Piperidinyl pain-sensitive peptide receptor compounds

Abstract

This invention provides novel piperidine-containing pain-sensitive peptide receptor ligand compounds and pharmaceutical compositions for the treatment of neurological disorders and conditions, wherein the ligand addresses the negative effects of the condition. These neurological disorders and conditions include: acute and chronic pain, substance abuse / dependence, alcohol addiction, anxiety, depression, sleep disorders, gastrointestinal disorders, kidney disease, cardiovascular disease, and Parkinson's disease.

Description

[0001] This patent application is a divisional application; its original application was filed on December 2, 2016, with application number 201680080898.5, and entitled "Piperidinyl Pain-Inducing Peptide Receptor Compound". The original application was an international application with international application number PCT / US2016 / 064854, international application date of December 2, 2016, and entered the Chinese national phase on August 2, 2018.

[0002] Statement regarding federally funded research This invention was made with government funding under grant numbers R01DA014026, R01DA027811, R43NS070664, R43HL115984, HHSN275201300005C, and HHSN275201500005C from the U.S. Department of Human Health and Services and the National Institutes of Health. The U.S. government owns certain rights in this invention.

[0003] Priority based on 35 USC § 119(e) This application claims priority to U.S. Provisional Patent Application No. 62 / 261,871, filed December 2, 2015, based on 35 USC § 119(e), the entire contents of which are incorporated herein by reference. Technical Field

[0004] This invention provides novel compounds and pharmaceutical compositions thereof that modulate nociceptin receptors. These compounds can be used to treat acute and chronic pain, substance abuse / dependence, alcohol addiction, anxiety, depression, sleep disorders, gastrointestinal disorders, kidney disease, cardiovascular disease, and to treat and / or prevent Parkinson's disease. Background Technology

[0005] NOP receptors, formerly known as opioid receptor-like receptors (ORL1, XOR1, and LC132), belong to the opioid receptor family and share nucleotide and amino acid homology with m, d, and k opioid receptors. However, as expected of opioid receptors, NOP receptors do not bind to opioid ligands with high affinity. The endogenous 17-amino acid peptide ligand of NOP, ororphanin FQ (N / OFQ), has low affinity for m, d, and k opioid receptors.

[0006] When N / OFQ is injected into the lateral ventricle of mice (icv or ICV), the hot plate escape jump latency and tail-flick latency are shortened due to the attenuation of stress-induced opioid-mediated antinociceptive effects. Further studies have shown the presence of NOP and N / OFQ precursor proteins and mRNAs in the pain processing pathway.

[0007] Mounting evidence demonstrates the crucial role of the N / OFQ-NOP receptor system in reward processes and drug abuse. Intermediate to high-density NOP receptors are present in regions involved in drug reward, including the nucleus accumbens, ventral tegmental area, medial prefrontal cortex, lateral hypothalamus, amygdala, and bed nucleus of the stria terminalis. ICV administration of N / OFQ inhibits basal and drug-induced dopamine release in the nucleus accumbens. N / OFQ has been shown to block the reward properties of several common substances of abuse. In particular, N / OFQ is able to block the acquisition of morphine, cocaine, amphetamines, and alcohol-induced conditioned position preference (CPP).

[0008] The inhibitory effect of N / OFQ on the CPP of morphine and its inhibition of morphine-induced dopamine release in the mesolimbic region suggest that N / OFQ can be used as an "anti-opioid" peptide targeting both pain and reward (Ciccocioppo, R., et al., Peptides, 2000, 21(7): 1071-1080). These studies confirm the involvement of the NOP receptor in drug addiction and suggest the use of NOP agonists as agents of drug abuse.

[0009] Approximately 100 million American adults suffer from some form of pain each year, and this condition costs the United States between $560 billion and $635 billion annually in lost productivity and medical expenses (“Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research; Institute of Medicine of the National Academies, June 2011”). Opioid analgesics are the primary means of pain management and are often the only treatment option that provides significant relief. However, opioid analgesics (primarily m-opioid receptor (MOP) agonists) are regulated substances with the potential for abuse and are rife with lifestyle side effects such as constipation, nausea, and intolerance, which compromise their long-term safety and effectiveness and contribute to other social problems (the abuse of prescription analgesics). Therefore, analgesics free from the adverse effects of opioids are crucial to meeting the enormous need for safe and effective pain management, as mandated by the recently enacted National Pain Strategy (NINDS, Interagency Pain Research Coordinating Committee. National Pain Strategy; NIH NINDS: 2015). (http: / / iprcc.nih.gov / National_Pain_Strategy / NPS_Main.htm).

[0010] Within the opioid receptor family of m, d (DOP), k (KOP), and norepinephrine peptide (NOP) opioid receptors, KOP and DOP agonists have also been investigated as analgesics. However, compared to MOP agonists, they did not exhibit strong analgesic effects and showed unfavorable dose intervals and symptoms such as irritability (for KOP agonists) (Wadenberg). CNS DrugRev. , 2003, 9(2):187-198) and seizures (for DOP agonists) (Negus et al., J. Pharmacol. Exp. Ther ., 1994, 270(3): 1025-1034; Negus et al., J. Pharmacol. Exp. Ther Adverse side effects of kinase inhibitors (K-type agonists-antagonists such as nalbuphine and butorphanol) have been used clinically for decades, but are considered to have weaker analgesic effects than MOP-based analgesics.

[0011] On the other hand, based on recent developments, NOP receptor-targeting ligands have clearly shown potential as analgesics (Lin et al., ACS Chem. Neurosci ., 2013, 4(2): 214-224; Linz et al., J. Pharm. Exp. Ther .,2014, 349(3): 535-548; Lambert et al., Br. J. Anaesthesia , 2015, 114(3): 364-366). The NOP receptor and its endogenous ligand N / OFQ are the fourth members of the opioid family. The NOP receptor is present in the same pain pathway as other opioid receptors and has a general inhibitory effect on neurotransmission. New data revealing the role of the NOP receptor in pain and analgesia suggest that NOP agonists, similar to m-opioid agonists such as morphine, may have the potential to be super analgesics, but without the other tendencies of dependence and respiratory depression (Podlesnik et al., 2015, 114(3): 364-366). Psychopharmacology , 2011, 213(1):53-60; Sukhtankar et al., Res. Dev. of Opioid-Related Ligands ACS , 2013, 1131:393-416).

[0012] Studies of systemic administration of non-peptide NOP agonists have revealed that NOP agonists have potent anti-nociceptive activity in several animal models of pain, particularly neuropathic and inflammatory pain (Khroyan et al., Eur. J. Pharmacol., 2009, 610(1-3):49-54; Khroyan et al., J. Pharmacol. Exp. Ther., 2011, 339(2):687-693; Sukhtankar et al., Psychopharmacology, 2014, 231(7):1377-1387). In particular, studies in non-human primates have been more encouraging and consistent than those in rodents, showing that peptide NOP agonists such as N / OFQ and UFP-112 induce spinal cord nociceptive responses in primates when administered intrathecally (Hu et al., Pain, 2010, 148(1):107-113), while the subcutaneously administered non-peptide NOP agonist Ro64-6198 induces nociceptive responses to capsaicin-induced aberrant and thermal pain (Podlesnik et al., Psychopharmacology, 2011, 213(1):53-60). The nociceptive potential and potency of NOP agonists are comparable to those of morphine (Sukhtankar et al., Psychopharmacology, 2014, 231(7):1377-1387), but importantly, there is no itch, respiratory depression, or enhancement at effective doses. These findings in primates strongly support the clinical potential of NOP agonists as a novel approach to analgesia without the adverse effects of opioids (Lin et al., ACS Chem. Neurosci., 2013, 4(2): 214-224).

[0013] Studies have shown that bifunctional NOP / m opioid agonists can also provide a novel approach to developing non-addictive analgesics (Khroyan et al., J. Pharmacol. Exp. Ther., 2007, 320(2): 934-943; Khroyan et al., J. Pharmacol. Exp. Ther., 2011, 339(2):687-693). Other studies have further confirmed that non-peptide bifunctional NOP / m agonists exhibit effective anti-nociceptive effects in rodent and primate models of pain (Linz et al., J. Pharm. Exp. Ther., 2014, 349(3): 535-548).

[0014] Parkinson's disease (PD) is clinically characterized by low / loss of motor function, rigidity, gait disturbance, and resting tremor, as well as other nonmotor symptoms such as depression and cognitive decline. PD is an expensive disease, both for the individual and for society. PD patients spend significantly more annually on direct costs (e.g., medication and hospitalization) and indirect costs (e.g., absenteeism, early retirement; infrequent home care) than healthy individuals. Therefore, from an economic perspective, therapies that prevent loss of motor function or cognitive impairment can significantly reduce indirect costs with minimal increase in overall healthcare costs. It has long been recognized that PD patients who respond stably to dopaminergic therapy (currently the preferred treatment) gradually develop two progressive clinical phenomena: fluctuating motor symptoms and motor disturbances (involuntary movements), which are even more debilitating, and for which there is "only one" FDA-approved treatment. L-DOPA (L,3,4-dihydroxyphenylalanine; L-DOPA), a precursor to dopamine (DA), is a milestone in PD therapy and is currently often administered in combination with COMT and MAO inhibitors to expand its bioavailability and therapeutic efficacy.

[0015] However, chronic L-DOPA therapy is associated with the eventual development of motor complications (fluctuations in motor symptoms and dyskinesia) (~80% of patients within 10 years), which limits its clinical efficacy and significantly reduces patients' quality of life. Therefore, developing drugs that can delay the development of dyskinesia and / or attenuate its manifestation in patients who have already developed dyskinesia is a major unmet medical need in PD. Levodopa-induced dyskinesia (LID) is a significant cause of disability and social distress in PD patients, leading to a risk of falls and the need for caregivers, especially in advanced PD cases with other neurodegenerative pathological features (i.e., memory impairment, hallucinations, and comorbidities) (Schrag et al., Mov. Disorders (2007, 22:938–945). Treatment options for movement disorders are very limited, and the only drugs available on the market for treating movement disorders, namely amantadine and glutamate antagonists, have poor clinical efficacy and very short duration of action.

[0016] The N / OFQ-NOP receptor system is widely expressed in the cerebral cortex and subcortical regions, particularly in striatal neurons, globus pallidus neurons, and substantia nigra (SN) neurons—regions where neurodegenerative changes occur in Parkinson's disease (PD). Endogenous N / OFQ has been shown to be one of the causes of PD symptoms because N / OFQ levels in SNr increase after loss or damage to dopamine (DA)-transmitting cells. This elevation has also been observed in the CSF of PD patients (Marti et al., 2010). NOP receptor antagonists reversed PD neurodegenerative (6-OHDA-half-dead rats, MPTP-treated mice, and rhesus monkeys) and functional (reserpine-treated or haloperidol-treated animals) models of Parkinson's disease. Genetic deletion of the N / OFQ gene prevented the effects of MPTP neurotoxicity in mice. Mechanistic studies reveal that the anti-Parkinson's disease effect of NOP antagonists is achieved through the normalization of the imbalance between excitatory (GLU) and inhibitory (GABA) inputs to substantia nigra neurons generated by striatal dopamine desensitization. NOP antagonists also enhance the symptomatic efficacy of levodopa. Therefore, NOP receptor antagonists can provide both symptomatic and neuroprotective benefits to PD patients.

[0017] On the other hand, the effects of NOP receptor agonists on aberrant involuntary movements (AIM, LID-related in rodents) have been demonstrated in kinesiopathy rats and non-human primates challenged by L-DOPA. Therefore, NOP receptor ligands show promising efficacy in animal models of Parkinson's disease.

[0018] International patent publications by Ito et al. (WO 2005 / 016913) and Spear et al. (WO 2014 / 106238) disclose compounds active against NOP receptors for the treatment of pain and CNS diseases. US patent applications by Zaveri et al. (2005 / 0228023), Tafesse (2015 / 0315201), and Mustazza et al. also disclose... J. Med. Chem. Patent application 2008, 51:1058-1062, discloses piperidine-containing compounds active against the NOP receptor. U.S. Patent Application No. 2013 / 0225552 by Allen et al. discloses heterobicyclic compounds as PDE 10 inhibitors. However, novel NOP receptor ligands are still needed. Summary of the Invention

[0019] This invention fulfills this and other needs by providing novel piperidine-based pain-sensitive peptide receptor compounds. These novel piperidine-based pain-sensitive peptide receptor compounds can be used to treat and prevent various disease states.

[0020] In one embodiment, a compound of structural formula (I) is provided:

[0021] Or a salt, hydrate, or solvation of the compound, wherein: A is or B is hydrogen; or, alternatively, A and B are missing and the carbon atoms attached to A and B are... The carbon atom adjacent to the amide carbonyl atom in the group; R1 and R2 together with the carbon atoms attached to R1 and R2 form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group; X is hydrogen, -C=NOR4, -C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; Y is hydrogen, -C=NOR7, -C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; T is =NR 10 =CR 11 R 12 -、-NR 13 R 14 - substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, or substituted heteroarylalkyl; when R1 and R2 form a phenyl ring and L is If R3 is neither hydrogen nor methyl; R4 is hydrogen, alkyl, or substituted alkyl; R5 is hydrogen, alkyl, or substituted alkyl; R6 is hydrogen, alkyl, substituted alkyl, or OR 15 R7 is hydrogen, alkyl, or substituted alkyl; R8 and R9 are independently hydrogen, alkyl, or substituted alkyl; R 10 It is hydrogen, alkyl, substituted alkyl, -OR 16 or -NR 17 R 18 ;R 11 It is hydrogen, alkyl, substituted alkyl, -C(O)R 19 or -CN;R 12 It is hydrogen, -C(O)R 20 or -CN;R 13 It is hydrogen or -C(O)R 21 ;R 14 It is hydrogen or -C(O)R 22 If R 13 and R14 Neither of them is hydrogen; R 15 It is hydrogen, alkyl, or substituted alkyl; R 16 It is hydrogen, alkyl, or substituted alkyl; R 17 It is hydrogen or -C(O)R 23 ;R 18 It is hydrogen or -C(O)R 24 ;R 19 and R 20 Independently is -NR 25 R 26 -OR 27 alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R 21 and R 22 Independently is -NR 28 R 29 -OR 30 alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R 23 and R 24 It is independently an alkyl or substituted alkyl group; R 25 R 26 R 27 R 28 R 29 and R 30 Independently, it is hydrogen, alkyl, or substituted alkyl; and L is (C3-C8) cycloalkyl, (C3-C8) substituted cycloalkyl, (C3-C8) cyclohexaalkyl, (C3-C8) substituted cyclohexaalkyl, , , or .

[0022] In addition, derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs of the compounds described herein, are also provided. Compositions comprising the compounds and supports provided herein are also provided.

[0023] Methods for treating, preventing, or improving symptoms of medical conditions such as, for example, Parkinson's disease, cardiovascular disease, gastrointestinal disorders, alcohol addiction, acute and chronic pain, anxiety, depression, pain, sleep disorders, and substance abuse / dependence are also provided herein. In performing these methods, an effective therapeutic amount of the compound or a pharmaceutical composition thereof is administered to the patient.

[0024] Methods for modulating pain-sensitive peptide receptors (Tt) using the compounds and compositions described herein are also provided herein. In carrying out this method, an effective therapeutic amount of the compound or pharmaceutical composition is administered. Detailed Implementation

[0025] definition Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. If a term has multiple definitions herein, the terminology used herein shall prevail unless otherwise stated.

[0026] "alkyl," either itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain, or cyclic monovalent hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Typical alkyl groups include, but are not limited to: methyl; ethyl, such as acetyl, vinyl, ethynyl; propyl, such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, propan-1-en-1-yl, propan-1-en-2-yl, propan-2-en-1-yl (allyl), cyclopropan-1-en-1-yl, cyclopropan-2-en-1-yl, propan-1-yn-1-yl, propan-2-yn-1-yl, etc.; butyl, such as butan-1-yl, butan-2-yl, 2-methylpropane. -1-yl, 2-methyl-propane-2-yl, cyclobut-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-propane-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuty-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and so on. The term "alkyl" is specifically intended to include groups having any degree or level of saturation, i.e., groups having only a single carbon bond, groups having one or more double carbon bonds, groups having one or more triple carbon bonds, and groups having a mixture of single, double, and triple carbon bonds. The terms "chain alkyl," "chain alkenyl," and "alkynyl" are used when a specific level of saturation is desired. In some embodiments, the alkyl group comprises 1 to 20 carbon atoms (C1-C2). 20 Alkyl group). In other embodiments, the alkyl group comprises 1 to 10 carbon atoms (C1-C1). 10 Alkyl groups. In other embodiments, the alkyl group comprises 1 to 6 carbon atoms (C1-C6 alkyl). The term "cyclic monovalent hydrocarbon radical" also includes polycyclic hydrocarbon ring systems having a single radical and between 3 and 12 carbon atoms. Exemplary polycyclic alkyl rings include, for example, norbornyl, pinyl, and adamantyl.

[0027] "Alkyl group," either itself or as part of another substituent, refers to a saturated branched, straight-chain, or cyclic alkane radical derived by removing a hydrogen atom from a single carbon atom of the parent alkane. Typical alkyl groups include, but are not limited to: methyl; ethyl; propionyl, such as propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl, etc.; butyl, such as butane-1-yl, butane-2-yl (sec-butyl), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (tert-butyl), cyclobutane-1-yl, etc.; and so on.

[0028] "Alkenyl," either itself or as part of another substituent, refers to an unsaturated branched, straight-chain, or cyclic alkane radical derived by removing a hydrogen atom from a single carbon atom of a parent alkane, having at least one carbon-carbon double bond. This group can be cis- or trans-conformed relative to the double bond. Typical alkenyl groups include, but are not limited to: vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; Butenyl groups, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuty-1,3-dien-1-yl, etc.; and so on.

[0029] "Alynyl", either itself or as part of another substituent, refers to an unsaturated branched, straight-chain, or cyclic alkane radical derived by removing a hydrogen atom from a single carbon atom of the parent alkyne and having at least one carbon-carbon triple bond. Typical alkynyl groups include, but are not limited to: ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and so on.

[0030] "Aryl," either itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, hexabenzobenzene, fluoranthene, fluorene, hexabenzobenzene, hexalene, and asymmetric indole. as -indacene), Symmetrical Indication Province ( s -indacene), indene, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentalene, phenalene, phenanthrene, phenanthrene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and other derivative groups. In some embodiments, the aryl group comprises 6 to 20 carbon atoms (C6-C4). 20 Aryl group). In other embodiments, the aryl group comprises 6 to 15 carbon atoms (C6-C5). 15 Aryl group). In other embodiments, the aryl group comprises 6 to 15 carbon atoms (C6-C5). 10 Aryl).

