Quinoline derivatives that act as kappa opioid receptor antagonists

Abstract

Disclosed herein are kappa opioid receptor (KOR) antagonist compounds of formula (I) and formula (II) and their pharmaceutically acceptable salts, as well as pharmaceutical compositions thereof. The compounds are useful in methods for treating a variety of diseases and disorders for which KOR antagonism is indicated, including substance abuse disorders, depression, anxiety, and other psychiatric conditions. TIFF2026506965000204.tif34128

Description

[Technical Field]

[0001] This application claims the benefit of 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 applications are incorporated in their entireties as if fully set forth herein. [Background technology]

[0002] background The kappa opioid receptor (KOR) is a member of the opioid receptor family and binds to the opioid peptide dynorphin as its major endogenous ligand. KOR is widely and specifically distributed in the brain, spinal cord, and peripheral tissues, particularly in brain regions involved in reward, cognitive function, and stress responses. Evidence suggests that dynorphin is increased under painful and stressful conditions, and that blockade of KOR produces anti-stress effects. Such findings have led to the development of KOR antagonists for the treatment of depression, anxiety, addictive disorders, and other stress-related psychiatric conditions [M. Urbano et al., Bioorganic & Medicinal Chemistry Letters, 24:2021-2032, 2014 (Non-Patent Document 1) ("Urbano 2014"); Jacobson et al., Annu. Rev. Pharmacol. Toxicol., 60:615-636 (2020) (Non-Patent Document 2); see also Handbook in Experimental Pharmacology, 271: Eds. Lee-Yuan Liu-Chen Saadet Inan (2022) (Non-Patent Document 3)].

[0003] Pharmacological studies with prototypic KOR antagonists (i.e., the morphinan-derived ligands nor-BNI and GNTI, and the non-morphinan JDTic) have confirmed the therapeutic potential of the KOR / dynorphin system [Urbano 2014]. However, such prototypic KOR antagonists exhibit a slow onset of action, ranging from hours to days, followed by weeks of antagonistic effects at minimally effective doses. Furthermore, such compounds have demonstrated poor permeability across the blood-brain barrier. For these reasons, more recent research has focused on developing KOR antagonists with improved pharmacokinetics and shorter durations of action.

[0004] The mechanism by which KOR antagonists exert their therapeutic effects is largely understood. Both direct modulation of KOR and modulation of downstream signaling pathways regulated by dynorphin-KOR signaling may contribute to the therapeutic effect. Indeed, KOR antagonists have been extensively and meticulously studied precisely because they are known to inhibit a prominent stress-induced neuroadaptation, namely, increased dynorphin expression in the nucleus accumbens (NAc). The NAc is a component of the mesolimbic system that plays a role in motivation and the pathology of psychiatric disorders. In addition to repeated exposure to drugs of abuse, stress triggers a complex series of intracellular events in the NAc involving the transcription factor CREB, a cAMP response element-binding protein. KOR antagonists alleviate depression-like symptoms caused by CREB-mediated increased dynorphin expression (WA Carlezon et al., Depression and Anxiety, 33:895-906, 2016). According to a model proposed by Carlezon et al., stress activates CREB in the NAc, leading to increased expression of dynorphin. This increased dynorphin in turn promotes activation of KOR. KOR is expressed in the cell bodies and terminals of mesocorticolimbic dopamine (DA) neurons, and activation of KOR inhibits DA release. Therefore, treatment with a KOR antagonist blocks the action of dynorphin and restores DA function, thereby producing antidepressant- and anxiolytic-like effects.

[0005] The neuropeptides oxytocin and vasopressin also function in pathways that play a role in neuropsychiatric disorders, including depression, anxiety, autism, schizophrenia, PTSD, addiction, and ADHD [Cid-Jofre et al., Int. J. Mol. Sci., 22:12077, (2021) (Non-Patent Document 5)]. These are amplifying neuropeptide pathways downstream of the dynorphin response that can be modulated by KOR antagonists, enabling multilevel modulation of indicated psychiatric disorders. Indeed, multilevel blockade of amplifying pathways is a well-established principle in disease-modifying drugs.

[0006] Mu and kappa opioid binding sites are found in the pituitary gland, where they are important for the release of oxytocin and vasopressin [Jordan et al., J. Neuroendocrinol., 8: 883-887, (1996) (Non-Patent Document 6); Shuster et al., Neuroscience, 96(2), 373-383, (2000) (Non-Patent Document 7); Morris et al., J. Clin. Pharmacol., 50:1112-1117, (2010) (Non-Patent Document 8)]. Oxytocin secretion is inhibited centrally by both mu and kappa agonists and directly by kappa agonists through activation of kappa receptors [Lutz-Bucher & Koch, Euro J Pharmacol., 66: 375-378, (1980) (Non-Patent Document 9)]. Thus, both kappa and mu opioid antagonists increased oxytocin levels; however, only kappa antagonists increased oxytocin and vasopressin levels when administered intracerebroventricularly (icv) [Van de Heijning et al., Eur J Pharmacol., 197:175-180, (1991) (Non-Patent Document 10), ibid., idem, 209:199-206, (1991) (Non-Patent Document 11)]. Furthermore, the endogenous kappa opioid receptor agonist dynorphin regulates the release of serotonin (5-HT), which, for example, influences social deficits during drug withdrawal in rodents; as seen in humans, these effects may lead to relapse [Pomrenze et al., Neuron 110:4125-4143, (2022) (Non-Patent Document 12)].

[0007] Physiologically, dynorphin / KOR signaling promotes REM sleep. Additionally, KOR antagonists normalize disrupted sleep in chronic pain while preventing sleepiness in the absence of pain, highlighting a pathophysiological role for KOR signaling, which is selectively recruited to promote wakefulness and improved survival. While this mechanism is likely beneficial in the short term, long-term disruption of the homeostatic need for sleep can be maladaptive and lead to persistent chronic pain. Thus, a novel approach for the treatment of chronic pain may result from normalizing chronic pain-associated sleep disruption through KOR antagonism [Ito, et al., Brain: 00; 1-14 (2022) (Non-Patent Document 13)]. Furthermore, sleep disturbances can not only be attributed to chronic pain, but are also a common symptom of major depressive disorder (MDD) and are a significant adverse effect of most existing antidepressant classes, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) [EC Settle, J. Clin. Psychiatry 59: 25-30 (1998)]. Therefore, the ability of KOR antagonism to normalize sleep disturbances without causing drowsiness is a major advantage in therapeutic intervention for MDD and in clinical situations characterized by sleep disturbances as an adverse effect of medication.

[0008] The mechanisms of action of KOR antagonists and the many previous developments and trials of KOR antagonists, including recent clinical findings (e.g., Aticaplant and ALKS-5461), provide compelling evidence that KOR antagonists offer therapeutic benefits for a wide range of disorders in humans, including mood, anxiety, and substance abuse disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The Research Domain Criteria (RDC) project provides an additional framework for classifying psychopathological disorders, which aims to classify such disorders based on observable behavioral and neurobiological dimensions. In this context, KOR antagonists have therapeutic benefits in at least two of the domains defined by the RDC: reward-related domains and domains related to the adverse effects of stress. Within these domains, the use of KOR antagonists has been recognized for the treatment of anhedonia (the "positive valence system") and for blocking the adverse effects of stress (the "negative valence system").

[0009] Benefiting from advances in this field, KOR antagonists have been recognized for their usefulness in treating major depression and substance abuse-related disorders, particularly in the context of fast-acting treatments that avoid the drawbacks associated with the prototype KOR antagonists described above. Further advances have shown that KOR antagonists may be particularly effective for treating stress-mediated symptoms and for treating social anxiety and phobias. Preventive therapies to prevent adverse symptoms resulting from stress have also been suggested, and in this regard, KOR antagonism has been proposed as a preventative treatment for PTSD in individuals at risk for PTSD. Because reward-related dysfunction often occurs in patients with mood and anxiety spectrum disorders and can also present with other conditions, such as schizophrenia or schizoaffective disorder, other therapeutic applications of KOR antagonism include the treatment of reward-related dysfunction.

[0010] KOR antagonism is an established therapeutic route for the treatment of a wide variety of disorders and conditions. Despite advances in the art, there remains a need for new and improved KOR antagonists for the treatment of a variety of conditions, including substance abuse disorders, major depression, anhedonia, and stress-related symptoms. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] M. Urbano et al., Bioorganic & Medicinal Chemistry Letters, 24:2021-2032, 2014 [Non-patent document 2] Jacobson et al., Annu. Rev. Pharmacol. Toxicol., 60:615-636 (2020) [Non-patent document 3] Handbook in Experimental Pharmacology, 271: Eds. Lee-Yuan Liu-Chen Saadet Inan (2022) [Non-patent document 4] WA Carlezon et al., Depression and Anxiety, 33:895-906, 2016 [Non-Patent Document 5] Cid-Jofre et al., Int. J. Mol. Sci., 22:12077, (2021) [Non-patent document 6] Jordan et al., J. Neuroendocrinol., 8: 883-887, (1996) [Non-Patent Document 7] Shuster et al., Neuroscience, 96(2), 373-383, (2000) [Non-patent document 8] Morris et al., J Clin. Pharmacol., 50:1112-1117, (2010) [Non-Patent Document 9] Lutz-Bucher & Koch, Euro J Pharmacol., 66: 375-378, (1980) [Non-Patent Document 10] Van de Heijning et al., Eur J Pharmacol., 197:175-180, (1991) [Non-Patent Document 11] Van de Heijning et al., Eur J Pharmacol., 209:199-206, (1991) [Non-Patent Document 12] Pomrenze et al., Neuron 110:4125-4143, (2022) [Non-Patent Document 13] Ito, et al., Brain: 00; 1-14 (2022) [Non-Patent Document 14] EC Settle, J. Clin. Psychiatry 59: 25-30 (1998) Summary of the Invention

[0012] overview The present disclosure addresses this need and others by providing, in various aspects, compounds of formula (I) or pharmaceutically acceptable salts thereof: TIFF2026506965000002.tif34128

[0013] In formula (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 another embodiment, X is NH and -YR 2 does not exist, i.e., does not exist.

[0014] In some embodiments, R 1 and R1a is independently selected from the group consisting of H, C1-C6 alkyl, and halo. 1 and R 1a together with the carbon atoms to which they are attached form a fused C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0015] R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, —(C1-C6 alkyl)C3-C8 cycloalkyl, and 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0016] R 9 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0017] R 3 is C1-C6 alkyl in each occurrence.

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

[0019] Substituent R 4 , R 5 , R 6 , R 7 , and R 8 are independently H, CN, OH, halo, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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-C10 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 heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), -(C1-C6 alkyl)(5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S)).

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

[0021] In formula (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 in may be substituted with 1 to 6 substituents independently selected from the group consisting of C1-C6 alkyl, halo, NO2, OH, CN, and C1-C6 haloalkyl.

[0022] In an additional aspect, the disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: TIFF2026506965000003.tif28128

[0023] In formula (II), Ar is (R 3 ) n and 5- or 6-membered heteroaryl substituted with , wherein 1-4 members of the heteroaryl are independently selected from N, O, and S.

[0024] In some embodiments, X is CH and Y is NH. In other embodiments, X is N and Y is a bond, C(O), and —C(═N—CN)NR 9 In yet a further embodiment, X is NH and -YR 2 does not exist (i.e., does not exist).

[0025] In embodiments, R 1 and R 1a is independently selected from the group consisting of H, C1-C6 alkyl, and halo.

[0026] In another embodiment, R 1 and R 1a taken together with the carbon atoms to which they are attached form a fused C3-C8 cycloalkyl or an optionally substituted 3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S.

[0027] In formula (II), when X is CH, (i)R 1 and R 1a is not H and Ar is other than oxadiazolyl, thiadiazolyl, and triazolyl; or (ii) optionally, R 1 or R 1a together with Y and the carbon atom to which they are attached form a fused 5- to 6-membered heterocycloalkyl.

[0028] R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S)).

[0029] R9 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0030] R 3 is independently in each occurrence C1-C6 alkyl or C1-C6 haloalkyl.

[0031] The subscript n is 0, 1, or 2.

[0032] R 4 , R 5 , R 6 , R 7 , and R 8 are independently H, CN, OH, halo, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), -(C1-C6 alkyl)(5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S)).

[0033] R and R' are independently selected from H and C1-C6 alkyl.

[0034] In formula (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 in may be substituted with 1 to 6 substituents independently selected from the group consisting of C1-C6 alkyl, halo, NRR', NO2, OR, CN, and C1-C6 haloalkyl.

[0035] Notwithstanding the definition of formula (II), formula (II) may also be represented by the following compounds: It should be understood that this does not include TIFF2026506965000004.tif32128.

