Pyrazole and imidazole derivatives as orexin antagonists, compositions, and methods

Abstract

The present invention is directed to substituted pyrazole and imidazole derivatives of compounds that are orexin receptor antagonists and are useful in the treatment or prevention of neurological and psychiatric disorders in which orexin receptors are involved or implicated. The invention also relates to pharmaceutical compositions containing these compounds, and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 856,822, filed on June 4, 2019, and the contents of the said Provisional Patent Application are incorporated in their entirety into this application. [Technical Field]

[0002] This disclosure relates to compounds, compositions, and methods for using orexin antagonists as therapeutic agents for the treatment or relief of human and animal diseases, in particular any pathological disorder in which both types of orexin receptors are pharmacologically involved or related. These important therapeutic uses include, but are not limited to, the treatment of central nervous system (CNS) disorders and neurological disorders in which orexin receptors are involved or modulated by orexin receptors, and such disorders and diseases include, but are not limited to, disorders that respond to orexin receptor antagonists, such as drug addiction and dependence, cognitive impairment, Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety, autism, and depression. [Background technology]

[0003] Orexin (also known as hypocretin) is composed of excitatory hypothalamic neuropeptides: orexin A (OX-A; 33-amino acid peptide) and orexin B (OX-B; 28-amino acid peptide). These were simultaneously discovered in 1998 by two research groups searching for novel signaling molecules: (1) Sakurai and collaborators (named orexin A and B) (Non-Patent Literature 1); and (2) de Lecea and collaborators (named hypocretin 1 and 2, respectively) (Non-Patent Literature 2). These neuropeptides are endogenous ligands for two G protein-coupled receptors (GPCRs) named OX1R and OX2R (also called Hcrt1 and Hcrt2, respectively), and are proteolytically derived from the same precursor peptide called preproorexin polypeptide (Non-Patent Literature 3). Although these endogenous ligands are structurally related, their binding affinities to the two GPCRs are different. Orexin A binds to OX1R with approximately 100 times higher affinity than orexin B, while both orexin A and orexin B bind to OX2R with the same affinity (Non-Patent Literature 4). Immediately after the discovery of orexin, its role in regulating sleep and wakefulness was thoroughly studied and understood. Therefore, orexin signaling was first considered for potential novel treatments in patients with narcolepsy or insomnia, and the discovery of small molecule modulators of orexin signaling facilitated the development of this class of compounds. Narcolepsy patients show decreased activity of hypothalamic orexin neurons and, consequently, decreased levels of circulating orexin in the cerebrospinal fluid. In contrast, activation of orexin neurons maintains wakefulness and alertness. The effects of orexin signaling on feeding and energy homeostasis were also established early on and found to correlate with the sleep-wake cycle (Non-Patent Literature 4). More recent studies have established the role of orexin signaling in other important physiological pathways, including neuroendocrine function (Non-Patent Document 5), glucose metabolism (Non-Patent Document 6), stress adaptation response (Non-Patent Document 7), and addiction / reward craving (Non-Patent Document 8).Small molecule orexin antagonists are broadly classified into three classes based on their overall receptor selectivity profile: (1) DORA (dual-acting, or non-selective OX1R / OX2R antagonists), (2) SORA-1 (selective OX1R antagonist), and (3) SORA-2 (selective OX2R antagonist). Although both OX2R knockout mice and OX1R / OX2R double knockout mice exhibit a narcolepsy phenotype, it has been shown that the effects are significantly suppressed in OX1R knockout mice (Non-Patent Literature 9). Furthermore, while both DORA and SORA-2 compounds inhibit the state of arousal, SORA-1 compounds do not, suggesting that the effects of narcolepsy are mediated by OX2R or a combination of OX1R and OX2R, and not by OX1R alone. Therefore, while the discovery and development of selective orexin antagonists are important for progress in this field, it is clear that their most important role is in the development of therapeutic agents for the biological processes of dysregulation involving orexin receptors, particularly for insomnia-related indications such as drug addiction. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Sakurai, T. et al., Cell 1998, 92, 573 [Non-Patent Document 2] de Lecea, L. et al, Proc. Natl. Acad. Sci. USA 1998, 95, 322. [Non-Patent Document 3] Sakurai T., et al. The Journal of biological chemistry. 1999; 274, 17771‐17776 [Non-Patent Document 4] Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366‐1375 [Non-Patent Document 5] Inutsuka, A.; Yamanaka, A. Front. Endocrinol. 2013, 4:18. doi: 10.3389 / fendo.2013.00018) [Non-Patent Document 6] Tsuneki, H., et al., Endocrinology, 2016, 157, 4146‐4157 [Non-Patent Document 7] Xiao, F., et al. Neuropharmacology, 2013, 67, 16‐24 [Non-Patent Document 8] Aston‐Jones, G., et al. Brain Res., 2010, 1314, 74‐90 [Non-Patent Document 9] Wang C., et al. Neurosci., 2018, 11, 220. doi: 10.3389 / fnmol.2018.00220 [Overview of the project]

[0005] This disclosure addresses the aforementioned therapeutic and / or other needs, as well as the challenges in the art, with respect to the chemical formula of Formula I:

[0006] [ka]

[0007] This is addressed by providing compounds and compositions containing the same, where the variables are as defined herein, and include any pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers thereof. In some embodiments, compounds of formula I and compositions containing the same can be used to treat conditions such as those described herein by their activity as lexin receptor antagonists, etc. Thus, compounds and / or compositions thereof may be referred to herein as "orexin receptor antagonists".

[0008] In some embodiments, the Disclosure also provides compositions comprising the compounds described above and / or pharmaceutically acceptable salts thereof. In some embodiments, the Disclosure provides methods for the treatment of CNS disorders, particularly drug addiction and dependence, post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety and depression, cognitive impairment and Alzheimer's disease (AD), in subjects who need or are at risk, the methods comprising the step of administering to the subject a therapeutically effective dose of an orexin receptor antagonist or a pharmaceutically acceptable salt thereof. In certain embodiments, the orexin receptor antagonist or a pharmaceutically acceptable salt thereof may be formulated to be administered regularly, for example, every 3, 6 to 24 hours, as deemed clinically beneficial, but not limited to these. Other embodiments and forms are also contemplated herein, as will be understood by those skilled in the art.

[0009] This disclosure relates to: condensed 6- and 5-membered ring structural derivatives of formula (I) (wherein the condensed 6- and 5-membered rings are as described herein by possible structural descriptions); pharmaceutically acceptable salts thereof; preparations thereof; pharmaceutical compositions comprising one or more compounds of formula (I); and the use thereof as pharmaceuticals and / or therapeutic agents, in particular (i.e., in preferred embodiments) their use as orexin receptor antagonists ("orexin receptor antagonists"). These novel activators described by formula (I) are non-peptide antagonists of the human orexin receptor and are potentially useful in treating disorders associated with orexinergic dysfunction, including but not limited to disorders such as drug addiction, anxiety, panic, cognitive impairment, irritability, or disorders of appetite, sleep, Alzheimer's disease (AD), metabolic syndrome, and hypertension, and these compounds in particular may have high therapeutic value in the treatment of anxiety disorders, addiction disorders, and sleep disorders.

[0010] In some embodiments, the present disclosure relates to formula (I)

[0011] [ka]

[0012] to provide a compound wherein: R1 is aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; the above aromatic, aryl, or heteroaryl is unsubstituted, mono-substituted, or di-substituted, and the substituents are (C 1‐4 ) alkyl, (C 1‐4 ) alkoxy, halogen (such as F, Cl, Br, or I), (C 1‐3 ) fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) cycloalkyl, independently selected from the group; R2 and R3 are independently H, halogen (such as F, Cl, Br, or I), an alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 ) alkoxy, (C 1‐3 ) fluoroalkyl, (C 1‐3 ) fluoroalkoxy, or (C 3‐7 ) cycloalkyl; R2 and R3 are each independently optionally substituted at each substitutable position with up to 3 substituents independently selected from one or both of R2 and / or R3; R4 is aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the above aromatic, aryl, or heteroaryl is unsubstituted, mono-substituted, di-substituted, or tri-substituted, and the substituents are (C 1‐4 ) alkyl, (C 1‐4 ) alkoxy, halogen (such as F, Cl, Br, or I), (C 1‐3 ) fluoroalkyl, (C 1‐3 ) fluoroalkoxy, (C 3‐7 ) cycloalkyl, and (C 3‐7) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X = CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in an (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X = O (oxygen)) is preferably in an (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 )It is a cycloalkyl; Here: The fused ring structure A-B-J-D-E is a 5-membered heteroaryl; The fused ring structure B-J-G-K-L is a 6-membered aromatic, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; Preferably: A = Nitrogen (N); and / or B = carbon (C) or nitrogen (N); and / or J = carbon (C) or nitrogen (N); and / or D = carbon (C); and / or E = carbon (C); and / or M = carbon (C), CH, CR2R3, CR2, CR3, or O; and / or G = carbon (C), CH, CR2R3, CR2, CR3, or O; and / or K = carbon (C), CH, CR2R3, CR2, CR3, or O; and / or L = carbon (C), CH, CR2R3, CR2, CR3, or O; Alternatively, these may be pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof.