[0031] "Arylalkyl", either on its own or as part of another substituent, refers to a group with a carbon atom (usually the terminal carbon atom or...). sp 3 An arylalkyl group is an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group, as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylvinyl-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylvinyl-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, etc. The terms aryl-chain alkyl, aryl-chain alkenyl, and / or arylynyl are used when a particular alkyl moiety is desired. In some embodiments, the arylalkyl group is (C6-C6) 30 ) arylalkyl, for example, the alkyl, alkenyl or ynyl moiety of the arylalkyl group is (C1-C1) 10 The alkyl group is (C6-C) while the aryl group is (C6-C). 20aryl. In other embodiments, the arylalkyl group is (C6-C6). 20 arylalkyl groups, for example, where the alkyl, alkenyl, or ynyl moiety of the arylalkyl group is (C1-C8) alkyl and the aryl moiety is (C6-C8) alkyl. 12 aryl. In other embodiments, the arylalkyl group is (C6-C6) 15 arylalkyl groups, for example, where the alkyl, alkenyl, or ynyl moiety of the arylalkyl group is (C1-C5) alkyl and the aryl moiety is (C6-C5) alkyl. 10 Aryl.

[0032] "Compound" means the compound covered by the structural formulas disclosed herein, and includes any specific compound whose structure is disclosed within those structural formulas. A compound can be identified by its chemical structure and / or chemical name. When the chemical structure and chemical name conflict, the chemical structure determines the identity of the compound. The compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Therefore, the chemical structures depicted herein cover all possible enantiomers and stereoisomers of the illustrated compounds (including pure stereoisomers (e.g., pure geometric forms, pure enantiomers, or pure diastereomers)) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be decomposed into enantiomers or stereoisomers of their constituents using separation techniques or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures depicted herein cover all possible tautomeristic forms of the illustrated compounds. The described compounds also include isotopically labeled compounds, where one or more atoms have atomic weights different from those conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of this invention include, but are not limited to: 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O, etc. The compound can exist in both solvated (including hydrated) and non-solvated or non-hydrated forms, and can exist as an N-oxide. Generally, the compound can be hydrated, solvated, or exist as an N-oxide. Some compounds can exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent for the purposes considered herein and are intended to be within the scope of this invention. Furthermore, it should be understood that when describing a portion of the structure of a compound, parentheses indicate the connection point between that portion of the structure and the rest of the molecule.

[0033] "Halogenated," either on its own or as part of another substituent, refers to the free radicals -F, -Cl, -Br, or -I.

[0034] "Heteroalkyl," "heteroalkyl," "heteroalkenyl," and "heteroyneyl," either alone or as part of other substituents, refer to an alkyl group, a chain alkyl group, a chain alkenyl group, and an alkynyl group, in which one or more carbon atoms (and, where applicable, any associated hydrogen atoms) are each independently substituted by the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatom groups capable of substituting carbon atoms include, but are not limited to: -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, etc., and combinations thereof. Heteratoms or heteroatom groups can be placed at any internal position within an alkyl group, a chain alkenyl group, or an alkynyl group. Typical heteroatom groups that can be included in these groups include, but are not limited to: -O-, -S-, -OO-, -SS-, -OS-, -NR. 501 R 502 -、=NN=、-N=N-、-N=N-NR 503 R 404 -PR 505 -、-P(O)2-、-POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 - etc., where R 501 R 502 R 503 R 504 R 505 R 506 R 507 and R 508 Independently, it is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cyclohexyl, substituted cyclohexyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

[0035] "Heteroaryl", either on its own or as part of another substituent, refers to a monovalent heteroaryl radical derived by removing a hydrogen atom from a single atom of the parent heteroaryl ring system, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromene, chromene, zoline, furan, imidazole, indazole, indole, indoline, inazine, isobenzofuran, isochromene, isoindoline, isodihydroindoline, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, naphthalene-intercalated diazoxide, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazolium, thiadiazole, thiazole, thiophene, triazole, xanthan, etc. In some embodiments, the heteroaryl group comprises 5 to 20 cyclic atoms (5-membered to 20-membered heteroaryl groups). In other embodiments, the heteroaryl group comprises 5 to 10 ring atoms (5-membered to 10-membered heteroaryl groups). Exemplary heteroaryl groups include heteroaryl groups derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0036] "Heteroarylalkyl", either on its own or as part of another substituent, refers to a group with a carbon atom (usually the terminal carbon atom or...) sp 3 A noncyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. The terms heteroarylalkyl, heteroarylalkenyl, and / or heteroarylynyl are used if a specific alkyl moiety is desired. In some embodiments, the heteroarylalkyl group is a 6- to 21-membered heteroarylalkyl group, for example, the alkyl, alkenyl, or ynyl moiety of the heteroarylalkyl group is a (C1-C6) alkyl group, while the heteroaryl moiety is a 5- to 15-membered heteroaryl group. In other embodiments, the heteroarylalkyl group is a 6- to 13-membered heteroarylalkyl group, for example, the alkyl, alkenyl, or ynyl moiety is a (C1-C3) alkyl group, while the heteroaryl moiety is a 5- to 10-membered heteroaryl group.

[0037] "Parent aromatic ring system" refers to a ring system with unsaturated or polycyclic rings having a conjugated π-electron system. Specifically, included within the definition of "parent aromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, fluorene, indene, indene, phenaene, etc. Typical parent aromatic ring systems include, but are not limited to: aceanthrylene, acenaphthene, acephenanthrylene, anthracene, azurite, benzene, chrysene, hexabenzobenzene, fluoranthene, fluorohexabenzone, hexaphene, hexalene, asymmetric indole, symmetric indole, indene, naphthalene, octylbenzene, octylbenzene, octylcyclooctadiene, olebenzene, penta-2,4-diene, pentanebenzene, pentabenzene, dinaphthalene, phenaene, phenanthrene, heptamethrin, pyrene, pinane, rubidium, triphenylene, trinaphthalene, etc.

[0038] A “parent heteroaromatic ring system” refers to a parent aromatic ring system in which one or more carbon atoms (and, where appropriate, any associated hydrogen atoms) are independently replaced by the same or different heteroatoms. Typical heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically, included within the definition of a “parent heteroaromatic ring system” are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromene, indole, dihydroindole, xaton, etc. Typical parent heterocyclic aromatic ring systems include, but are not limited to: arsindole, carbazole, β-carboline, chromene, chromene, zoline, furan, imidazole, indazole, indole, dihydroindole, inazine, isobenzofuran, isochromene, isoindole, isodihydroindole, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, naphthalene-intercalated diazoxide, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthan, etc.

[0039] "Preventing" or "prevention" refers to reducing the risk of developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a patient who is susceptible to the disease or has symptoms of the disease but has not yet felt or shown them). Therapies performed to prevent or avoid disease or disorder are called "prophylaxis." In some embodiments, the compounds provided herein offer superior prophylaxis due to lower long-term side effects over a longer period.

[0040] "Salt" refers to the salt of a compound that possesses the pharmacological activity required by the parent compound. Such salts include: (1) acid addition salts, which form with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, The salt is formed from organic acids such as camphor sulfonic acid, 4-methyl-bicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-hexanoic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, and mucoconic acid; or (2) when the acid proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when it is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucosamine.

[0041] When "substitution" is used to modify a specific group or free radical, it refers to the independent replacement of one or more hydrogen atoms of that specific group or free radical by the same or different substituents. Substituent groups used to replace saturated carbon atoms in a specific group or free radical include, but are not limited to: -R a Halogenated, -O - =O, -OR b -SR b -S - =S, -NR c R c =NR b =N-OR b Trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b -N-NR c R c -NR b S(O)2R b =N2, -N3, -S(O)2R b -S(O)2NR b R b -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2O - -OS(O)2OR b -OS(O)2NR c NRc 、- -P(O)(O - )2、-P(O)(OR b )(O - )、-P(O)(OR b )(OR b )、-C(O)R b 、-C(O)NR b -OR b -C(S)R b 、-C(NR b )R b 、-C(O)O - 、-C(O)OR b 、-C(S)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-OC(S)R b 、-OC(O)O - 、-OC(O)OR b 、-OC(O)NR c R c 、-OC(NCN)NR c R c -OC(S)OR b 、-NR b C(O)R b 、-NR b C(S)R b 、-NR b C(O)O - 、-NR b C(O)OR b 、-NR b C(NCN)OR b 、-NR b S(O)2NR c R c 、-NR b C(S)OR b 、-NR b C(O)NR c R c 、-NR b C(S)NR c R c 、-NR b C(S)NR b C(O)R a 、-NR b S(O)2ORb -NR b S(O)2R b -NR b C(NCN)NR c R c -NR b C(NR b )R b and -NR b C(NR b )NR c R c , where R a Independently, each R is an alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl group; b Independently, it is hydrogen, R a , substituted alkyl, substituted heteroalkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl and substituted heteroarylalkyl; and each R c R is independent b Or, as an alternative, two Rs c The nitrogen atoms are bonded together to form 4-, 5-, 6-, or 7-membered cyclohexaalkyl, substituted cyclohexaalkyl, or cyclohexaalkyl fused with an aryl group, which may, depending on the case, include 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S. As a specific example, -NR c R c This means it includes –NH2, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl.

[0042] Similarly, substituent groups used to replace unsaturated carbon atoms in specific groups or free radicals include, but are not limited to: -R a Halogenated, -O - -OR b -SR b -S - -NR c R c Trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2R b -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2O - -OS(O)2OR b -P(O)(O) - )2、-P(O)(OR b (O) - -P(O)(OR) b (OR) b-C(O)R b -C(S)R b -C(NR) b )R b -C(O)O - -C(O)OR b -C(S)OR b -C(O)NR c R c -C(NR) b )NR c R c -OC(O)R b -OC(S)R b -OC(O)O - -OC(O)OR b -OC(S)OR b -OC(O)NR c R c -OS(O)2NR c NR c -NR b C(O)R b -NR b C(S)R b -NR b C(O)O - -NR b C(O)OR b -NR b S(O)2OR a -NR b S(O)2R a -NR b C(S)OR b -NR b C(O)NR c R c -NR b C(NR b )R b and -NR b C(NR b )NR c R c , where R a R b and R c As defined above.

[0043] Substituent groups used to replace nitrogen atoms in heteroalkyl or cyclohexaalkyl groups include, but are not limited to: -R a -O - -OR b -SR b -S- -NR c R c Trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R b -S(O)2O - -S(O)2OR b -OS(O)2R b -OS(O)2O - -OS(O)2OR b -P(O)(O) - )2、-P(O)(OR b (O) - -P(O)(OR) b (OR) b -C(O)R b -C(S)R b -C(NR) b )R b -C(O)OR b -C(S)OR b -C(O)NR c R c -C(NR) b )NR c R c -OC(O)R b -OC(S)R b -OC(O)OR b -OC(S)OR b -NR b C(O)R b -NR b C(S)R b -NR b C(O)OR b -NR b C(S)OR b -NR b C(O)NR c R c -NR b C(NR b )R b and -NR b C(NR b )NR c R c , where R a R b and R c As defined above.

[0044] The substituent groups listed above that are used to replace other specific groups or atoms will be obvious to those skilled in the art.

[0045] Substituents used to replace specific groups can be further replaced, and are usually selected from one or more of the same or different groups mentioned above.

[0046] compound

[0047] This invention provides novel piperidinyl pain-sensitive peptide receptor ligands for treating neurological diseases and conditions, which address the negative effects of these conditions. These neurological diseases and conditions include, for example, acute and chronic pain, substance abuse / dependence, alcohol addiction, anxiety, depression, sleep disorders, gastrointestinal disorders, kidney disease, cardiovascular disease, and Parkinson's disease.

[0048] In some embodiments, compounds of structural formula (I) are provided:

[0049] Or its salt, aqueous compound or solvate, wherein A is or ; B is hydrogen; or, alternatively, A and B are missing and the carbon atoms attached to A and B are hydrogen atoms. The carbon atom adjacent to the amide carbonyl atom in the formula; R1 and R2 together with the carbon atoms attached to R1 and R2 form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group; X is hydrogen, -C=NOR4, -C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; Y is hydrogen, -C=NOR7, -C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; T is =NR 10 =CR 11 R 12 -、-NR 13 R 14 - substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; R3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, or substituted heteroarylalkyl; when R1 and R2 form a phenyl ring and L is If R3 is neither hydrogen nor methyl; R4 is hydrogen, alkyl, or substituted alkyl; R5 is hydrogen, alkyl, or substituted alkyl; R6 is hydrogen, alkyl, substituted alkyl, or OR 15 R7 is hydrogen, alkyl, or substituted alkyl; R8 and R9 are independently hydrogen, alkyl, or substituted alkyl; R 10 It is hydrogen, alkyl, substituted alkyl, -OR 16 or -NR 17 R 18 ;R 11 It is hydrogen, alkyl, substituted alkyl, -C(O)R 19 or -CN;R 12 It is hydrogen, -C(O)R 20 or -CN;R 13 It is hydrogen or -C(O)R 21 ;R 14 It is hydrogen or -C(O)R 22 If R 13 and R 14 Neither of them is hydrogen; R 15 It is hydrogen, alkyl, or substituted alkyl; R 16 It is hydrogen, alkyl, or substituted alkyl; R 17 It is hydrogen or -C(O)R 23 ;R 18 It is hydrogen or -C(O)R 24 ;R 19 and R 20 Independently is -NR 25 R 26 -OR 27 alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R 21 and R 22 Independently is -NR 28 R 29 -OR 30 alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R 23 and R 24 It is independently an alkyl or substituted alkyl group; R 25 R 26 R 27 R 28 R 29 and R 30 Independently, it is hydrogen, alkyl, or substituted alkyl; and L is (C3-C8)cycloalkyl, (C3-C8) substituted cycloalkyl, (C3-C8) cyclohexaalkyl, (C3-C8) substituted cyclohexaalkyl, , , or .

[0050] In some embodiments, R1 and R2 together with the carbon atoms attached to R1 and R2 form a phenyl, substituted phenyl, pyridyl, or substituted pyridyl group.

[0051] In some embodiments, L is a (C3-C8)cycloalkyl, a (C3-C8) substituted cycloalkyl, or a (C3-C8) cyclohexaalkyl. In other embodiments, L is... or n is 0, 1, or 2, and K is -NR. 31 -or-O- and R 31 It is hydrogen, alkyl, or substituted alkyl. In other embodiments, L is a substituted cyclohexyl group. In other embodiments, L is... Z is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; and U is hydrogen, alkyl, or omitted. In other embodiments, Z is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl. In other embodiments, Z is... , , or And U is hydrogen. In other embodiments, Z is methyl and U is methyl. In other embodiments, Z is , while U is missing.

[0052] In some embodiments, A is In other embodiments, R1 and R2 form a phenyl, substituted phenyl, pyridyl, or substituted pyridyl group. In still other embodiments, compounds of structural formula (II) are provided:

[0053] Where D is -CH- or -N-, R 32 It is alkyl, halogenated, -OR 33 -NHR 34 -CF3 or -CN; n is an integer between 0 and 4; R 33 It is hydrogen, alkyl, -(CO)NR 35 R 36 or -SO2NR 37 R 38 And R 34 R 35 R 36 R 37 and R 38Independently, X is hydrogen or alkyl. In other embodiments, X is hydrogen, -C=NOR4, -C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; while Y is hydrogen, -C=NOR7, -C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, or substituted heteroalkyl. In other embodiments, X is hydrogen; while Y is -C=NOR7, -C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, or substituted heteroalkyl. In other embodiments, X is -C=NOR4, -C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; while Y is hydrogen. In other embodiments, X is -C=NOR4, -C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, or substituted heteroalkyl; while Y is -C=NOR7, -C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, or substituted heteroalkyl.

[0054] In some embodiments, A is In other embodiments, R1 and R2 form a phenyl, substituted phenyl, pyridyl, or substituted pyridyl group. In still other embodiments, compounds of structural formula (III) are provided:

[0055] Where E is -CH- or -N-, R 39 It is alkyl, halogenated, -OR 40 -NHR 41 -CF3 or -CN; o is an integer between 0 and 4; R 40 It is hydrogen, alkyl, -(CO)NR 42 R 43 or -SO2NR 44 R 45 And R 41 R 42 R 43 R 44 and R 45 It is either hydrogen or alkyl.

[0056] In some embodiments, A and B are missing, and the attached carbon atoms are... The carbon atom adjacent to the amide carbonyl atom in the form of R1 and R2. In other embodiments, R1 and R2 form a phenyl, substituted phenyl, pyridyl, or substituted pyridyl group. In still other embodiments, compounds of structural formula (IV) are provided:

[0057] Where J is -CH- or -N-, R 46It is alkyl, halogenated, -OR 47 -NHR 48 -CF3 or -CN; p is an integer between 0 and 4; R 47 It is hydrogen, alkyl, -(CO)NR 49 R 50 -SO2NR 51 R 52 And R 48 R 49 R 50 R 51 and R 52 It is either hydrogen or alkyl.

[0058] Table 1 lists compounds of structural formula (II). In some embodiments, the 1,4 substituents on the cyclohexyl ring are cis-oriented relative to each other.

[0059] Table 1

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] Table 2 lists compounds of structural formula (III). In some embodiments, the 1,4-substituents on the cyclohexyl ring are cis-oriented relative to each other.

[0094] Table 2

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] Table 3 lists compounds of structural formula (IV). In some embodiments, the 1,4-substituents on the cyclohexyl ring are cis-oriented relative to each other.

[0108] Table 3

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] Preparation of compounds Those skilled in the art will understand that the piperidine-containing pain-sensitive peptide receptor compound of formula (I), as well as the embodiments represented by formulas (II), (III), and (IV), can be synthesized by a variety of synthetic routes. Exemplary synthetic methods for the compounds of formula (II) are shown in embodiments 1 to 6 and 10, and are described below in examples 1 to 6 and 10. Table 1 also provides the compounds of formula II. 1H NMR or TLC data.

[0121] Exemplary synthetic methods for compounds of formula (III) are shown in schemes 7 and 8, and are described below in examples 7 and 8. Table 2 provides information on compounds of formula (III). 1 H NMR or TLC data.

[0122] Exemplary routes for compounds of formula (IV) are shown in Scheme 9 and are described below in Example 9. Table 3 provides information on compounds of formula (IV) where indicated. 1 H NMR data.

[0123] Composition and method of application

[0124] The compositions provided herein contain therapeutically effective amounts of one or more of the compounds and carriers provided herein, the compounds being used to prevent, treat, or improve one or more symptoms of the diseases or disorders described herein. Suitable carriers for administering the compounds include any such carriers known to those skilled in the art as being suitable for a particular mode of administration. Furthermore, the compound may be formulated as the sole active ingredient in the composition, or it may be combined with other active ingredients.