[0036] In an additional aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] In yet a further aspect, the present disclosure provides a method for treating a disorder in a subject suffering from a disorder for which antagonism of the kappa opioid receptor (KOR) is therapeutically indicated, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0038] In another aspect, the present disclosure provides a method for treating a disorder in a subject suffering from the disorder, wherein the disorder is selected from those disclosed herein, such as substance abuse or addiction, psychiatric disorders, obesity and eating disorders, migraine, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, and seizures, The method comprises administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0039] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a disorder disclosed herein in a subject suffering from the disorder. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the manufacture of a medicament for treating a disorder disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0040] Detailed Description The present disclosure relates, in part, to compounds that antagonize the kappa opioid receptor (KOR). One advantage of the compounds is their potency combined with their selectivity for the KOR, particularly relative to the mu opioid receptor (MOR).

[0041] definition "Alkyl" refers to a straight or branched chain hydrocarbyl containing from 1 to about 20 carbon atoms. For example, an alkyl can have from 1 to 10 carbon atoms or from 1 to 6 carbon atoms. Exemplary alkyls include straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, as well as branched chain isomers of straight chain alkyl groups, such as, but not limited to, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3), -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), -CH2C Also included are H(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Alkyl groups can be unsubstituted or substituted with one or more substituents described herein, such as halogens.

[0042] The terms "halogen," "halide," and "halo" refer to -F or fluoro, -Cl or chloro, -Br or bromo, or -I or iodo, respectively.

[0043] The term "alkenyl" refers to a straight- or branched-chain hydrocarbyl group containing from 2 to about 20 carbon atoms and having 1 to 3, 1 to 2, or at least 1 carbon-carbon double bond. Alkenyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0044] "Alkyne" or "alkynyl" refers to a straight- or branched-chain unsaturated hydrocarbon having the indicated 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. Alkynyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0045] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic, or polycyclic 3- to 14-membered ring system, such as a C3-C8 cycloalkyl. The cycloalkyl may be attached via any atom. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0046] "Aryl", when used alone or as part of another term, means an aryl having the specified number of carbon atoms, whether fused or not, or C6-C6 if no number is specified. 10 Aryl or C6-C 14 "aryl" refers to a carbocyclic aromatic group having up to 14 carbon atoms, such as phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, etc. (See, e.g., Lang's Handbook of Chemistry (Dean, JA, ed.) 13 th ed. Table 7-2

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

[0047] The term "heteroatom" refers to N, O, and S. Compounds of the present disclosure containing an N or S atom may be oxidized to the corresponding N-oxide, sulfoxide, or sulfone compound.

[0048] "Heteroaryl," alone or in combination with any other moiety 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 and containing one or more, e.g., 1 to 4, 1 to 3, or 1 to 2 heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or heteroatom is the point of attachment of the heteroaryl ring structure such that a stable compound is created. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. Heteroaryl groups can be unsubstituted or substituted with one or more substituents described herein.

[0049] A "heterocycloalkyl" 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 in which 1 to 3 carbon atoms within the ring are replaced by an O, S, or N heteroatom. Ring heteroatoms can also include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. Heterocycloalkyls can be fused to other ring systems, such as 5- or 6-membered aryl or heteroaryl rings. The point of attachment of a heterocycloalkyl ring can be at a carbon or heteroatom that maintains a stable ring structure. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. Heterocycloalkyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0050] The terms "nitrile" or "cyano" may be used interchangeably and refer to the group --CN.

[0051] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. When ranges are used herein with respect to physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations and specific embodiments within that range are intended to be included. The term "about," when referring to a numerical value or numerical range, means that the stated numerical value or numerical range is an approximation within experimental variation (or within statistical experimental error); thus, the numerical value or numerical range will, in some cases, vary by 1% to 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude other specific embodiments, such as any composition of matter, composition, method, or process described herein, from "consisting of" or "consisting essentially of" the stated feature.

[0052] The compounds described herein may exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis or trans conformations. The compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the compounds, including tautomeric forms of the compounds of the present disclosure. The compounds of the present disclosure may also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms may result from loss of water. The specific composition of the open-chain and cyclized forms may vary depending on how the compound is isolated, stored, or administered. For example, a compound may exist primarily in an open-chain form under acidic conditions, but may cyclize under neutral conditions. All forms are included in the disclosure.

[0053] Some compounds described herein may have asymmetric centers, and therefore can exist in different enantiomeric and diastereomeric forms.The compounds described herein may be in the form of optical isomers or diastereomers.Therefore, the present disclosure encompasses the compounds described herein in the form of their optical isomers, diastereoisomers, and mixtures thereof, including racemic mixtures, and their use.The optical isomers of the disclosed compounds can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or by chemical separation of stereoisomers through the use of optically active resolving agents.

[0054] Unless otherwise indicated, the term "stereoisomer" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers is 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 the other stereoisomer of the compound, e.g., more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomer of the compound. The stereoisomers described above may be considered as compositions comprising the two stereoisomers present in the respective weight percentages described herein.

[0055] In the event of a discrepancy between a depicted structure and the name given to that structure, the depicted structure shall prevail. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by a bold or dashed line, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof. In some cases, however, when more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry. Those skilled in the art of organic synthesis will know whether compounds have been prepared as single enantiomers from the methods used to prepare them.

[0056] As used herein, the term "isotopologue" refers to an isotopically enriched compound. As used herein, and unless otherwise indicated, the term "isotopically enriched" refers to an atom having an isotopic composition different from that atom's naturally abundant isotopic composition. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition different from that atom's naturally occurring isotopic composition. In an isotopologue, "isotopic enrichment" refers to the proportion of a specific isotope of a given atom incorporated into a molecule in a certain amount, replacing that atom's naturally occurring isotopic composition. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at that specified position. Because the naturally occurring deuterium distribution is approximately 0.0156%, a compound synthesized using non-enriched starting materials will have a deuterium enrichment of approximately 0.0156% at any position.

[0057] Thus, as used herein, and unless otherwise indicated, the term "isotopic enrichment factor" refers to the ratio between the isotopic composition of a specified isotope and the natural isotopic composition.

[0058] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D," it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium atom of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The isotopic enrichment and isotopic enrichment factor 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.

[0059] As used herein, and unless specified to the contrary, the term "compound" is inclusive in that it encompasses a compound or its pharmaceutically acceptable salts, stereoisomers, isotopologues, and / or tautomers. Thus, for example, a compound includes pharmaceutically acceptable salts of tautomers of a compound. Similarly, a compound includes pharmaceutically acceptable salts of isotopologues of a compound.

[0060] In the present disclosure, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water soluble and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, hydroxynaphtho ... te), lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosaliclate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0061] The terms "treat," "treating," and "treatment" refer to the amelioration or eradication of a disease or symptoms associated with a disease. In various embodiments, the terms refer to minimizing or slowing the spread, progression, or worsening of a disease that results from administering one or more prophylactic or therapeutic compounds described herein to a patient with such a disease.

[0062] The terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of disease in a patient resulting from the administration of a compound described herein.

[0063] The term "effective amount" refers to an amount of a compound or other active ingredient described herein sufficient to provide a therapeutic or preventative benefit in the treatment or prevention of a disease, or to delay or minimize symptoms associated with a disease. Furthermore, a therapeutically effective amount with respect to a compound described herein means an amount of a therapeutic agent alone or in combination with other therapeutic agents that provides a therapeutic benefit in the treatment or prevention of a disease. When used in connection with a compound described herein, the term can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease, or enhances the therapeutic effect of another therapeutic agent or is synergistic with another therapeutic agent.

[0064] A "patient" or "subject" includes animals such as humans, cows, horses, sheep, lambs, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, the animals are mammals, such as non-primates and primates (e.g., monkeys and humans). In one embodiment, the patient is a human, e.g., a human infant, child, adolescent, or adult. In this disclosure, the terms "patient" and "subject" are used interchangeably.

[0065] compound In various aspects, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: TIFF2026506965000005.tif34128

[0066] In formula (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 another embodiment, X is NH and -YR 2 does not exist, i.e., does not exist.

[0067] In some embodiments, R 1 and R 1a is independently selected from the group consisting of H, C1-C6 alkyl, and halo. 1 and R 1a taken together with the carbon atoms to which they are attached form a fused C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S.

[0068] R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, —(C1-C6 alkyl)C3-C8 cycloalkyl, and 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0069] R 9 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0070] R 3 is C1-C6 alkyl in each occurrence.

[0071] The subscript n is 0, 1, or 2.

[0072] Substituent R 4 , R 5 , R 6 , R 7 , and R 8are independently H, CN, OH, halo, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), -(C1-C6 alkyl)(5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S)).

[0073] R and R' are independently selected from H and C1-C6 alkyl.

[0074] In formula (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 in may be substituted with 1 to 6 substituents independently selected from the group consisting of C1-C6 alkyl, halo, NO2, OH, CN, and C1-C6 haloalkyl.

[0075] In an additional aspect, the disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: TIFF2026506965000006.tif28128

[0076] In formula (II), Ar is (R 3 ) n and 5- or 6-membered heteroaryl substituted with , wherein 1-4 members of the heteroaryl are independently selected from N, O, and S.

[0077] In some embodiments, X is CH and Y is NH. In other embodiments, X is N and Y is a bond, C(O), and —C(═N—CN)NR 9 In yet a further embodiment, X is NH and -YR 2 does not exist (i.e., does not exist).

[0078] In embodiments, R 1 and R 1a is independently selected from the group consisting of H, C1-C6 alkyl, and halo.

[0079] In another embodiment, R 1 and R 1a taken together with the carbon atoms to which they are attached form a fused C3-C8 cycloalkyl or an optionally substituted 3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S.

[0080] In formula (II), when X is CH, (i)R 1 and R 1ais not H and Ar is other than oxadiazolyl, thiadiazolyl, and triazolyl; or (ii) optionally, R 1 or R 1a together with Y and the carbon atom to which they are attached form a fused 5- to 6-membered heterocycloalkyl.

[0081] R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S)).

[0082] R 9 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0083] R 3 is independently in each occurrence C1-C6 alkyl or C1-C6 haloalkyl.

[0084] The subscript n is 0, 1, or 2.

[0085] R 4 , R 5 , R 6 , R 7 , and R 8 are independently H, CN, OH, halo, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 10aryl), -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 heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), -(C1-C6 alkyl)(5- to 10-membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S)).

[0086] R and R' are independently selected from H and C1-C6 alkyl.

[0087] In formula (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 in may be substituted with 1 to 6 substituents independently selected from the group consisting of C1-C6 alkyl, halo, NRR', NO2, OR, CN, and C1-C6 haloalkyl.

[0088] Notwithstanding the definition of formula (II), formula (II) may also be represented by the following compounds: It should be understood that this does not include TIFF2026506965000007.tif32128.

[0089] In some embodiments, the compound or pharmaceutically acceptable salt thereof is of formula (IIA), wherein the definition of each substituent is the same as in formula (II) disclosed herein. TIFF2026506965000008.tif28128

[0090] In various embodiments, Ar is a 5-membered heteroaryl (wherein 1 to 4 members of the heteroaryl are independently selected from N, O, and S). In exemplary embodiments, Ar is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isoxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. In certain embodiments, Ar is selected from the group consisting of pyrazolyl, oxazolyl, and isoxazolyl.

[0091] In additional embodiments, X is N and Y is a bond.

[0092] In one embodiment, X is CH and Y is NH. In another embodiment, X is N and Y is -C(=N-CN)NR 9 In an exemplary embodiment, R 9 is H.

[0093] In some embodiments, R 2 is an optionally substituted 3-6 membered heterocycloalkyl (wherein one ring member is O). For example, in various embodiments, R 2 is optionally substituted TIFF2026506965000009.tif15138. In an exemplary embodiment, R 2 teeth TIFF2026506965000010.tif12128.

[0094] In additional embodiments, R 2 is substituted with 1 to 3 substituents selected from halo and OH, and combinations thereof. 2is substituted with only halo, e.g., 1, 2, or 3 halo. For example, in one embodiment, halo is F. In another embodiment, R 2 is substituted with only OH, for example, 1, 2, or 3 OH.

[0095] In some embodiments, the subscript n is 0. In other embodiments, n is 1.

[0096] In some embodiments, R 1 and R 1a One of them is H and the other is halo. For example, R 1 is H and R 1a is a halo or R 1 is the halo, and R 1a is H. In additional embodiments, R 1 and R 1a One of R is H and the other is F. In an exemplary embodiment, R 1 is H and R 1a is F or R 1 and R 1a Each of these is H. R 1 and R 1a All these combinations are contemplated.

[0097] In some embodiments, R 1 and R 1a taken together with the carbon atoms to which they are attached form an optionally substituted fused C3-C8 cycloalkyl or an optionally substituted 3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S. In one embodiment, R 1 and R 1a together with the carbon atom to which they are attached form an optionally substituted fused 3- to 6-membered heterocycloalkyl. 1 and R 1a taken together with the carbon atom to which they are attached form an optionally substituted C3-C8 cycloalkyl. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0098] In various embodiments, R 1 or R 1a together with Y and the carbon atom to which they are attached form a fused 5-6 membered heterocycloalkyl ring. An exemplary heterocycloalkyl is pyrrolidinyl.