[0013] In some preferred embodiments, the present disclosure provides compounds of formula II, where the ring structure represented by the A-B-J-D-E variables of formula (I) condensed into a six-membered ring is formula (II):

[0014] [ka]

[0015] As shown by, it is preferable to have an imidazolo ring structure, Here: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, or I, etc.), alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X=CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X=O (oxygen)) is preferably in (R) absolute configuration; Y=NH, O, none (to attach R4 directly to the CZ1Z2 group), CH2OR4, CH2, NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 2‐7 )It is a cycloalkyl; Preferably: M = carbon, CH, CR2R3, CR2, CR3, or O; and / or G = carbon, CH, CR2R3, CR2, CR3, or O; and / or K = carbon, CH, CR2R3, CR2, CR3, or O; and / or L is carbon, CH, CR2R3, CR2, CR3, or O.

[0016] In some preferred embodiments, the present disclosure provides a compound of formula III, wherein the ring structure represented by the A-B-J-D-E variables of formula (I) fused to a six-membered ring is of formula (III):

[0017]

Chemical formula

[0018] is a pyrazolo ring structure as represented by: where: R1 is aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; the above aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituents are independently selected from the group consisting of (C 1‐4 ) alkyl, (C 1‐4 ) alkoxy, halogen, (C 1‐3 ) fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) cycloalkyl; R2 and R3 are independently H, halogen (such as F, Cl, Br, or I), an alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 ) alkoxy, (C 1‐3 ) fluoroalkyl, (C 1‐3 ) fluoroalkoxy, or (C3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )Cycloalkyl, or (C 1‐3 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X = CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in an (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X = O (oxygen)) is preferably in an (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 )It is a cycloalkyl; Preferably: M = carbon (C), CH, CR2R3, CR2, CR3, or O; and / or G = carbon (C), CH, CR2R3, CR2, CR3, or O; and / or K = carbon (C), CH, CR2R3, CR2, CR3, or O; and / or L = carbon (C), CH, CR2R3, CR2, CR3, or O.

[0019] In some preferred embodiments, the present disclosure provides an imidazole condensed 6-membered ring, which is of formula II-a:

[0020] [ka]

[0021] The compound provided is as shown, and here: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, or I, etc.), alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) An alkyl crosslinked cyclic structure is formed; R6 = H, halogen (F, Cl, Br, I), alkyl, substituted alkyl, or R5 and R6 are linked as alkyl, (C 1‐3 ) An alkyl crosslinked cyclic structure is formed; X=CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X=O (oxygen)) is preferably in (R) absolute configuration; Y=NH, O, none (to attach R4 directly to the CZ1Z2 group), CH2OR4, CH2, NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 )It is a cycloalkyl; In some preferred embodiments, the present disclosure provides an imidazole condensed 6-membered ring, which is a compound of formula II-b:

[0022]

Chem.

[0023] To provide a compound as shown herein, where: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); heteroaryl is preferably 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; the above aromatic, aryl, or heteroaryl is an unsubstituted, monosubstituted, or disubstituted form, and the substituents are (C 1‐4 )alkyl, (C 1‐4 )alkoxy, halogen (such as F, Cl, Br, or I), (C 1‐3 )fluoroalkyl, (C 1‐3 )fluoroalkoxy, and (C 3‐7 )cycloalkyl, independently selected from the group consisting of; R2 and R3 are independently H, halogen (such as F, Cl, Br, or I), an alkyl group, substituted alkyl, (C 1‐4 )alkyl, (C 1‐4 )alkoxy, (C 1‐3 )fluoroalkyl, (C 1‐3 )fluoroalkoxy, or (C 3‐7 )cycloalkyl; R2 and R3 are each independently optionally substituted at each substitutable position with up to 3 substituents independently selected from one or both of R2 and R3; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the above aromatic, aryl, or heteroaryl is an unsubstituted, monosubstituted, disubstituted, or trisubstituted form, and the substituents are (C 1‐4 )alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 )fluoroalkyl, (C1‐3 ) fluoroalkoxy, (C 3‐7 ) cycloalkyl, and (C 3‐7 ) heterocycloalkyl, independently selected from the group consisting of; R5 = CH3, alkyl, substituted alkyl; optionally R5 and R6 are connected as alkyl to form a (C 1‐3 ) alkyl-bridged cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, substituted alkyl, or R5 and R6 are connected as alkyl to form a (C 1‐3 ) alkyl-bridged cyclic structure; X = CH2, O, (to provide a 5-membered pyrrolidine ring) none; the carbon atom at the 2-position of piperidine or pyrrolidine is preferably in the (S) absolute configuration; in contrast, the carbon atom at the 2-position of the morpholine ring (when X = O (oxygen)) is preferably in the (R) absolute configuration; Y = NH, O, (to directly attach R4 to the CZ1Z2 group) none, CH2OR4, CH2, or NR4R7 (where R7 = H, alkyl); Z1 and Z2 are independently = H, F, (C0] 1‐4 ) alkyl, (C 1‐3 ) fluoroalkyl, (C ! 1‐3 ) fluoroalkoxy, or (C 2‐7 ) cycloalkyl.

[0024] In some preferred embodiments, the present disclosure provides a compound in which the imidazole-fused 6-membered ring is as shown in Formula II-c:

[0025]

Chemical formula

[0026] where: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, or I, etc.), alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, substituted alkyl; R5 and R6 are connected as alkyl, (C1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X=CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X=O (oxygen)) is preferably in (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 It is a cycloalkyl compound.

[0027] In some preferred embodiments, the present disclosure provides a pyrazole condensed 6-membered ring, which is based on formula III-a:

[0028] [ka]

[0029] The compound provided is as shown, and here: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4)alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, or I, etc.), alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X=CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X=O (oxygen)) is preferably in (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 It is a cycloalkyl compound.

[0030] In some preferred embodiments, the present disclosure provides a pyrazole condensed 6-membered ring, which is a compound of formula III-b:

[0031] [ka]

[0032] The compound provided is as shown, and here: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, etc.), alkyl group, substituted alkyl group, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X = CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in an (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X = O (oxygen)) is preferably in an (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 )It is a cycloalkyl; In some preferred embodiments, the present disclosure provides a pyrazole condensed 6-membered ring, which is a compound of formula III-c:

[0033] [ka]

[0034] The compound provided is as shown, and here: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, or I, etc.), alkyl group, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X = CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in an (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X = O (oxygen)) is preferably in an (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 2‐7 )It is a cycloalkyl; In some preferred embodiments, the present disclosure provides a pyrazole condensed 6-membered ring, which is a compound of formula III-d:

[0035] [ka]

[0036] The compound provided is as shown, and here: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, etc.), alkyl group, substituted alkyl group, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; or R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X = CH2, O, or none (to provide a 5-membered pyrrolidine ring); the carbon atom at position 2 of piperidine or pyrrolidine is preferably in an (S) absolute configuration; in contrast, the carbon atom at position 2 of the morpholine ring (when X = O (oxygen)) is preferably in an (R) absolute configuration; Y=NH, O, none (to directly attach R4 to the CZ1Z2 group), CH2OR4, CH2, or NR4R7 (where R7=H, which is alkyl); Z1 and Z2 are independently = H, F, (C 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, or (C 1‐3 ) Fluoroalkoxy, (C 2‐7 )It is a cycloalkyl; In some preferred embodiments, this disclosure relates to the embodiment of formulas II-aa-ac, II-ba-bc, and II-ca-cc:

[0037] [ka]

[0038] The compound provides which, according to the exemplary formulas shown herein, preferably has a stereocenter and a major skeletal ring as shown in the following: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, or substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, I, etc.), alkyl group, substituted alkyl group, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )Cycloalkyl, (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; Y=NH, O, (none to attach R4 directly to the CZ1Z2 group (CH2 in formulas II-aa-ac, II-ba-bc, and II-ca-cc)), CH2OR4, CH2, or NR4R7 (where R7=H, alkyl).

[0039] In some preferred embodiments, the present disclosure relates to the formulas III-aa-ac, III-ba-bc, and III-ca-cc of the embodiments:

[0040] [ka]

[0041] The compound provides which, according to the exemplary formulas shown herein, preferably has a stereocenter and a major skeletal ring as shown in the following: R1 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the heteroaryl is preferably a 5 or 6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogens (F, Cl, Br, or I, etc.), (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently H, halogen (F, Cl, Br, I, etc.), alkyl group, substituted alkyl group, (C1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, or (C 3‐7 ) is a cycloalkyl group; R2 and R3 are each independently and optionally substituted with up to three substituents independently selected from one or both of R2 and R3 at their respective substituted positions; R4 = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and the substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) Fluoroalkoxy, (C 3‐7 )cycloalkyl, and (C 3‐7 ) Independently selected from the group consisting of heterocycloalkyls; R5 = CH3, alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; R6 = H, halogen (F, Cl, Br, I), alkyl, or substituted alkyl; R5 and R6 are connected as alkyl, (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; Y=NH, O, (none to attach R4 directly to the CZ1Z2 group (CH2 in formulas III-aa-ac, III-ba-bc, and III-ca-cc)), CH2OR4, CH2, NR4R7 (where R7=H, alkyl).

