicate using a 10-point, 1:3 dilution series starting at a nominal concentration of 10 μmol.

[0500] The Discover X OPRMu1-U20S cell line was cultured in 150 mm culture dishes at 37°C, 5% CO2, and 95% relative humidity (RH). The growth medium consisted of DMEM / F12 1:1 medium supplemented with 10% (v / v) heat-inactivated fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin and streptomycin).

[0501] On day 1 of the assay, 5000 cells in 20 μL assay buffer (Discover X Cell Plate Seeding Reagent 5) were seeded into each well of a Corning 3570 standard white plate and incubated at 37°C, 5% CO2 and 95% RH for 16 to 24 hours.

[0502] On day 2, 100 nmol of the test compound in DMSO was added to the appropriate wells, and the plate was then incubated at 37 °C, 5% CO2, and 95% RH for 30 minutes. Next, 2.2 μL of DAMGO OPRMu1 agonist (commercially available) or DMSO in the assay medium was added. (EC80 excitation consisted of 1.8 μL of 3.7 μM DAMGO and 0.4 μL of assay buffer, resulting in a final assay concentration of 303 nM). After incubation at 37 °C, 5% CO2, and 95% RH for 3 hours, 10 μL of the Path Hunter assay mixture was added to each well, and the plate was then incubated in the dark at room temperature for 1 hour. The luminescence of the wells was measured on a Perkin Elmer Envision.

[0503] The percentage of inhibition is calculated from the median ratio as follows:

[0504]

[0505] in:

[0506] The test compound is defined as a pore containing the test compound;

[0507] Low control was defined as well containing DAMGO excitation (200 nM final) = 0% inhibition; and

[0508] High control is defined as well containing DMSO = 100% inhibition.

[0509] Reagent list:

[0510] DMEM medium (Invitrogen 11965)

[0511] F12 medium (Invitrogen 11765)

[0512] Heat-inactivated fetal bovine serum (Invitrogen 10082147)

[0513] 100× Non-essential amino acids (Invitrogen 11140-050)

[0514] HEPES (pH 7.3) 1M, (Invitrogen 15630-080)

[0515] Sodium pyruvate 100× (Invitrogen 11360-070)

[0516] Penicillin and streptomycin (Invitrogen 15640)

[0517] Trypsin 0.25% EDTA (Invitrogen 25200056)

[0518] Calcium / magnesium-free DPBS (Invitrogen 14190-136)

[0519] Anhydrous DMSO (Sigma D2650)

[0520] DAMGO OPRMu1 agonist MW513.19 (Sigma E7384-5MG)

[0521] β-Funaltrexamine hydrochloride OPRM1 antagonist MW (SIGMA O003-2MG)

[0522] PathHunter cell plate seeding reagent 5 (Discover X 93-0563R5A)

[0523] Corning 3750 standard 384-hole white plate with cover.

[0524] PathHunter assay mixture (DiscoverX 93-0001): 1 part Galacton Star / 5 parts Emerald II / 19 parts pH CellAssay Buffer.

[0525] OPRDelta 1 Tango B-Inhibitor Protein Assay Protocol - Antagonist Mode. Tango OPRDelta1-U20S dividing cell lines were cultured in 150 mm culture dishes at 37°C, 5% CO2, and 95% relative humidity (RH). The growth medium consisted of McCoys 5A medium supplemented with 10% (v / v) dialyzable fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin-streptomycin).

[0526] On day 1 of the assay, 16,000 cells were seeded in 10 μL of assay medium (DMEM-Glutamax—containing sodium pyruvate, 10% fetal bovine serum deprived by activated charcoal-dextran (CDS), 25 mM HEPES, 0.1 mM non-essential amino acids, and an antibiotic mixture (penicillin-streptomycin)) into each well of a 384 Greiner 788092 black low-profile, clear-bottom, low-volume plate. 50 nL of the test compound in DMSO was added to the appropriate wells, and the plate was then incubated at 37 °C, 5% CO2, and 95% RH for 30 min. Next, 1.1 μL of SNC80 OPRD1 agonist (commercially available) or DMSO (EC80 activation consists of 1.1 μL of 3.7 μM SNC80, final assay concentration = 370 nM) in the assay medium was added to the appropriate wells and incubated at 37 °C, 5% CO2 and 95% RH for 16 to 24 hours.

[0527] On the second day, 2.5 μL of LiveBLAzer was added. TM A mixture of FRET B / G (CCF4-AM) solutions (solutions A, B, C, and D) was added to each well, and the plate was subsequently incubated in the dark at room temperature for 2 hours. Fluorescence in the wells was measured using an Envision instrument with excitation filters at 405 nm, 460 nm, and 590 nm, and bottom readout.