[0125] The composition contains one or more of the compounds provided herein. In some embodiments, the compound is formulated into suitable formulations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or elixirs, for oral administration; or by oral inhalation, surface application, transdermal application, and as a sterile solution or suspension for parenteral administration via nebulizers, pressurized metered-dose inhalers, and dry powder inhalers. In some embodiments, the compounds described above are formulated into compositions using techniques and processes well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0126] In these compositions, one or more compounds or their derivatives at effective concentrations are mixed with a suitable carrier. The compound may be derivatized as a salt, ester, enol ether or enol ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug before formulation, as described above. The concentration of the compound in the composition is the amount delivered at the time of administration that is effective in treating, preventing, or improving one or more symptoms of the disease or disorder described herein. In some embodiments, the composition is formulated for single-dose administration. To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed, or mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or improved, one or more symptoms are improved.

[0127] The active compound is contained in a carrier in an amount sufficient to exert a useful therapeutic effect without causing undesirable side effects in the treated patient. By testing the compound in in vitro and in vivo systems, as is well known to those skilled in the art, the effective therapeutic concentration can be empirically predicted, and the human dose can then be deduced. The human dose is then typically fine-tuned in clinical trials and titrated until a response is observed.

[0128] The concentration of the active compound in the composition depends on the absorption, inactivation, and excretion rates of the active compound; the physicochemical properties of the compound; the dosage regimen; and other factors known to those skilled in the art. For example, the amount delivered may be sufficient to improve one or more symptoms of the disease or disorder described herein.

[0129] In instances where the solubility of a compound is insufficient, methods for solubilizing the compound can be employed, such as using liposomes, prodrugs, complexing / chelating agents, nanoparticles, emulsions, or tertiary templating. These methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO); the use of... ® Surfactants or surface modifiers, such as cyclodextrins, or ligands, can be used to enhance dissolution by ionization (i.e., dissolution in an aqueous sodium bicarbonate solution). Derivatives of compounds, such as prodrugs, can also be used to formulate effective compositions.

[0130] When compounds are mixed or added, the resulting mixture can be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on many factors, including the desired method of administration and the solubility of the compound in the chosen carrier. The effective concentration is sufficient to improve the symptoms of the treated disease, disorder, or condition, and this effective concentration can be determined empirically.

[0131] Compositions are provided for administration to humans and animals in appropriate dosage forms for indications, such as dry powder inhalers (DPIs); pressurized metered-dose inhalers (pMDIs); nebulizers; tablets; capsules; pills; sublingual strips / biodigestible strips, tablets, or capsules; powders; granules; lozenges; lotions; ointments; suppositories; fast-melting agents; transdermal patches or other transdermal application devices / formulations; non-gastrointestinal sterile solutions or suspensions; and oral solutions or oral suspensions and oil-water emulsions containing appropriate amounts of the compound or its derivatives. In some embodiments, the therapeutically active compound and its derivatives are formulated and administered in a unit-dosage form or multiple-dosage form. As used herein, a unit-dose form refers to a physically separate unit, individually packaged and known in the art, suitable for human and animal subjects. Each unit dose contains a predetermined amount of the therapeutically active compound, combined with a desired carrier, sufficient to produce the desired therapeutic effect. Examples of single-dose formulations include ampoules and syringes, as well as individually packaged tablets or capsules. Single-dose formulations can be administered in fractions or multiples thereof. Multiple-dose forms are multiple identical single-dose formulations packaged in a single container, administered as separate single-dose units. Examples of multiple-dose forms include vials, bottles of tablets or capsules, or bottles containing several pints or gallons. Therefore, a multiple-dose form is where multiple unit doses are not separated during packaging.

[0132] By dissolving, dispersing, or mixing the active compound and optional excipients as defined above in a carrier such as, for example, water, saline, dextran aqueous solution, glycerol, ethylene glycol, ethanol, etc., liquid compositions, such as solutions or suspensions, colloidal dispersions, emulsions, or liposome formulations, can be prepared. If desired, the compound to be applied may also contain small amounts of non-toxic excipients such as wetting agents, emulsifiers, solubilizers, pH buffers, etc., for example, acetic acid, sodium citrate, cyclodextrin derivatives, sorbitol monolaurate, sodium triethanolamine acetate, triethanolamine oleate, and other such reagents.

[0133] The actual methods for preparing this dosage form are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or a more recent edition thereof.

[0134] Dosage forms or compositions containing 0.005% to 100% of the active ingredient, with the balance consisting of a carrier or transporter, can be prepared. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001% to 100% of the active ingredient, 0.1% to 95% in one embodiment and 0.4% to 10% in another embodiment.

[0135] In some embodiments, the composition is a lactose-free composition containing excipients, well-known in the art, listed as, for example... US Pharmacopeia (USP) 25-NF20 (2002). Typically, lactose-free compositions contain an active ingredient, a binder / filler, and a matching amount of lubricant. In particular, lactose-free formulations contain an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0136] Anhydrous compositions and dosage forms including the active ingredient are also provided, as water can promote the degradation of certain compounds. For example, adding water (e.g., 5%) is widely accepted as a way to simulate long-term storage to determine properties such as shelf life or the stability of formulations over time. See, for example, Jens T. Carstensen. Drug Stability: Principles & Practice , 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-380. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be very significant because moisture and / or humidity are frequently encountered during the manufacture, handling, packaging, storage, transportation, and use of formulations.

[0137] The anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture components and under low-moisture or low-humidity conditions.

[0138] Anhydrous compositions should be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions are typically packaged using materials known to prevent contact with water, enabling them to be contained in suitable formulation boxes. Examples of suitable packaging include, but are not limited to, sealing foil, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0139] Oral dosage forms can be solid, colloidal, or liquid. Solid dosage forms include tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed chewable tablets and tablets that may be enteric-coated, sugar-coated, or film-coated. Capsules may be hard gelatin capsules or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent forms in combination with other ingredients known to those skilled in the art.

[0140] In some embodiments, the formulation is a solid dosage form, such as, for example, capsules or tablets. Tablets, pills, capsules, lozenges, etc., may contain one or more of the following components or compounds with similar properties: binders, lubricants, diluents, glidants, disintegrants, colorants, sweeteners, flavorings, humectants, enteric coatings, film coatings, and release modifiers. Examples of binders include: microcrystalline cellulose, methyl paraben, polyalkylene oxides, tragacanth gum, glucose solution, gum arabic paste, gelatin solution, molasses, polyvinylpyrrolidone, povidone, cross-linked povidone, sucrose, and starch and starch derivatives. Lubricants include: talc, starch, magnesium stearate / calcium stearate, lycopoise, and stearic acid. Diluents include, for example: lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silica. Disintegrants include: sodium crosscarboxymethyl cellulose, sodium carboxymethyl starch, alginate, corn starch, potato starch, bentonite, methyl cellulose, agar, and carboxymethyl cellulose. Colorants include, for example: any approved, water-soluble FD and C dyes, mixtures thereof; and non-water-soluble FD and C dyes known to those skilled in the art that float on alumina hydrates and pre-colored additives or anti-counterfeiting / milky additives. Sweeteners include: sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, and any number of spray-dried flavorings. Flavorings include: natural flavorings extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant sensation or mask an unpleasant taste, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include: propylene glycol monostearate, sorbitol monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Enteric coating agents include: fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Film coating agents include: hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalates. Release modifiers include, for example, Eudragit. ® Polymers of series and cellulose esters.

[0141] The compound or its derivatives can be provided in compositions that prevent them from being affected by the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with antacids or other such ingredients.

[0142] When the dosage unit form is a capsule, it can contain liquid carriers such as fatty oils in addition to the materials mentioned above. Furthermore, the dosage form can contain various other materials in the physical form of the modifier unit, such as sugar coatings and other enteric coatings. The compound can also be administered as a component of elixirs, suspensions, slurries, tablets, powders, chewing gums, etc. Slurries may contain sucrose as a sweetener, as well as some preservatives, dyes and colorants, and flavorings, in addition to the active compound.

[0143] The active material can also be mixed with other active materials that do not impair the desired effect or with materials that complement the desired effect (such as antacids, H2 blockers, and diuretics). The active ingredient is the compound described herein or a derivative thereof. It may include high concentrations, up to about 98% by weight of the active ingredient.

[0144] In all embodiments, it is known to those skilled in the art that tablet formulations and capsule formulations can be coated to adjust or maintain the solubility of the active ingredient. Therefore, for example, conventional digestible enteric coatings, such as phenyl salicylate, waxes, and cellulose phthalate acetate, can be applied.

[0145] Liquid oral dosage forms include: aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent formulations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and slurries. Emulsions are either oil-in-water or water-in-oil emulsions.

[0146] Emulsions are clear, sweet, hydroalcoholic preparations. The carriers used in elixirs include solvents. Slurries are concentrated aqueous solutions of sugars such as sucrose and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed throughout the other in the form of spheres. The carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances for non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and humectants. Acceptable substances for effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and carbon dioxide sources. Colorants and flavorings are used in all of the above dosage forms.

[0147] Solvents include glycerin, sorbitol, ethanol, and slurries. Examples of preservatives include glycerin, methylparaben and propylparaben, benzoic acid, sodium benzoate, and alcohols. Examples of non-aqueous solutions used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, acacia, tragacanth gum, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspensors include sodium carboxymethyl cellulose, pectin, tragacanth gum, magnesium aluminum silicate, and acacia. Sweeteners include sucrose, slurries, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, dehydrated sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene dodecyl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include: any approved and certified water-soluble FD and C dyes and mixtures thereof. Flavoring agents include: natural flavorings extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant taste.

[0148] Regarding solid dosage forms, in some embodiments, solutions or suspensions in the form of, for example, propylene carbonate, vegetable oils, and triglycerides are encapsulated in gelatin capsules. Such solutions, their preparation, and encapsulation are disclosed in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. Regarding liquid dosage forms, solutions in the form of, for example, polyethylene glycol, can be diluted with a sufficient quantity of liquid (e.g., water) carrier to facilitate measurement and administration.

[0149] Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, ethylene glycol, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other such carriers, and then encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those disclosed in U.S. Patent Nos. RE28,819 and 4,358,603. In general, such formulations include, but are not limited to: those containing the compounds provided herein; dialkylated mono- or polyalkylene glycols, including, but not limited to: 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol 350 dimethyl ether, polyethylene glycol 550 dimethyl ether, polyethylene glycol 750 dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol; and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0150] Other formulations include, but are not limited to, dilute alcohol solutions containing acetals. The alcohols used in these formulations are any water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower) alkyl groups of lower alkyl aldehydes such as acetals.

[0151] It is also conceivable that the medication can be administered subcutaneously, intramuscularly, or intravenously, and in some embodiments, parenterally, characterized by injection. The injection can be prepared in a conventional manner, either as a liquid solution or suspension, or as a solid form suitable for dissolving or suspending in a liquid prior to injection, or as an emulsion. The injections, solutions, and emulsions also contain one or more excipients. Suitable excipients include, for example, water, saline, dextrose, glycerol, or ethanol. Furthermore, if desired, the composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubilizers, and other such agents, such as, for example, sodium acetate, sorbitol monolaurate, triethanolamine oleate, and cyclodextrin.

[0152] Furthermore, implantable slow-release or sustained-release systems are envisioned to maintain a constant dose level (see, for example, U.S. Patent No. 3,710,795). In summary, the compounds provided herein are dispersed in an internal solid matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, polysiloxane carbonate copolymer, hydrophilic polymers such as acrylates and methacrylate hydrogels, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. The internal solid matrix is ​​surrounded by an outer polymer membrane insoluble in bodily fluids (e.g., polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, chloroether rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer). The compound diffuses through the outer polymer membrane in a rate-controlled release step. The percentage of active compound contained in this topical gastrointestinal composition is highly dependent on its specific properties, the compound's activity, and the needs of the treated individual.

[0153] The parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Parenteral formulations include: sterile solutions ready for injection; sterile dried soluble products, such as lyophilized powders, ready to be mixed with a solvent just before use, including tablets for subcutaneous injection; sterile suspensions ready for injection; sterile dried insoluble products ready to be mixed with a carrier just before use; and sterile emulsions. The solution may be an aqueous solution or a non-aqueous solution.

[0154] If administered intravenously, appropriate carriers include physiological saline or phosphate-buffered saline (PBS) and solutions containing thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0155] Carriers used in topical gastrointestinal preparations include: aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspensions and dispersants, emulsifiers, polyvalent chelating agents or chelating agents, and other substances.

[0156] Examples of aqueous carriers include: sodium chloride injection, Ringer's injection, isotonic dextran injection, sterile water for injection, and dextran and lactated Ringer's injection. Non-aqueous gastrointestinal carriers include: non-volatile plant-derived oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at inhibitory or antifungal concentrations must be added to gastrointestinal preparations packaged in multi-dose containers. These antimicrobial agents include: phenols or cresols, mercury, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride, and benzyl chloride. Isotonic agents include: sodium chloride and dextran. Buffers include: phosphates and citrates. Antioxidants include: sodium bisulfate. Local anesthetics include: procaine hydrochloride. Suspensions and dispersants include: sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 (Tween ® 80). Multivalent chelating solvents or chelating agents for metal ions include EDTA. Transport carriers also include: ethanol, polyethylene glycol, and propylene glycol for water-soluble carriers; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0157] The concentration of the compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. It is known in the art that the exact dosage depends on the patient's or animal's age, weight, body surface area, and condition.

[0158] Unit doses of topical gastrointestinal preparations are packaged in ampoules, vials, or syringes with needles. As is known and customary in the art, all topical preparations must be sterile.

[0159] For example, intravenous or arterial infusion of a sterile aqueous solution containing the active compound is an effective method of administration. Another embodiment is the injection of a sterile aqueous solution, sterile oily solution, or sterile suspension containing the active material, as needed, to produce the desired pharmacological effect.

[0160] The injection is designed for both local and systemic administration. In some embodiments, a therapeutically effective dose is formulated such that the concentration of the active compound in the treated tissue is at least about 0.01% w / w to about 90% w / w or higher, and in some embodiments higher than 0.1% w / w.

[0161] The compound can be suspended by micronization or other suitable methods, or it can be derivatized to produce a more soluble active product or a prodrug. The form of the resulting mixture depends on many factors, including the desired method of administration and the solubility of the compound in the chosen carrier or support. An effective concentration is sufficient to improve the symptoms of the disease, and this effective concentration can be determined empirically.

[0162] The active ingredient provided herein can be administered using controlled-release devices or delivery devices well known to those skilled in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, and 5,891,474. Examples described are 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500, and 6,740,634. Dosage forms utilizing, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeable systems, multilayer coatings, microparticles, liposomes, and microspheres can be used to provide the slow or controlled release of one or more active ingredients, or combinations of such dosage forms, to provide the desired release distribution in varying proportions. Appropriate controlled-release formulations known to those skilled in the art (including those described herein) can be readily selected for use with the active ingredients provided herein.

[0163] All controlled-release products share a common goal: to improve drug therapy based on the therapeutic effects achieved by their counterparts that are not controlled-release products. Ideally, the use of optimally designed controlled-release formulations in treatment is characterized by curing or controlling the disease with the least amount of drug substance in the shortest time. The advantages of controlled-release formulations include: prolonged drug activity, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to influence the time of action or other properties such as drug concentration levels in the blood, and therefore can affect the occurrence of side effects, such as adverse effects.

[0164] Most controlled-release formulations are designed so that the initial release of the drug (active ingredient) produces the desired therapeutic effect immediately, followed by a gradual and sustained release of additional amounts of the drug to maintain this level of therapeutic or preventative effect over an extended period. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount metabolized and excreted from the body. Controlled release of the active ingredient can be triggered by a variety of conditions, including but not limited to: pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0165] In some embodiments, the agent can be administered via intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other administration methods. In some embodiments, a pump (see Sefton) can be used. CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials can be used. In other embodiments, the controlled-release system can be positioned near the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release , vol. 2, pp. 115-138 (1984). In some embodiments, the controlled-release device is introduced into the body of the treated individual near sites of inappropriate immune activation or tumor sites. Other controlled-release systems are discussed in Langer's report ( Science249:1527-1533 (1990)). The active ingredient can be dispersed in an internal solid matrix (e.g., polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, polysiloxane carbonate copolymer, hydrophilic polymers such as acrylates and methacrylates hydrogels, collagen, crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate), the internal solid matrix The body matrix is ​​surrounded by an outer polymer membrane insoluble in body fluids (e.g., polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, chloroether rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer). The active ingredient then diffuses through the outer polymer membrane in a rate-controlled release step. The percentage of active ingredient contained in this topical gastrointestinal composition is highly dependent on its specific properties and the needs of the treated individual.

[0166] Also of interest are lyophilized powders, which can be reconstituted into solutions, emulsions, and other mixtures for application. They can also be reconstituted and formulated into solids or gels.

[0167] A sterile lyophilized powder is prepared by dissolving the compound or its derivatives provided herein in a suitable solvent. The solvent may contain excipients prepared from the powder to improve the stability or other pharmacological properties of the powder or the reconstituted solution. Excipients that may be used include, but are not limited to, antioxidants, buffers, and swelling agents. In some embodiments, the excipients are selected from: dextran, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, and other suitable reagents. The solvent may contain buffers such as citric acid, sodium phosphate, or potassium phosphate, or other such buffers with a substantially neutral pH known to those skilled in the art. The desired formulation is provided by subsequent aseptic filtration under standard conditions known to those skilled in the art, followed by lyophilization. In some embodiments, the resulting solution is dispensed into vials for lyophilization. Each vial contains a single or multiple doses of the compound. The lyophilized powder can be stored under suitable conditions, such as about 4 °C to room temperature.

[0168] The lyophilized powder is reconstituted with water for injection, providing a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound chosen. The exact amount can be determined empirically.

[0169] Prepare surface mixtures as described for both topical and systemic application. The resulting mixtures may be solutions, suspensions, emulsions, etc., and are formulated as creams, gels, ointments, lotions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, rinses, sprays, suppositories, bandages, skin patches, or any other formulation suitable for surface application.

[0170] For example, the compound or its derivatives can be formulated as aerosols for surface application by inhalation (see, for example, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids used to treat inflammatory diseases, particularly asthma). These formulations for respiratory application can be in the form of aerosols or solutions for nebulizers, or as fine powders used alone or in combination with an inert carrier such as lactose as an inhaler. In this context, in some embodiments, the particles of the formulation have a median mass geometric diameter of less than 5 micrometers, and in other embodiments, less than 10 micrometers.

[0171] Oral inhalation formulations of compounds or derivatives suitable for inhalation include: metered-dose inhalers, dry powder inhalers, and liquid formulations administered from nebulizers or metered-dose liquid dispersion systems. For both metered-dose inhalers and dry powder inhalers, crystalline forms of the compound or derivative are the preferred physical form of the drug to achieve longer product stability.

[0172] In addition to methods for reducing particle size known to those skilled in the art, supercritical fluid processing can also produce crystals of compounds or derivatives. This process offers significant advantages in the production of such particles for inhalation delivery by producing breathable particles of the desired size in a single step (e.g., International Patent Application Publication No. WO2005 / 025506). The particle size can be selectively controlled for the microcrystals to ensure a substantial fraction of the compound or derivative is deposited in the lungs. In some embodiments, these particles have a median aerodynamic diameter of about 0.1 micrometers to about 10 micrometers; in other embodiments, about 1 micrometer to about 5 micrometers; and in still other embodiments, about 1.2 micrometers to about 3 micrometers.