[0042] In a more preferred embodiment, the present disclosure relates to the following formulas: I, II, III, II-a, II-b, II-c, III-a, III-b, and III-c:

[0043] [ka]

[0044] The present invention provides compounds thereof, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [Modes for carrying out the invention]

[0045] The term "alkyl" as used herein refers to C1-C 100 (For example, methyl, ethyl, propyl, etc., including but not limited to these, (for example, general formula C (n) H (2n+1)The term "fluoroalkyl" means a linear or branched carbon chain having fluorine atoms. The term "fluoroalkyl" as used herein means an alkyl group substituted with at least one fluorine atom. The term "alkoxy" as used herein means an alkyl group bonded to oxygen (i.e., R-O). The term "fluoroalkoxy" as used herein means an alkoxy group substituted with at least one fluorine atom. The term "heterocycloalkyl" as used herein means a cycloalkyl group containing at least one heteroatom (e.g., N and / or O) in its ring. The term "aryl" as used herein means a monocyclic or bicyclic carbocyclic aromatic or aryl ring structure. Phenyl is an example of a monocyclic aromatic or aryl ring structure. The term "heteroaryl" as used herein means a monocyclic or bicyclic aromatic or aryl ring structure having 1 to 3 heteroatoms or heteroatomic groups selected from O, N, NH, and S in a chemically stable arrangement within each ring. In embodiments of such "heteroaryl" structures with a bicyclic aromatic or aryl ring structure: both rings may be aromatic or aryl; one or both rings may contain the heteroatom or heteroatomic group.Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazole, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyradadinyl (e.g., 3-pyramidinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-thiazolyl). Examples include lyazolyl, 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, prinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). The terms "cycloalkyl" or "cycloalkenyl" refer to monocyclic or condensed or (C) compounds that are not aromatic or aryl. 1‐3 ) refers to an alkyl-bridged bicyclic carbocyclic ring structure. The cycloalkenyl ring has a degree of unsaturation of 1 or more. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl, and dekalinyl. The "halogen" can be F, Cl, Br, or I, but preferred embodiments have the halogen as F, Cl, or Br. The term "substituted," as used herein, means replacing one functional group with another with respect to a particular group (e.g., alkyl, aryl, heteroaryl, aromatic) (e.g., substitution of an alkyl with fluorine to provide a fluoroalkyl).

[0046] Furthermore, unless otherwise specified, any embodiments provided herein are intended to represent the unlabeled and isotope-labeled forms of the compounds. The isotope-labeled compounds have the structure represented by the formulas described herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I is an example. This disclosure relates to various isotope-labeled compounds as defined herein, for example 3 H, 13 C, and 14 This includes compounds containing radioactive isotopes such as 13C. Such isotope-labeled compounds are: (preferably) 14 Metabolic studies (using C); (for example) 2 H or 3 It is useful in studies of reaction dynamics (using H); detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays; or in radiation therapy for patients. 18 F or 18 F-labeled compounds may be particularly preferred for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the schemes or examples and preparations described below, by replacing the non-isotopically labeled reagents with readily available isotope-labeling reagents.

[0047] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereocenter in their structure. This stereocenter may be located in an R or S structure, and the notations R and S are used in accordance with the rules set out in Pure Appl. Chem. (1976), 45, 11-30. This disclosure also relates to all stereoisomer forms of the compounds, such as enantiomers and diastereomers, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, International Publication 01 / 062726 (see also U.S. Patent Publication 2017 / 0022208 and U.S. Patent Publication 2017 / 0253603). Furthermore, multiple substituents on the piperidinyl or pyrrolidinyl ring may be in a cis or trans ring system relative to the plane of the piperidinyl or pyrrolidinyl ring. Such forms or geometric isomers, although not explicitly expressed in the formulas described herein, are intended to be included within the scope of this disclosure. With respect to the methods and compositions of this disclosure, any reference to one or more compounds is intended to encompass each possible isomer of the compound, and mixtures thereof, unless a specific isomer is specifically referred to.

[0048] pharmaceutically acceptable salts, as used herein, refer to the agents or compounds according to the present invention in the form of therapeutically effective non-toxic basic and acidic salts of the above-mentioned compounds. Acid addition salts of compounds that arise in their free base form can be obtained by treating the free base form with a suitable acid, such as: inorganic acids, e.g., hydrohalogens such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, e.g., acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic, salicylic acid, p-aminosalicylic acid, pamoic acid, etc. See, for example, International Publication No. 01 / 062726 (see also U.S. Patent Publication No. 2017 / 0022208 and U.S. Patent Publication No. 2017 / 0253603).

[0049] Compounds containing acidic protons can be converted to therapeutically effective, non-toxic base-addition salt forms, such as metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts; alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium salts; salts containing organic bases; and salts containing amino acids such as arginine and lysine. Conversely, the above-mentioned salt forms can be converted to free forms by treatment with appropriate bases or acids. Compounds and their salts can also be in solvate form, which is included within the scope of this disclosure. Examples of such solvates include hydrates and alkoxides.

[0050] The compounds of the present invention also include prodrugs, analogues, or derivatives. The term “prodrug” is a recognized technique in the art and is intended to encompass compounds or agents that are converted to orexin antagonists under physiological conditions. A common method for preparing prodrugs is to select a moiety that is hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent. In other embodiments, prodrugs are converted to orexin antagonists by the enzymatic activity of a host animal.

[0051] This disclosure also relates to isotopically labeled compounds of all formulas, in particular 2 This includes H (deuterium) labeled compounds, and these compounds are identical to all compounds of the formulas described herein, except that one or more atoms are replaced by atoms having the same atomic number but with atomic weights different from those commonly found in nature. All isotope-labeled compounds of the formulas, in particular 2 H (deuterium)-labeled compounds and their salts are within the scope of this disclosure. 2Substitution with H (deuterium) can result in higher metabolic stability, for example, leading to an extension of the in vivo half-life or a reduction in dosage requirements, or it can result in reduced inhibition of cytochrome P450 enzymes, for example, leading to an improved safety profile. In another embodiment of the present invention, all compounds of the formula are not isotope-labeled. However, isotope-labeled compounds of all formulas can be prepared by anyone skilled in the art in the same manner as described below, but using suitable isotope variations of suitable reagents or starting materials.

[0052] In some embodiments, the Disclosure provides methods for preparing the compounds disclosed herein. In preferred embodiments, the compounds of the Disclosure are prepared using the methods described in the following Examples, or preferred modifications thereof as will be understood by those skilled in the art. In some embodiments, the above methods may include the use of intermediate compounds, such as those disclosed herein, the specific uses of which will be described in more detail in the Examples section. Thus, in some embodiments, the Disclosure provides intermediates (for example, intermediates A to J shown in the Examples section below) that can be used in the preparation of compounds of the formulas disclosed herein, for example, but not limited to Examples 1 to 21. In some embodiments, the Disclosure also provides intermediates used in the preparation of intermediates A to J. In preferred embodiments, such intermediates include: intermediate A, intermediate A1, intermediate A2, intermediate A3, and / or intermediate A4; intermediate B and / or intermediate B1; intermediate C and / or intermediate C1; intermediate D and / or intermediate D1 or; intermediate E and / or intermediate E1; intermediate F, intermediate F1, and / or intermediate F2; intermediate G and / or intermediate G1; intermediate H and / or intermediate H1; intermediate I, intermediate I1, and / or intermediate I2; intermediate J and / or intermediate J1. In some embodiments, the compound of Example 1 can be produced using intermediate A and intermediate F. In some embodiments, the compound of Example 2 can be produced using intermediate A and intermediate B. In some embodiments, the compound of Example 3 can be produced using intermediate A and intermediate C. In some embodiments, the compound of Example 4 can be produced using intermediate J and intermediate D. In some embodiments, the compound of Example 5 can be produced using intermediates A and D. In some embodiments, the compound of Example 6 can be produced using intermediates J and E. In some embodiments, the compound of Example 7 can be produced using intermediates A and E. In some embodiments, the compound of Example 8 can be produced using intermediates I and E. In some embodiments, the compound of Example 9 can be produced using intermediates I and D.In some embodiments, the compound of Example 10 can be produced using intermediates J and B. In some embodiments, the compound of Example 11 can be produced using intermediates I and B. In some embodiments, the compound of Example 12 can be produced using intermediates I and F. In some embodiments, the compound of Example 13 can be produced using intermediates J and F. In some embodiments, the compound of Example 14 can be produced using intermediates I and C. In some embodiments, the compound of Example 15 can be produced using intermediates J and C. In some embodiments, the compound of Example 16 can be produced using intermediates J and G. In some embodiments, the compound of Example 17 can be produced using intermediates A and H. In some embodiments, the compound of Example 18 can be produced using intermediates I and H. In some embodiments, the compound of Example 19 can be produced using intermediates I and G. In some embodiments, the compound of Example 20 can be produced using intermediates J and H. In some embodiments, the compound of Example 21 can be produced using intermediates J and G. Where used herein, the phrase "can be used" is equivalent to "can be reacted with" (as shown, for example, in the Examples section below). While such methods can be used to prepare the compounds of Examples 1-21, those skilled in the art will understand that other methods may also be used.

[0053] The compounds of this disclosure can be used for a variety of in vivo therapeutic methods, and the compounds can also be used in vitro to inhibit orexin receptor type 1 and / or type 2 (i.e., orexin receptor type 1 and / or type 2 antagonists). For example, in some embodiments, Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor and / or human orexin-2 receptor can be incubated with one or more antagonists or potential antagonists (e.g., the compounds of Examples 1-21) and one or more indicator compounds with one or more agonists (e.g., fluorescent calcium indicators such as Fluo-4 AM), and the antagonist activity can be measured using a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices). The antagonist activity can be measured at a 50% inhibitory concentration (IC2). 50 It can be recorded as a value. Other suitable methods for identifying antagonist compounds are also known to those skilled in the art.