[0528] The percentage of inhibition is calculated from the median ratio as follows:

[0529]

[0530] in:

[0531] The test compound is defined as a pore containing the test compound;

[0532] Low control was defined as wells containing SNC80 excitation (370 nM final) = 0% inhibition; and

[0533] High control is defined as well containing DMSO = 100% inhibition.

[0534] Reagent list:

[0535] Tango TM OPRD1-bla U20S(Invitrogen K1778)

[0536] McCoy 5A medium (Invitrogen 16600-082)

[0537] Dialysis-grade fetal bovine serum (Invitrogen 26400-036)

[0538] 100× Non-essential amino acids (Invitrogen 11140-050)

[0539] HEPES (pH 7.3) 1M, (Invitrogen 15630-080)

[0540] Sodium pyruvate 100× (Invitrogen 11360-070)

[0541] Penicillin and streptomycin (Invitrogen 15640)

[0542] Trypsin 0.25% EDTA (Invitrogen 25200056)

[0543] Calcium / magnesium-free DPBS (Invitrogen 14190-136)

[0544] DMEM, high glucose, GlutaMAX (Invitrogen 10569-010)

[0545] Fetal bovine serum, deprived by activated charcoal (Invitrogen 12676-011)

[0546] Anhydrous DMSO (Sigma D2650)

[0547] SNC80 OPRD1 agonist MW449.63 (Sigma S2812)

[0548] SDM25N hydrochloride OPRD1 antagonist MW468.98 (Tocris 1410)

[0549] LiveBLAzer TM -FRET / BG spiking mixture: (Invitrogen K1030 (5 mg)), consisting of solutions A, B, C, and D:

[0550] Solution A (6μL): LiveBLAzer TM -FRET / BG substrate (CCF4-AM)

[0551] Solution B (60 μL)

[0552] Solution C (904 μL)

[0553] Solution C (250 μL of 1N NaOH must be added to 45 mL of Solution C before use)

[0554] A 200 mM stock solution was prepared from solution D (30 μL) [Probinicid] (Sigma P8161) in NaOH-H2O.

[0555] Biological Examples

[0556] The results are provided in Table 2 below. The activities of representative compounds are expressed as IC50 against κ opioid receptors (KOR) and μ opioid receptors (MOR). 50 Table 2 also shows the selectivity of representative compounds against KOR.

[0557] Table 2. Activities of representative compounds

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

Claims

1. Compounds of formula (I) or their pharmaceutically acceptable salts: in: X is CH and Y is NH; Or X is N and Y is -C (=N-CN)NR 9 ; Or X is NH and -YR 2 Empty; R 1 and R 1a Independently selected from H, C1-C6 alkyl groups, and halogens; Or R 1 and R 1a Together with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl groups or optionally substituted 3- to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O and S); R 2 Selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl and 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S); R 9 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl); R 3 In each case, it is a C1-C6 alkyl group; n is 0, 1, or 2; R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10 Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10 Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), -(C1-C6 alkyl)(3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), -(C1-C6 alkyl)(5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S)), wherein: R and R' are independently selected from H and C1-C6 alkyl groups, and R 1 R 1a R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN, and C1-C6 haloalkyl groups.

2. Compounds of formula (II) or their pharmaceutically acceptable salts: in: Ar is (R) 3 ) n Substituted 5- or 6-membered heteroaryl groups (where 1 to 4 heteroaryl members are independently selected from N, O and S); X is CH and Y is NH; Or X is N and Y is selected from bond, C(O) and -C (=N-CN)NR. 9 ; Or X is NH and -YR 2 Empty; R 1 and R 1a Independently selected from H, C1-C6 alkyl groups, and halogens; Or R 1 and R 1a Together with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl groups or optionally substituted 3- to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O and S); When X is CH, then: (i)R 1 and R 1a At least one of them is not H and Ar is not Diazole, thiadiazole, or triazole; or (ii) Optionally, R 1 or R 1a Together with Y and the carbon atoms they are bonded to, they form fused 5- to 6-membered heterocyclic alkyl groups; R 2 Selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O and S) and -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O and S)); R 9 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl); R 3 In each case, it is independently a C1-C6 alkyl or a C1-C6 haloalkyl; n is 0, 1, or 2; R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10 Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10 Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)); R and R' are independently selected from H and C1-C6 alkyl groups; R 1 R 1a R 2 R 3 R 4 R 5 R 6 R 7 and R 8 Any alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl groups may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NRR', NO2, OR, CN and C1-C6 haloalkyl; And the compound mentioned therein is not:

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIA):

4. The compound according to claim 2 or 3 or a pharmaceutically acceptable salt thereof, wherein Ar is a 5-membered heteroaryl group (wherein 1 to 4 heteroaryl members are independently selected from N, O and S).