[0099] In an additional aspect, the present disclosure provides 4 is selected from the group consisting of H, CN, halo, and C1-C6 alkyl. 4 is C1-C6 alkyl.

[0100] In still further aspects, R 5 and R 7 is independently selected from the group consisting of H, halo, and CN. For example, in some embodiments, R 5 and R 7 At least one of R is H. In another embodiment, 5 and R 7 are H respectively.

[0101] Additional aspects include R 6 is selected from the group consisting of halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C8 cycloalkyl. 6 is C1-C6 alkyl.

[0102] R in various aspects 8 is H, CN, halo, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 In some embodiments, R is selected from the group consisting of aryl, 5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), and -CONRR'. 8 is halo or 5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S). An exemplary embodiment is 8is halo, such as F.

[0103] In various aspects, the present disclosure provides compounds of formula (I), wherein: X is CH and Y is NH; R 1 and R 1a one is H and the other is F; R 2 is an optionally substituted 3- to 6-membered heterocycloalkyl (wherein one ring member is O); n is 0 or 1; R 4 is selected from the group consisting of H, CN, halo, and C1-C6 alkyl; R 5 and R 7 are independently selected from the group consisting of H, halo, and CN, where R 5 and R 7 at least one of is H; R 6 is selected from the group consisting of halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C8 cycloalkyl; R 8 is H, CN, halo, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 It is selected from the group consisting of aryl, 5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), and -CONRR'.

[0104] Exemplary embodiments of compounds of Formula (I) and Formula (II) and their pharmaceutically acceptable salts are described throughout the Examples and Table 1 below.

[0105] Table 1: Representative compounds of formula (I) TIFF2026506965000011.tif130128TIFF2026506965000012.tif211106TIFF2026506965000013.tif196106TIFF2026506965000014.tif20 5106TIFF2026506965000015.tif214106TIFF2026506965000016.tif225106TIFF2026506965000017.tif222106TIFF2026506965000018.t if203106TIFF2026506965000019.tif215106TIFF2026506965000020.tif203106TIFF2026506965000021.tif223106TIFF20265069650000 22.tif195106TIFF2026506965000023.tif207106TIFF2026506965000024.tif218106TIFF2026506965000025.tif221106TIFF20265069650 00026.tif200106TIFF2026506965000027.tif220106TIFF2026506965000028.tif222106TIFF2026506965000029.tif200106TIFF2026506 965000030.tif220106TIFF2026506965000031.tif198106TIFF2026506965000032.tif209106TIFF2026506965000033.tif219106TIFF202 6506965000034.tif223106TIFF2026506965000035.tif221106TIFF2026506965000036.tif211106TIFF2026506965000037.tif217106TIFF F2026506965000038.tif197106TIFF2026506965000039.tif217106TIFF2026506965000040.tif210106TIFF2026506965000041.tif176128

[0106] Pharmaceutical composition The present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds disclosed herein, or pharmaceutically acceptable salts, stereoisomers, isotopologues, and / or tautomers thereof, in combination with a pharmaceutically acceptable carrier. In some embodiments, the compositions further contain one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavoring agents, in accordance with pharmaceutical compounding practices.

[0107] In one embodiment, the pharmaceutical composition comprises a compound selected from those shown in Table 1, or a pharmaceutically acceptable salt, stereoisomer, isotopologue, and / or tautomer thereof, and a pharmaceutically acceptable carrier.

[0108] The pharmaceutical compositions of the present disclosure are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0109] The "therapeutically effective amount" of the compound or its pharmaceutically acceptable salt, stereoisomer, isotopologue, and / or tautomer to be administered will be adjusted depending on such considerations and will be the minimum amount necessary to exhibit antagonism at the kappa opioid receptor. Such an amount may be below an amount that is toxic to normal cells or the subject as a whole. Generally, an initial therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer) administered ranges from about 0.01 to about 200 mg per kg of patient body weight or from about 0.1 to about 20 mg per kg of patient body weight per day, with a typical initial range being about 0.3 to about 15 mg / kg / day. Oral unit dosage forms, such as tablets and capsules, may contain from about 0.1 mg to about 1000 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer). In another embodiment, such dosage forms contain about 50 mg to about 500 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain about 25 mg to about 200 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain about 10 mg to about 100 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In a further embodiment, such dosage forms contain about 5 mg to about 50 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage forms may be administered once daily or twice daily.

[0110] In certain embodiments, the compounds described herein or pharmaceutically acceptable salts or solvates thereof are substantially pure in that they contain 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 by-products produced, e.g., in one or more steps of the synthetic method.

[0111] The compositions of the present disclosure can be administered orally, topically, parenterally, by inhalation or aerosol, or rectally in dosage unit formulations. As used herein, the term "parenteral" includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

[0112] Suitable oral compositions described herein include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs.

[0113] In another aspect, also included is a pharmaceutical composition suitable for single unit dose administration comprising a disclosed compound or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof and a pharmaceutically acceptable carrier.

[0114] The composition of the present disclosure suitable for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.For example, the liquid formulation of the compound of the present disclosure contains one or more agents selected from the group consisting of sweeteners, flavorings, colorings and preservatives, in order to provide the compound of the present disclosure with pharmaceutically palatable taste.

[0115] For tablet compositions, the compound of the present disclosure mixed with non-toxic pharmaceutically acceptable excipients is used to manufacture 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 disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained therapeutic effects over a desired period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used.

[0116] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0117] In aqueous suspensions, the compounds of the present disclosure are mixed with suitable excipients to maintain a stable suspension, examples of which include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxpropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia.

[0118] Oral suspensions may also contain dispersing or wetting agents, such as naturally occurring phosphatides, for example, lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example, sucrose or saccharin.

[0119] Oily suspensions may be formulated by suspending the compounds of the present disclosure in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.

[0120] Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0121] Dispersible powders and granules suitable for preparing aqueous suspension by adding water provide the compound of the present disclosure in combination with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0122] The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as acacia gum or tragacanth gum, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. The suspension may also contain sweeteners and flavoring agents.

[0123] Syrups and elixirs may be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable, aqueous, or oily suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any mild, fixed oil may be employed, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0124] The compound of the present disclosure can be administered in the form of suppositories for rectal administration of drugs.These compositions can be prepared by mixing the drug with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release the drug.Such materials are cocoa butter and polyethylene glycol.

[0125] The composition for parenteral administration is administered in sterile medium.Depending on the vehicle used and the concentration of drug in the preparation, parenteral preparation can be either suspension or solution containing dissolved drug.Adjuvants such as local anesthetic, preservative and buffer can also be added to parenteral composition.

[0126] How to use In another aspect, the present disclosure provides a method for antagonizing KOR.The method comprises contacting an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof with the receptor.Contacting can occur, for example, in vivo or in vitro, depending on various aspects.

[0127] The present disclosure also provides, in some aspects, a method for treating a disorder in a subject suffering from the disorder, wherein the disorder is a disorder for which antagonism of the kappa opioid receptor (KOR) is indicated for treatment.

[0128] As summarized above, KOR is a member of the opioid receptor family that binds to the opioid peptide dynorphin as its primary endogenous ligand. The term "antagonism" generally refers to a molecule that interacts with the receptor and thereby functions as an antagonist by either binding to the receptor at the binding site of the receptor's natural ligand or at a position other than the binding site. Thus, phrases such as "antagonism of KOR" refer to antagonistic interaction with KOR by binding to KOR at either the dynorphin site or at a position other than the binding site (i.e., allosteric binding).

[0129] In another aspect, the present disclosure provides a method for treating the disorder in a subject suffering from the disorder, comprising administering to the subject the compound described herein or its pharmaceutically acceptable salt.The disorder is selected from one or more of substance abuse or addiction, psychiatric disorder, obesity and eating disorder, migraine, postpartum depression, neurodegenerative disease or disorder, epilepsy, status epilepticus and seizure.

[0130] In some embodiments, the disorder is disturbed sleep caused by or associated with pain, a psychiatric disorder described herein, or medication for a psychiatric disorder. The pain can be chronic pain or neuropathic pain. In various embodiments, sleep disturbances can be characterized by sleep disorders such as those caused by disorders of sleep initiation and maintenance (DIMS, insomnia), excessive sleepiness, sleep-wake rhythm disorders, or partial awakenings (parasomnia) [Cormier RE. Sleep Disturbances. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 77]. In another embodiment, sleep disturbance is insomnia, such as those caused by abnormal frequency and / or duration of wake periods. In some embodiments, disturbed sleep is characterized by disturbances in sleep stages, such as rapid eye movement (REM) sleep. Treatment in this context, according to the methods described herein, can result in normalization of sleep, i.e., reduction or elimination of sleep disorders. In various embodiments, normalized sleep includes restoration of REM sleep, prolongation of REM sleep duration, reduction in frequency of REM sleep interruptions, and combinations thereof.

[0131] In some embodiments, the disorder is one of substance abuse or addiction, for example, the disorder can be selected from gambling, drug addiction, substance abuse, alcoholism, alcohol abuse, and drug-induced depression or mood disorder.

[0132] In another embodiment, the disorder is a mental disorder. Examples of mental disorders that can be treated 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 phobia, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorders (ASD).

[0133] The term "anxiety disorder," as understood in the art, generally refers to various forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders, including generalized anxiety disorder, panic disorder, stress-related disorders, obsessive-compulsive disorders, phobias, social anxiety disorder, separation anxiety disorder, and post-traumatic stress disorder (PTSD). In one embodiment, the anxiety disorder is social anxiety disorder. In another embodiment, the anxiety disorder is a phobia.

[0134] Generalized anxiety disorder is characterized by chronic and long-lasting anxiety that is not focused on any particular object or situation. People with generalized anxiety disorder experience nonspecific, persistent fear and worry and / or may exhibit excessive anxiety about everyday things. Generalized anxiety disorder is the most common anxiety disorder among older adults.

[0135] Individuals with panic disorder may unexpectedly experience brief attacks of intense fear and anxiety. Accompanying symptoms include tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. The APA defines an attack as a sudden, intense feeling of fear or discomfort that peaks within 10 minutes, can last for several hours, and may be triggered by stress, fear, or even exertion, although the specific cause is not always clear. A diagnosis of panic disorder also includes chronic effects of the attack, including anxiety about the potential impact of the attack, persistent fear of future attacks, or significant behavioral changes triggered by the attack. Therefore, individuals with panic disorder may experience symptoms outside of a specific panic episode. For example, sufferers may mistake normal changes in heart rate for concerns about cardiac health or as a sign of another panic attack. In some cases, individuals may experience heightened awareness of bodily functions (hypervigilance) during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness, i.e., extreme hypochondria.

[0136] Obsessive-compulsive disorder (OCD) is an anxiety disorder primarily characterized by recurrent obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). OCD thought patterns are based on the belief in nonexistent cause-and-effect relationships. Compulsions can be completely illogical, such as walking in a particular pattern to alleviate obsessive thoughts of imminent harm. Compulsions can also be completely unexplained and often result from a stress-induced urge to complete a ritual. Some people with OCD experience only obsessions without overt compulsions, and even fewer experience only compulsions.

[0137] Phobias are the single largest category of anxiety disorders, encompassing all cases in which a specific stimulus or situation provokes fear or anxiety. Affected individuals typically anticipate frightening consequences from encountering the object of their fear; examples include social phobia, specific phobia, agoraphobia, and phobias of animals, places, or bodily fluids.

[0138] Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can develop after extreme situations such as combat, rape, hostage situations, or even serious accidents. It can also result from chronic exposure to severe stressors; for example, soldiers may survive individual battles but suffer from prolonged combat stress. Common PTSD symptoms include flashbacks, avoidance behaviors, and depression.

[0139] The methods described herein can be useful for treating depressive disorders, depression, or depressive disorders, examples of which include major depression, medication-resistant depression, dysthymia, and bipolar disorder.

[0140] In embodiments, the methods described herein are useful for treating mood or affective disorders, including major depressive disorder (MDD), bipolar disorder, anhedonia, dysthymia, major depression, psychotic major depression (PMD), psychotic depression, postpartum depression, seasonal affective disorder (SAD), and catatonic depression, a rare and severe form of major depression accompanied by impaired motor behavior and other symptoms.

[0141] As used herein, the terms "anhedonia" and "anhedonic symptoms" are interchangeable and are defined as the inability to experience pleasure from activities that are normally considered enjoyable, such as exercise, hobbies, music, sexual activity, or social interactions. Anhedonia is similar to the criteria for "depressive disorder with melancholic features" in DSM-5, which describes melancholic depression, characterized by loss of pleasure in most or all activities, lack of response to pleasant stimuli, depressed mood that is more pronounced than feelings of sadness or loss, worsening symptoms in the morning, early awakening, slowed psychomotor function, excessive weight loss, or excessive guilt. In various embodiments, treatment of depressive disorder with melancholic features should be understood to include treatment of both the depressive disorder and its associated melancholic features. In one embodiment, the mood disorder is anhedonia. In another embodiment, the mood disorder is major depression. In yet another embodiment, the mood disorder is seasonal affective disorder (SAD).