[0054] Accordingly, in some embodiments, the present disclosure provides compounds that can be used for in vivo treatment and / or in vitro for various disease conditions (e.g., as orexin receptor type 1 and / or type 2 antagonists). In some embodiments, the present disclosure provides compounds of formulas I, II, III, IIa, IIb, IIc, IIIa, IIIb, IIIc, IIaa, IIab, IIac, IIba, IIbb, IIbc, IIca, IIcb, IIcc, IIIaa, IIIab, IIIac, IIIba, IIIbb, IIIbc, IIIca, IIIcb, and / or IIIcc:

[0055] [ka]

[0056] [ka]

[0057] We provide, or may disclose and / or intend to disclose herein, a compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, herein: R1 is selected from the group consisting of aromatic, aryl, 5- or 6-membered heteroaryl, substituted aromatic, substituted aryl, and substituted 5- or 6-membered heteroaryl; optionally, the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted with one R1 substituent, or disubstituted with two R1 substituents, each R1 substituent being (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyls; halogens are arbitrarily selected from the group consisting of F, Cl, Br, and I; R2 and R3 are H, halogen, alkyl, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) independently selected from the group consisting of cycloalkyl groups; R2 and R3 are independently and optionally substituted with up to three R2-R3 substituents at their respective substituted positions, and each R2-R3 substituent is H, halogen, alkyl, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) independently selected from the group consisting of cycloalkyls; halogens are optionally selected from the group consisting of F, Cl, Br, and I; R4 is selected from the group consisting of aromatic, aryl, 5- or 6-membered heteroaryl, substituted aromatic, substituted aryl, and substituted 5- or 6-membered heteroaryl; the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted with one R4 substituent, disubstituted with two R4 substituents, or trisubstituted with three R4 substituents, each R4 substituent being (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 )Cycloalkyl, (C 3‐7 ) independently selected from the group consisting of heterocycloalkyls; the halogen is optionally selected from the group consisting of F, Cl, Br, and I; R5 is selected from the group consisting of CH3, alkyl, and substituted alkyl groups; R6 is selected from the group consisting of H, halogens, alkyls, and substituted alkyls; the halogen is selected from the group consisting of F, Cl, Br, and I; R5 and R6 can optionally be connected as alkyl groups (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X is absent to provide a pyrrolidine ring, CH2 to provide a piperidine ring, or O to provide a morpholine ring; the carbon atom at position 2 of the piperidine or pyrrolidine ring is optionally in (S) absolute configuration; the carbon atom at position 2 of the morpholine ring is optionally in (R) absolute configuration; Y is either absent or selected from the group consisting of NH, O, CH2OR4, CH2, and NR4R7, where R7 is H or alkyl; Z1 and Z2 are H, F, and (C respectively. 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 2‐7 ) Independently selected from the group consisting of cycloalkyl groups; Here again: A-B-J-D-E is a five-membered heteroaryl; B-J-M-G-K-L is a six-membered ring selected from the group consisting of aromatic, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl compounds; Also, optionally here: A is N; and / or B is C or N; and / or J is C or N; and / or D is C; and / or E is C; and / or M is selected from the group consisting of C, CH, CR2R3, CR2, CR3, and O; and / or G is selected from the group consisting of C, CH, CR2R3, CR2, CR3, and O; and / or K is selected from the group consisting of C, CH, CR2R3, CR2, CR3, and O; and / or L is selected from the group consisting of C, CH, CR2R3, CR2, CR3, and O.

[0058] In some embodiments, this disclosure is shown below. Preferred compounds:

[0059] [ka]

[0060] The present invention provides pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof.

[0061] In some embodiments, the Disclosure provides compositions comprising the above compound and / or one or more of its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations. In some embodiments, the Disclosure provides pharmaceutical compositions comprising: the compound, its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations; and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. In some embodiments, the Disclosure provides a therapeutically effective amount of the above compound, or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations. In some embodiments, the Disclosure provides the pharmaceutical compositions further comprising at least one second therapeutic agent. In some embodiments, the Disclosure provides a method for preventing or treating a condition selected from the group consisting of central nervous system (CNS) disorders, drug addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD) in a subject in need, by administering to the subject one or more of the above compounds and / or a composition comprising one or more of the above compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In some embodiments, the method may include the step of administering a therapeutically effective amount of the above compound, a composition comprising a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the composition comprises a pharmaceutically acceptable salt or isotope of the above compound. In some embodiments, the composition may include an unlabeled form of the compound or an isotope-labeled form of the compound, in which the compound has the structure shown by the formula above, and one or more atoms are replaced with atoms having a selected atomic weight or mass number.In some embodiments, the Disclosure provides the use of the compounds disclosed herein, their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations in the preparation of agents for the prevention and / or treatment of conditions selected from the group consisting of central nervous system (CNS) disorders, drug addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD) in patients in need. In some embodiments, the use may include a composition comprising a therapeutically effective amount of the compound, its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations. In some embodiments, the use may include a composition comprising a pharmaceutically acceptable salt or isotope of the compound. In some embodiments, the use may include a composition comprising an unlabeled form of the compound or an isotope-labeled form of the compound, in which the compound has the structure represented by the formula above, and one or more atoms are replaced with atoms having a selected atomic weight or mass number. This disclosure also provides intermediates of the compounds disclosed herein, and methods for preparing such compounds. In some embodiments, the preparation method may include a step of using any of the intermediates disclosed herein (for example, one or more of intermediates A to J). Other embodiments are also contemplated, as will be understood by those skilled in the art.

[0062] This disclosure also provides pharmaceutical compositions comprising one or more compounds of this disclosure (or pharmaceutically acceptable salts thereof, etc.) (as active ingredients, as therapeutic agents) and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition contains a therapeutically effective amount of one or more of the above compounds, etc. (i.e., one or more activators) or a suitable fraction thereof. The composition may optionally contain additional activators. In some embodiments, the purity of the peptide product is at least about 90%, 95%, or 98%. Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials, and vehicles. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, flow enhancers, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption retarders, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavorings, colorants, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is well known in the art. Conventional vehicles and carriers, for example, include, but are not limited to, oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents (e.g., physiological saline, buffered physiological saline (e.g., phosphate-buffered saline (PBS)) and isotonic solutions (e.g., Ringer's solution)), and organic solvents (e.g., dimethyl sulfoxide and alcohols (e.g., ethanol, glycerol, and propylene glycol)). Unless any conventional excipient or carrier is incompatible with the peptide product, this disclosure includes the use of conventional excipients and carriers in formulations containing peptide products.See, for example, Remington: The Science and Practice of Pharmacy, 2nd Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004). The appropriateness of a particular prescription may depend on various factors, such as the chosen route of administration. Possible routes of administration of pharmaceutical compositions containing the compounds disclosed herein include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, and topical), topical (percutaneous, transmucosal, intranasal (e.g., by nasal spray or droplets), eye (e.g., by eye drops), lung (e.g., by oral or nasal inhalation), cheek, sublingual, rectum (e.g., by suppositories), vagina (e.g., by suppositories), and / or other preferred routes.

[0063] The term "therapeutic effective amount" refers to the amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of growth of, delay the onset of, slow the progression of, or reverse a medical condition, or to alleviate to some extent one or more symptoms or complications of the medical condition, in at least a certain proportion of the subjects who ingest the compound. The term "therapeutic effective amount" also refers to the amount of a compound sufficient to induce a biological or medical response in cells, tissues, organs, or humans, as required by a physician or clinician. The terms "treat" and "treatment" include reducing, alleviating, inhibiting, reversing, or suppressing the progression of a medical condition or one or more symptoms or complications associated with the condition, or reducing, alleviating, or eradicating one or more causes of the condition. A reference to "treatment" of a medical condition includes the prevention of the condition. The terms “prevent” and “preventing” include eliminating, reducing the risk of growth of, and delaying the onset of a medical condition or one or more symptoms or complications associated with such condition. The term “medical condition” (or simply “condition”) includes diseases and disorders. The terms “disease” and “disorder” are used interchangeably herein.

[0064] Throughout this specification, the word “comprise,” or its variations such as “comprises,” or “comprising,” implies that it includes the complete entity (or component) or group of complete entities (or components) being referred to, but does not exclude any other complete entities (or components) or group of complete entities (or components). The singular forms “a, an” and “the” include the plural unless explicitly stated otherwise in the context. The symbol “=" means “is” when used in the writing of an expression. The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. The term “agent” is used herein to refer to a chemical compound (e.g., an organic substance, or a mixture of chemical compounds). Examples of activators include those with known structures, and due to their orexin antagonist activity, these may be suitable as “therapeutic agents” in the methods and compositions disclosed herein. Furthermore, those skilled in the art will recognize that the following abbreviations, which may be used herein, are common.

[0065] Me: Methyl Et: Ethyl t-Butyl:tert-butyl Ar: Aryl Ph: Phenyl BINAP:2,2'-bis(diphenylphosphin)-1,1'-binaphthyl Bn: Benzyl Ac: Acetyl Boc:tert-butyloxycarbonyl BSA: Bovine serum albumin CbzCl: Benzyl chloroformate CDI: Carbonyldiimidazole DCM: Dichloromethane DCE: Dichloroethane DEAD: Diethyl azodicarboxylate DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide CH2Cl2: Dichloromethane EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide Et3N: Triethylamine æ:ethyl acetate EtOH: Ethanol HCl: Hydrogen chloride HOAt: 1-hydroxy-7-aza-10-benzotriazole HOBT: Hydroxybenzotriazole hydrate LCMS: Liquid Chromatography Mass Spectrometry HPLC: High-performance liquid chromatography Hunik's base: N,N-diisopropylethylamine MeOH: methanol MgSO4: Magnesium sulfate MTBE: Methyl tert-butyl ether NaHCO3: Sodium Bicarbonate Na2CO3: Sodium carbonate K2CO3: Potassium carbonate NaOH: Sodium hydroxide NMM: N-methylmorpholine PtO2: Platinum Oxide Pd: Palladium Pd / C: Palladium Carbon PyClu:1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate RT or rt: Room temperature SOCl2: Thionyl Chloride THF: Tetrahydrofuran TFA: Trifluoroacetic acid X-Phos:2-(dicyclohexyl-phosphino)-2',4',6'-triisopropylbiphenyl HATU:(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) NMR: nuclear magnetic resonance ESI: Electrospray Ionization MS: Mass spectrometry reaction: reaction All references cited herein are incorporated herein by reference in their entirety. Specific embodiments are described further in the following embodiments. These embodiments are provided merely as examples and are not intended to limit the scope of the claims in any way. [Examples]

[0066] I. General synthesis methods and procedures A. Overview All temperatures are expressed in °C. Commercially available starting materials were used in their as-obtained state without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under a nitrogen atmosphere. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. The compounds described herein were characterized by LC-MS data under the conditions listed below (retention time t). R (The units are given in minutes; the molecular weight obtained from the mass spectrum is given in units of g / moles).