[0173] The non-flammable and inert HFA propellant is selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane), and is provided either alone or in proportion to match the density of the crystal particles of the compound or derivative. The proportions are also selected to ensure that the product suspension avoids the formation of undesirable sediments or pastes (capable of precipitating irreversible agglomerates) and instead promotes the formation of a loosely flocculated system that is easily dispersed upon shaking. Loosely flocculated systems are recognized as providing optimal stability to pMDI cartridges. Due to the nature of this formulation, it does not contain ethanol and is free of surfactants / stabilizers.

[0174] The compound can be formulated for topical or surface application, such as in the form of gels, creams, and lotions, for application to the skin and mucous membranes such as the eyes, as well as for application to the eyes or to the cisterns or spine. Surface application for transdermal delivery and also for application to the eyes or mucous membranes, or for inhalation therapy, is conceivable. Nasal solutions of the active compound can also be administered alone or in combination with other excipients.

[0175] For nasal application, the formulation may contain an esterified phosphate compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier may contain a solubilizer or suspending agent such as propylene glycol, a surfactant, an absorption enhancer such as lecithin or cyclodextrin, or a preservative.

[0176] Solutions, especially those intended for ophthalmic applications, can be prepared as isotonic solutions of 0.01% to 10% with a pH of approximately 5 to 7.4 and appropriate salt content.

[0177] Other routes of administration are also envisioned, such as transdermal patch administration including iontophoresis devices and electrophoresis devices, as well as rectal administration.

[0178] Transdermal patches, including iontophoresis devices and electrophoresis devices, are well known to those skilled in the art. Such patches are disclosed, for example, in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

[0179] For example, dosage forms for rectal administration, intended for systemic action, include rectal suppositories, capsules, and tablets. Rectal suppositories, as used herein, refer to solids inserted into the rectum that melt or soften at body temperature, releasing one or more pharmacologically or therapeutically active ingredients. The substances used in rectal suppositories are a matrix or carrier and agents that raise the melting point. Examples of matrices include cocoa butter, glycerol-gelatin, carbon wax (polyethylene glycol), and suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids. Mixtures of various matrices can be used. Agents that raise the melting point of suppositories include cetylene and waxes. Rectal suppositories can be prepared using compression methods or by molding. In one embodiment, the weight of the rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same substances and methods as those used for oral administration formulations.

[0180] The compounds or derivatives thereof provided herein can also be formulated to target specific tissues, receptors, or other regions of the body of a subject to be treated. Many such targeting methods are well known to those skilled in the art. All of these targeting methods are contemplated for use in the compositions of the present invention. For non-limiting examples of targeting methods, see U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0181] In some embodiments, liposome suspensions, including tissue-targeting liposomes such as tumor-targeting liposomes, are also suitable as transport carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. In general, liposomes such as multilayered vesicles (MLVs) can be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) within a flask. A solution of the compounds provided herein in phosphate-buffered saline (PBS) free of divalent cations is added, and the flask is shaken until the lipid membrane spreads. The resulting vesicles are washed to remove unencapsulated compounds, granulated by centrifugation, and then resuspended in PBS.

[0182] A compound or derivative may be encapsulated into an article comprising: an encapsulation material; a compound or derivative thereof provided herein within the encapsulation material, the compound or derivative thereof being effective in treating, preventing or improving one or more symptoms of the aforementioned disease or disorder (see above); and a label indicating that the compound or composition or derivative thereof is for treating, preventing or improving one or more symptoms of the aforementioned disease or disorder (see above).

[0183] The articles provided herein contain encapsulating materials. Encapsulating materials for encapsulating products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of encapsulating materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any encapsulating material suitable for the selected formulation and desired mode of administration and treatment. A wide range of formulations of the compounds and compositions provided herein are contemplated, such as for various treatments of any of the diseases or disorders described herein.

[0184] dose Regarding the treatment or prevention of infectious diseases, the compound or its pharmaceutical composition described herein is applied or administered in a therapeutically effective amount. In treatments for humans, the physician determines the most appropriate dosage regimen based on preventive or curative treatment and on the age, weight, stage of disease, and other specific factors of the patient to be treated. The amount of active ingredient effective in preventing or treating an infectious disease in the formulations provided herein will vary depending on the nature and severity of the disease or condition and the route of administration of the active ingredient. Frequency and dosage are also based on the specific therapy being administered (e.g., a therapeutic or preventive agent), the severity of the infection, the route of administration, and the patient's age, physical condition, weight, response, and medical history, varying according to the specific factors of each patient.

[0185] Exemplary dosages of the formulation include milligrams or micrograms of the active compound per kilogram of the treated person (e.g., about 1 microgram per kilogram to about 50 milligrams per kilogram; about 10 micrograms per kilogram to about 30 milligrams per kilogram; about 100 micrograms per kilogram to about 10 milligrams per kilogram; or about 100 micrograms per kilogram to about 5 milligrams per kilogram).

[0186] In some embodiments, the therapeutically effective dose should result in a serum concentration of the active ingredient of about 0.001 ng / ml to about 50-200 mg / ml. In other embodiments, the composition should provide a dose of the compound of about 0.0001 mg to about 70 mg per kilogram of body weight per day. Unit dosage forms are prepared to provide about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg, and in some embodiments, each unit dosage form provides a composition of about 10 mg to about 500 mg of the active ingredient or main component.

[0187] The active ingredient can be applied in a single dose or divided into many smaller doses administered at intervals. It should be understood that the exact therapeutic dose and duration of treatment depend on the disease being treated and can be determined empirically using known trial protocols or by extrapolation from in vivo or in vitro data or subsequent clinical trials. Note that concentration and dose values ​​can also vary depending on the severity of the condition to be alleviated. It should also be understood that for any given patient, the specific dosage regimen should be adjusted at any time according to individual needs and the professional judgment of the person administering the composition or monitoring its administration, and the concentration ranges stated herein are merely exemplary and not intended to limit the scope or practical application of the claimed compositions.

[0188] Those skilled in the art will understand that, in some cases, the dosage of the active ingredient required may exceed the range disclosed herein. Furthermore, please note that clinicians or treating physicians know how and when to discontinue, adjust, or terminate treatment based on the patient's response.

[0189] Regarding systemic administration, the effective therapeutic dose can initially be estimated by in vitro assays. For example, doses can be formulated in animal models to achieve a range of circulating concentrations that includes the IC50 values ​​determined in cell culture. 50 (i.e., the concentration of the test compound that is lethal to 50% of cell culture) or the IC50 determined in cell culture. 100 (That is, the concentration of a compound that would be lethal to 100% of cell cultures). This information can be used to precisely determine the effective dose for humans.

[0190] Using techniques well-known in the art, it is also possible to estimate the initial dose from in vivo data (e.g., animal models). Those skilled in the art can easily optimize human administration based on animal data.

[0191] As an alternative, by using the IC of the specific compounds disclosed herein 50 MIC and / or I 100 IC50 with known reagents 50MIC and / or I 100 By comparing and adjusting the initial dose accordingly, the initial dose can be determined from the known dosage of the reagent.

[0192] In cases of local application or selective ingestion, the effective locally concentrated compound used may be independent of plasma concentration. Those skilled in the art can optimize the effective dose for local treatment without excessive experimentation.

[0193] Ideally, the therapeutically effective dose of the compounds described herein would provide therapeutic benefits without causing significant toxicity. For example, by determining the LD50... 50 (A dose that would be lethal to 50% of the population) or LD 100 (At a dose lethal to 100% of the population), the toxicity of a compound can be determined using standard pharmaceutical process steps in cell culture or laboratory animals. The dose ratio between toxicity and therapeutic effect is the therapeutic index. Compounds exhibiting a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a dose range that is non-toxic to the treated individual. The doses of the compounds described herein are preferably within a cyclic concentration range that includes effective doses with little or no toxicity. This dose can vary within this range based on the dosage form and route of administration used. Individual physicians can choose the exact formulation, route of administration, and dose taking into account the patient's condition (see, for example, Fingl et al., 1975). In: The Pharmacological Basis of Therapeutics (Ch.1, p.1).

[0194] Treatment can be repeated intermittently. In some embodiments, the same formulation provided herein can be administered repeatedly, and the administrations can be spaced at intervals of at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0195] Methods of using compounds and compositions

[0196] The compounds and compositions described herein can be widely used in a variety of applications to treat or prevent neurological disorders and other ailments in a treated subject. The method generally involves administering to a treated subject a therapeutically effective amount of the compound or a pharmaceutical composition thereof.

[0197] The compounds and compositions described herein may be used to treat and prevent, for example: pain (e.g., neurodegenerative pain, sensitization associated with neurodegenerative pain, and inflammatory pain, sickle cell disease pain, acute pain), fibromyalgia, migraine, substance abuse or dependence (e.g., nicotine, cocaine, methamphetamine), alcohol addiction; neurotic disorders such as anxiety, depression (e.g., major depressive disorder), post-traumatic stress disorder, mood disorders, affective disorders (e.g., depression and dysthymia; bipolar disorder, e.g., bipolar depression; mania; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder). Deficit Hyperactivity Disorder (ADHD), obsessive-compulsive disorder, vertigo, epilepsy, schizophrenia, schizophrenia-related disorders, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizotypal personality disorder, paranoid personality disorder, psychosis, psychotic disorder, brief psychotic disorder, co-occurring psychotic disorder, psychotic disorder due to general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), affective disorders, aggression, delirium, Parkinson's psychosis, excitatory psychosis, Tourette syndrome. Syndrome), organic psychosis or NOS psychosis, epileptic seizures, agitation, behavioral disorders; such as neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, cognitive impairment, cognitive impairment associated with schizophrenia (CIAS), ataxia, restless lower limb syndrome (RLS), multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medication, insomnia, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual anxiety disorder.

[0198] Pain-sensitive peptide receptor compounds can be used to treat or prevent kidney disease and urinary incontinence, including but not limited to kidney disease and urinary incontinence characterized by inappropriate antidiuretic hormone secretion, water retention imbalance, and / or salt excretion. For example, U.S. Patent No. 6,869,960 discloses a group of spiroperidol ORL-1 ligands, which are generally considered to be therapeutic agents for kidney disease.

[0199] Pain-sensitive peptide receptor compounds can also be used to treat or prevent cardiovascular diseases, including but not limited to systolic hypertension, myocardial infarction, bradycardia, arrhythmia, hypertension, hypotension, thrombosis, anemia, arteriosclerosis, and angina. For example, U.S. Patent No. 7,241,770 discloses a series of pain-sensitive peptide agonists, which are generally considered to be therapeutic agents for cardiovascular diseases.

[0200] Pain-sensitive peptide receptor compounds can also be used to treat gastrointestinal disorders, including but not limited to diarrhea and pain, such as diarrhea and pain in inflammatory bowel disease, Crohn's disease, and inflammatory bowel syndrome.

[0201] The compounds disclosed herein can be used as novel non-dopaminergic targets for the treatment of Parkinson's disease (PD) and related dyskinesia. Several studies have not found that N / OFQ and NOP receptors play a pathogenic role in the substantia nigra-striatal pathway affected in PD (see below). The NOP receptor, namely the G-protein-coupled receptor, is the fourth member of the opioid receptor family and does not bind with known opioid agents with high affinity (Mollereau et al., FEBS Lett., 1994, 341:33-8). The endogenous ligand of NOP is a 17-amino acid peptide called N / OFQ. N / OFQ has low affinity for m, d, and k opioid receptors (Gintzler et al., Eur. J. Pharmacol., 1997, 325:29-34). The N / OFQ-NOP receptor system is widely expressed in the cortical and subcortical regions of the brain, particularly in neurons of the striatum, globus pallidus, and substantia nigra.

[0202] Endogenous N / OFQ is one of the causes of PD symptom development, and N / OFQ levels in SNr increase after loss or damage to dopamine (DA)-transmitting cells (Marti et al., Mov. Disord., 2010, 25:1723-32). This increase has also been observed in the CSF of PD patients (Marti et al., 2010); ii) NOP receptor antagonists reverse PD neurodegenerative (6-OHDA-half-destroyed rats, MPTP-treated mice, and rhesus monkeys) and functional (reserpine-treated or haloperidol-treated) models of Parkinson's disease; iii) genetic deletion of the N / OFQ gene prevents mice from being affected by the neurotoxic effects of MPTP. Mechanistic studies reveal that the anti-Parkinsonian effect of NOP antagonists is achieved by normalizing the imbalance between excitatory (GLU) and inhibitory (GABA) inputs generated by striatal DA desensitization and acting on substantia nigra-thalamic neurons. NOP antagonists also enhance the symptomatic efficacy of levodopa.

[0203] By acting on the striatum, which conversely reduces N / OFQ tension and upregulates NOP receptors after DA cell loss, NOP receptor agonists (commercially available SCH221510; Varty et al., J. Pharmaco. Exp. Ther., 2008, 326:672-82) attenuate abnormal involuntary movements [AIM, levodopa-induced dyskinesia (LID)-associated in rodents] in L-DOPA-induced dyskinesia rats and non-human primates (Marti, M. et al., 2012). This effect can be separated from the typical dyskinesia effect of NOP agonists because the anti-dyskinesia dose is 100-fold lower than the typical low-motor dose.

[0204] From a clinical perspective, the NOP receptor antagonists disclosed herein can be used to treat symptoms and neurodegeneration associated with PD, while NOP receptor agonists are effective in treating LID.

[0205] Genetic deletion of the N / OFQ gene prevented mice from experiencing the neurotoxic effects of MPTP. Mechanistic studies revealed that the anti-Parkinson's disease effect of NOP antagonists is achieved through the normalization of the imbalance between excitatory (GLU) and inhibitory (GABA) inputs to substantia nigra neurons generated by striatal DA desensitization. NOP antagonists also enhance the symptomatic efficacy of levodopa. Therefore, NOP receptor antagonists can provide symptomatic and neuroprotective benefits to PD patients. On the other hand, it has been shown that NOP receptor agonists attenuate AIM expression in L-DOPA-induced kinetic rats and non-human primates.

[0206] In this art, pain-sensitive peptide receptor agonists are known for blocking reward responses to several common drug abuses such as morphine, cocaine, amphetamines, and alcohol. Administration of NOP ligands inhibits basal dopamine release and drug-induced dopamine release in the reward zones of the rodent brain. The inhibitory effect of NOP agonists on drug reward responses and their inhibition of drug-induced dopamine release in the mesolimbic region of the brain suggest the potential use of NOP agonists as drug abuse agents. The compounds disclosed herein can be used to treat substance abuse and addiction.

[0207] Although other opioid receptors, namely m, d, and k opioid receptors, have long been associated with "opioid analgesics," the use of NOP receptors and their agonists and antagonists as potential analgesics has only recently gained attention due to data on the antinociceptive efficacy of NOP ligands in rodent and non-human primate models of acute pain, neuropathic pain, and inflammatory pain (Khroyan et al., Eur. J. Pharmacol., 2009, 610:49-54; Khroyan et al., J. Pharmacol. Exper. Therap., 2011, 339:687-93; Khroyan et al., J. Pharmacol. Exp. Ther., 2007, 320:934-43; Lin and Ko, ACS Chem. Neurosci., 2013, 4:214-24; Toll et al., J. Pharmacol. Exp. Ther., 2009, ). (331:954-64). NOP receptors are widely distributed in the central and peripheral nervous systems and are located in the same pain processing pathway as the other three opioid receptors. However, unlike opioid receptors, the pharmacology of NOP receptors in nociception is quite different and complex.

[0208] NOP agonists have been shown to have effective antinociceptive efficacy in rodent models of chronic pain (Khroyan et al., J. Pharmacol. Exper. Therap., 2011, 339:687-93; Sukhtankar et al., J. Pharmacol. Exp. Ther., 2013, 346:11-22). NOP antagonists can enhance the antinociceptive efficacy of morphine in chronic pain (Khroyan et al., Eur. J. Pharmacol., 2009, 610:49-54). NOP agonists, which are effective as analgesics, did not exhibit reward effects or abuse potential in rodent models, suggesting that NOP agonists have a potential advantage over traditional opioids as non-addictive analgesics (Khroyan et al., J. Pharmacol. Exper. Ther., 2011, 339:687-93; Toll et al., J. Pharmacol. Exp. Ther., 2009, 331:954-64). The compounds disclosed herein can be used as analgesics (NOP agonists), or particularly as adjuncts to opioid pain therapy (NOP antagonists) for chronic pain, neuropathic pain, and inflammatory pain.

[0209] Although all pain-sensitive peptide receptor ligands have binding affinity for the NOP receptor, they can modulate the receptor's "intrinsic activity (functional efficacy)" within a range of 0% to 100%. NOP ligands with 0% functional efficacy that block the receptor's function are classified as NOP antagonists. Ligands with 75% functional efficacy that activate the receptor are generally classified as NOP agonists. Ligands with between 15% and 75% functional efficacy are generally classified as NOP partial agonists. By modifying the chemical structure, the binding affinity and functional efficacy (agonist, partial agonist, antagonist) of NOP ligands can be adjusted, as illustrated in our previous studies using various chemical scaffolds (Zaveri et al., J. Med. Chem., 2004, 47:2973-6; Zaveri et al., AAPS J., 2005, 7:E345-52; Zaveri et al., "Structure-activity relationships of Nociceptin Receptor (NOP) Ligands and the Design of Bifunctional NOP / mu opioid receptor-targeted Ligands", in Research and Development of Opioid-Related Analgesics, Ko, MC; Husbands, SM, Eds., American Chemical Society, 2013, Chapter 8, pp. 145-160).

[0210] combination therapy

[0211] The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients. In some embodiments, the compound may be administered in combination with or sequentially with another therapeutic agent. These other therapeutic agents include those known for treating, preventing, or improving one or more conditions associated with drug addiction, pain, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, mental disorders, kidney disease, gastrointestinal disorders, and cardiovascular diseases.

[0212] It should be understood that any suitable combination of the compounds and pharmaceutical compositions provided herein with one or more of the above-described therapeutic agents and, where appropriate, with one or more additional pharmacologically active substances is considered within the scope of this disclosure. In some embodiments, the compounds and pharmaceutical compositions provided herein are administered before or after the administration of one or more additional active ingredients.

[0213] All disclosures and patents listed herein are incorporated herein by reference in their entirety.