[0142] In additional aspects, the methods described herein are useful for treating schizophrenia or schizoaffective disorder, or obesity or eating disorders such as bulimia, anorexia nervosa, and the like.

[0143] In yet a further embodiment, the method is used to treat migraine. Prophylactic therapy is also contemplated, in which administration of a KOR antagonist compound described herein prevents migraine headaches in individuals at risk of or prone to migraine recurrence.

[0144] In another embodiment, the method described herein is useful for treating postpartum depression (PND).Soon after birth, a significant drop in progesterone levels can lead to the onset of PND.PND symptoms range from mild depression to more severe psychosis requiring hospitalization.PND can be accompanied by or manifest as severe anxiety and irritability.PND cannot be treated with traditional antidepressants because it fails to respond to typical treatment regimens, and women suffering from PND show a higher incidence of premenstrual syndrome (PMS).

[0145] In various aspects, the methods described herein are useful for treating neurodegenerative diseases or disorders, including mood and behavioral disorders associated with neurodegenerative diseases. The range of neurodegenerative diseases contemplated herein includes diseases and disorders associated with the progressive loss of neuronal structure or function or the death of neurons.Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic disorders; ataxia and convulsions; seizures caused by schizoaffective disorder or by drugs administered to treat schizophrenia; benign forgetfulness; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis (MLS); closed head injury; coma; contusion, such as spinal cord injury and head injury; dementia, including multi-infarct dementia and senile dementia; impairment of consciousness; Down's syndrome; neuroleptic-induced acute Drug-induced or medication-induced parkinsonism, such as akathisia, acute dystonia, parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, and medication-induced postural tremor; epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; akinesia and akinesia (rigidity), including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy Movement disorders including dyskinesias (such as benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (such as tics, including complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremors (such as rest tremor, postural tremor, and intention tremor) and dystonias (axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, as well as blepharospasm, oral dystonia, and cerebrovascular accidents). muscle spasms and disorders associated with muscle spasms or weakness, including jaw dystonia, and focal dystonias such as spasmodic dysphonia and torticollis; ocular nerve damage such as eye injury, retinopathy, or macular degeneration; neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest; Parkinson's disease; convulsions; status epilepticus; stroke; tinnitus; renal tubular sclerosis; and neurodegenerative diseases caused by viral infections such as acquired immune deficiency syndrome (AIDS) and encephalopathy.The methods also contemplate treatments for preventing the loss of neuronal function characteristic of neurodegenerative diseases.

[0146] In some embodiments, the methods described herein are useful for treating epilepsy, a brain disorder characterized by recurrent seizures over a long period of time. Various types of epilepsy that may be considered for treatment include generalized epilepsy, childhood absence epilepsy, juvenile myoclonic epilepsy, awakening grand mal epilepsy, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, and benign focal childhood epilepsy.

[0147] In embodiments, the methods described herein are useful for treating status epilepticus. Status epilepticus (SE) can include convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic unilateral epileptiform discharges.

[0148] Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and may include early status epilepticus, established status epilepticus, refractory status epilepticus, or very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by the persistence of status epilepticus seizures despite first-line therapy and is therefore treated with second-line therapy. Refractory status epilepticus is characterized by the persistence of status epilepticus seizures despite first- and second-line therapy and is typically treated with general anesthesia. Very refractory status epilepticus is characterized by the persistence of status epilepticus seizures despite first- and second-line therapy and general anesthesia for 24 hours or more.

[0149] Non-convulsive status epilepticus includes focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, and minimal non-convulsive status epilepticus, as well as generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0150] In some embodiments, the methods described herein are useful for treating seizures. As used herein, the term "seizure" refers to physical symptoms or behavioral changes that occur after an episode of abnormal electrical activity in the brain. In addition, the term "seizure" is often used interchangeably with "convulsion," which refers to the rapid and uncontrollable shaking of a person's body. During a convulsion, a person's muscles repeatedly contract and relax. Depending on the type of behavior and brain activity, two specific categories of seizures are defined: generalized and partial (also called focal or focal). The classification of seizures informs the diagnosis of epilepsy.

[0151] Electrical stimulation of the entire brain causes a generalized seizure, while concentrated electrical stimulation of a single part of the brain causes a focal seizure. The part of the brain that produces the seizure is sometimes called a focal point.

[0152] Generalized seizures are classified into six types. The most common, dramatic, and therefore best known is the generalized convulsion, also known as a grand mal seizure. In this type of seizure, the affected person loses consciousness and usually collapses. Following the loss of consciousness, there is a "tonic" phase in which the whole body becomes rigid for 30-60 seconds, followed by a "clonic" phase in which there are intense muscle reflexes for 30-60 seconds, after which the affected person progresses into a profound "postictal" or postictal period. During a grand mal seizure, the person may experience injuries and accidents, such as tongue biting and urinary incontinence.

[0153] Second, absence seizures cause a brief loss of consciousness, typically lasting a few seconds, with few or no symptoms. Individuals affected by absence seizures, most often children, typically pause in activity with a blank stare. These seizures begin and end abruptly and may occur several times a day. Individuals are usually unaware of the seizures, except that they may have a sense of "time passing." Third, myoclonic seizures consist of sporadic muscle jerks, usually on both sides of the body. Individuals may describe the jerks as brief electric shocks. In severe cases, these seizures may result in dropping or involuntary throwing of objects. Fourth, clonic seizures are repetitive, rhythmic muscle jerks occurring simultaneously on both sides of the body. Fifth, tonic seizures are characterized by muscle rigidity. Finally, atonic seizures consist of a sudden, generalized loss of muscle tone, especially in the arms and legs, often leading to falls.

[0154] In various aspects, seizures described herein include epileptic seizures; acute repetitive seizures; cluster seizures; persistent seizures; discontinuous seizures; persistent seizures; recurrent seizures; status epilepticus seizures, such as refractory convulsive status epilepticus and non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galactosomiasis; generalized onset seizures; infantile spasms; Jacksonian seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures; Sylvan seizures; visual reflex seizures; and withdrawal seizures. [Example]

[0155] The present disclosure is further illustrated by the following examples, which are non-limiting and constitute additional aspects of the present disclosure.

[0156] General methods. Commercially available reagents and solvents were used without purification unless otherwise stated. Extraction solvents: ACS grade. Reaction solvents: Reagent grade. Reagents: Highest quality from Alfa Aesar, Fisher, Combi-Blocks, and Aldrich unless otherwise stated. TLC: Silica gel 60 F254 aluminum plates (whatman, Al Sil G / UV type, 250 μm layer); visualization by UV absorption. Flash chromatography was performed on silica gel 60 (0.40-0.63 mm, 230-440 mesh, EM Science). Medium pressure column chromatography was performed using a Biotage Flash+ system. NMR: 1 H and 13 C spectra were acquired on a Bruker AV NEO 500 MHz spectrometer and a Bruker AVIII 400 MHz spectrometer. 1 H and 13 C NMR data are reported in parts per million (ppm) as chemical shifts (δ) relative to residual signals of the deuterated solvent as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m = multiplet, and br = broad), and coupling constants in Hz. Reactions were monitored on an Agilent 1260 Infinity equipped with an Agilent 6120 Quadrupole LC / MS detector. Purity was determined by LCMS using an Agilent SB-C18 column (1.8 μm, 2.1 × 50 mm) with UV detection at wavelengths of 254 nm and 230 nm. Elution was performed in aqueous CH3CN containing 0.1% HC02H, with a gradient from 10 to 90% over 5 min at 25 °C, at a flow rate of 1.0 mL / min. All test compounds were >95% pure. High-resolution mass spectra were acquired on an Agilent 6230 TOF LC / MS system using electrospray ionization (ESI) in positive mode.

[0157] Compound synthesis The following exemplary procedures are provided to illustrate the synthesis of specific compounds described in this disclosure. One of ordinary skill in the art can readily adapt the procedures, starting materials, and reagents for the synthesis of any compound described herein.

[0158] 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) TIFF2026506965000042.tif32128Step 1. 2-Chloro-6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline (int-5) 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 h. POCl3 was removed under reduced pressure. The residue was quenched with ice / water and basified with saturated aqueous NaHCO3 to approximately pH 7, 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-3. TIFF2026506965000044.tif18147

[0159] A mixture of int-3 (50 mg, 0.12 mmol), int-4 (25 mg, 0.11 mmol), Pd(dppf)Cl (8 mg, 0.012 mmol), and KCO (33 mg, 0.24 mmol) in dioxane / HO (0.8 / 0.2 mL) was flushed with nitrogen. The mixture was heated at 120 °C for 2 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 × 30 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-5. TIFF2026506965000045.tif24143

[0160] Step 2. (3R,4S)-3-Fluoro-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine A mixture of ketone int-7 (275 mg, 2.75 mmol), chiral amine int-6 (400 mg, 1.83 mmol), NaBH(OAc) (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 h. 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 CHCl:MeOH to give compound int-8. LCMS: (M+1) m / z = 303.

[0161] To a solution of int-8 (470 mg, 1.15 mmol) in CHCl (1 mL) was slowly added HCl (4 M dioxane) (2.9 mL, 11.5 mmol) at room temperature, 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, quenched with PL-HCOMPSPE 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 used without further purification. LCMS (M+H) m / z = 203

[0162] 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) 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 h under microwave irradiation. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by preparative TLC using CHCl / MeOH to give 1. TIFF2026506965000048.tif44145

[0163] 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) 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 h. POCl3 was removed under reduced pressure. The residue was quenched with ice / water, basified with saturated NaHCO3 (aq) to approximately pH 7, 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. TIFF2026506965000050.tif18138

[0164] 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 under microwave irradiation for 7 h. The mixture was cooled to room temperature, diluted with EtOAc (60 mL), and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure, and the product was purified by column chromatography using CHCl / EtOAc to give int-13. LCMS: (M+1) m / z = 518, 520.

[0165] To a suspension of int-13 (150 mg, 0.29 mmol), CsCO (283 mg, 0.87 mmol), and Pd(dppf)Cl (21 mg, 0.029 mmol) in THF (3 mL) was added EtB (1 M in THF) (868 μL, 0.87 mmol). 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 NaSO and concentrated under reduced pressure, and the product was purified by column chromatography using CHCl / EtOAc to give product int-14. TIFF2026506965000051.tif24142

[0166] To a solution of int-14 (95 mg, 0.2 mmol) in CHCl (1 mL) was slowly added HCl (4 M dioxane) (0.5 mL, 2.0 mmol) 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 used without further purification. LCMS (M+H) m / z = 368

[0167] A mixture of int-15 (11 mg, 0.027 mmol), int-16 (3.7 mg, 0.032 mmol), NaBH(OAc) (11.4 mg, 0.054 mmol), DIPEA (4.7 μL, 0.027 mmol), and AcOH (3.1 μL, 0.054 mmol) in 1,2-dichloroethane (0.4 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl:MeOH, 95:5) to give 2. TIFF2026506965000052.tif38145

[0168] Example 3: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine TIFF2026506965000053.tif76145 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 vial at 160 °C for 6 min under microwave irradiation. The mixture was stirred with 1 mL of water for 5 min. The solid was filtered and washed with water (3x) and hexane (2x). Quinolone product. TIFF2026506965000054.tif11151

[0169] A mixture of the above quinolone product (160 mg, 0.65 mmol) in POCl (3 mL) was stirred at 90 °C for 1 h. POCl was removed under reduced pressure. The residue was quenched with ice / water, and the product was extracted with EtOAc (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude material was purified by column chromatography using hexane / EtOAc to give 2-chloroquinoline int-19. TIFF2026506965000055.tif11137

[0170] 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 under microwave irradiation at 140° C. for 3.5 h. The mixture was concentrated under reduced pressure and purified by column chromatography using hexane / EtOAc to give int-21. TIFF2026506965000056.tif25143

[0171] A mixture of int-21 (370 mg, 1.0 mmol), N,N-dimethylacetamide dimethyl acetal (1.02 mL, 7.0 equiv.), and DIPEA (523 μL, 3.0 mmol) was heated at 125° C. for 20 h. 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 used in the next step without further purification.

[0172] A mixture of the above intermediate (880 mg, 2.0 mmol) with 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 to give imidazole int-22. TIFF2026506965000057.tif24145

[0173] A mixture of int-22 (180 mg, 0.42 mmol) in 10% HSO was stirred at 45 °C for 2 h. The mixture was basified with saturated aqueous NaHCO to pH 7, and the product was extracted with EtOAc (2x). The organic phase was dried over NaSO and concentrated under reduced pressure. The product int-23 was obtained and used without further purification. TIFF2026506965000058.tif24146

[0174] A mixture of int-23 (40 mg, 0.105 mmol), int-24 (20 mg, 0.126 mmol), NaBH(OAc) (46 mg, 0.21 mmol), DIPEA (16 μL, 0.126 mmol), and AcOH (12 μL, 0.21 mmol) in 1,2-dichloroethane (0.6 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 3. TIFF2026506965000059.tif51146

[0175] Example 4: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (4) TIFF2026506965000060.tif36128 Compound 4 was obtained by the procedure of Example 3 using the appropriate amine and int-23. 27 H 35 F2N5O[M+H] + Calculated value: 484.2883, measured value: 484.2874.