[0067] LC-MS under acidic conditions Method A: Agilent 1100 series with mass spectrometry detection (MS: Agilent single quadrupole). Column: Zorbax SB (3.5 μm, 4.6 × 150 mm). Conditions: MeCN (0.1% FA) [Gradient Eluent A]; Water (0.1% FA) [Gradient Eluent B]. Gradient: 95% B + 5% B, 5 minutes (flow rate: 0.8 ml / min). Detection: UV280 / 254 nm + MS.

[0068] Method B: Agilent 1100 series with mass spectrometry detection (MS: Agilent single quadrupole). Column: X-Bridge C18 (3.5 μm, 4.6 × 150 mm). Conditions: MeCN (0.1% FA) [Gradient Eluent A]; Water (0.1% FA) [Gradient Eluent B]. Gradient: 95% B + 5% B, 5 minutes (flow rate: 0.8 ml / min). Detection: UV280 / 254 nm + MS.

[0069] Overall, the compounds of the present invention can be prepared by methods known to those skilled in the art and by the current art in the art. Schemes 1 to 4 below illustrate the synthetic routes of the compounds of the present invention. Alternatively, various parts of the molecules shown by the general schemes described herein can be synthesized using other equivalent schemes that would be readily apparent to a synthetic organic chemist or medicinal chemist of ordinary skill.

[0070] B. Intermediate synthesis 1. Intermediate product A:

[0071] [ka]

[0072] synthesis Step 1: Synthesis of Compound A1: Ethyl-3-phenyl-1H-pyrazole-5-carboxylic acid (0.5 g, 2.31 mmol) was dissolved in acetone (10.0 mL). K2CO3 (0.96 g, 6.9 mmol) was added, followed by 1-bromo-2-chloroethane (0.1 mL, 11.6 mmol). The reaction mixture was heated at 55°C for 16 hours. LC-MS data showed the formation of the desired product with an m / z of 279.0, as well as trace amounts of byproducts. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: Â:hexane gradient). 0.6 g of the liquid product was isolated (yield 93.2%). 14 H 15The calculated MS(ESI) mass for ClN2O2 is 278.7; m / z = 279.0 [M+H]. + That was the case.

[0073] Step 2: Synthesis of Compound A2: Compound A1 (0.55 g, 1.97 mmol) was dissolved in dry THF (6.0 mL). DIBAL (12.0 mL, 1.0 M solution, 11.8 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed the formation of the desired product with an m / z of 237.0. The reaction mixture was quenched with 1.0 N NaOH aqueous solution and diluted with ethyl acetate (10.0 mL). The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (10.0 mL × 3). The ÃO layer was separated, washed with water, and then washed with brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 0.4 g of crude product (yield 85.6%). 12 H 13 The calculated MS(ESI) mass for ClN2O is 236.7; m / z = 237.0 [M+H]. + That was the case.

[0074] Step 3: Synthesis of Compound A3: Compound A2 (0.47 g, 1.97 mmol) was dissolved in dry DMF (12.0 mL). NaH (0.12 g, 2.96 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed the formation of the desired product with an m / z of 201.1. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The complex ethyl acetate layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: ԅ:hexane gradient). 0.26 g of solid product was obtained (yield 65.3%). 12 H 12 The calculated MS(ESI) mass for N2O is 200.2; m / z = 201.1 [M+H]. + That was the case.

[0075] Step 4: Synthesis of Compound A4: Compound A3 (0.25 g, 1.25 mmol) was dissolved in DCM (5.0 mL). NBS (0.24 g, 1.37 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LCMS data showed the formation of the desired product with an m / z of 280.9. The solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: ԅ:hexane gradient). 0.29 g of liquid product was obtained (yield 81.7%). 12 H 11 The calculated MS(ESI) mass for BrN2O is 279.1; m / z = 280.9 [M+H]. + That was the case.

[0076] Step 5: Synthesis of Intermediate A: Compound A4 (0.025 g, 0.09 mmol) was dissolved in anhydrous THF (1.0 mL) under an N2 atmosphere. The reaction mixture was cooled to -78.0 °C and n-BuLi (0.12 mL, 1.6 M) was added to the reaction mixture. The reaction mixture was stirred at -78.0 °C for 30.0 minutes. Dry CO2 gas was passed through the reaction mixture at -65 °C and the reaction mixture was gradually warmed to room temperature. LCMS data showed the formation of the desired product with m / z 245, a debrominated byproduct (m / z=201), and some unknown byproducts. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated and the debrominated product was recovered. The aqueous layer was acidified with 1 M HCl solution and evaporated to dry state to obtain 0.022 g of solid product. 13 H 12 The calculated MS(ESI) mass for N2O3 is 244.3; m / z = 245.0 [M+H]. + , 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 4.06-4.15 (m,2H) 4.16-4.25 (m,2H) 5.03-5.10 (s,2H) 7.32-7.40 (m,3H) 7.60-7.69 (m,2H).

[0077] 2. Intermediate B:

[0078] [ka]

[0079] synthesis Step 1: Synthesis of Compound B1: 2-chloro-5-trifluoromethylpyridine (0.33 g, 1.82 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.36 g, 1.81 mmol) were dissolved in dry DMSO (5.0 mL). DIPEA (1.6 mL, 9.1 mmol) was added, and the reaction mixture was stirred at 100°C for 4 hours. TLC showed product formation. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The ethyl acetate complex layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using an ISCO combiflash chromatography system (mobile phase: Depositphotos:hexane gradient). 0.24 g of the desired liquid product (yield 39.0%) was isolated. 16 H 22 The calculated MS(ESI) mass for F3N3O2 is 345.0; m / z = 346.1 [M+H]. + That was the case.

[0080] Step 2: Synthesis of Intermediate B: Compound B1 (0.24 g, 0.71 mmol) was dissolved in dry dioxane (3.0 mL). A 4.0 M HCl solution (1.77 mL, 7.08 mmol) was added to the dioxane, and the reaction mixture was stirred at 50°C for 4 hours. LC-MS showed the formation of a product with an m / z of 246. The reaction mixture was concentrated under reduced pressure to obtain a solid product (0.19 g, yield 78.4%). 11 H 14 The calculated MS(ESI) mass for F3N3 is 245.2; m / z = 246.0 [M+H]. + , 1H NMR (400MHz, chloroform-d) δ ppm 1.76-2.01(m,1H)2.01-2.15(m,1H)2.15-2.28(m,1H)2.36(br s,1H)3.25-3.46(br s,1H)3.48(br s,1H)4.04(br s, 2H) 4.31 (br s, 1H) 7.47 (br s, 1H) 7.86 (br s, 1H) 8.19 (br s, 1H) 9.41-10.42 (br s, 1H).

[0081] 3. Intermediate C:

[0082] [ka]

[0083] synthesis Step 1: Synthesis of Compound C1: 2-chloro-5-ethylpyrimidine (0.2 g, 1.37 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.28 g, 1.37 mmol) were dissolved in dry DMF (5.0 mL). Cs2CO3 (0.89 g, 2.75 mmol) was added, and the reaction mixture was stirred at 120°C for 24 hours. TLC showed the formation of the product. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The ethyl acetate complex layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using an ISCO combiflash chromatography system (mobile phase: Depositphotos:hexane gradient). 0.27 g of the desired liquid product (yield 64.2%) was isolated. C 16 H 26 The calculated MS(ESI) mass for N4O2 is 306.4; m / z = 307.1 [M+H]. + .

[0084] Step 2: Synthesis of Intermediate C: Compound C1 (0.27 g, 0.88 mmol) was dissolved in dry dioxane (3.0 mL). A 4.0 M HCl solution (2.2 mL, 8.81 mmol) was added to the dioxane, and the reaction mixture was stirred at 60°C for 4 hours. LC-MS showed the formation of a product with an m / z of 207. The reaction mixture was concentrated under reduced pressure to obtain a solid product (0.31 g, quantitative yield). C 11 H 18 The calculated MS(ESI) mass for N4 is 206.3; m / z = 207.1 [M+H]. + That was the case.