[0214] Example

[0215] The starting materials and reagents used to prepare these compounds were obtained from commercial suppliers such as Sigma-Aldrich (St. Louis, Missouri), Strem Chemicals (Newburyport, Massachusetts), and AK Scientific (Union City, California). 1 ¹H NMR spectra were recorded on a Varian Gemini 300 MHz spectrometer (300 MHz and 75 MHz respectively), and relative to a chloroform internal standard at δ 7.27. The results are reported below. 1 1H NMR data: chemical shift (δ ppm), peak number (s=single, d=double, t=triple, q=quadruple, m=multiple), coupling constant (Hz), accumulation, and partition. Mass spectra were obtained using a ThermoFinnigan LCQ Duo LC / MS / MS or API 150 EX MS (Applied Biosystems) instrument and an electrospray ionization probe. Thin-layer chromatography was performed on Analtech Uniplate silica TLC plates. Rapid chromatography was performed using Merckgrade 9385 silica gel ranging from 230 to 400 mesh.

[0216] Example 1: 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole(61) and 1-(1-((1s, 4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H Synthesis of -indole-3-carboxaldehyde oxime (81) Scheme I describes the synthesis.

[0217] Option I

[0218] Scheme I: Materials and Conditions a) AcOH, sodium triacetoxyborohydride (STAB), MgSO4, DCE, room temperature (general process step A); b) i. TFA, CH2Cl2, ii. 4-Isopropyl-cyclohexanone, STAB, AcOH, DCE (general process step B, 2 steps); c) MnO2, CH2Cl2; d) POCl3, DMF; and e) NH2OH·HCl, NaOAc·3H2O, EtOH:H2O (2:1), 110 °C.

[0219] General process step A: Reductive amination using N-Boc piperidinoneAniline-based material (1.00 equivalent) and N-Boc-piperidinone (1.05 to 1.50 equivalent) were placed in a round-bottom flask. 1,2-DCE (0.25 M) was added, and the mixture was stirred until both components dissolved. MgSO4 (100 wt% limiting agent) and icy AcOH (1.00 to 2.30 equivalent) were added to the solution at ambient temperature, and the solution was stirred for 90 minutes. At this stage, sodium triacetoxyborohydride (STAB) (1.50 to 2.30 equivalent) was added. The reaction mixture was stirred at room temperature and monitored by TLC (EtOAc:hexane). After 1 to 2 days, TLC analysis showed that the reaction mixture was ≥90% complete. The reaction mixture was quenched with saturated NaHCO3 (aqueous solution) and stirred until the reaction mixture became alkaline and bubbling ceased. A two-phase layer was precipitated, and the organic layer was washed twice with H2O and salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide a brown oily substance. This brown oily substance was purified by rapid chromatography using EtOAc:hexane to provide the desired product, which was directly used in the following reaction.

[0220] t butyl-4-(indololin-1-yl)piperidine-1-carboxylic acid ester ( I-1 ) See General Process Step A: Dihydroindole (10.0 g, 83.9 mmol, 1.00 equivalent), N-Boc piperidinone (17.6 g, 88.1 mg, 1.05 equivalent), AcOH (4.80 mL, 83.9 mmol, 1.00 equivalent), STAB (26.7 g, 12.6 mmol, 1.50). MgSO4 is not used in this reaction. The crude oil was purified by rapid chromatography using 10:90 EtOAc:hexane to provide dihydroindole I-1 (24.3 g, 96% yield). 1 H NMR (300 MHz, CDCl3) δ 7.06 (t, J = 6.0 Hz, 2H), 6.03 (t, J = 6.0 Hz, 1H), 6.43 (d, J = 6.0 Hz, 1H), 4.25 (m, 2H), 3.52 (m, 1H), 3.35 (t, J = 6.3Hz, 2H), 2.79 (m, 2H), 1.80 (d, J = 9.3 Hz, 2H), 1.60 (m, 4H), 1.49 (s, 9H); MS(APCI) m / z 303.06 [M+H] + .

[0221] General process step B: Removal of Boc and its interaction with 4- i Reductive amination of Pr cyclohexanone : Step 1 A solution of N-Boc intermediate (1.00 equivalents) in CH2Cl2 (0.25–0.30 M) was cooled to 0 °C, and TFA (6 to 30 equivalents) was added over several minutes. After the addition was complete, the ice bath was removed, and the reaction mixture was warmed to room temperature and monitored by TLC (EtOAc:hexane). The reaction mixture was then completed after 2 hours. The reaction mixture was concentrated under vacuum, and then EtOAc was added, thus removing EtOAc under vacuum. The oily residue was then dissolved in EtOAc, and the mixture was stirred while adding saturated NaHCO3 (aqueous solution) until a residual base remained in the aqueous layer. Chromatography was performed, and the aqueous layer was extracted with EtOAc until the UV activity in the aqueous layer was at its lowest (3 to 8 times). The EtOAc layers were combined, washed with salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide the piperidine intermediate.

[0222] Step 2 The piperidine intermediate (1.00 equivalent) obtained from the previous steps and 4- i Pr-cyclohexanone (1.00 to 1.50 equivalents) was dissolved in 1,2-DCE (0.070 M). Ice-cold AcOH (1.00 to 2.30 equivalents) was added to the reactant, and the mixture was stirred for 20 minutes. After 20 minutes, STAB (1.50 to 2.30 equivalents) was added in three portions. An Ar gasbag was fitted on top of the reactant, and the reaction was monitored by TLC (MeOH:CH2Cl2:NH4OH (aqueous solution)). After 2 to 3 days, when the reaction was ≥95% complete, saturated NaHCO3 (aqueous solution) was added until a residual base remained in the aqueous layer. At this stage, the aqueous layer was precipitated and extracted twice with CH2Cl2. The organic layers were combined, washed twice with H2O and salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide a crude residue, which was purified by rapid chromatography using EtOAc:hexane:NH4OH (aqueous solution).

[0223] syn -1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)dihydroindole( I-2 ) See General Process Step B: step Step I The reactants were: dihydroindole I-1 (24.4 g, 80.5 mmol, 1.00 equivalent), TFA (38.0 mL, 496 mmol, 6.20 equivalent), and CH2Cl2 (300 mL, 0.27 M). The combined EtOAc layers were immediately dried with MgSO4 without washing with water or salt solution. A gray solid (13.6 g, 84% yield) was obtained. Step 2See General Process Step B: NH piperidine (13.6 g, 67.2 mmol, 1.00 equivalent) obtained from the preceding steps. i Pr-cyclohexanone (9.40 g, 67.2 mmol, 1.00 equivalent), AcOH (3.85 mL, 67.2 mmol, 1.00 equivalent), STAB (21.3 g, 101 mmol, 1.50 equivalent). Purification was achieved by rapid chromatography using a 10:90:1.5 solution of EtOAc:hexane:NH4OH to provide intermediate I-2 as a pale golden oil (33% yield). f = 0.25 (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (300 MHz, CDCl3) δ7.05 (t, J = 5.7 Hz, 2H), 6.60 ( J = 5.7 Hz, 1H), 6.41 (d, J = 5.7 Hz, 1H),3.37 (m, 3H), 3.10 (d, J = 8.7 Hz, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.27 (m,1H), 2.14 (t, J = 8.7 Hz, 2H), 1.54-1.82 (m, 11H), 1.38 (m, 2H), 1.13 (m,1H), 0.88 (d, J = 5.1 Hz, 6H); MS(ESI) m / z 327.4 [M+H] + .

[0224] syn -1-(1-(4-isopropylcyclohexyl)piperidine-4-yl)-1 H -Indole(61)Dihydroindole I-2 (4.63 g, 14.2 mmol, 1.00 equivalent) was dissolved in 180 mL of CH2Cl2. 4 ÅMS (56.8 g, 4 g / mmol dihydroindole) was added to this solution, followed by MnO2 (12.3 g, 142 mmol, 10.0 equivalent) and then another 20 mL of CH2Cl2. An argon gas chamber was fitted to the reaction vessel, and the viscous suspension was stirred and monitored by TLC (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution)). The reaction was completed after 16 hours. The mixture was filtered through a large-diatomaceous earth filter and the residual solids were washed five times with CH2Cl2. The filtrate was concentrated under vacuum to provide a crude oily substance. This substance was dissolved in EtOAc, and 10% HCl (aqueous solution) was added while vigorously stirred to obtain a white precipitate. The white solid was filtered and washed three times with EtOAc, then air-dried for at least one hour. The white solid was then suspended in EtOAc, and 70% NaHCO3 (aqueous solution) was added. The mixture was stirred until more than 90% of the solid dissolved. EtOAc chromatography was performed, followed by washing with H2O and salt solution, drying with MgSO4, filtration, and concentration under vacuum to provide a viscous oil. This viscous oil was purified by rapid chromatography using a 10:90:1.5 EtOAc:hexane:NH4OH (aqueous solution) to provide indole in the form of a grayish-white solid. 1 (3.65 g, 79% yield). R f = 0.25 (10:90:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 6.0Hz, 1H), 7.26 (m, 1H), 7.20 (t, J = 6.0 Hz, 1H), 7.11 (t, J = 6.0 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 4.23 (m, 1H), 3.20 (d, J = 9.0 Hz, 2H), 2.30 (m,3H), 2.08 (m, 4H), 1.51-1.78 (m, 7H), 1.40 (m, 2H), 1.17 (m, 1H), 0.9 (d, J=4.8 Hz, 6H); MS(ESI) m / z 325.4 [M+H] + .

[0225] syn -1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-3-carboxaldehyde ( I-3 ) POCl3 (3.66 mL, 40.0 mmol, 4.00 equivalent) was added to a stirred solution of 25.0 mL DMF at 0 °C. The solution was stirred at 0 °C for 15 minutes. During this stage, indole I-3 (3.10 g, 10.0 mmol, 1.00 equivalent) dissolved in 10 mL DMF by means of heat. The warm solution of indole I-3 was then added to the reactant, and the reactant was washed with 5.00 mL DMF. The reactant was now a red solution, and it was stirred at 0 °C for 15 to 20 minutes. TLC (50:50:3 drops of EtOAc:hexane:NH4OH (aqueous solution)) showed that the reaction was complete. The reactant was then infused into a saturated NaHCO3 (aqueous solution) ice bath, and then CH2Cl2 was added. The mixture was vigorously stirred for 30 minutes, a layer precipitated on it, and the aqueous layer was extracted with CH2Cl2 until UV activity was minimal (5 to 6 times). The organic layer was then washed three times with H2O and salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide a dark red oil. This dark red oil was purified by rapid chromatography using a 50:50:1.5 solution of EtOAc:hexane:NH4OH to provide aldehyde I-3 as a pale yellow solid (2.15 g, 74% yield). f = 0.20 (50:50:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (300 MHz, CDCl3) δ 10.0(s, 1H), 8.33 (m, 1H), 7.89 (s, 1H), 7.43 (m, 1H), 7.33 (m, 2H), 4.29 (m,1H), 3.28 (d, J = 7.8 Hz, 2H), 2.40 (m, 3H), 2.19 (m, 3H), 1.55-1.78 (m, 8H), 1.42 (m, 2H), 1.17 (m, 1H), 0.9 (d, J = 5.7 Hz, 6H); MS(ESI) m / z 353.1 [M+H] + .

[0226] syn -1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-3-formaldehyde oxime (81)Aldehyde I-3 (2.15 g, 6.10 mmol, 1.00 equivalent), NH₂OH·HCl (551 mg, 7.93 mmol, 1.30 equivalent), and NaOAc·3H₂O (1.08 g, 7.93 mmol, 1.30 equivalent) were placed in a round-bottom flask. Anhydrous EtOH (20.5 mL) and 10 mL of H₂O were added, and a condenser and Ar gas bag were attached to the top of the reaction mixture. The suspension was heated to reflux (approximately 110 °C in an oil bath), and the suspension was monitored by TLC (40:60:3 drops of EtOAc:hexane:NH₄OH (aqueous solution)). After 2 hours, the reaction was complete. The reaction mixture was cooled to room temperature, and a white precipitate formed on the surface. The mixture was diluted with EtOAc and saturated NaHCO₃ (aqueous solution), and stirred until the mixture became a biphasic solution. Chromatographic precipitation, followed by washing twice with H₂O and salt solution, drying with MgSO₄, filtration, and concentration under vacuum, yielded oxime 2 as a white solid (1.74 g, 78% yield). The two isomers of the oxime were in a ratio of approximately 3:2. R f = 0.50 (top spot), 0.45 (bottom spot) (40:60:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 ¹H NMR (300 MHz, CDCl₃, major isomer) δ 10.8 (br, ¹H), 8.47 (s, ¹H), 7.78 (m, ²H), 7.41 (d, ¹H) J = 6.0, 1H), 7.28 (m,1H), 7.23 (m, 1H), 4.31 (m, 1H), 3.30 (d, J = 8.7 Hz, 2H), 2.55 (m, 1H), 2.46(t, J = 7.8, 2H), 2.23 (m, 3H), 1.86 (m, 2H), 1.60-1.80 (m, 6H), 1.43 (m,2H), 1.19 (m, 1H), 0.91 (d, J = 5.1, 6H); 1 ¹H NMR (300 MHz, CDCl₃, minor isomer) δ 8.30 (s, ¹H), 8.07 (d, ¹H) J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J = 6.0 Hz, 1H), 7.28 (t, J= 5.4 Hz, 1H), 7.20 (t, J = 5.4 Hz, 1H), 4.23 (m, 1H), 3.22(d, J = 5.7 Hz, 2H), 2.35 (m, 3H), 2.13 (m, 4H), 1.55- 1.80 (m, 7H), 1.43 (m,2H), 1.17 (m, 1H), 0.91 (d, J = 5.1 Hz, 6H); MS(ESI) m / z 368.5 [M+H] + .

[0227] Example 2: Benzyl((1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -indol-2-yl)methyl 17) Carbamate and (1-(1-((1s, 4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H Synthesis of -indol-2-yl)methylamine (3) Scheme II describes the synthesis.

[0228] Option II

[0229]

[0230] Scheme II Materials and Conditions :a) i. N-Boc piperidone, AcOH, STAB, MgSO4, DCE, room temperature (general process step A). ii. TFA, CH2Cl2, iii. 4-Isopropylcyclohexanone, STAB, AcOH, DCE (General process step B, 2 steps); b) i. propyl-2-yn-1-ylcarbamate, catalyst PdCl2(PPh3)2, catalyst cuprous iodide (CuI), DMF: different- Pr2NEt (3:1), ii. Catalysts Cu(OAc)2, PhMe, reflux (general process step C, 2 steps); and c) H2 gas bag, catalyst 10% Pd / C, NH3 / MeOH.

[0231] syn-N -(2-Iodophenyl)-1-(4-Isopropylcyclohexyl)piperidine-4-amine II-1 ) : i.See General Process Step A. 2-Iodoaniline (15.0 g, 63.3 mmol, 1.00 equivalent), N-Boc-piperidinone (18.5 g, 95.0 mmol, 1.50 equivalent), icy AcOH (8.40 mL, 146 mmol, 2.30 equivalent), STAB (30.9 g, 146 mmol, 2.30 equivalent), DCE (250 mL, 0.25 M). MgSO4 was not used in this reaction. The product was purified by rapid chromatography using EtOAc:hexane at a ratio of 5:95, providing the desired bicyclic compound (75% yield) as a white solid, and this product was used directly in the following reaction. R f = 0.15 (5:95 of EtOAc:hexane, UV).

[0232] ii. See General Process Step B: Step 1. N-Boc piperidine (43.5 g, 0.108 mol, 1.00 equivalent), TFA (200 mL, 2.61 mol, 24.0 equivalent), and CH2Cl2 (300 mL, 0.36 M) were used to obtain a light brown solid NH piperidine intermediate (42.0 g, because NaTFA had a 128% yield), which was used directly in the next step.

[0233] See General Process Step B: Step 2. NH piperidine (0.108 mol, 1.00 equivalent), 4- i Pr-cyclohexanone (22.7 g, 0.162 mol, 1.50 equivalents), icy AcOH (14.2 mL, 0.248 mol, 2.30 equivalents), STAB (52.6 g, 0.248 mol, 2.30 equivalents), and DCE (1.54 L, 0.070 M). Compound II-1 was purified by rapid chromatography using EtOAc:hexane:NH4OH (aqueous solution) in a ratio of 6:94:1.5 → 9:91:1.5, yielding a golden oil. (The cis-diastereomer has a higher R-value compared to the anti-diastereomer.) FThe purified oily substance was dissolved in EtOAc and transferred to an Erlenmeyer flask, and then 10% HCl (aqueous solution) was added. After the addition of 10% HCl (aqueous solution), a white precipitate formed, and the suspension was stirred for 10 minutes. The white precipitate was then filtered, washed twice with EtOAc, and then air-dried for more than 1 hour. The white precipitate was then suspended in EtOAc in an Erlenmeyer flask, and then saturated NaHCO3 (aqueous solution) was added until alkalinity was achieved, and then stirred overnight. At this stage, the mixture is now a clear biphasic solution. Chromatography was performed, and the EtOAc layer was washed with salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide iodoaniline II-1 in the form of a light golden oil (24.0 g, 39% yield after 3 steps). f = 0.30 (10:90:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (CDCl3, 300 MHz) δ 7.65 (dd, J = 5.7, 0.9, 1H), 7.184 (t, J = 6.0, 1H), 6.58 (d, J = 6.0, 1H), 6.41 (dt, J = 5.7, 0.9, 1H), 4.12 (d, J = 5.7 Hz, 1H), 3.36 (m, 1H), 2.93 (m, 2H), 2.25 (m, 3H), 2.15 (d, J = 8.4 Hz,2H), 1.47-1.74 (m, 8H), 1.38 (m, 2H), 1.13 (m, 1H), 0.89 (d, J = 4.8 Hz, 6H); MS(ESI) m / z : 427 [M+H] + .

[0234] General process step C: Coupling and cyclization of scallion heads

[0235] Step 1. Iodoaniline (1.00 equivalent) and terminal alkynes (3.00 to 5.00 equivalent) are soluble in DMF and iIn Pr2Net (3:1, 0.40 M), PdCl2(PPh3)2 (0.0400 equivalents) and CuI (0.100 equivalents) were simultaneously added to the reaction mixture. An argon gas bag with a three-way connector was placed on top of the reaction vessel, and the vessel was purged and then refilled with argon (repeated a total of 3 times). The reactants were covered with aluminum foil and stirred overnight at ambient temperature. The reactants were monitored by TLC (EtOAc:hexane:NH4OH (aqueous solution)). Once monitoring was complete, the reactants were diluted with EtOAc and H2O and stirred for 10 minutes. A two-phase layer precipitated, and the organic layer was washed twice with H2O and salt solution, dried with MgSO4, filtered, and concentrated under vacuum. The crude material obtained by rapid chromatography was purified and then used directly in the following reactions without further processing.