[0176] Example 5: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (5) TIFF2026506965000061.tif34128 Compound 5 was obtained by the procedure of Example 3 using the appropriate amine and int-23. 27 H 35 F2N5O[M+H] + Calculated value: 484.2883, measured value: 484.2866.

[0177] Example 6: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (6) TIFF2026506965000062.tif38128 Compound 6 was obtained by the procedure of Example 3 using the appropriate amine and int-23. 27 H 36 FN5O[M+H] + Calculated value: 466.2977, measured value: 466.2954.

[0178] Example 7: 1-(6-ethyl-4-methyl-3,8-bis(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (7) 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 under microwave irradiation at 125° C. for 8 hours. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc to give product int-25. TIFF2026506965000064.tif24140

[0179] A mixture of int-25 (60 mg, 0.116 mmol), int-26 (36 mg, 0.174 mmol), Pd(dppf)Cl (8.5 mg, 0.012 mmol), and KCO (32 mg, 0.23 mmol) in dioxane / HO (0.8 / 0.2 mL) was flushed with nitrogen. The mixture was heated at 120 °C for 2 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 × 30 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-27. TIFF2026506965000065.tif24144

[0180] A mixture of int-27 (29 mg, 0.061 mmol) in 10% HSO was stirred at 45°C for 1 h. The mixture was basified with saturated aqueous NaHCO to pH 7, and the product was extracted with EtOAc (2x). The organic phase was dried over NaSO and concentrated under reduced pressure. int-28 was obtained and used without further purification. TIFF2026506965000066.tif31144

[0181] A mixture of int-28 (24 mg, 0.056 mmol), int-24 (10.6 mg, 0.067 mmol), NaBH(OAc) (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 at room temperature overnight. The mixture was diluted with EtOAc and washed with brine, and the organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 7. TIFF2026506965000067.tif44145

[0182] Example 8: (R)-6-ethyl-4-methyl-3,8-bis(1-methyl-1H-pyrazol-3-yl)-2-(2-methylpiperazin-1-yl)quinoline (8) 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 under microwave (mw) irradiation at 130°C for 7 h. The mixture was cooled to room temperature, diluted with EtOAc (60 mL), and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc to give int-35. TIFF2026506965000069.tif24144

[0183] A mixture of int-35 (Example 8; 45 mg, 0.078 mmol), int-26 (24 mg, 0.117 mmol), Pd(dppf)Cl (5.7 mg, 0.0078 mmol), and KCO (23 mg, 0.164 mmol) in dioxane / HO (0.8 / 0.2 mL) was flushed 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 NaSO and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-36. TIFF2026506965000070.tif31144

[0184] A mixture of int-36 (30 mg, 0.057 mmol) and TFA (87 μL, 1.13 mmol) in CHCl (500 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 CHCl / MeOH to give 8. LCMS: (M+1) m / z = 430.

[0185] Example 9: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-N-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (9) A mixture of int-25 (100 mg, 0.19 mmol), int-4 (44 mg, 0.21 mmol), Pd(dppf)Cl (14 mg, 0.019 mmol), and KCO (53 mg, 0.38 mmol) in dioxane / HO (0.8 mL / 0.2 mL) was flushed 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 NaSO and concentrated under reduced pressure. The residue was purified by column chromatography using CHCl / MeOH to give int-37. TIFF2026506965000072.tif31145

[0186] A mixture of int-37 (78 mg, 0.165 mmol) and 10% H2SO4 (4 mL) was stirred at 45 °C for 2 h. The mixture was basified with saturated aqueous NaHCO3 to pH 7, and the product was extracted with EtOAc (2x). 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. TIFF2026506965000073.tif25145

[0187] A mixture of int-38 (11 mg, 0.025 mmol), int-24 (5.0 mg, 0.031 mmol), NaBH(OAc) (11 mg, 0.05 mmol), DIPEA (5.4 μL, 0.031 mmol), and AcOH (3 μL, 0.05 mmol) in 1,2-dichloroethane (0.4 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with brine, and the organic phase was dried over NaSO 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.

[0188] Example 10: (R,E)-N'-cyano-N-ethyl-4-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-methylpiperazine-1-carboximidamide (10) 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 h. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CHCl / MeOH to give 10. TIFF2026506965000075.tif31145

[0189] Example 11: (R,E)-N'-cyano-4-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinolin-2-yl)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboximidamide A mixture of int-15 (Example 2; 10 mg, 0.027 mmol), int-40 (10 mg, 0.041 mmol), DIPEA (4.7 μL, 0.027 mmol) and iPrOH (0.3 mL) was heated at 120° C. for 2 h. The mixture was concentrated under reduced pressure, and the product was purified by preparative TLC using CHCl / MeOH to give 11. LCMS: (M+1) m / z = 519.

[0190] 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 A mixture of int-35 (Example 8; 30 mg, 0.052 mmol), int-41 (15 mg, 0.078 mmol), Pd(dppf)Cl (4 mg, 0.005 mmol), and KCO (15 mg, 0.109 mmol) in dioxane / HO (0.8 / 0.2 mL) was flushed 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 NaSO and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc to give int-42 in 89% yield (24 mg). TIFF2026506965000078.tif30144

[0191] A mixture of int-42 (20 mg, 0.038 mmol) and 4.0 M HCl in dioxane (194 μL, 0.78 mmol) in CHCl (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 CHCl / MeOH to give 12. LCMS: (M+1) m / z = 416.

[0192] Example 13: (R)-6-Ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-2-(2-methylpiperazin-1-yl)quinoline (13) TIFF2026506965000079.tif31128 Compound 13 was prepared by the procedure of Example 2 and is the same as 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.

[0193] Example 14: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (14) TIFF2026506965000080.tif34128 Compound 14 was obtained by the procedure of Example 3 using the appropriate amine and int-23. LCMS: (M+1) m / z=484.

[0194] 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) TIFF2026506965000081.tif32128 Compound 15 was obtained by the procedure of Example 1 using the appropriate amine and int-5. LCMS: (M+1) m / z=532.

[0195] Example 16: (3R,4S)-4-((1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)piperidin-4-yl)amino)tetrahydro-2H-pyran-3-ol (16) TIFF2026506965000082.tif34128 Compound 16 was obtained by the procedure of Example 3 using the appropriate amine and int-23. LCMS: (M+1) m / z=482.

[0196] Example 17: (3S,4R)-4-((1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)piperidin-4-yl)amino)tetrahydro-2H-pyran-3-ol (17) TIFF2026506965000083.tif35128 Compound 17 was obtained by the procedure of Example 3 using the appropriate amine and int-23. LCMS: (M+1) m / z=482.

[0197] 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) TIFF2026506965000084.tif33128 Compound 18 was obtained by the procedure of Example 3 using the appropriate amine and int-23. 26 H 34 FN5O[M+H] + Calculated value: 452.2820, measured value: 452.2812.

[0198] Example 19: 1-(3-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethyl-8-fluoro-4-methylquinolin-2-yl)-N-((1-fluorocyclopropyl)methyl)piperidin-4-amine (19) TIFF2026506965000085.tif33128 Compound 19 was obtained by the procedure of Example 3 using the appropriate amine and int-23. 26 H 33 F2N5[M+H] + Calculated value: 454.2777, measured value: 454.2767.

[0199] Example 20: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-N-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (20) TIFF2026506965000086.tif33128 Compound 20 was obtained by the procedure of Example 9 using the appropriate amine and int-38. LCMS: (M+1) m / z=532.

[0200] Example 21: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-N-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (21) TIFF2026506965000087.tif32128 Compound 21 was obtained by the procedure of Example 9 using the appropriate amine and int-38. LCMS: (M+1) m / z=532.

[0201] Example 22: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine (22) TIFF2026506965000088.tif32128 Compound 22 was obtained by the procedure of Example 9 using the appropriate amine and int-38. LCMS: (M+1) m / z=532.

[0202] Example 23: 1-(6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinolin-2-yl)piperidin-4-amine (23) A mixture of int-5 (10 mg, 0.027 mmol), int-43 (8.2 mg, 0.04 mmol), DIPEA (9 μL, 0.054 mmol) and n-BuOH (0.5 mL) was heated at 155°C for 6 h under microwave irradiation. The mixture was cooled to room temperature and concentrated under reduced pressure, and the product was purified by preparative TLC using hexane / EtOAc. int-44 was obtained in 77% yield (11 mg). LCMS: (M+1) m / z = 530.

[0203] A mixture of int-44 (8 mg, 0.015 mmol) and 4.0 M HCl in dioxane (76 μL, 0.3 mmol) in CHCl (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 CHCl / MeOH to give compound 23. HRMS (ESI-TOF) C 25 H 31 N7[M+H] + Calculated value: 430.2714, measured value: 430.2717.

[0204] Example 24: 2-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-6-ethyl-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-5-yl)quinoline (24) 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 h under microwave irradiation. The mixture was cooled to room temperature, diluted with EtOAc (40 mL), and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure, and the product was purified by column chromatography using CHCl / MeOH. Int-46 was obtained in 41% yield (9 mg). LCMS: (M+1) m / z = 528.

[0205] A mixture of int-46 (8 mg, 0.015 mmol) and 4.0 M HCl in dioxane (38 μL, 0.152 mmol) in CHCl (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 CHCl / MeOH to give compound 24. HRMS (ESI-TOF) C 25 H 29 N7[M+H] + Calculated value: 428.2557, measured value: 428.2551.

[0206] 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) A mixture of Int-1A (200 mg, 0.66 mmol), Int-2A (172 mg, 0.79 mmol), DIPEA (345 μL, 1.98 mmol), and iPrOH (345 μL) was heated at 135°C for 12 h 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% yield (230 mg). TIFF2026506965000092.tif31146

[0207] A mixture of Int-3A (220 mg, 0.45 mmol) and 4.0 M HCl in dioxane (1.7 mL, 6.79 mmol) in CHCl (2 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the crude material was dissolved in MeOH and filtered through a PL-HCO MP Agilent cartridge, which was washed with MeOH (3x). The organic phase was concentrated under reduced pressure to give Int-4A in 86% yield (150 mg), which was used without further purification. HRMS (ESI-TOF) C H F N [M+H] + Calculated value: 386.2151, measured value: 386.2164.

[0208] 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 CHCN (500 μL) was stirred at 120 °C for 20 h. The mixture was diluted with EtOAc and washed successively with brine and saturated aqueous NaHCO. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl:MeOH, 95:5) to give 192 in 55% yield (33 mg). HRMS (ESI-TOF) calculated for CHFNO [M+H]: 456.2570, found: 456.2580.

[0209] 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) TIFF2026506965000093.tif27128 Compound 193 was obtained by the procedure of Example 25 using Int-4A and the appropriate tosylate. HRMS (ESI-TOF) calculated for C25H31F2N5O [M+H]+ 456.2570, found 456.2580.

[0210] 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) A mixture of Int-1A (100 mg, 0.33 mmol), Int-6A (85 mg, 0.39 mmol), DIPEA (172 μL, 0.99 mmol), and 1-BuOH (345 μL) was heated at 150°C for 9 h 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% yield (112 mg). TIFF2026506965000095.tif31144

[0211] A mixture of Int-7A (100 mg, 0.2 mmol) and 4.0 M HCl in dioxane (0.77 mL, 3.08 mmol) in CHCl (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the crude material was dissolved in MeOH and filtered through a PL-HCO MP Agilent cartridge, which was washed with MeOH (3x). The organic phase was concentrated under reduced pressure to give Int-8A in 90% yield (71 mg). The product was used without further purification. HRMS (ESI-TOF) C H F N [M+H] + Calculated value: 386.2151, measured value: 386.2150.

[0212] 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 CHCN (500 μL) was stirred at 150 °C for 5 h. The mixture was filtered through a PL-HCO MP Agilent cartridge and washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl:MeOH, 95:5) to give 194 in 50% yield (12 mg). HRMS (ESI-TOF) calculated for CHFNO [M+H]: 456.2570, found: 456.2579.

[0213] 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) TIFF2026506965000096.tif28128 Compound 195 was obtained using the appropriate chiral amine and tosylate following the procedure used for the synthesis of 192. HRMS (ESI-TOF) calculated for C25H31F2N5O [M+H]+ 456.2570, found 456.2582.

[0214] 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) TIFF2026506965000097.tif29128 Compound 196 was obtained using the appropriate chiral amine and tosylate following the procedure used for the synthesis of 192. HRMS (ESI-TOF) calculated for C25H31F2N5O [M+H]+ 456.2570, found 456.2587.