[0085] 4. Intermediate D:

[0086] [ka]

[0087] synthesis Step 1: Synthesis of Intermediate D1: [(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidine-2-yl]methanamine (0.35 g, 1.4 mmol) and 2-chloro-5-ethylpyrimidine (0.2 g, 1.4 mmol) were dissolved in dry DMF (4.0 mL). K2CO3 (0.39 g, 2.82 mmol) was added, and the reaction mixture was stirred at 120°C for 6 hours. TLC showed the formation of the product. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The complex ethyl acetate layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using a combiflash chromatography system (mobile phase: Depositphotos:hexane gradient). 0.33 g of product was obtained (yield 65.4%). 21 H 30 The calculated MS(ESI) mass for N4O is 354.5; m / z = 355.2 [M+H]. + , 1H NMR(400MHz,chloroform-d)δ ppm 0.85-0.94(d,J=8.0Hz,3H)1.16(t,J=8.0Hz,3H)1.25-1.47(m,2H)1.50-1.84(m,2H)2.05-2.25(m,1H)2.35-2. 47(q,J=8.0Hz,2H)2.47-2.60(m,1H)2.62-2.83(m,2H)3.33-3.46(m,2H)3.77(s,3H)3.78-3.85(m,2H)5.68(br s,1H)6.84(d,J=8.66Hz,2H)7.24-7.31(m,2H)8.12(s,2H).

[0088] Step 2: Synthesis of Intermediate D: Compound D1 (0.1 g, 0.3 mmol) was dissolved in MeOH (3.0 mL). 20.0% Pd-OH / C (30.0 mg) was added, and the reaction mixture was stirred at ambient temperature for 24 hours. TLC showed little initial material and product formation. Another 20.0% Pd-OH / C (30.0 mg) was added, and the reaction mixture was stirred at room temperature for another 24 hours. TLC showed completion of the reaction. LCMS data showed product formation with an m / z of 235. The reaction mixture was filtered over Celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 66.0 mg of crude product. The crude product was used in the next step without purification. 13 H 22 The calculated MS(ESI) mass for N4 is 234.3; m / z = 235.2 [M+H]. + That was the case.

[0089] 5. Intermediate E:

[0090] [ka]

[0091] synthesis Step 1: Synthesis of Compound E1: [(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidine-2-yl]methanamine (0.32 g, 1.29 mmol) and 2-chloro-5-trifluoromethylpyridine (0.23 g, 1.29 mmol) were dissolved in dry DMF (5.0 mL). K2CO3 (0.36 g, 2.58 mmol) was added, and the reaction mixture was stirred at 120 °C for 4 hours. TLC showed product formation, and LCMS showed product formation with an m / z of 394. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The ethyl acetate complex layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using an ISCO combiflash chromatography system (mobile phase: DCM:MeOH (90:10 v / v mL)). The product band was isolated. 0.41 g of pure product was obtained at m / z = 394 (yield 81.4%). 21 H 26 The calculated MS(ESI) mass for F3N3O is 393.5; m / z = 394.1 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 0.88(d,J=7.04Hz,3H)1.19-1.46(m,2H)1.54-1.65(m,1H)1.65-1.83(m,1H)2.07-2.22(m,1H) )2.50-2.65(m,1H)2.65-2.80(m,2H)3.20-3.38(m,2H)3.78(s,3H)3.79-3.84(m,2H)5.67(br s,1H)6.32(d,J=8.80Hz,1H)6.80-6.89(m,2H)7.15-7.29(m,2H)7.49(dd,J=8.80,2.35Hz,1H)8.28-8.32(m,1H).

[0092] Step 2: Synthesis of Intermediate E: Compound E1 (0.02 g, 0.5 mmol) was dissolved in MeOH (5.0 mL). 10.0% Pd / C (60.0 mg) was added, and the reaction mixture was stirred at ambient temperature for 24 hours under an H2 atmosphere. TLC showed completion of the reaction. LCMS data showed the formation of a product with an m / z of 274. The reaction mixture was filtered over Celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 0.16 g of crude product. The crude product was used in the next step without purification. C 13 H 18 The calculated MS(ESI) mass for F3N3 is 273.3; m / z = 274.1 [M+H]. + That was the case.

[0093] 6. Intermediate F:

[0094] [ka]

[0095] synthesis Step 1: Synthesis of Compound F1: N-Boc-L-prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.9 mL, 4.97 mmol) was added, followed by DMAP (0.61 g, 4.97 mmol). The reaction mixture was cooled in an ice bath, and p-TsCl (0.52 g, 2.73 mmol) was added. The reaction mixture was stirred and gradually warmed to room temperature over 16 hours. LC-MS showed the formation of a product with m / z values ​​of 256 and 300. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain 0.88 g of product (quantitative yield). 17 H 25 The calculated MS(ESI) mass for NO5S is 355.5; m / z = 300.1, 256.1 [M+H]. + That was the case.

[0096] Step 2: Synthesis of Compound F2: Compound F1 (0.88 g, 2.48 mmol) and 3-phenyl-1H-pyrazole (0.43 g, 2.98 mmol) were dissolved in dry DMF (5.0 mL). Cs2CO3 (1.61 g, 4.96 mmol) was added, and the reaction mixture was stirred at 70°C for 4 hours. LC-MS showed the formation of a product with an m / z of 328. The reaction mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The HCl layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: HCl:hexane gradient). 0.73 g of pure product was obtained (yield 89.5%). 19 H 25 The calculated MS(ESI) mass for N3O2 is 327.4; m / z = 328.3 [M+H]. + That was the case.

[0097] Step 3: Synthesis of intermediate F: Compound F2 (0.73 g, 2.24 mmol) was dissolved in dry dioxane (10.0 mL). A 4.0 M HCl solution (2.8 mL, 11.2 mmol) was added to the dioxane, and the reaction mixture was stirred at 50°C for 16 hours. LC-MS showed the formation of a product with an m / z of 228. The reaction mixture was filtered and washed with hexane (5.0 mL x 3) to obtain 0.53 g of solid product (quantitative yield). 14 H 17 The calculated MS(ESI) mass for N3 is 227.1; m / z = 228.2 [M+H]. + , 1 H NMR (400MHz, chloroform-d) δ ppm 1.74-1.94(m,1H)1.94-2.05(m,1H)2.06-2.15(m,1H)2.16-2.35(m,1H)3.21-3.45(m,2H)4.33(br s,1H)4.86(dd,J=14.82,3.96Hz,1H)5.07(br dd,J=14.67,8.66Hz,1H)6.75(d,J=2.20Hz,1H)7.34-7.48(m,3H)7.76-7.87(m,2H)8.44(d,J=2.49Hz,1H)9.51-10.12(br,1H).

[0098] 7. Intermediate G:

[0099] [ka]

[0100] synthesis Step 1: Synthesis of Compound G1: N-Boc-L-prolinol (0.2 g, 0.99 mmol) was dissolved in dry DMF (4.0 mL). NaH (0.08 g, 2.0 mmol) was added under ice cooling. 2-Chloro-5-ethylpyrimidine (0.2 g, 1.5 mmol) was added under cooling, and the reaction mixture was gradually warmed at room temperature for 3 hours with stirring. LC-MS showed the formation of a product with an m / z of 308.2. The reaction mixture was diluted with water. The product was extracted three times with ethyl acetate. The ethyl acetate layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: ethyl acetate:hexane gradient). 0.3 g of pure product was obtained (quantitative yield). C 16 H 25 The calculated MS(ESI) mass for N3O3 is 307.4; m / z = 308.2 [M+H]. + That was the case.

[0101] Step 2: Synthesis of Intermediate G: HBS-037-152 (0.3 g, 0.99 mmol) was dissolved in dry dioxane (4.0 mL). A 4.0 M HCl solution (2.48 mL, 9.9 mmol) was added to the dioxane, and the reaction mixture was stirred at 60°C for 4 hours. LC-MS showed the formation of a product with an m / z of 208.1. The reaction mixture was concentrated under reduced pressure to obtain 0.32 g of liquid product. 11 H 17 The calculated MS(ESI) mass for N3O is 207.3; m / z = 208.1 [M+H]. + That was the case.

[0102] 8. Intermediate H:

[0103] [ka]

[0104] synthesis Step 1: Synthesis of compound H1: N-Boc-L-prolinol (0.2 g, 0.99 mmol) was dissolved in dry DMF (4.0 mL). NaH (0.08 g, 2.0 mmol) was added, followed by 2-chloro-5-trifluoromethylpyridine (0.27 g, 1.5 mmol). The reaction mixture was heated at 70°C for 3 hours. LC-MS showed the formation of a product with an m / z of 347.1. The reaction mixture was diluted with water. The product was extracted three times with ethyl acetate. The  layer was separated and dried on anhydrous Na₂SO₄. The solvent was evaporated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: Â:hexane gradient). 0.3 g of pure product was obtained (yield 86.0%). 16 H 21 The calculated MS(ESI) mass for F3N2O3 is 346.3; m / z = 347.1 [M+H]. + That was the case.

[0105] Step 2: Synthesis of intermediate H: Compound H1 (0.3 g, 0.86 mmol) was dissolved in dry dioxane (2.0 mL). A 4.0 M HCl solution (2.14 mL, 8.6 mmol) was added to the dioxane, and the reaction mixture was stirred at 60°C for 4 hours. LC-MS showed the formation of a product with an m / z of 247.1. The reaction mixture was filtered and washed with hexane (5.0 mL x 3) to obtain 0.27 g of solid product (quantitative yield). 11 H 13 The calculated MS(ESI) mass for F3N2O is 246.2; m / z = 247.1 [M+H]. + , 1H NMR(400MHz,chloroform-d)δ ppm 1.87-1.99(m,1H)1.99-2.08(m,1H)2.08-2.17(m,1H)2.17-2.29(m,1H)3.32-3.49(m,2H)3.96-4.09( m,1H)4.60-4.77(m,2H)7.00(d,J=8.73Hz,1H)7.77(dd,J=8.73,2.35Hz,1H)8.37-8.42(m,1H)9.74(br s,1H)10.32(br s,1H).