[0236] Step 2. The endyne obtained in step 1 (1.00 equivalents) was loaded into a round-bottom flask. Cu(OAc)₂ (0.200 to 0.400 equivalents) was added, followed by PhMe (0.25 M). The reactant was fitted with a reflux condenser, and then an Ar gas bag was fitted on top of the condenser. The reactant was then heated to reflux and monitored by TLC (30:70:3 drops of EtOAc:hexane:NH₄OH (aqueous solution)). After 1 to 2 hours, the TLC showed that the reaction was complete. The reactant was cooled to room temperature, EtOAc and H₂O were added, and the compound was stirred for 30 minutes. The compound was filtered through a silicide diatomaceous earth filter, and the silicide diatomaceous earth filter was washed 3 to 4 times with EtOAc. Chromatography was performed, and the organic layer was washed once with H₂O. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, washed with salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide a crude solid. This solid was adsorbed onto silica gel, loaded onto a column, and purified by rapid chromatography to provide a pure indole intermediate.

[0237] syn -Benzyl((1-(1-(4-isopropylcyclohexyl)piperidine-4-yl)-1 H -indol-2-yl)methyl)carbamic acid Ester (17) : i. See General Process Step C: Step 1. Iodoaniline II-1 (5.60 g, 13.1 mmol, 1.00 equivalent), N-benzylprop-2-yn-1-carbamate (8.69 g, 45.9 mmol, 3.50 equivalent), DMF (25.0 mL), and iPr2Net (8.25 mL), PdCl2(PPh3)2 (368 mg, 0.524 mmol, 0.0400 equivalents), and CuI (250 mg, 1.31 mmol, 0.100 equivalents). The crude product was purified by rapid chromatography using EtOAc:hexane:NH4OH (aqueous solution) in ratios of 20:80:1.5 to 5:75:1.5, yielding the desired internal alkyne as a pale yellow solid (6.26 g, 98% yield), which was directly used in the next reaction. R f = 0.25 (25:75:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV).

[0238] See General Process Step C: Step 2. Endoethynium (6.26 g, 12.8 mmol, 1.00 equivalent), Cu(OAc)₂ (700 mg, 3.85 mmol, 0.300 equivalent), and PhMe (51.0 mL, 0.25 M). The crude solid was purified by rapid chromatography using EtOAc:hexane:NH₄OH (aqueous solution) in ratios of 15:85:1.5 to 20:80:1.5 to 30:70:1.5 to provide a pale yellow solid. The solid was then ground with a minimal amount of 1:1 EtOAc:hexane to provide indole 3 as a white solid (64% yield after two steps). R f = 0.30 (25:75:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (CDCl3, 300 MHz) δ 7.65 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.32(m, 5H), 7.16 (t, J = 8.1 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.38 (s, 1H), 5.17 (s, 2H), 4.90 (br, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.15 (m, 1H), 3.10 (d, J = 10.2 Hz, 2H), 2.57 (dq, J = 12.6, 3.3 Hz, 2H), 2.31 (m, 1H), 2.10 (t, J=12.6 Hz, 2H), 1.35-1.80 (m, 11H), 1.17 (m, 1H), 0.93 (d, J = 6.9 Hz, 6H); MS(ESI) m / z 488.4 [M+H] + .

[0239] syn -(1-(1-(4-isopropylcyclohexyl)piperidine-4-yl)-1 H -Indole-2-yl)methylamine (3) Indole 17 (2.83 g, 5.80 mmol, 1.00 equivalent) and 10% Pd / C (425 mg, 15% w / w) were suspended in 7N NH3 in a MeOH mixture. The reaction vessel was fitted with an H2 gasket, purged from the atmosphere, and refilled with H2, and this process was repeated (3 times in total). After another 2 to 3 hours, indole 17 slowly dissolved, and the reaction mixture was monitored by TLC (100:3 drops of EtOAc:NH4OH (aqueous solution)). The reaction mixture was completed after a total of 4 hours. The reaction mixture was filtered through a silicide diatomaceous earth filter and thoroughly washed with MeOH. The filtrate was concentrated under vacuum and purified by rapid chromatography using MeOH:EtOAc:NH4OH (aqueous solution) at ratios of 0:100:1.5 to 2:98:1.5 to provide diamine 3 (2.00 g, 98% yield) as a white solid. f = 0.35 (5:95:3 drops of MeOH:EtOAc:NH4OH (aqueous solution), UV); 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J =6.3 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 7.14 (dt, J = 5.4, 0.9 Hz, 1H), 7.06(dt, J = 5.4, 0.9 Hz, 1H), 6.38 (s, 1H), 4.25 (m, 1H), 4.04 (s, 2H), 3.20 (d, J = 9.0 Hz, 2H), 2.61 (dq, J = 7.2, 1.8 Hz, 2H), 2.36 (m, 1H), 2.24, (t, J =8.4 Hz, 2H), 1.87 (dd, J= 9.3, 1.5 Hz, 2H), 1.50-1.80 (m, 8H), 1.42 (m, 2H),1.16 (m, 1H), 0.92 (d, J = 4.8 Hz, 6H); MS(ESI) m / z 354.5 [M+H] + .

[0240] Example 3: (1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2-yl)methanol (30) and (E)-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H Synthesis of 1-indole-2-carboxaldehyde oxime (1) Scheme III describes the synthesis.

[0241] Option III

[0242] Scheme III Materials and Conditions :a) i. Terminal alkyne, catalyst PdCl2(PPh3)2, catalyst CuI, DMF: i Pr2Net (3:1) ii. Catalyst Cu(OAc)2, PhMe, reflux (general process step C, 2 steps); and b) i. MnO2, CH2Cl2, ii. NH2OH·HCl, NaOAc·3H2O, EtOH:H2O (2:1), 110 °C.

[0243] syn -(1-(1-(-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2-yl)methanol (30) See General Process Step C: Step i. Iodoaniline II-1 (3.97 g, 9.30 mmol, 1.00 equivalent), propargyl alcohol (2.61 g, 46.5 mmol, 5.00 equivalent), DMF (17.2 mL), and i Pr2Net (5.8 mL), PdCl2(PPh3)2 (261 mg, 0.372 mmol, 0.0400 equivalents), and CuI (177 mg, 0.930 mmol, 0.100 equivalents) were used. The crude product was purified by rapid chromatography using EtOAc:hexane:NH4OH (aqueous solution) in ratios of 40:60:1.5 to 50:50:1.5, yielding the desired internal alkyne in a dark red colloidal form (2.86 g, 87% yield), which was directly used in the next reaction.

[0244] See General Process Step C: Step 2.Endoethynylene (2.86 g, 8.07 mmol, 1.00 equivalent), Cu(OAc)₂ (440 mg, 2.42 mmol, 0.300 equivalent), and PhMe (32.3 mL, 0.25 M). The material (adsorbed onto silica gel) was loaded onto a column and purified by rapid chromatography using EtOAc:hexane:NH₄OH (aqueous solution) in ratios of 25:75:1.5 to 35:65:1.5, yielding a pale yellow solid. The solid was then ground using a minimal amount of 1:1 EtOAc:hexane to provide indole 30 as a white solid (1.82 g, 56% yield after two steps). f = 0.25 (25:75:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz,1H), 6.44 (s, 1H), 4.81 (d, J = 4.8 Hz, 2H), 4.37 (m, 1H), 3.19 (d, J = 11.6Hz, 2H), 2.61 (dq, J = 12.4, 3.2 Hz, 2H), 2.37 (m, 1H), 2.26 (t, J = 11.6 Hz, 2H), 1.89 (d, J = 12.0 Hz, 2H), 1.70 (m, 5H), 1.55 (m, 2H), 1.40 (m, 2H), 1.16 (m, 1H), 0.92 (d, J = 6.8 Hz, 6H); MS(ESI) m / z 355.27 [M+H] + .

[0245] syn -1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2-formaldehyde oxime (1) : i.MnO2 (3.83 g, 44.0 mmol, 12.0 equivalent) was added to a solution of indole 30 (1.30 g, 3.67 mmol, 1.00 equivalent) in 36.7 mL of CH2Cl2 at room temperature, and the reaction mixture was stirred overnight. At this stage, TLC (30:70:1.5 EtOAc:hexane:NH4OH (aqueous solution)) showed that the reaction was complete. The reaction mixture was filtered through a silicide packing material, washed three times with CH2Cl2, and the filtrate was concentrated under vacuum to provide the aldehyde in colloidal form (1.27 g, 98%). This compound was used directly in the following process steps.

[0246] ii. The recently obtained aldehyde (1.26 g, 3.57 mmol, 1.00 equivalent), NH₂OH·HCl (372 mg, 5.36 mmol, 1.50 equivalent), and NaOAc·3H₂O (730 mg, 5.36 mmol, 1.50 equivalent) were placed in a round-bottom flask. Then, EtOH (12.0 mL) and H₂O (6.00 mL) were added, and a reflux condenser with an Ar gas bladder was attached to the reactant. The reactant (white suspension) was then heated to 110 °C. At approximately 50 °C, the reactant became a pale yellow solution, and at approximately 70 to 80 °C, a white precipitate began to form. Now, at 110 °C, the reactant was a thick white paste, and after 10 minutes, TLC (20:80:3 drops of EtOAc:hexane:NH₄OH (aqueous solution)) showed that the reaction was complete. The reactants were cooled to room temperature, CH₂Cl₂ and saturated NaHCO₃ (aqueous solution) were added, and the mixture was stirred for 20 minutes to provide a clear two-phase mixture. Chromatography was performed, and the aqueous layer was extracted once with CH₂Cl₂. The organic layers were combined, washed twice with H₂O and salt solution, dried with MgSO₄, filtered, and concentrated under vacuum to provide a white foam. 2 mL of EtOAc was added to the foam, followed by 10 mL of MeOH, and the suspension was stirred for 10 minutes. The solid was then filtered, washed three times with cold MeOH, and dried under vacuum to provide oxime 1 as a white solid (1.10 g, 84% yield). f =0.25 (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (CDCl3, 300 MHz) δ 10.7(br, 1H), 8.70 (s, 1H), 7.59 (m, 2H), 7.18 (t, J = 5.7 Hz, 1H), 7.07 (t,J =5.7 Hz, 1H), 6.83 (s, 1H), 4.89 (m, 1H), 3.24 (d, J = 8.4 Hz, 2H), 2.65 (dq, J = 9.6, 2.1 Hz, 2H), 2.45 (m, 1H), 2.31 (t, J = 8.7 Hz, 2H), 1.56-1.93 (m,9H), 1.43 (m, 2H), 1.19 (m, 1H), 0.94 (d, J = 4.8 Hz, 6H); MS(ESI) m / z 368.32 [M+H] + .

[0247] Example 4: 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -indol-2-yl)ethane-1- Alcohols (32) and 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2-yl)aminosulfonic acid ethyl Synthesis of ester (11) The scheme describes the synthesis.

[0248] Option IV

[0249] Scheme IV: Materials and Conditions :a) i. Terminal alkyne, catalyst PdCl2(PPh3)2, catalyst CuI, DMF: different- Pr2Net (3:1) ii. Catalyst Cu(OAc)2, PhMe, reflux (general process step C, 2 steps). iii. TBAF, THF, and b) ClSO2NH2, CH2Cl2.

[0250] syn -2-(1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indol-2-yl)ethane-1-ol (32) : i. See General Process Step C: Step 1. Iodoaniline II-1 (1.60 g, 3.75 mmol, 1.00 equivalent), (but-3-yn-1-yloxy) tert-butyl Dimethylsilane (2.41 g, 13.1 mmol, 3.50 equivalents), DMF (11.3 mL), and iPr₂NEt (3.80 mL), PdCl₂(PPh₃)₂ (105 mg, 0.150 mmol, 0.0400 equivalents), and CuI (71.4 mg, 0.375 mmol, 0.100 equivalents). The crude oil was purified by rapid chromatography using EtOAc:hexane:NH₄OH (aqueous solution) in ratios of 7:93:1.5 to 10:90:1.5, yielding the desired internal alkyne in a brown oily form (1.60 g, 88% yield), which was then used directly in the reactions below.

[0251] See General Process Step C: Step 2. Endoyne (1.60 g, 3.31 mmol, 1.00 equivalent), Cu(OAc)₂ (601 mg, 3.31 mmol, 1.00 equivalent), and PhMe (13.3 mL, 0.25 M). The reaction time was 4 hours. The crude product was purified by rapid chromatography using a ratio of 2:98:1.5 to 6:94.15 to provide the desired indole (1.00 g, 63% yield) in the form of a pale yellow oil, which was then used directly in the reaction below.

[0252] ii. At room temperature, a solution of previously synthesized indole (1.10 g, 2.28 mmol, 1.00 equivalent) in 15.0 mL of THF was mixed with TBAF (1.0 M, 4.55 mL, 2.00 equivalent), and the mixture was stirred and monitored by TLC (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution)). Once the reaction was complete (approximately 2 hours), the mixture was concentrated under vacuum, and the crude product was flash-distilled using EtOAc:hexane:NH4OH (aqueous solution) in a ratio of 25:75:1.5 to 50:50:1.5, yielding alcohol 32 (792 mg, 94% yield) as a white solid. f = 0.25 (30:70:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (CDCl3, 300 MHz) δ 7.65 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 9.0Hz, 1H), 7.13 (t, J = 5.4 Hz, 1H), 7.07 (t, J = 5.4 Hz, 1H), 6.33 (s, 1H), 4.14 (m, 1H), 3.94 (t, J= 4.8 Hz, 2H), 3.20 (d, J = 8.7 Hz, 2H), 3.09 (t, J = 4.8 Hz, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.36 (m, 1H), 2.22 (t, J = 8.7 Hz,2H), 1.51-1.87 (m, 9H), 1.42 (m, 2H), 1.27 (m, 1H), 0.92 (d, J = 4.8 Hz, 6H); MS(ESI) m / z 369.27 [M+H] + .

[0253] syn -2-(1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1 H ethyl indole-2-yl)aminosulfonate (11) At 0 °C, by dropping the mixture onto the reactants, the reaction of alcohol 32 (200 mg, 0.543 mmol, 1.00 equivalent) and... i A solution of Pr2Net (0.946 mL, 5.43 mmol, 10.0 equivalent) in 5.00 mL of CH2Cl2 was supplemented with a solution of aminosulfonyl chloride (7.00 mL, 3.26 mmol, 6.00 equivalent) (approximately 0.50 M in CH2Cl2). The ice bath was removed, and the reaction mixture was stirred for 1 hour. At this point, TLC (40:60:3 drops of EtOAc:hexane:NH4OH (aqueous solution)) showed that the reaction was complete. The reaction mixture was diluted with EtOAc, and then 10% NaHCO3 (aqueous solution) was added. A white precipitate formed, which was filtered and washed with EtOAc. The filtrate separated into two layers, and the EtOAc layer was washed twice with H2O and salt solution, dried with MgSO4, filtered, and concentrated under vacuum. The crude material was flash-distilled in an aqueous solution of EtOAc:hexane:NH4OH in a ratio of 40:60:1.5 to provide aminosulfonate 11 as a white solid (35 mg, 14% yield). f = 0.25 (40:60:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 6.3 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.15 (t, J = 5.7 Hz, 1H), 7.07 (t, J= 5.7 Hz, 1H), 6.34 (s, 1H), 4.50 (t, J = 5.1 Hz, 2H), 4.13 (m, 1H), 3.28 (t, J = 5.1 Hz, 2H), 3.22 (d, J = 8.4 Hz, 2H), 2.64 (m, 2H), 2.40 (m, 1H), 2.27 (t, J = 8.4Hz, 2H), 1.84 (d, J = 8.4 Hz, 2H), 1.76 (m, 2H), 1.55-1.70 (m, 3H), 1.41 (m,2H), 1.26 (m, 2H), 1.17 (m, 1H), 0.92 (d, J = 5.1 Hz, 6H); MS(ESI) m / z 448.3 [M+H] + .

[0254] Example 5: (5-Fluoro-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -indol-2-yl)methanol Synthesis of (29) Scheme V describes the synthesis.

[0255] Option V

[0256] Option V: Materials and Conditions a) i. N-Boc piperidone, AcOH, STAB, MgSO4, DCE, room temperature (general process step A). ii. TFA, CH2Cl2, iii. 4- different- Pr-cyclohexanone, STAB, AcOH, DCE (general process step B, 2 steps); and b) i. Terminal alkyne, catalyst PdCl2(PPh3)2, catalyst CuI, DMF: different- Pr2Net (3:1) ii. Catalyst Cu(OAc)2, PhMe, reflux (general process step C, 2 steps).

[0257] syn - N -(4-Fluoro-2-iodophenyl)-1-(4-isopropylcyclohexyl)piperidine-4-amine (V-1) : i.See General Process Step A. 4-Fluoro-2-iodoaniline (3.80 g, 16.0 mmol, 1.00 equivalent), N-Boc piperidinone (4.69 g, 24.0 mmol, 1.50 equivalent), MgSO4 (3.80 g, 100 wt%), icy AcOH (2.11 mL, 36.8 mmol, 2.30 equivalent), STAB (7.80 g, 36.8 mmol, 2.30 equivalent), and DCE (80.0 mL, 0.20 M). The crude product was purified by rapid chromatography using 12:88 EtOAc:hexane to provide the desired bicyclic intermediate (6.70 g, 99% yield) in white solid form, and this crude product was used directly in the next reaction.

[0258] ii. See General Process Step B: Step 1. N-boc piperidine intermediate (5.00 g, 11.9 mmol, 1.00 equivalent), TFA (27.3 mL, 357 mmol, 30.0 equivalent), CH2Cl2 (60.0 mL, 0.20 M). The reactants described above were processed to obtain a grayish-white solid (4.94 g, because NaTFA was 130%), and this material was used directly in the next reaction.

[0259] See General Process Step B: Step 2. NH piperidine intermediate (11.9 mmol, 1.00 equivalent), 4- i Pr-cyclohexanone (2.51 g, 17.9 mmol, 1.50 equivalent), glacial AcOH (1.57 mL, 27.4 mmol, 2.30 equivalent), MgSO4 (3.81 g, 100 wt%), STAB (5.81 g, 27.4 mmol, 2.30 equivalent), and DCE (150 mL, 0.080 M). The crude product was purified by rapid chromatography using a 10:90:1.5 solution of EtOAc:hexane:NH4OH to provide intermediate V-1 as a deep orange-brown oil (55% yield after 3 steps). f = 0.25 (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (CDCl3, 300 MHz) δ 7.41 (dd, J = 6.0, 2.1 Hz, 1H), 6.95 (dt, J = 6.0, 2.1 Hz, 1H), 6.51 (dd, J= 6.9, 3.6 Hz, 1H), 3.91 (d, J = 6.0 Hz,1H), 3.28 (m, 1H), 2.92 (m, 2H), 2.24 (m, 3H), 2.04 (m, 2H), 1.47-1.73 (m,8H), 1.38 (m, 2H), 1.13 (m, 1H), 0.88 (d, J = 5.1 Hz, 6H); MS(ESI) m / z 445.1 [M+H] + .