[0215] Example 30: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisoxazol-5-yl)quinolin-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (197) 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 CHCN (10 mL) was stirred at 120 °C for 20 h under microwave irradiation. The mixture was filtered through a PL-HCO MP Agilent cartridge, and the cartridge was washed with MeOH (3x). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography using CHCl / MeOH to give int-10 in 69% yield (915 mg). TIFF2026506965000099.tif24144

[0216] A mixture of int-10A (940 mg, 3.26 mmol) and 4.0 M HCl in dioxane (12 mL, 48.9 mmol) in CHCl (10 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the product was dissolved in MeOH and filtered through a PL-HCO MP Agilent cartridge. The cartridge was washed with MeOH (4x), and the organic phase was concentrated under reduced pressure. Int-11A was obtained in 94% yield (580 mg), and the product was used without further purification. HRMS (ESI-TOF) C9H17FN2O [M+H] + Calculated value 189.1398, measured value 189.1399.

[0217] A mixture of Int-12A (15 mg, 0.05 mmol), Int-11A (19 mg, 0.1 mmol), DIPEA (9 μL, 0.05 mmol) and 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 CHCl / MeOH. 197 was obtained in 52% yield (11.9 mg). HRMS (ESI-TOF) CHFO [M+H] + The calculated value is 457.2410 and the measured value is 457.2420.

[0218] Example 31: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisoxazol-5-yl)quinolin-2-yl)-3-fluoro-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine (198) 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 CHCN (10 mL) was stirred at 120 °C for 24 h under microwave irradiation. The mixture was filtered through a PL-HCO MP Agilent cartridge, and the cartridge was washed with MeOH (3x). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography using CHCl / MeOH to give Int-14A in 74% yield (490 mg). TIFF2026506965000101.tif24146

[0219] A mixture of Int-14A (29 mg, 0.1 mmol) and 4.0 M HCl in dioxane (0.38 mL, 1.5 mmol) in CHCl (300 μL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the salt was used without further purification. HRMS (ESI-TOF) C9H17FN2O [M+H] + Calculated for 189.1398, found 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-HCO MP Agilent cartridge, and the cartridge was washed with MeOH (3×). The organic phase was concentrated under reduced pressure, and the product was purified by preparative TLC using CHCl / MeOH. 198 was obtained in 26% yield (2 steps, 6.1 mg). HRMS (ESI-TOF) of C H F NO [M+H] + Calculated value: 457.2410, measured value: 457.2408.

[0220] Example 32: (3S,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisoxazol-5-yl)quinolin-2-yl)-3-fluoro-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine (208) A mixture of Int-12A (50 mg, 0.164 mmol), Int-16A (50 mg, 0.23 mmol), DIPEA (86 μL, 0.492 mmol) and 1-BuOH (500 μL) was heated at 150°C for 9 h 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% yield (21 mg). TIFF2026506965000103.tif38146

[0221] A mixture of Int-17A (15 mg, 0.03 mmol) and 4.0 M HCl in dioxane (115 μL, 0.46 mmol) in CHCl (200 μL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the product was used without further purification. HRMS (ESI-TOF) CHFNO [M+H] + Calculated value: 387.1991, measured value: 387.1995.

[0222] 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 CHCN (300 μL) was stirred at 120°C for 15 h. The mixture was filtered through a PL-HCO MP Agilent cartridge, and the cartridge was washed with MeOH (3×). The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl:MeOH, 95:5) to give 208 in 20% yield (2.1 mg). HRMS (ESI-TOF) of CHFNO [M+H] + Calculated value: 457.2410, measured value: 457.2410.

[0223] Example 33: ((R)-4,4-Difluoro-1-methylpiperidin-2-yl)((R)-4-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-3-methylpiperazin-1-yl)methanone (205) TIFF2026506965000104.tif48149 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 CHCl was stirred overnight at room temperature. The mixture was transferred to a separatory funnel with EtOAc and washed with brine (2×). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-21A in 95% yield (36 mg). HRMS (ESI-TOF) C [M+H] + Calculated value 617.3058, measured value 617.3065.

[0224] A mixture of Int-21A (30 mg, 0.048 mmol) and 4 M HCl in dioxane (182 μL, 0.729 mmol) in CHCl (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the solid was dissolved in MeOH, filtered through a PL-HCO MP Agilent cartridge, and washed with MeOH (3×). The organic phase was concentrated under reduced pressure, and the product was purified by preparative TLC using CHCl / MeOH to give 200 in 76% yield (19 mg). HRMS (ESI-TOF) of C H F N O [M+H] + Calculated value 517.2533, measured value 517.2533.

[0225] A mixture of 200 (15 mg, 0.029 mmol), 37% aqueous formaldehyde (7 μL, 0.087 mmol), NaBH(OAc) (11.5 mg, 0.054 mmol), and AcOH (3.1 μL, 0.054 mmol) in 1,2-dichloroethane (0.3 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with brine, and the organic phase was dried over NaSO and concentrated under reduced pressure. The crude material was purified by preparative TLC (CHCl:MeOH, 95:5) to give 205 in 52% yield (8 mg). HRMS (ESI-TOF) calculated for CHFNO [M+H]: 531.2690, found: 531.2679.

[0226] Example 34: (R)-5-(6-ethyl-8-fluoro-2-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-2-methylpiperazin-1-yl)-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole (207) TIFF2026506965000105.tif44146 A mixture of Int-19A (26 mg, 0.06 mmol), Int-22A (15 mg, 0.13 mmol), DIPEA (42 μL, 0.24 mmol) and iPrOH (300 μL) was stirred at 105°C overnight. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH) to give 206 in 82% yield (24 mg). HRMS (ESI-TOF) C26H34FN5O3 [M+H] + Calculated value: 484.2719, measured value: 484.2714.

[0227] A mixture of 206 (10 mg, 0.02 mmol) and DAST (3.7 mg, 0.022 mmol) in CHCl was stirred at room temperature for 3 h. The mixture was quenched with 5% aqueous sodium bicarbonate, and the product was extracted with EtOAc (2×). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude material was purified by column chromatography using hexane / EtOAc to give 207 in 32% yield (3.1 mg). HRMS (ESI-TOF) calculated for CHFNO [M+H]: 486.2675, found: 486.2686.

[0228] 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) 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 h under microwave irradiation. The mixture was diluted with EtOAc (30 mL) and washed with brine (2x). The organic phase was dried over NaSO and concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. Int-25 was obtained in 49% yield (37 mg). TIFF2026506965000107.tif24146

[0229] 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) was added Et3B (1 M in THF) (282 μL, 0.282 mmol). The reaction was heated at 50 °C for 1 h. The mixture was diluted with EtOAc and washed with brine (2x). The organic phase was dried over Na2SO4 and concentrated under reduced pressure, and the product was purified by column chromatography using CHCl2 / EtOAc to give Int-26 in 58% yield (26 mg). HRMS (ESI-TOF) C 27 H 36 FN5O2[M+H] + Calculated value: 482.2926, measured value: 482.2927.

[0230] To a solution of Int-26 (185 mg, 0.384 mmol) in CHCl (1 mL) was slowly added HCl (4 M dioxane) (1.44 mL, 5.76 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure. The crude material was dissolved in MeOH, filtered through a PL-HCO MP Agilent cartridge, and washed with MeOH (3×). The organic phase was concentrated under reduced pressure to give Int-27 in 75% yield (110 mg). The product was used without further purification. HRMS (ESI-TOF) C 22 H 28 FN5[M+H] + Calculated value: 382.2402, measured value: 382.2403.

[0231] 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 CHCN (2 mL) was stirred at 110 °C for 12 h under microwave irradiation. The mixture was filtered through a PL-HCO MP Agilent cartridge and washed with MeOH (3x). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography using CHCl / MeOH to give 115 in 58% yield (75 mg). HRMS (ESI-TOF) showed C 26 H34 FN5O[M+H] + Calculated value: 452.2820, measured value: 452.2825.

[0232] 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) 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 h. POCl3 was removed under reduced pressure. The residue was quenched with ice / water, basified with saturated aqueous NaHCO3 to approximately pH 7, and the product was extracted with EtOAc (2x). 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 as a light brown solid (420 mg, 50% yield). TIFF2026506965000109.tif18148

[0233] 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 under microwave irradiation for 4 h. The mixture was concentrated under reduced pressure, and the product was purified by column chromatography using hexane / EtOAc. int-46a was obtained in 66% yield (71 mg). TIFF2026506965000110.tif18151

[0234] A mixture of int-46a (60 mg, 0.146 mmol) in 10% HSO (1 mL) and THF (1 mL) was stirred at 40 °C for 2 h. The mixture was basified with saturated aqueous NaHCO to pH 7.5, and the product was extracted with EtOAc (2x). The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was obtained in 88% yield (47 mg) and was used without further purification. TIFF2026506965000111.tif25143

[0235] A mixture of int-47 (10 mg, 0.027 mmol), int-48 (4.7 mg, 0.033 mmol), NaBH(OAc) (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 NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 71 in 80% yield (9.9 mg). HRMS (ESI-TOF) CHFNO [M+H] + Calculated value: 456.2570, measured value: 456.2557.

[0236] 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) Compound 72 was obtained using the appropriate 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.

[0237] 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) Compound 73 was obtained using the appropriate 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.

[0238] Example 39: (R)-1-(4-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-3-methylpiperazin-1-yl)-2-(pyrrolidin-1-yl)ethan-1-one (47) 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 stirred at 140 °C overnight. The mixture was transferred to a separatory funnel with EtOAc (100 mL) and washed with brine (3x). 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% yield (247 mg). TIFF2026506965000115.tif24143

[0239] A mixture of Int-3b (130 mg, 0.28 mmol) and 4 M HCl in dioxane (715 μL, 5.6 mmol) in CHCl (5 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and Int-4b was used without further purification. HRMS (ESI-TOF) CHO [M+H] + Calculated value: 370.2038, measured value: 370.2042.

[0240] [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 CHCl was stirred at room temperature for 3 h. The mixture was transferred to a separatory funnel with EtOAc and washed with brine (2×). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography using CHCl / MeOH to give 47 in 70% yield (21 mg). TIFF2026506965000116.tif37145

[0241] Example 40: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (49) A mixture of Int-4b (25 mg, 0.062 mmol), Int-6b (9 mg, 0.08 mmol), NaBH(OAc) (39 mg, 0.186 mmol), DIPEA (21.6 μL, 0.124 mmol), and AcOH (10.6 μL, 0.186 mmol) in 1,2-dichloroethane (0.5 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl:MeOH, 95:5) to give 49 in 89% yield (26 mg). HRMS (ESI-TOF) calculated for C26H36FN5O2 [M+H]+ 468.2769, found 468.2758.

[0242] Example 41: (R)-5-(2-(4-((3,3-difluorocyclobutyl)methyl)-2-methylpiperazin-1-yl)-6-ethyl-8-fluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole (59) A mixture of Int-4b (10 mg, 0.024 mmol), Int-7b (8.2 mg, 0.03 mmol), DIPEA (12.6 μL, 0.072 mmol) and CH3CN (200 μL) was stirred at 60 °C for 28 h. The mixture was diluted with EtOAc and washed successively with brine and saturated aqueous NaHCO3. 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 59 in 62% yield (7.1 mg). HRMS (ESI-TOF) calculated for CH3OF3NO [M+H]+: 474.2475, found: 474.2478.

[0243] Example 42: 5-(6-ethyl-8-fluoro-4-methyl-2-((2R)-2-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (199) A mixture of Int-4 (12 mg, 0.029 mmol), Int-8 (17 mg, 0.059 mmol), DIPEA (10.3 μL, 0.072 mmol) in CHCN (500 μL) was stirred at 110 °C for 7 h under microwave irradiation. The mixture was diluted with EtOAc and washed successively with brine and saturated aqueous NaHCO. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give CYM-3252 in 28% yield (4 mg). HRMS (ESI-TOF) calculated for CHFNO [M+H]: 482.2926, found: 482.2921.

[0244] Example 43: (R)-5-(6-chloro-8-fluoro-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (50) TIFF2026506965000120.tif41142 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 h under microwave irradiation. The mixture was transferred to a separatory funnel with EtOAc (30 mL) and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by preparative TLC using CHCl / MeOH to give cpd-5 in 27% yield (3.2 mg). LCMS: (M+1) m / z = 474.

[0245] Example 44: (R)-5-(8-chloro-4,6-dimethyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (51) TIFF2026506965000121.tif41136 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 h under microwave irradiation. The mixture was transferred to a separatory funnel with EtOAc (30 mL) and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by preparative TLC using CHCl / MeOH to give 51 in 23% yield (2.8 mg). LCMS: (M+1) m / z = 470.

[0246] Example 45: (R)-5-(8-fluoro-6-methoxy-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (37) 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 h under microwave irradiation. The mixture was transferred to a separatory funnel with EtOAc (50 mL) and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-17b in 69% yield (100 mg). TIFF2026506965000123.tif24139

[0247] A mixture of Int-17b (100 mg, 0.172 mmol), sodium tetramethoxyborate (91 mg, 0.576 mmol), Pd(dba) (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 h. The mixture was transferred to a separatory funnel with EtOAc (50 mL) and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-18 in 16% yield (15 mg). LCMS: (M+1) m / z = 472.