[0106] 9. Intermediate I:

[0107] [ka]

[0108] synthesis Step 1: Synthesis of Compound I1: Ethyl benzoyl acetate (0.5 g, 2.6 mmol) was dissolved in DMSO (5.0 mL). NBS (0.51 g, 2.86 mmol) was added, and the reaction mixture was stirred at ambient temperature for 24 hours. LC-MS showed the formation of a product with an m / z of 270.9. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified using a combiflash system (mobile phase: Depositphotos:hexane gradient). 0.42 g of product was obtained (yield 59.7%). 11 H 11 The calculated MS(ESI) mass for BrO3 is 271.1; m / z = 270.9 [M+H]. + That was the case.

[0109] Step 2: Synthesis of Compound I2: Compound I1 (0.42 g, 1.55 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). 2-aminopyridine (0.15 g, 1.55 mmol) was added, and the reaction mixture was stirred at 80°C for 1 hour. LC-MS showed the formation of a product with an m / z of 267.1. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combiflush system (mobile phase: Â:hexane gradient). 0.24 g of product was obtained (yield 58.0%). 16 H 14 The calculated MS(ESI) mass for N2O2 is 266.3; m / z = 267.1 [M+H]. + That was the case.

[0110] Step 3: Synthesis of Intermediate I: Compound I2 (0.24 g, 0.9 mmol) was dissolved in MeOH (5.0 mL). 1.0 N NaOH aqueous solution (4.51 mL, 4.51 mmol) was added, and the reaction mixture was stirred at 60°C for 3 hours. LC-MS showed the formation of a product with an m / z of 239. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M HCl aqueous solution (pH=5). The precipitate was filtered and washed with water (10.0 mL × 3) to obtain 0.2 g of solid product. 14 H 10 The calculated MS(ESI) mass for N2O2 is 238.2; m / z = 239.1 [M+H]. + , 1 ¹H NMR (400MHz, chloroform-d) δ ppm 7.04 (t, J=6.93Hz, 1H) 7.33-7.48 (m, 4H) 7.70-7.78 (m, 3H) 9.41 (d, J=7.04Hz, 1H).

[0111] 10. Intermediate J:

[0112] [ka]

[0113] synthesis Synthesis of intermediate J: Compound J1 (0.2 g, 0.75 mmol) was dissolved in MeOH (6.0 mL) (synthesized as reported in Journal of Medicinal Chemistry; 2011, 54 (13), 4752-4772). 1.0 N NaOH aqueous solution (3.8 mL, 3.8 mmol) was added, and the reaction mixture was stirred at 60°C for 3 hours. LC-MS showed the formation of a product with an m / z of 239.1. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 1.0 M HCl aqueous solution (pH=5). The precipitate was filtered and washed with water (10.0 mL × 3) to obtain 0.18 g of solid product. 14 H 10 The calculated MS(ESI) mass for N2O2 is 238.2; m / z = 239.1 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 6.90-7.03(m,1H)7.27-7.47(m,4H)7.75-7.78(ddd, J=4.86, 3.21, 1.54Hz, 2H)8.18-8.28(dd,J=8.99,0.70Hz,1H)8.49-8.56(dd,J=6.90,0.73Hz,1H).

[0114] II. Synthesis of Example Compounds A. Example 1:

[0115] [ka]

[0116] Synthesis of Compound Example 1: Intermediate A (0.02 g, 0.082 mmol) was dissolved in dry DMF (0.7 mL). HATU (0.05 g, 0.12 mmol) was added, followed by DIPEA (0.06 mL, 0.33 mmol). Intermediate F was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 454. The reaction mixture was diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The ethyl acetate complex layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: Â:hexane (75:25 v / v mL)). The desired band was isolated to obtain 0.009 g of product (yield 23.5%). 27 H 27 The calculated MS(ESI) mass for N5O2 is 453.5; m / z = 454.1 [M+H]. + , 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.30-1.57(m,2H)1.78-1.95(m,1H)1.95-2.08(m,2H)2.58(dt,J=10.51 ,7.40Hz,1H)2.98-3.23(m,1H)3.64-3.92(m,1H)4.02-4.27(m,3H)4.32 -4.54(m,2H)4.54-4.71(m,1H)4.87-5.05(m,1H)6.50-6.62(m,1H)7.23 -7.42(m,6H)7.47(d,J=2.20Hz,1H)7.51-7.61(m,2H)7.66-7.86(m,2H).

[0117] B. Example 2:

[0118] [ka]

[0119] Synthesis of Compound Example 2: Intermediate A (0.034 g, 0.14 mmol) was dissolved in dry DMF (1.5 mL). HATU (0.05 g, 0.14 mmol) was added, followed by DIPEA (0.12 mL, 0.7 mmol). Intermediate B (0.025 g, 0.07 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 472. The reaction mixture was diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The ethyl acetate complex layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (75:25 v / v mL)). The desired product band was isolated. 13.0 mg of pure product was obtained (yield 39.0%). 24 H 24 The calculated MS(ESI) mass for F3N5O2 is 471.5; m / z = 472.1 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.52-1.77(m,3H)1.96-2.21(m,1H)2.57-2.71(m,1H)3.16-3.28(m,1H)3.45-3.59(m,2H)4.0 9‐4.29(m,4H)4.60‐4.81(m,1H)4.84‐4.94(d,J=15.70Hz,1H)5.01(d,J=15.70Hz,1H)6.56(br d,J=8.80Hz,2H)7.22-7.36(m,3H)7.49-7.58(m,3H)7.99-8.32(br s,1H).

[0120] C. Example 3:

[0121] [ka]

[0122] Synthesis of Compound Example 3: Intermediate A (0.025 g, 0.1 mmol) was dissolved in dry DMF (0.7 mL). HATU (0.08 g, 0.2 mmol) was added, followed by DIPEA (0.18 mL, 1.0 mmol). Intermediate C (0.036 g, 0.1 mmol) was dissolved in dry DMF (1.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 433. The reaction mixture was diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The complex ethyl acetate layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: Depositphotos). The desired product band was isolated to obtain 0.02 g of pure product (yield 46.0%). C 24 H 28 The calculated MS(ESI) mass for N6O2 is 432.5; m / z = 433.1 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.12-1.25(t,J=8.0Hz,3H)1.37-1.65(m,2H)1.52-2.18(m,1H)2.36-2.49(m,2H)2.49-2.74(m,1H )2.82-3.25(m,1H)3.43-3.86(m,2H)3.90-4.30(m,5H)4.47-4.64(m,1H)4.75-5.13(m,2H)6.02(br t,J=4.58Hz,1H)7.25-7.39(m,3H)7.39-7.59(m,2H)7.98-8.17(br s,2H).

[0123] D. Example 4:

[0124] [ka]

[0125] Synthesis of Compound Example 4: Intermediate J (0.046 g, 0.192 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.049 g, 0.26 mmol) and HOBt (0.035 g, 0.26 mmol) were added, followed by Et3N (0.1 mL, 0.6 mmol). Intermediate D (0.03 g, 0.13 mmol) was dissolved in dry DCM (1.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 455. The reaction mixture was diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The complex ethyl acetate layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: DCM:MeOH (97:03 v / v mL)). The desired product band was isolated, yielding 0.027 g of product (yield 31.3%). 27 H 30 The calculated MS(ESI) mass for N6O is 454.6; m / z = 455.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 0.52-0.54(d,J=4.0Hz,1H)1.02-1.03(d,J=4.0Hz,2H)1.08-1.19(m,4H)1.19-1.47(m,3H )1.59-1.91(m,1H)2.23-2.33(m,1H)2.42(q,J=7.58Hz,1H)2.67-2.94(m,1H)3.06-3.51( m,2H)3.73-4.11(m,1H)4.46-5.09(m,1H)5.16-5.78(m,1H)6.62-6.83(m,1H)7.05-7.15( m,1H)7.27-7.45(m,3H)7.59-7.77(m,4H)8.08-8.14(m,1H)8.19-8.42(d,J=6.97Hz,1H).

[0126] E. Example 5:

[0127] [ka]

[0128] Synthesis of Compound Example 5: Intermediate A (0.025 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.039 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added, followed by Et3N (0.07 mL, 0.5 mmol). Intermediate D (0.024 g, 0.1 mmol) was dissolved in dry DCM (1.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 461. The reaction mixture was concentrated and diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The complex ethyl acetate layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: DCM:MeOH (97:03 v / v mL)). The desired product band was isolated, yielding 25.4 mg of the product (yield 53.9%). 26 H 32 The calculated MS(ESI) mass for N6O2 is 460.6; m / z = 461.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 0.50(d,J=7.04Hz,1H)0.98(d,J=7.04Hz,2H)1.16(td,J=7.57,5.98Hz,4H)1.2 0‐1.41(m,2H)1.53‐1.85(m,1H)2.42(qd,J=7.57, 2.24Hz,2H)2.70(tdd,J=13. 35, 13.35, 5.06, 3.15Hz, 1H) 3.13-3.52 (m, 2H) 3.75-4.00 (m, 2H) 4.00-4.19 (m, 3H)4.36-4.72(m,1H)4.74-4.94(m,2H)5.03(dt,J=12.10,4.29Hz,1H)5.53(br d,J=4.84Hz,1H)7.24-7.39(m,3H)7.46-7.60(m,2H)8.04(s,1H)8.10(s,1H).