[0260] syn -(5-Fluoro-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2-yl)methanol (29) : i. See General Process Step C: Step 1. Intermediate V-1 (600 mg, 1.35 mmol, 1.00 equivalent), propargyl alcohol (378 mg, 6.75 mmol, 5.00 equivalent), DMF (3.12 mL), and i Pr₂NEt (1.13 mL), PdCl₂(PPh₃)₂ (38.0 mg, 0.0540 mmol, 0.0400 equivalents), and CuI (25.7 mg, 0.135 mmol, 0.100 equivalents) were used. The crude product was purified by rapid chromatography using a 40:60:1.5 solution of EtOAc:hexane:NH₄OH to provide the desired endyne (440 mg, 87%) in a reddish-brown oily form. This crude product was used directly in the next reaction.

[0261] See General Process Step C: Step 2. Endoyne (440 mg, 1.18 mmol, 1.00 equivalent), Cu(OAc)₂ (64.4 mg, 0.354 mmol, 0.300 equivalent), and PhMe (4.75 mL, 0.21 M). The crude product was purified by rapid chromatography using a 25:75:1.5 solution of EtOAc:hexane:NH₄OH to provide a pale yellow solid. The solid was then ground with EtOAc to provide indole 29 as a white solid (143 mg, 29% yield after two steps). R f = 0.20 (25:75:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (300 MHz, CDCl3) δ 7.58 (dd, J =9.0, 4.2 Hz, 1H), 7.20 (dd, J= 9.3, 2.7 Hz, 1H), 6.92 (dt, J = 9.3, 2.7 Hz,1H), 6.38 (s, 1H), 4.78 (s, 2H), 4.35 (m, 1H), 3.19 (d, J = 11.7 Hz, 2H), 2.55 (dq, J = 12.6, 3.6 Hz, 2H), 2.35 (m, 1H), 2.26 (dt, J = 11.7, 1.8 Hz, 2H), 1.88 (dd, J = 12.0, 2.4 Hz, 2H), 1.48-1.79 (m, 9H), 1.40 (m, 2H), 1.15(m, 1H), 0.91 (d, J = 6.6 Hz, 6H); MS(ESI) m / z 373.4 [M+H] + .

[0262] Example 6: (1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2,3-diyl)dimethyl Synthesis of alcohols (51) Scheme VI describes the synthesis.

[0263] Solution VI

[0264] Solution VI: Materials and Conditions a) (t-BuCO)₂O, catalyst DMAP, (isopropyl)₂NEt, CH₂Cl₂; and b) i. POCl3, DMF ii. NaBH4, EtOH, iii. NaOH, catalyst Bu4NI, THF.

[0265] syn-(1-(1-(-4-isopropylcyclohexyl)piperidin-4-yl)-1 H methyl indole-2-yl)neovalerate (35) At room temperature (rt), a solution of ethanol 30 (7.29 g, 20.6 mmol, 1.00 equivalent) in CH2Cl2 (138 mL, 0.15 M) was treated with DMAP (503 mg, 4.12 mmol, 0.200 equivalent) and... i Pr2Net (18.4 mL, 103 mmol, 5.00 equivalents). Next, add ( tBuCO)₂O (6.70 mL, 33.0, 1.60 equivalents) was added, and the reaction mixture was stirred overnight. TLC (30:70:3 drops of EtOAc:hexane:NH₄OH (aqueous solution)) showed that the reaction was complete. The reaction mixture was concentrated under vacuum, and the crude oil was purified by rapid chromatography using EtOAc:hexane:NH₄OH (aqueous solution) in a ratio of 5:95:1.5, to provide 35 (8.59 g, 95%) as a white solid. f = 0.70 (30:70:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.20(t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.56 (s, 1H), 5.25 (s, 2H), 4.17 (m, 1H), 3.31 (d, J = 12.0 Hz, 2H), 2.78 (q, J = 12.0 Hz, 2H), 2.55 (q, J = 6.4 Hz, 1H), 2.32 (t, J = 11.6 Hz, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.80(m, 2H), 1.64 (m, 5H), 1.43 (m, 2H), 1.22 (s, 9H), 1.20 (m, 1H), 0.92 (d, J =6.4 Hz, 6H); MS(ESI) m / z 439.3 [M+H] + .

[0266] syn-(1-(1-(-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -Indole-2,3-diyl)diethanol (51) : i.At 0 °C, POCl3 (9.43 mL, 103 mmol, 5.00 equivalent) was added to DMF (83.0 mL), and the mixture turned pale yellow. Indole 35 (9.00 g, 20.6 mmol, 1.00 equivalent) was independently dissolved in 20 mL of DMF with the aid of heat, and then cooled to room temperature (RT). After dissolving POCl3 at 0 °C with stirring for 15 minutes, a solution of indole 35 was slowly added, forming a red solution. Once this addition was complete, the reaction mixture was stirred at 0 °C for 40 minutes. TLC (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution)) showed that the reaction was complete. The reaction mixture was then infused into an ice:NaHCO3 (saturated aqueous solution) slurry, and then EtOAc was added. The mixture was vigorously stirred until it was warmed to room temperature, and NaHCO3 (saturated aqueous solution) was added to ensure an alkaline pH. The aqueous layer was precipitated and extracted once with EtOAc. The EtOAc layers were combined, washed three times with water and salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide an aldehyde in the form of a pale yellow solid (9.55 g, 99%), which was used directly in the next step.

[0267] ii. The aldehyde (9.55 g, 20.5 mmol, 1.00 equivalent) was suspended in anhydrous EtOH (100 mL, 0.20 M) and added in portions of NaBH4 (1.55 g, 41.0 mmol, 2.00 equivalent) at room temperature. Note that another portion of 1.00 equivalent of NaBH4 and a small amount of CH2Cl2 were added to aid in the solubilization of the reaction mixture. The reaction mixture was monitored by TLC (40:60:3 drops of EtOAc:hexane:NH4OH (aqueous solution)) and, once monitoring was complete, the mixture was concentrated to approximately 50% of its volume under vacuum. EtOAc was added, followed by 50% NaHCO3 (aqueous solution), and the mixture was stirred until bubbling ceased. The EtOAc layer was precipitated, and the EtOAc layer was washed twice with water and salt solution, dried with MgSO4, filtered, and concentrated in vacuum to provide foam (9.60 g, quantitative yield), which was then directly taken in the next step.

[0268] iii.An alcohol (9.60 g, 20.5 mmol, 1.00 equivalent) was dissolved in THF (130 mL, 0.16 M), followed by the addition of Bu4NI (1.51 g, 4.10 mmol, 0.20 equivalent). At room temperature, finely ground NaOH powder (8.20 g, 205 mmol, 10.0 equivalent) was added, and the reaction mixture was stirred for approximately 90 minutes, resulting in a thick, fluffy white precipitate. TLC (60:40:3 drops of EtOAc:hexane:NH4OH (aqueous solution)) showed the reaction was complete. The reaction mixture was diluted with EtOAc and water, and chromatographically separated. The aqueous layer was extracted twice with EtOAc, and then the EtOAc layers were combined, washed twice with water and salt solution, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid chromatography in EtOAc:hexane:NH4OH (aqueous solution) at ratios of 60:40:1.5 to 80:20:1.5 to 90:10:1.5 to provide diol 51 (4.70 g, 60%) in white foam form. f = 0.20 (80:20:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV); 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.4 Hz, 1H), 7.13 (t, J = 8.0Hz, 1H), 4.86 (s, 2H), 4.83 (s, 2H), 4.38 (m, 1H), 3.17 (d, J = 11.6 Hz, 2H), 2.59 (q, J =12.0 Hz, 2H), 2.37 (m, 1H), 2.25 (t, J = 11.0 Hz, 2H), 1.52-1.89(m, 9H), 1.43 (m, 2H), 1.18 (m, 1H), 0.92 (d, J = 6.4 Hz, 6H); MS(ESI) m / z 385.4 [M+H] + .

[0269] Example 7: (E, Z)-3-(hydroxyimino)-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)in Synthesis of dolin-2-one (228)

[0270] Scheme VII describes the synthesis.

[0271] Option VII

[0272] Scheme VII: Materials and Conditions a) HCO2NH4, Pd / C, 10%, MeOH, 2 hours, 45°C o C; b) 4-isopropylcyclohexanone, HOAc, MgSO4, NaBH(OAc)3, DCE, 48 hours, room temperature; c) ceric ammonium nitrate (CAN), MeCN / H2O, 2 hours, room temperature; d) NH2OH . HCl, NaOAc, EtOH / H2O, 20 hours, room temperature.

[0273] 1-(piperidin-4-yl)-2,3-dihydro-1 H -Indole-2-one (VII-2) : 1-(1-benzylpiperidinyl-4-yl)-2,3-dihydro-1H-indol-2-one VII-1 (using according to Forbes (2001) Tetrahedron Letters) 2 The process steps employed (6943-6945) involved preparing an ice-chilled solution (25.7 g, 82.6 mmol, 1.00 equivalent) in 600 mL of MeOH, followed by the addition of ammonium formate (46.9 g, 743 mmol, 9.00 equivalent), and then adding 10% (5.14 g) of Pd / C in 226 mL of MeOH as an ice-chilled slurry. The reaction mixture was equipped with a reflux condenser and heated to 45°C. o C was maintained for 2.5 hours. The solution was filtered through Celite diatomaceous earth packing and concentrated. Using CH2Cl2 / MeOH 90 / 10 (total 500 mL) for grinding, and then using CH2Cl2 / MeOH / NH4OH 100 / 0 / 0 to 79 / 20 / 1 as eluent, rapid chromatography was performed to produce 15.94 g of title material in 89% yield, consistent with the reported value (WO 2002 / 085357, Sun et al.).

[0274] 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)dihydroindole-2,3-dione (VII-4) : 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)indoline-2-one (VII-3) (according to Zaveri et al. (2004) Journal of Medicinal Chemistry) 47:2973-2976 (prepared from intermediate VII-2) (3.43 g, 10.1 mmol, 1.00 equivalent) was added to a stirred solution of CAN (22.1 g, 40.3 mmol, 4.00 equivalent) in 17.0 mL of H2O in 336 mL of MeCN, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with CH2Cl2 and saturated NaHCO3 (aqueous solution). Chromatography was performed, and the aqueous solution was extracted twice with CH2Cl2. The combined organic layers were filtered through a silicide diatomaceous earth filter, washed with saturated NaCl (aqueous solution), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography using CH2Cl2 / MeOH at a ratio of 99 / 1 to 90 / 10, yielding 2.73 g of the title material in 76% yield. 1 H NMR(300 MHz, CDCl3) 7.62 (1H, d, J = 5.1 Hz), 7.56 (1H, t, J = 6 Hz), 7.20 (1H,d, J = 6 Hz), 7.10 (1H, t, J = 5.7 Hz), 4.19-4.22 (1H, m), 3.16 (2H, d, J =8.7 Hz), 2.30-2.40 (3H, m), 2.20 (2H, t, J = 8.1 Hz), 1.60-1.79 (7H, m), 1.49-1.54 (2H, m), 1.36-1.43 (2H, m), 1.13-1.15 (1H, m), 0.90 (6H, d, J = 5.1Hz). MS(ESI) m / z 355.27(M+H) + .

[0275] (E, Z)-3-(hydroxyimino)-1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)indoline- 2-Keto (228)Hydroxylamine hydrochloride (147 mg, 2.12 mmol, 1.50 equivalent) was added to a stirred solution of intermediate VII-4 (500 mg, 1.41 mmol, 1.00 equivalent) in EtOH (17.6 mL), followed by the addition of NaOAc (231 mg, 2.82 mmol, 2.00 equivalent). H2O (2.78 mL) was added to solubilize the reactant, and the mixture was stirred at room temperature for 20 hours. The reactant was diluted with CH2Cl2 and saturated NaHCO3 (aqueous solution). Chromatography was performed, and the aqueous solution was extracted twice with CH2Cl2. The combined organic layers were washed twice with H2O, dried over Na2SO4, filtered, and concentrated. The reaction was repeated on a scale of 1.12 g, and the crude residues from both reactions were combined. The residue was purified by grinding with 1 / 1 EtOAc / hexanes to produce 1.54 g of the title material in 91% yield. 1 H NMR (300 MHz, DMSO- d 6 ), 13.4 (1H, s), 8.00 (1H, d, J = 9 Hz), 7.40 (1H, t, J = 9 Hz), 7.18 (1H, d, J = 6 Hz), 7.05 (1H, t, J = 6Hz), 4.00-4.02 (1H, m), 3.06 (2H, d, J = 9 Hz), 2.24-2.36 (3H, m), 2.08 (2H,t, J = 12 Hz), 1.52-1.69 (7H, m), 1.31-1.44 (4H, m), 1.06 (1H, s), 0.85 (6H,d, J = 6 Hz). MS(ESI) m / z 370.3(M+H) + Elemental analysis (Anal. Calcd.) C 22 H 31 N3O2 . 1.00HCl . 0.4 H2O . Calculated values ​​for 0.1 CH2Cl2: C, 62.95; H, 7.89; N, 9.97; obtained: C, 62.61; H, 7.54; N, 9.73.

[0276] Example 8: 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindoline-3-yl)-N-Synthesis of methoxyacetamide (247) Scheme VIII describes the synthesis.

[0277] Scheme VIII

[0278] Scheme VIII Materials and Conditions: a) tert-butyl glyoxylate / DMSO, K2CO3, THF, activated molecular sieves, 2 hours, 80 o C; b) H2(g), Pd / C, THF, 2 hours, room temperature; c) TFA, CH2Cl2, 1.5 hours, room temperature; d) NH2OCH3 . HCl, T3P, diisopropylethylamine, THF, 17 hours, room temperature.

[0279] 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidine-4-yl)-2-oxoindoline-3-ylidene)tert-butyl acetate Ester (VIII-1) A 34% solution of tert-butyl glyoxylate in DMSO (based on Yao et al.) was added to a stirred solution of intermediate VII-3 (4.96 g, 14.6 mmol, 1.00 equivalent) in THF (146 mL). Tetrahedron Prepared in 2007, 63:10657-10670 (15.2 g, 117 mmol, 8.00 equivalents), then K2CO3 (4.03 g, 29.1 mmol, 2.00 equivalents) and activated molecular sieve (50 g) were added. The reactants were fitted with a reflux condenser and refluxed at 80°C. o The mixture was stirred at C for 2 hours. The reactants were cooled to room temperature, filtered, and then diluted with EtOAc, H2O, and a minimal amount of NaCl (aqueous solution). Chromatography was performed, and the aqueous solution was extracted twice with EtOAc. The combined organic layers were washed twice with NaCl (aqueous solution), dried over Na2SO4, filtered, and concentrated. The reaction was repeated on a scale of 12.7 g, and the crude residues from both rounds were combined. The residues were purified by rapid chromatography using a hexane / EtOAc / NH4OH mixture of 85 / 15 / 0 to 35 / 64 / 1, yielding 16.9 g of the title product in 72% yield. 1 H NMR (400 MHz, CDCl3) 8.53 (1H, d, J = 8 Hz), 7.31 (1H, td, J = 8, 4Hz), 7.10 (1H, d, J = 8 Hz), 7.02 (1H, t, J= 8 Hz), 6.83 (1H, s), 4.21-4.26(1H, m), 3.13 (2H, d, J = 6 Hz), 2.29-2.45 (3H, m), 2.18 (2H, t, J = 12 Hz),1.59-1.71 (7H, m), 1.56 (9H, s), 1.34-1.52 (4H, m), 1.13 (1H, s), 0.89 (6H,d, J = 8 Hz). MS(ESI) m / z 453.3(M+H) + .

[0280] 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindoline-3-yl)tert-butyl acetate (VIII-2) Pd / C, 10% (305 mg), was added to a stirred solution of intermediate VIII-1 (3.05 g, 6.74 mmol, 1.00 equivalent) in THF (67.0 mL). The reactants were evacuated to atmospheric pressure and replaced with H2(g) at 1 atm. The reactants were stirred at room temperature for 2 hours, filtered through a silicide packing material, and concentrated. The reaction was repeated at scales of 7.00 g and 6.80 g, and the crude residues from the three rounds were combined. The residue was purified by rapid chromatography using hexane / EtOAc / NH4OH at a ratio of 95 / 5 / 0 to 35 / 64 / 1, yielding 12.9 g of the title product in 76% yield. MS (ESI) m / z 455.4(M+H) + . 1 H NMR (400 MHz, CDCl3) 7.26 (1H, d, J = 8 Hz), 7.22 (1H, d, J = 8Hz), 7.16 (1H, d, J = 8 Hz), 7.00 (1H, t, J = 8 Hz), 4.25-4.29 (1H, m), 3.73-3.76 (1H, m), 3.13 (2H, d, J = 12 Hz), 2.97 (1H, dd, J = 16, 8 Hz), 2.65 (1H,dd, J = 16, 8 Hz), 2.28-2.45 (4H, m), 2.18 (2H, t, J= 12 Hz), 1.48-1.72(10H, m), 1.39 (9H, s), 1.12 (1H, s), 0.89 (6H, d, J = 8 Hz).

[0281] With 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxindoline-3-yl)acetic acid, 2,2-Trifluoroacetic acid compound (VIII-3) TFA (284 mL) was added fractionally to an ice-cold solution of intermediate VIII-2 (12.9 g, 28.4 mmol, 1.00 equivalent) in CH2Cl2 (284 mL). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The mixture was concentrated and azeotropically dried with toluene five times to yield 14.5 g of the title product in the form of TFA salt in >100% yield. MS (ESI) m / z 399.2(M+H) + .

[0282] 2-(1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxoindoline-3-yl)-N-methoxy Acetamide (247) O-methylhydroxylamine hydrochloride (943 mg, 11.29 mmol, 9.00 equivalent) was added to a stirred solution of intermediate VIII-3 (641 mg, 1.25 mmol, 1.00 equivalent) in THF (15.7 mL) at 78% free base equivalent, followed by the addition of DiPEA (3.93 mL, 22.6 mmol, 18.0 equivalent), and the reaction mixture was stirred for 5 minutes at room temperature. Propylphosphoanhydride solution (T3P) was then added. ® (2.24 mL, 7.53 mmol, 6.00 equivalents), and the reactant was stirred for 17 hours at room temperature. The reactant was diluted with EtOAc and H2O. Chromatography was performed, and the aqueous solution was extracted twice with EtOAc. The combined organic layers were filtered through a silicide packing, washed with saturated NaCl (aqueous solution), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography using [hexane / EtOAc] / iPrOH / NH4OH at a concentration of 100 / 0 / 0 to 94 / 5 / 1. 1 H NMR (400MHz, CDCl3) 9.79 (1H, s), 7.30 (1H, d, J = 8 Hz), 7.26 (1H, d, J = 16 Hz), 7.17 (1H, d, J = 8 Hz), 7.03-7.06 (1H, m), 4.24 (1H, s), 3.79 (3H, br s), 3.14 (2H, d, J= 12 Hz), 2.63-2.70 (2H, m), 2.30-2.43 (3H, m), 2.18 (2H, t, J = 12 Hz), 1.59-1.71 (8H, m), 1.48-1.53 ​​(2H, m), 1.35-1.41 (2H, m), 1.14 (1H,s), 0.89 (6H, d, J = 8 Hz). MS(ESI) m / z 428.44 (M+H) + Elemental analysis C 25 H 37 N3O3 . 1.00HCl . Calculated values ​​for 0.9 H2O: C, 62.52; H, 8.35; N, 8.75; Result: C, 62.39; H, 8.20; N, 8.66.