[0248] 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 min. The mixture was concentrated under reduced pressure, and the product was used without further purification. LCMS: (M+1) m / z = 372.

[0249] A mixture of the intermediate obtained above, Int-6b (4.3 mg, 0.038 mmol), NaBH(OAc) (8 mg, 0.038 mmol), DIPEA (2.5 μL, 0.019 mmol), and AcOH (2.1 μL, 0.038 mmol) in 1,2-dichloroethane (0.4 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC using CHCl / MeOH to give 37 in 32% yield (2.9 mg) (2 steps). LCMS: (M+1) m / z = 470.

[0250] Example 46: (R)-5-(6-ethyl-2-(2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-8-fluoro-4-methylquinolin-3-yl)-3-methyl-1,2,4-oxadiazole (34) 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 at 140 °C overnight. The mixture was transferred to a separatory funnel with EtOAc (50 mL) and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-20b in 19% yield (30 mg). LCMS: (M+1) m / z = 484.

[0251] 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 min. The mixture was concentrated under reduced pressure and the product was used without further purification. LCMS: (M+1) m / z = 384

[0252] A mixture of Int-21b (8 mg, 0.016 mmol), Int-6b (3.7 mg, 0.032 mmol), NaBH(OAc) (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 at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC using CHCl / MeOH to give 34 in 64% yield (5.0 mg) (2 steps). LCMS: (M+1) m / z = 482.

[0253] Example 47: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (26) and (S)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (27) 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 h. The mixture was transferred to a separatory funnel with EtOAc (30 mL) and washed with brine (3x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by preparative TLC using CHCl / MeOH. Compound 26 was obtained in 12% yield (2.7 mg). LCMS: (M+1) m / z = 454. Compound 27 was obtained in 6% yield (1.4 mg). LCMS: (M+1) m / z = 454.

[0254] Example 48: (S)-5-(6-ethyl-8-fluoro-4-methyl-2-(3-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (38) TIFF2026506965000126.tif50145 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 h. The mixture was transferred to a separatory funnel with EtOAc (40 mL) and washed with brine (3x). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc to give a 15% yield (18 mg). LCMS: (M+1) m / z = 470.

[0255] 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 min. The mixture was concentrated under reduced pressure, and the product was used without further purification. LCMS: (M+1) m / z = 370.

[0256] A mixture of Int-26b (21.5 mg, 0.038 mmol), Int-6b (5.2 mg, 0.0456 mmol), NaBH(OAc) (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 at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC using CHCl / MeOH to give 38 in 84% yield (15 mg). LCMS: (M+1) m / z = 468.

[0257] Example 49: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(3-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methyl-1,2,4-oxadiazole (39) TIFF2026506965000127.tif48145 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 h. The mixture was transferred to a separatory funnel with EtOAc (40 mL) and washed with brine (3x). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in 10% yield (12 mg). LCMS: (M+1) m / z = 470.

[0258] 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 min. The mixture was concentrated under reduced pressure, and the product was used without further purification. LCMS: (M+1) m / z = 370.

[0259] A mixture of Int-29b (12.0 mg, 0.025 mmol), Int-6b (3.4 mg, 0.03 mmol), NaBH(OAc) (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 at room temperature overnight. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC using CHCl / MeOH to give 39 in 95% yield (11.1 mg). LCMS: (M+1) m / z = 468.

[0260] Example 50: (R)-5-(6-ethyl-8-fluoro-4-methyl-2-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)quinolin-3-yl)-3-methylisoxazole (63) 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 h. POCl3 was removed under reduced pressure. The residue was quenched with ice / water, basified with saturated aqueous NaHCO3 to pH 7, and the product was extracted with EtOAc (2x). 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 38% yield (130 mg). TIFF2026506965000129.tif18140

[0261] 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 h under microwave irradiation. The mixture was transferred to a separatory funnel with EtOAc (100 mL) and washed with brine (4x). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane / EtOAc to give Int-11b in 16% yield (16.2 mg). TIFF2026506965000130.tif31144

[0262] A mixture of Int-11b (15 mg, 0.032 mmol) with 4 M HCl in dioxane (40 μL, 0.16 mmol) and CHCl (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and Int-12b was used without further purification. LCMS: (M+1) m / z=369.

[0263] A mixture of Int-12b (15 mg, 0.037 mmol), Int-6b (5 mg, 0.041 mmol), NaBH(OAc) (16 mg, 0.074 mmol), DIPEA (6.5 μL, 0.037 mmol), and AcOH (4.2 μL, 0.074 mmol) in 1,2-dichloroethane (0.5 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC using CHCl / MeOH to give 50 in 81% yield (14 mg). HRMS (ESI-TOF) calculated for CHFNO [M+H]: 467.2817, found: 467.2831.

[0264] biological activity General Methods and Materials OPR Kappa 1 Tango B-Arrestin Assay Protocol – Antagonist Mode The purpose of this assay is to confirm the efficacy of this compound as an OPRK1 antagonist. The assay uses Tango OPRK1-bla U2OS cells, which express OPRK1 bound to the GAL4-VP16 transcription factor via a TEV protease site. The cells also express a β-arrestin / TEV protease fusion protein and a β-lactamase (BLA) reporter gene under the control of a UAS response element. Stimulation of the OPRK1 receptor by an agonist triggers translocation of the β-arrestin fusion protein to the GPCR, which releases GAL4-VP16 from the receptor via proteolysis. The liberated VP16-GAL4 translocates to the nucleus, where it induces transcription of the BLA gene. BLA expression is monitored by measuring fluorescence resonance energy transfer (FRET) of a cleavable, fluorogenic, cell-permeable BLA substrate. As designed, test compounds that are OPRK1 antagonists inhibit agonist activation and translocation of the fusion protein, thereby preventing proteolysis of GAL4-VP16 and BLA transcription, and do not result in an increase in FRET in the wells. Compounds were tested in quadruplicate using ten 1:3 dilution series starting from a nominal concentration of 10 micromolar.

[0265] The Tango OPRK1-U20S dividing cell line was routinely cultured in 150 mm dishes at 37°C, 5% CO2, and 95% relative humidity (RH). Growth medium consisted of McCoys 5A medium supplemented with 10% v / v dialyzed fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1x antibiotic mixture (penicillin-streptomycin).

[0266] On day 1 of the assay, 16,000 cells in 10 μL of assay medium (DMEM-Glutamax supplemented with sodium pyruvate, charcoal-dextran-stripped (CDS) 10% fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, and antibiotic mixture (penicillin-streptomycin)) were seeded 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 16–24 h.

[0267] On day 2, 50 nL of test compound in DMSO was added to the appropriate wells, and the plate was incubated for 30 minutes at 37°C, 5% CO2, and 95% RH. Next, 0.65 μL of commercially available U50488 OPRK1 agonist or DMSO was added to the assay medium (this EC80 challenge consisted of 0.6 μL of 111 nM U50488, resulting in a final assay concentration of 6 nM). After 4 hours of incubation at 37°C, 5% CO2, and 95% RH, 2.5 μL of LiveBLazer™ FRET B / G (CCF4-AM) mix (solutions A, B, C, and D) was added to each well and incubated for 2 hours at room temperature in the dark. Fluorescence in the wells was measured on a Perkin Elmer Envision using a 409 nm excitation filter, 460 nm and 590 nm emission filters, and a bottom readout.

[0268] Percent inhibition was calculated from the median ratio as follows: TIFF2026506965000131.tif10128 expression Test compounds are defined as wells containing test compounds; Low control is defined as wells containing U50488 challenge (6 nM final) = 0% inhibition; High controls are defined as wells containing DMSO = 100% inhibition.

[0269] Reagent list: Tango(TM) OPRK1-bla U20S cells (Invitrogen K1576) McCoy's 5A medium (Invitrogen 16600-082) Dialyzed fetal bovine serum (Invitrogen 26400-036) Non-essential amino acids 100x (Invitrogen product number 11140-050) HEPES (pH7.3) 1M (Invitrogen 15630-080) Sodium pyruvate 100x (Invitrogen 11360-070) Penicillin Streptomycin (Invitrogen 15640) Trypsin 0.25% EDTA (Invitrogen 25200056) Calcium / Magnesium-free DPBS (Invitrogen 14190-136) DMEM, high glucose, GlutaMAX (Invitrogen 10569-010) Charcoal-stripped fetal bovine serum (Invitrogen 12676-011) DMSO dry (Sigma D2650) U50488 OPRK1 agonist MW410.29 (Tocris 67198-19-0) GNTI dihydrochloride OPRK1 antagonist MW571.5 (Tocris 1282) Norbinaltorphimine dihydrochloride MW770.75 (Tocris 0347)

[0270] LiveBLAzer™-FRET / BG Loading Mix: (Invitrogen K1030 (5 mg)), composed of solutions A, B, C, and D: Solution A (6 μL): LiveBLAzer(TM)-FRET / BG substrate (CCF4-AM) Solution B (60μL) Solution C (904μL) Solution C (250 μl of 1N NaOH must be added to 45 mL of Solution C before use) Solution D (30 μL) [Provinicid] (Sigma P8161) Make a 200 mM stock solution in NaOH-H2O.

[0271] OPRMu1 Discover X-β-Arrestin Assay - Antagonist Mode The purpose of this assay is to confirm the potency and specificity of compounds synthesized to be OPRK1 antagonists. The assay evaluates the activation of OPRMu1 in membrane recruitment of β-arrestin. In addition, the assay evaluates GPCR-β-arrestin proximity using low-affinity fragment complementation of beta-galactosidase (beta-gal). The assay utilizes U20S cells expressing OPRMu1 fused to a complementary beta-gal fragment (enzyme receptor). If designed, compounds acting as antagonists will prevent receptor activation and reduce luminescence in the wells. Compounds were tested in quadruplicate using ten 1:3 dilution series starting from a nominal concentration of 10 micromolar.

[0272] The Discover X OPRMu1-U20S cell line was cultured in 150 mm dishes at 37°C, 5% CO2, and 95% relative humidity (RH). 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 1x antibiotic mixture (penicillin streptomycin).

[0273] On day 1 of the assay, 5000 cells in 20 μL of assay buffer (Discover X cell plating reagent 5) were seeded into each well of a 384 Corning 3570 standard white plate and incubated at 37°C, 5% CO2, and 95% RH for 16–24 h.

[0274] On day 2, 100 nL of test compound in DMSO was added to the appropriate wells, and the plate was then incubated for 30 minutes at 37°C, 5% CO2, and 95% RH. Next, 2.2 μL of DAMGO OPRMu1 agonist (commercially available) or DMSO in assay medium was added. (The EC80 challenge consisted of 1.8 μL of 3.7 μM DAMGO and 0.4 μL of assay buffer, for a final assay concentration of 303 nM.) After 3 hours of incubation at 37°C, 5% CO2, and 95% RH, 10 μL of Path Hunter detection mix was added to each well, and the plate was then incubated in the dark at room temperature for 1 hour. Fluorescence of the wells was measured on a Perkin Elmer Envision.

[0275] Percent inhibition was calculated from the median ratio as follows: TIFF2026506965000132.tif10128 expression Test compounds are defined as wells containing test compounds; Low control is defined as well containing DAMGO challenge (200 nM final) = 0% inhibition; High controls are defined as wells containing DMSO = 100% inhibition.

[0276] Reagent list: DMEM medium (Invitrogen 11965) F12 medium (Invitrogen 11765) Heat-inactivated fetal bovine serum (Invitrogen 10082147) Non-essential amino acids 100x (Invitrogen 11140-050) HEPES (pH7.3) 1M (Invitrogen 15630-080) Sodium pyruvate 100x (Invitrogen 11360-070) Penicillin Streptomycin (Invitrogen 15640) Trypsin 0.25% EDTA (Invitrogen 25200056) Calcium / Magnesium-free DPBS (Invitrogen 14190-136) DMSO dry (Sigma D2650) DAMGO OPRMu1 agonist MW513.19 (Sigma E7384-5MG) B-Funaltrexamine Hydrochloride OPRM1 Antagonist MW (SIGMA O003-2MG) PathHunter Cell Plating 5 Reagent (Discover X 93-0563R5A) Corning 3750 Standard 384-Well White Plate with Lid

[0277] PathHunter Detection Mix (DiscoverX 93-0001): 1 part Galacton Star, 5 parts Emerald II, and 19 parts PH Cell Assay Buffer

[0278] OPRDelta 1 Tango B-Arrestin Assay Protocol – Antagonist Mode The Tango OPRDelta1-U20S dividing cell line was cultured in 150-mm dishes at 37°C, 5% CO2, and 95% relative humidity (RH). Growth medium consisted of McCoys 5A medium supplemented with 10% (v / v) dialyzed fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin-streptomycin).