5. The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazolyl, imidazole, ... azole group, iso azole group, diazole group, iso Diazole, thiazolyl, isothiazolyl, and thiadiazole.

6. The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazolyl, azole and isopropyl Azolium group.

7. The compound or its pharmaceutically acceptable salt according to any one of claims 2 to 6, wherein X is N and Y is a bond.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein X is CH and Y is NH.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein X is N and Y is -C (=N-CN)NR. 9 .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 9 It is H.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 2 It is an optional substituted 3- to 6-membered heterocyclic alkyl group (one of which is O).

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 2 Selected from the alternatives:

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R 2 yes 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 2 It is substituted by 1 to 3 substituents selected from halogens and OH.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 2 Replaced by halogens.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 15, wherein the halogen is F.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 2 It is replaced by OH.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein n is 0.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein n is 1.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 1 and R 1a One of them is H and the other is a halogen.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 1 and R 1a One of them is H and the other is F.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 1 It is H and R 1a It is F.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 1 and R 1a Each of them is H.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 1 and R 1a Together with the carbon atoms they are bonded to, they form optionally substituted fused C3-C8 cycloalkyl groups or optionally substituted 3- to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O and S).

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 and 24, wherein R 1 and R 1a Together with the carbon atoms they are bonded to, they form optionally substituted fused C3-C8 cycloalkyl groups.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the fused C3-C8 cycloalkyl group is cyclopropyl.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 26, wherein R 1 or R 1a Together with Y and the carbon atoms they bind to, they form fused 5- to 6-membered heterocyclic alkyl groups.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the fused 5- to 6-membered heterocyclic alkyl group is a pyrrolidinyl group.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein R 4 Selected from H, CN, halogens and C1-C6 alkyl groups.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein R 4 It is a C1-C6 alkyl group.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein R 5 and R 7 It is independently selected from H, halogens and CN.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein R 5 and R 7 At least one of them is H.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein R 5 and R 7 Each of them is H.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 33, wherein R 6 It is selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl and C3-C8 cycloalkyl.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein R 6 It is a C1-C6 alkyl group.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 35, wherein R 8 Selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 5 to 10 heteroaryl (of which 1 to 4 heteroaryl members are independently selected from N, O and S), and -CONRR'.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36, wherein R 8 It is a halogen or a 5 to 10-membered heteroaryl group (of which 1 to 4 heteroaryl members are independently selected from N, O and S).

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein R 8 It is F.

39. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X is CH and Y is NH; R 1 and R 1a One of them is H and the other is F; R 2 It is an optional substituted 3- to 6-membered heterocyclic alkyl group (one of which is O); n is 0 or 1; R 4 Selected from H, CN, halogens, and C1-C6 alkyl groups; R 5 and R 7 Independently selected from H, halogens, and CN, wherein R 5 and R 7 At least one of them is H; R 6 Selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl; and R 8 Selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 5 to 10 heteroaryl (of which 1 to 4 heteroaryl members are independently selected from N, O and S), and -CONRR'.

40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following table:

41. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, and a pharmaceutically acceptable carrier.

42. A method for treating a disorder in a subject suffering from a disorder, wherein the disorder is a disorder therapeutically adapted to κ-opioid receptor (KOR) antagonism, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40.

43. A method for treating a disorder in a subject suffering from the disorder, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein the disorder is selected from substance abuse or addiction, mental disorders, obesity and eating disorders, migraines, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, seizures, and sleep disruption associated with the drug treatment of pain, mental disorders or disorders.

44. The method of claim 43, wherein the obstacle is substance abuse or addiction.

45. The method of claim 44, wherein substance abuse or addiction is selected from gambling, drug addiction, drug abuse, alcohol dependence, alcohol abuse, and substance-induced depression or mood disorder.

46. ​​The method of claim 43, wherein the disorder is a mental disorder.

47. The method of claim 46, wherein the mental disorder is selected from anxiety disorders, depressive disorders, mood disorders, schizophrenia spectrum disorders, stress-related disorders, obsessive-compulsive disorders, social phobia, generalized anxiety disorder (GAD), social anxiety disorder, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorder (ASD).

48. The method of claim 43, wherein the condition is sleep disruption related to pain, mental disorder, or drug treatment for mental disorder.

49. The method of claim 43 or 48, wherein the pain is chronic pain or neuropathic pain.

50. The method according to any one of claims 43, 48 and 49, wherein the sleep is REM sleep.

51. The method according to any one of claims 43 and 48 to 50, wherein the sleep interruption is sleep disorder, sleep deprivation, or a combination thereof.

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