[0283] Example 9: 2-(1'-(cis-4-isopropylcyclohexyl)-3-oxo-1 H -spiro[isoquinoline-4,4'-piperidine]-2(3H-) Acetonitrile (339); 2-(2-aminoethyl)-1'-(cis-4-isopropylcyclohexyl)-1,2-dihydro-3H-spiro[isoquinoline-4, 4'-piperidin]-3-one (340); and N-(2-(1'-(cis-4-isopropylcyclohexyl)-3-oxo-1 H -spiro[isoquinoline-4,4'- Piperidine-2(3H)-yl)ethyl)aminosulfonamide (344) Scheme IX describes the synthesis.

[0284] Solution IX

[0285] Solution IX: Materials and Conditions a) NaH, BrCH2CN, THF, 14 hours, room temperature; b) H2, PtO2 hydrate, MeOH, concentrated hydrochloric acid, 50 o C, 3 hours; c) Chlorosulfonyl isocyanate, benzyl alcohol, CH2Cl2, 5 o C, then Et3N, CH2Cl2, amine, 14 hours, room temperature; and d) H2, 10% Pd / C, MeOH, NH3, 4 hours.

[0286] 2-(1'-(cis-4-isopropylcyclohexyl)-3-oxo-1 H -spiro[isoquinoline-4,4'-piperidine]-2(3H)-yl)ethyl Nitriles (339) For IX-1 (such as Mustazza, J . Med. Chem.,The solution of 339 (1.65 g, 4.84 mmol) prepared as described in 2008, 51:1058-1062) in 40 mL of THF under argon atmosphere was added dropwise to 60% NaH (0.969 g, 24.2 mmol) in mineral oil, and the mixture was stirred at room temperature for 0.5 h. The mixture was cooled in an ice bath, and a solution of bromoacetonitrile (1.74 g, 14.5 mmol) in 20 mL of THF was added dropwise over 0.25 h, and the mixture was allowed to reach room temperature and stirred for 14 h. The mixture was treated with saturated sodium bicarbonate, extracted with ethyl acetate, dried over magnesium sulfate, and evaporated to dryness. Purification was achieved by silica gel chromatography eluting with methanol / ethyl acetate / hexane / ammonium hydroxide (2:49:49:0.1) to yield 1.31 g of 339 in 71% yield. A portion of the base was converted to hydrochloride. 1 H NMR (300 MHz, DMSO, d6) δ 10.2(1H, m), 7.51 (1H, d, 6 Hz), 7.41 (1H, t, J = 6Hz), 7.35 (1H, t, 6 Hz), 7.34(1H, d, J = 6Hz), 4.74 (2H, s), 4.56 (2H, s), 3.4-3.5 (4H, m), 3.2 (1H, m), 2.18 (2H, d, J = 11 Hz), 1.84 (4H, m), 1.68 (4H, m), 1.41 (2H, m), 1.14 (2H,m), 0.88 (6H, d, J = 5Hz). MS m / z 380 (M+H) + .

[0287] 2-(2-Aminoethyl)-1'-(cis-4-isopropylcyclohexyl)-1,2-dihydro-3H-spiro[isoquinoline-4,4'-piperazine] [Pyridine]-3-one (340) Platinum oxide hydrate (178 mg) was added to a solution of 339 (1.37 g, 3.61 mmol) dissolved in 30 ml of methanol and 3.3 ml of concentrated hydrochloric acid, and at 50 °C... o At C, under a hydrogen atmosphere, the mixture was stirred for 3 hours. The mixture was cooled to room temperature, filtered through Celite diatomaceous earth, and evaporated to dryness. The residue was purified by silica gel chromatography using methanol / dichloromethane / ammonium hydroxide (11:89:0.1) to produce 1.37 g of 340 in 90% yield. A portion of the base was converted to hydrochloride. 1H NMR (300 MHz, DMSO, d6) δ 10.6 (1H, m), 8.06 (3H, m), 7.54 (1H, d, J =6 Hz), 7.38 (1H, t, 6 Hz), 7.32 (1H, t, J = 6 Hz), 7.26 (1H, d, J = 6 Hz), 4.68 (2H, s), 3.68 (2H, m), 3.45 (3H, m), 3.18 (2H, m), 3.03 (2H, m), 2.23(2H, d, J = 11 Hz), 1.87 (4H, d, J = 8 Hz), 1.67 (3H, m), 1.41 (2H, m), 1.15(1H, m), 0.88 (6H, d, J = 5 Hz). MS m / z 384 (M+H) + .

[0288] syn-phenyl(N-(2-(1'-(4-isopropylcyclohexyl)-3-oxo-1) H -spiro[isoquinoline-4,4'-piperidine]-2 (3H)-yl)ethyl)aminosulfonyl)carbamate (IX-2) A solution of chlorosulfonyl isocyanate (0.76 g, 5.4 mmol) in 20 mL of dichloromethane was cooled in an ice bath under an argon atmosphere and treated with benzyl alcohol (0.58 g, 5.4 mmol). After stirring for 0.25 hours, the mixture was added to a solution of IX-2 (1.29 g, 3.36 mmol) in 20 mL of dichloromethane containing triethylamine (0.68 g, 6.72 mmol), and the solution was cooled in an ice bath under an argon atmosphere. The resulting mixture was then subjected to 5... o The mixture was stirred at C for 1 hour and then stirred at room temperature for 14 hours. The mixture was treated with saturated sodium bicarbonate, extracted with dichloromethane, dried over magnesium sulfate, and evaporated to dryness. Purification was achieved by silica gel chromatography with elution using methanol / dichloromethane / ammonium hydroxide (3:97:0.1) to produce 1.68 g of IX-2 in 84% yield. 1H NMR (300 MHz, CDCl3) δ7.28-7.38 (6H, m), 7.11-7.25 (3H, m), 6.94 (1H, m), 5.27 (1H, m), 5.07 (2H,s), 4.31 (1H, m), 3.57 (3H, m), 3.2 (4H, m), 3.0 (1H, m), 2.35 (1H, m), 2.04(2H, m), 1.87 (5H, m), 1.58 (3H, m), 1.31 (2H, m), 1.18 (1H, m), 0.89 (6H, d,J = 5 Hz). MS m / z 597 (M+H) + .

[0289] N-(2-(1'-(cis-4-isopropylcyclohexyl)-3-oxo-1 H -spiro[isoquinoline-4,4'-piperidine]-2(3H)-yl) Ethyl)aminosulfonamide (344) A solution of IX-2 (1.51 g, 2.53 mmol) dissolved in 80 mL of methanol and 10 mL of 7N ammonia-methanol was added with 10% Pd / C (150 mg), and the mixture was stirred for 4 hours under a hydrogen atmosphere. The mixture was filtered through Celite diatomaceous earth and then evaporated to dryness. The residue was purified by chromatography using methanol / ethyl acetate / hexane / ammonium hydroxide (14:43:43:0.1) to produce 0.625 g of 344 in 40% yield. 1 H NMR (300 MHz, CDCl3) 7.51(1H, d, J = 6 Hz), 7.33 (1H, t, J = 6Hz), 7.25 (1H, t, J = 6Hz), 7.18 (1H, d,J = 6 Hz), 5.2 (1H, m), 4.57 (2H, s), 3.74 (2H, t, J = 4 Hz), 3.38 (2H, t, J= 4 Hz), 2.81 (3H,m), 2.33 (2H,m), 2.23 (2H, m), 2.04 (2H, m), 1.71 (2H, m),1.59 (6H, m), 1.36 (2H, m), 1.12 (1H, m), 0.87 (6H, (d, 5 Hz). MS m / z 463 (M+H) + Some of the base is converted to hydrochloride. Elemental analysis (C 24 H 38 N4O3S . HCl . H2O) C, H, N.

[0290] Example 10:2-(1-(1-cis-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -indol-3-yl)ethane-1-amine Synthesis of (86) Scheme X describes the synthesis.

[0291] Option X

[0292] Solution X: Materials and Conditions a) Alkyne X-1, LiCl, K2CO3, catalyst Pd(OAc)2, DMF, 100 °C; and b) AcCl, MeOH, room temperature.

[0293] (2-(1-(1-(cis-4-isopropylcyclohexyl)piperidine-4-yl)-2-(triethylsilyl)-1 H -Indole-3- tert-butyl carbamate (X-2) Iodoaniline II-2 (401 mg, 0.940 mmol, 1.00 equivalent), alkynyl X-1 (320 mg, 1.13 mmol, 1.20 equivalent), and LiCl (39.8 mg, 0.940 mmol, 1.00 equivalent) were placed in a 100 mL round-bottom flask. DMF (13.4 mL, 0.070 M) was added, followed by K2CO3 (390 mg, 2.82 mmol, 3.00 equivalent) and Pd(OAc)2 (21.1 mg, 0.0940 mmol, 0.100 equivalent). The reactants were fitted with a three-way valve and an Ar gasket, and then the reactants were purged three times under vacuum and refilled with Ar. The reactant was then heated in an oil bath at 100 °C and monitored by TLC (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution)). A black color formed in the reactant after approximately 60 minutes, and TLC indicated completion after approximately 80 to 90 minutes. The reactant was cooled to room temperature and then diluted with EtOAc and H2O, and stirred for 10 minutes. The reaction mixture was then filtered through a small silage diatomaceous earth filter, and the aqueous layer was extracted once with EtOAc. The EtOAc layers were combined, washed twice with H2O and salt solution, dried with MgSO4, filtered, and concentrated under vacuum to provide a crude product. This crude product was purified by rapid chromatography using an 8:92:1.5 EtOAc:hexane:NH4OH (aqueous solution) to provide intermediate X-2 (360 mg, 66%) in white foam form. f = 0.30 (20:80:3 drops of EtOAc:hexane:NH4OH (aqueous solution), UV, I2, pAA); 1 HNMR (300 MHz, CDCl3) δ 7.69 (d, J = 6.0 Hz, 1H), 7.61 (d, J= 6.0 Hz, 1H), 7.16 (t, J = 5.7 Hz, 1H), 7.06 (t, J = 5.7 Hz, 1H), 4.56 (m, 1H), 4.25 (m,1H), 3.40 (q, J = 4.8 Hz, 2H), 3.21 (d, J = 8.7 Hz, 2H), 3.01 (t, J = 5.1 Hz, 2H), 2.71 (dq, J = 8.7, 2.1 Hz, 2H), 2.35 (m, 1H), 2.15 (t, J = 8.7 Hz, 2H),1.85-1.38 (m, 21H), 1.16 (m, 1H), 1.05-0.90 (m, 20H); MS(ESI) m / z 467.6 [M+H] + .

[0294] 2-(1-(1-cis-4-isopropylcyclohexyl)piperidin-4-yl)-1 H -indol-3-yl)ethane-1-amine (86) At 0 °C, AcCl (806 μL, 11.3 mmol, 6.00 equivalent) was added to MeOH (19.0 mL, 0.10 M), and the reaction mixture was stirred for 5 minutes. Then, indole-X-2 (1.10 g, 1.89 mmol, 1.00 equivalent) was added to the reaction mixture. After stirring at 0 °C for 10 minutes, a white slurry was formed. The ice bath was then removed, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After 4 hours, TLC (10:90:3 dropwise) was performed. i The reaction mixture (PrOH:CH2Cl2:NH4OH (aqueous solution)) indicates that the reaction is complete. EtOAc (approximately 50 mL) is added to the stirred reaction mixture, and after several minutes, a white precipitate forms. This white precipitate is filtered, washed three times with cold EtOAc, and dried under vacuum to provide indole 86 hydrochloride. 665 mg (80%) of the desired salt is obtained. f = 0.10 (10:90:3 drops) i PrOH:CH2Cl2:NH4OH (aqueous solution), UV, I2); 1 ¹H NMR (free base) (300 MHz, CDCl₃) δ 7.61 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 6.3 Hz, 1H), 7.21(t,J = 6.0 Hz, 1H), 7.11 (m, 2H), 4.18 (m, 1H), 3.19 (d, J = 8.7 Hz, 2H), 3.03 (t, J = 4.8 Hz, 2H), 2.93 (t, J = 4.8 Hz, 2H), 2.35 (m, 1H), 2.26 (dt, J = 8.4, 1.8 Hz, 2H), 2.07 (m, 6H), 1.78-1.52 (m, 7H), 1.42 (m, 2H), 1.15 (m,1H), 0.90 (d, J = 5.1 Hz, 6H); MS(ESI) m / z 368.5 [M+H] + .

[0295] Example 11: In vitro characterization of receptor binding affinity for pain-sensitive peptides, m and k opioid receptors As described below, the binding affinity of all compounds for the pain-sensitive peptide (NOP), m, and k opioid receptors was tested. The binding assays were rapid and simple, and were performed using Chinese hamster ovary cells transfected with human NOP or opioid receptors. The results of these assays are listed in Tables 4, 5, and 6. For compounds of formulas (II), (III), and (IV), Tables 4, 5, and 6 respectively give the range of receptor binding affinity of the compounds at the pain-sensitive peptide and opioid receptors.

[0296] Receptor binding affinity for NOP, m, d, and k receptors was determined using radioligand binding assays, each using one of the following radioligands: [ 3 H]N / OFQ (for NOP), [ 3 H]DAMGO (for m-opioid receptors), and [ 3 H]U-696593 (for ketoopioid receptors). IC 50 The value is determined by the curve fitting program Prism, where the Ki value is determined by equation K. i = IC 50 / (1 + L / K d ) is determined, where K d yes[ 3 H]-binding affinity of radioactive ligands, while L is the [ 3 H] - Concentration of radioactive ligands.

[0297] Cell culture:All receptors were found in CHO cells transfected with human receptor cDNA. Cells were grown in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum in 100 mm plastic culture dishes with 0.4 mg / ml G418 and 0.1% penicillin / streptomycin. For binding assays, cells were scraped from the culture plate at confluence.

[0298] Receptor binding: Binding to the cell membrane was achieved in 96-well plates, as previously reported by Zaveri, NT, et al., J. Med. Chem., 2004, 47:2973-2976; and Adapa, ID, et al. Neuropeptides , 1997, 31(5):403-408; and Dooley, CT, et al., J. Pharmacol. Exp. Ther As described in ., 1977, 283(2):735-741. Cells were removed from the culture plate by scraping with a rubber spatula, homogenized in a Tris buffer using a Polytron homogenizer, then centrifuged once and washed by an additional centrifugation at 27,000 g for 15 minutes. The particles were then resuspended in 50 mM Tris at pH 7.5, and the suspension was […]. 3 H]Pain-sensitive peptide, [ 3 H]DAMGO, or [ 3 H]U69593 was incubated to bind to NOP, m, or k opioid receptors, respectively. The total incubation volume was 1.0 ml, and the sample was incubated at 25˚C for 60 to 120 minutes. The amount of protein in the binding reactant was in the range of approximately 15 μg to 30 μg. The reaction was terminated by filtration using a Tomtec 96 harvester (Orange, CT) with a glass fiber filter. The bound radioactivity was counted on a Pharmacia Biotech b-plate liquid scintillation counter (Piscataway, NJ), and the bound radioactivity was expressed as counts per minute. IC50 was determined using at least six concentrations of the test compound. 50 The value was calculated using Graphpad / Prism (ISI, San Diego, California). 50 Value. K i The value is determined by the method of Cheng and Prusoff (Cheng, Y., et al ., Biochem Pharmacol ., 1973, 22(23):3099-3108) confirmed.

[0299] Regarding the binding affinity of each compound in the table below, values ​​marked "A" represent Ki values ​​less than 15 nM; values ​​marked "B" represent Ki values ​​between 15 and 150 nM; values ​​marked "C" represent Ki values ​​between 150 nM and 5000 nM; and values ​​marked "D" represent Ki values ​​greater than 5000 nM.

[0300] Table 3:

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] Table 4

[0307]

[0308] Table 5

[0309]

[0310] The compounds disclosed herein exhibit selectivity for NOP receptors that is 1 to more than 10,000 times higher than that for m-opioid receptors and k-opioid receptors.

[0311] Based on the foregoing description, it should be understood that although specific embodiments of the invention have been described herein for illustrative purposes, various modifications may be made without departing from the spirit and scope of the invention. Therefore, the invention is limited only by the appended claims.

Claims

1. A compound with structural formula (I): （I） Or a salt, hydrate, or solvate of the compound, wherein: A is or ; B is hydrogen; Alternatively, A and B are missing, and the carbon atoms attached to A and B are... The carbon atom adjacent to the amide carbonyl atom in the group; R1 and R2 together with the carbon atoms attached to R1 and R2 form aryl, substituted aryl, heteroaryl or substituted heteroaryl; X is hydrogen, -C=NOR4, -C(O)NR5R6, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; Y is hydrogen, -C=NOR7, -C(O)NR8R9, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; T is = NR 10 =CR 11 R 12 -、-NR 13 R 14 - substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; When R1 and R2 form a phenyl ring and L is If R3 is neither hydrogen nor methyl; R4 is hydrogen, alkyl, or substituted alkyl; R5 is hydrogen, alkyl, or substituted alkyl; R6 is hydrogen, alkyl, substituted alkyl, or OR. 15 ; R7 is hydrogen, alkyl, or substituted alkyl; R8 and R9 are independently hydrogen, alkyl, or substituted alkyl; R 10 It is hydrogen, alkyl, substituted alkyl, -OR 16 or -NR 17 R 18 ; R 11 It is hydrogen, alkyl, substituted alkyl, -C(O)R 19 Or -CN; R 12 It is hydrogen, -C(O)R 20 Or -CN; R 13 It is hydrogen or -C(O)R 21 ; R 14 It is hydrogen or -C(O)R 22 ; If R 13 and R 14 Neither of them is hydrogen; R 15 It is hydrogen, alkyl, or substituted alkyl; R 16 It is hydrogen, alkyl, or substituted alkyl; R 17 It is hydrogen or -C(O)R 23 ; R 18 It is hydrogen or -C(O)R 24 ; R 19 and R 20 Independently is -NR 25 R 26 -OR 27 Alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R 21 and R 22 Independently is -NR 28 R 29 -OR 30 Alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl; R 23 and R 24 It is independently an alkyl or substituted alkyl group; R 25 R 26 R 27 R 28 R 29 and R 30 It is independently hydrogen, alkyl, or substituted alkyl; and L represents (C3-C8) cycloalkyl, (C3-C8) substituted cycloalkyl, (C3-C8) heteroalkyl, (C3-C8) substituted cycloalkyl. , , or .

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