[0279] On assay day 1, 16,000 cells in 10 μL of assay medium (DMEM-Glutamax supplemented with sodium pyruvate, charcoal-dextran-stripped (CDS) 10% fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, and antibiotic mix (penicillin-streptomycin)) were seeded into each well of a 384 Greiner 788092 black, low-profile, clear-bottom, low-volume plate. 50 nL of 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, 1.1 μL of SNC80 OPRD1 agonist (commercially available) or DMSO (EC80 challenge consisted of 1.1 μL of 3.7 μM SNC80, final assay concentration = 370 nM) in assay medium was added to the appropriate wells and incubated at 37 °C, 5% CO2 and 95% RH for 16–24 h.

[0280] On day 2, 2.5 μL of LiveBLazer™ FRET B / G(CCF4-AM) mix (solutions A, B, C, and D) was added to each well, and the plate was then incubated for 2 hours in the dark at room temperature. Fluorescence in the wells was measured on a Perkin Elmer Envision using a 405 nm excitation filter, 460 nm and 590 nm emission filters, and a bottom read.

[0281] Percent inhibition was calculated from the median ratio as follows: TIFF2026506965000133.tif10128 expression Test compounds are defined as wells containing test compounds; Low control is defined as wells containing SNC80 challenge (370 nM final) = 0% inhibition; High controls are defined as wells containing DMSO = 100% inhibition.

[0282] Reagent list: Tango(trademark) OPRD1-bla U20S (Invitrogen K1778) McCoy's 5A medium (Invitrogen 16600-082) Dialyzed fetal bovine serum (Invitrogen 26400-036) Non-essential amino acids 100x (Invitrogen 11140-050) HEPES (pH7.3) 1M (Invitrogen 15630-080) Sodium pyruvate 100x (Invitrogen 11360-070) Penicillin Streptomycin (Invitrogen 15640) Trypsin 0.25% EDTA (Invitrogen 25200056) Calcium / Magnesium-free DPBS (Invitrogen 14190-136) DMEM, high glucose, GlutaMAX (Invitrogen 10569-010) Charcoal-stripped fetal bovine serum (Invitrogen 12676-011) DMSO dry (Sigma D2650) SNC80 OPRD1 agonist MW449.63 (Sigma S2812) SDM25N Hydrochloride OPRD1 Antagonist MW468.98 (Tocris 1410)

[0283] LiveBLAzer™-FRET / BG Loading Mix: (Invitrogen K1030 (5 mg)), composed of solutions A, B, C, and D: Solution A (6 μL): LiveBLAzer(TM)-FRET / BG substrate (CCF4-AM) Solution B (60μL) Solution C (904μL) Solution C (250 μl of 1N NaOH must be added to 45 mL of Solution C before use) Solution D (30 μL) [Provinicid] (Sigma P8161) Make a 200 mM stock solution in NaOH-H2O.

[0284] Biological Examples The results of the assay are provided below in Table 2. The activity of representative compounds is shown in IC for kappa opioid receptors (KOR) and mu opioid receptors (MOR). 50 Table 2 also shows the selectivity of representative compounds for KOR.

[0285] (Table 2) Activity of representative compounds TIFF2026506965000134.tif58128TIFF2026506965000135.tif168142TIFF2026506965000136.tif200142TIFF2026506965000137.tif203142TIFF2026506965000138.tif217142TIFF2026506965000139.tif220142TIFF2026506965000140.tif212142TIFF2026506965000141.tif203142TIFF2026506965000142.tif214142TIFF2026506965000143.tif204142TIFF2026506965000144.tif196142TIFF2026506965000145.tif207142TIFF2026506965000146.tif207142TIFF2026506965000147.tif208142TIFF2026506965000148.tif216142TIFF2026506965000149.tif197142TIFF2026506965000150.tif201142TIFF2026506965000151.tif215142TIFF2026506965000152.tif225142TIFF2026506965000153.tif205142TIFF2026506965000154.tif210142TIFF2026506965000155.tif206142TIFF2026506965000156.tif208142TIFF2026506965000157.tif219142TIFF2026506965000158.tif199142TIFF2026506965000159.tif204142TIFF2026506965000160.tif203142TIFF2026506965000161.tif200142TIFF2026506965000162.tif222142TIFF2026506965000163.tif201142TIFF2026506965000164.tif206142TIFF2026506965000165.tif224142TIFF2026506965000166.tif218142TIFF2026506965000167.tif163142.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: During the ceremony X is CH and Y is NH; Or, X is N and Y is -C(=N-CN)NR 9 Is it; Or, X is NH and -YR 2 does not exist; R 1 and R 1a are independently H, C 1 ~C 6 selected from the group consisting of alkyl, and halo; Or, R 1 and R 1a together with the carbon atoms to which they are attached to form fused C 3 ~C 8 forming a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl, wherein 1 to 4 ring members are independently selected from N, O, and S; R 2 is H, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, -(C 1 ~C 6 Alkyl)C 3 ~C 8 cycloalkyl, and 3- to 6-membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S; R 9 is H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 8 Cycloalkyl, and -(C 1 ~C 6 Alkyl)(C 3 ~C 8 cycloalkyl); R 3 In each case, C 1 ~C 6 is alkyl; n is 0, 1, or 2; R 4 , R 5 , R 6 , R 7 , and R 8 are independently H, CN, OH, halo, NRR', C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, O(C 1 ~C 6 alkyl), O(C 1 ~C 6 haloalkyl), -C(O)(C 1 ~C 6 alkyl), -C(O)O(C 1 ~C 6 alkyl), -C(O)(C 6 ~C 10 aryl), -SO 2 (C 1 ~C 6 alkyl), -(C 1 ~C 6 alkyl)C(O)O(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C 1 ~C 6 alkyl)C(O)N(RR'), C 6 ~C 10 Aryl, C 3 ~C 8 Cycloalkyl, O(C 3 ~C 8 cycloalkyl), -(C 1 ~C 6 Alkyl)(C 6 ~C 10 aryl), -(C 1 ~C 6 Alkyl)(C 3 ~C 8 cycloalkyl), 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), -(C 1 ~C 6 alkyl)(3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), 5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), -(C 1 ~C 6 alkyl)(5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S)), wherein: R and R' are independently H and C 1 ~C 6 alkyl; 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 in 1 ~C 6 Alkyl, Halo, NO 2 , OH, CN, and C 1 ~C 6 It may be optionally substituted with 1 to 6 substituents independently selected from the group consisting of haloalkyl.

2. A compound of formula (II) or a pharmaceutically acceptable salt thereof: During the ceremony Ar is (R 3 ) n wherein 1 to 4 members of the heteroaryl are independently selected from N, O, and S; X is CH and Y is NH; Or, X is N and Y is a bond, C(O), and -C(=N-CN)NR 9 More selected? Or, X is NH and -YR 2 does not exist; R 1 and R 1a are independently H, C 1 ~C 6 selected from the group consisting of alkyl, and halo; Or, R 1 and R 1a together with the carbon atoms to which they are attached to form fused C 3 ~C 8 forming a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl, wherein 1 to 4 ring members are independently selected from N, O, and S; where X is CH, (i)R 1 and R 1a is not H and Ar is other than oxadiazolyl, thiadiazolyl, and triazolyl; or (ii) optionally, R 1 or R 1a together with Y and the carbon atom to which they are attached form a fused 5- to 6-membered heterocycloalkyl; R 2 is H, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, -(C 1 ~C 6 Alkyl)C 3 ~C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and —(C 1 ~C 6 alkyl) (3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); R 9 is H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 8 Cycloalkyl, and -(C 1 ~C 6 Alkyl)(C 3 ~C 8 cycloalkyl); R 3 is independently C in each case 1 ~C 6 Alkyl or C 1 ~C 6 haloalkyl; n is 0, 1, or 2; R 4 , R 5 , R 6 , R 7 , and R 8 are independently H, CN, OH, halo, NRR', C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, O(C 1 ~C 6 alkyl), O(C 1 ~C 6 haloalkyl), -C(O)(C 1 ~C 6 alkyl), -C(O)O(C 1 ~C 6 alkyl), -C(O)(C 6 ~C 10 aryl), -SO 2 (C 1 ~C 6 alkyl), -(C 1 ~C 6 alkyl)C(O)O(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C 1 ~C 6 alkyl)C(O)N(RR'), C 6 ~C 10 Aryl, C 3 ~C 8 Cycloalkyl, O(C 3 ~C 8 cycloalkyl), -(C 1 ~C 6 Alkyl)(C 6 ~C 10 aryl), -(C 1 ~C 6 Alkyl)(C 3 ~C 8 cycloalkyl), 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), -(C 1 ~C 6 alkyl)(3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), 5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), -(C 1 ~C 6 alkyl)(5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S); R and R' are independently H and C 1 ~C 6 alkyl; 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 in 1 ~C 6 Alkyl, Halo, NRR', NO 2 , OR, CN, and C 1 ~C 6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of haloalkyl; wherein the compound is isn't it.

3. The compound has the formula (IIA):

3. The compound of claim 2, wherein the compound is: or a pharmaceutically acceptable salt thereof.

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

5. 5. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isoxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

6. 6. The compound of any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from the group consisting of pyrazolyl, oxazolyl, and isoxazolyl.

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

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

9. X is N and Y is -C(=N-CN)NR 9 7. The compound according to any one of claims 1 to 6, wherein:

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

11. R 2 is an optionally substituted 3- to 6-membered heterocycloalkyl, wherein one ring member is O, or a pharmaceutically acceptable salt thereof.

12. R 2 may be substituted 12. The compound of any one of claims 1 to 11, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

13. R 2 but 13. The compound according to any one of claims 1 to 12, wherein:

14. R 2 is substituted with 1 to 3 substituents selected from halo and OH, or a pharmaceutically acceptable salt thereof.

15. R 2 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is substituted with halo.

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

17. R 2 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is substituted with OH.

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

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

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

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

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

23. R 1 and R 1a 20. The compound of any one of claims 1 and 3 to 19, or a pharmaceutically acceptable salt thereof, wherein each is H.

24. R 1 and R 1a together with the carbon atoms to which they are attached to form an optionally substituted fused C 3 ~C 8 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl, wherein 1 to 4 ring members are independently selected from N, O, and S.

25. R 1 and R 1a together with the carbon atoms to which they are attached to form an optionally substituted fused C 3 ~C 8 25. The compound of any one of claims 1 to 19 and 24, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

26. Condensation C 3 ~C 8 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is cyclopropyl.

27. R 1 or R 1a or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 2 to 26, wherein, together with Y and the carbon atom to which they are attached, form a fused 5- to 6-membered heterocycloalkyl.

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

29. R 4 H, CN, halo, and C 1 ~C 6 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

30. R 4 C 1 ~C 6 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein:

31. R 5 and R 7 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein: is independently selected from the group consisting of H, halo, and CN.

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

33. R 5 and R 7 or a pharmaceutically acceptable salt thereof.

34. R 6 Halo, CN, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 3 ~C 8 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, selected from the group consisting of cycloalkyl.

35. R 6 C 1 ~C 6 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein:

36. R 8 H, CN, Halo, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 6 ~C 10 36. The compound of any one of claims 1 to 35, wherein the compound is selected from the group consisting of aryl, 5- to 10-membered heteroaryl, wherein 1 to 4 members of the heteroaryl are independently selected from N, O, and S, and -CONRR', or a pharmaceutically acceptable salt thereof.

37. R 8 is halo or a 5- to 10-membered heteroaryl, wherein 1 to 4 members of the heteroaryl are independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

38. R 8 or a pharmaceutically acceptable salt thereof.

39. X is CH and Y is NH; R 1 and R 1a one of which is H and the other is F; R 2 is an optionally substituted 3- to 6-membered heterocycloalkyl (wherein one ring member is O); n is 0 or 1; R 4 H, CN, halo, and C 1 ~C 6 selected from the group consisting of alkyl; R 5 and R 7 is independently selected from the group consisting of H, halo, and CN, where R 5 and R 7 at least one of is H; R 6 Halo, CN, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 3 ~C 8 cycloalkyl; R 8 H, CN, Halo, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 6 ~C 10 selected from the group consisting of aryl, 5-10 membered heteroaryl (wherein 1-4 members of the heteroaryl are independently selected from N, O, and S), and -CONRR'; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

40. The compound is selected from the group consisting of the compounds of the following table:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

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

42. 1. A method for treating a disorder in a subject suffering from a disorder for which antagonism of a kappa opioid receptor (KOR) is therapeutically indicated, comprising: Administering to said subject a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof. The method comprising:

43. 1. A method for treating a disorder in a subject suffering from the disorder, comprising: Administering to said subject a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof. wherein the disorder is selected from substance abuse or addiction, psychiatric disorders, obesity and eating disorders, migraine, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, seizures, and sleep disturbances associated with pain, psychiatric disorders, or medication for psychiatric disorders.

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

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

46. 44. The method of claim 43, wherein the disorder is a psychiatric disorder.

47. 47. The method of claim 46, wherein the psychiatric 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 phobia, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorders (ASD).

48. 44. The method of claim 43, wherein the condition is sleep disturbance associated with pain, a psychiatric disorder, or medication for a psychiatric disorder.

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

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

51. 51. The method of any one of claims 43 and 48-50, wherein the sleep disturbance is sleep disruption, insomnia, or a combination thereof.

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