[0129] F. Example 6:

[0130] [ka]

[0131] Synthesis of Compound Example 6: Intermediate J (0.017 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.03 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added, followed by Et3N (0.05 mL, 0.4 mmol). Intermediate E (0.02 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 494. The reaction mixture was concentrated and diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The complex ethyl acetate layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: Â:hexane (50:50 v / v mL)). The desired product band was isolated, yielding 0.018 g of product (yield 50.6%). 27 H 26 The calculated MS(ESI) mass for F3N5O is 493.5; m / z = 494.2 [M+H]. + , 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 0.55 (br d,J=4.99Hz,1H)1.05(d,J=4.0Hz,2H)1.16-1.52(m,3H)1.57-1.98(m,2H)2.60-3.01(m,1H)3.12-3.59(m,2H)3.74-4.22(m,1H)4.43-5.25 (m,1H)5.55-6.10(m,1H)6.45-6.47(d,J=8.0Hz,1H)6.65-6.89(m,1H)6.98-7.21(m,1H)7.26-7.60(m,5H)7.63-7.74(m,2H)7.97-8.31(br s,1H)8.18‐8.45(br d,1H).

[0132] G. Example 7:

[0133] [ka]

[0134] Synthesis of Compound Example 7: Intermediate A (0.025 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.04 g, 0.2 mmol) and HOBt (0.028 g, 0.2 mmol) were added, followed by Et3N (0.14 mL, 1.0 mmol). Intermediate E (0.024 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 500. The reaction mixture was concentrated and diluted with a saturated solution of NaHCO3. The product was extracted with ethyl acetate. The complex ethyl acetate layer was washed with water, followed by washing with brine. The organic layer was separated and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: Â:hexane (50:50 v / v mL)). The desired product band was isolated, yielding 0.027 g of product (yield 52.8%). 26 H 28 The calculated MS(ESI) mass for F3N5O2 is 499.5; m / z = 500.2 [M+H]. + , 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 0.48-0.57(d,J=8.0Hz,1H)1.00-1.01(d,J=4.0Hz,2H)1.06-1.46(m,4H)1.62-1.80(m,1H)2.59-2.81(m,1H)3.20-3.45(m,2H)3.74-4.03(m ,2H)4.05-4.26(m,3H)4.37-5.08(m,3H)5.67-5.81(m,1H)5.95-6.43( d,J=8.0Hz,1H)7.22-7.46(m,3H)7.46-7.55(m,3H)8.16-8.36(s,1H).

[0135] H. Example 8:

[0136] [ka]

[0137] Synthesis of Compound Example 8: 2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I) (0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added, followed by Et3N (0.07 mL, 0.5 mmol). Intermediate E (0.03 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 494.2. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: Â:hexane (30:70 v / v mL)). The desired product band was isolated, yielding 24.5 mg of the desired product (yield 47.3%). 27 H 26 The calculated MS(ESI) mass for F3N5O is 493.5; m / z = 494.2 [M+H]. + , 1 ¹H NMR (400MHz, chloroform-d) δ ppm 0.55-1.12 (d,3H) 1.13-1.58 (m,2H) 1.65-2.43 (m,2H) 2.69-3.1 (m,1H) 3.12-3.35 (m,1H) 3.35-3.51 (m,1H) 3.73-4.64 (m,2H) 4.76-5.32 (m,1H) 5.71 (br d,J=8.51Hz,1H)6.51(d,J=8.66Hz,1H)6.63-6.85(m,1H)6.99-7.20(m,1H)7. 20-7.48(m,4H)7.52-7.58(m,1H)7.61-7.77(m,2H)7.85-8.24(m,1H)8.28(br d,J=6.90Hz,1H).

[0138] I. Example 9:

[0139] [ka]

[0140] Synthesis of Compound Example 9: 2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I) (0.02 g, 0.08 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.032 g, 0.17 mmol) and HOBt (0.023 g, 0.17 mmol) were added, followed by Et3N (0.12 mL, 0.8 mmol). Intermediate D (0.02 g, 0.08 mmol) was dissolved in dry DCM (2.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 455. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: Â:MeOH (98:2.0 v / v mL)). A pure product band of 21.2 mg was obtained (yield 55.5%). 27 H 30 The calculated MS(ESI) mass for N6O is 454.6; m / z = 455.3 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 0.50-0.57(m,2H)0.97-1.22(m,4H)1.22-1.50(m,2H)1.55-1.94(m,2H)2.25( dquin,J=14.88, 7.39, 7.39, 7.39, 7.39Hz,2H)2.35‐2.59(m,1H)2.75‐2.92(m ,1H)2.99-3.41(m,2H)4.11-4.64(m,1H)4.83-5.25(m,1H)6.69-6.81(m,1H)7 .06‐7.17(m,1H)7.17‐7.29(m,1H)7.29‐7.44(m,3H)7.55‐7.68(m,2H)7.72(br d,J=6.82Hz,1H)8.09(br d,J=5.72Hz,1H)8.31(d,J=6.90Hz,1H).

[0141] J. Example 10:

[0142] [ka]

[0143] Synthesis of Compound Example 10: Intermediate J (0.03 g, 0.13 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.049 g, 0.25 mmol) and HOBt (0.034 g, 0.25 mmol) were added, followed by DIPEA (0.2 mL, 1.23 mmol). Intermediate B (0.045 g, 0.13 mmol) was dissolved in dry DCM (2.0 mL) and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 466. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (50:50 v / v mL)). The desired product band was isolated, yielding 0.052 g of the product (yield 88.2%). 25 H 22 The calculated MS(ESI) mass for F3N5O is 465.5; m / z = 466.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.43-2.02(m,4H)2.59-2.73(m,1H)3.06-3.29(m,1H)3.47-3.63(m,2H)4.66-4.86(m,1H)6.48-6.65(d,J=8.0Hz,1H)6.65-6.78(br s,1H)6.86(br t,J=6.75Hz,1H)7.17-7.44(m,4H)7.44-7.62(m,1H)7.62-7.72(m,3H)8.33(br s,1H)8.47(br d,J=6.90Hz,1H).

[0144] K. Example 11:

[0145] [ka]

[0146] Synthesis of Compound Example 11: 2-phenylimidazo[1,2-a]-pyridine-3-carboxylic acid (intermediate I) (0.024 g, 0.1 mmol) was dissolved in a mixture of dry THF:DMF (2.0 mL, 1:1). HATU (0.038 g, 0.1 mmol) was added, followed by DIPEA (0.05 g, 0.4 mmol). Intermediate B (0.032 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 466. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: SiO:hexane (75:25 v / v mL)). The desired product band was isolated, yielding 0.01 g of the product (yield 20.0%). 25 H 22 The calculated MS(ESI) mass for F3N5O is 465.5; m / z = 465.9 [M+H]. + , 1 H NMR (400MHz, chloroform-d) δ ppm 1.47-2.04(m,4H)2.60(br s,1H)3.09-3.34(m,1H)3.51-3.66(m,2H)4.78(br s,1H)6.33-6.51(br s,1H)6.58(br d,J=8.51Hz,1H)6.90(br t,J=6.60Hz,1H)7.26-7.46(m,4H)7.49-7.61(br d,J=8.0Hz,1H)7.61-7.71(m,3H)8.35(br s,1H)8.58(br d,J=5.80Hz,1H).

[0147] L. Example 12:

[0148] [ka]

[0149] Synthesis of Compound Example 12: 2-phenylimidazo[1,2-a]-pyridine-3-carboxylic acid (intermediate I) (0.036 g, 0.15 mmol) was dissolved in dry THF (2.5 mL). HATU (0.058 g, 0.15 mmol) was added, followed by DIPEA (0.078 g, 0.6 mmol). Intermediate F (0.04 g, 0.15 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 3 hours. LCMS data showed the formation of a product with an m / z of 448. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (30:70 v / v mL)). The desired product band was isolated, yielding 0.031 g of the product (yield 45.0%). 28 H 25 The calculated MS(ESI) mass for N5O is 447.5; m / z = 447.9 [M+H]. + , 1 H NMR(400MHz,DMSO‐d6)δ ppm 1.37‐1.59(m,2H)1.64‐1.96(m,2H)2.87‐3.06(m,1H)3.56‐3.84(m,1H)4.55(br s,3H)6.71(s,1H)6.90-6.91(m,1H)7.22-7.50(m,8H)7.58-7.70(m,2H)7.71-7.90(m,3H)8.53(br d,J=6.68Hz,1H).

[0150] M. Example 13:

[0151] [ka]

[0152] Synthesis of Compound Example 13: Intermediate J (0.04 g, 0.16 mmol) was dissolved in dry THF (2.5 mL). HATU (0.064 g, 0.16 mmol) was added, followed by DIPEA (0.087 g, 0.67 mmol). Intermediate F (0.044 g, 0.16 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 3 hours. LCMS data showed the formation of a product with an m / z of 448. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (30:70 v / v mL)). The desired product band was isolated, yielding 0.048 g of product (yield 64.0%). 28 H 25 The calculated MS(ESI) mass for N5O is 447.5; m / z = 448.0 [M+H]. + , 1 H NMR(400MHz,DMSO‐d6)δ ppm 1.18‐1.45(m,1H)1.45‐1.67(m,1H)1.68‐1.85(m,1H)1.90(m,1H)2.86(m,1H)3.06(m,1H)4.35‐4.58(m,2H)4.63(br s,1H)6.75(br s,1H)6.89-7.16(m,1H)7.16-7.35(m,2H)7.35-7.60(m,6H)7.71-7.87(m,5H)8.79(br d,J=6.68Hz,1H).

[0153] N. Example 14:

[0154] [ka]

[0155] Synthesis of Compound Example 14: 2-phenylimidazo[1,2-a]-pyridine-3-carboxylic acid (intermediate I) (0.029 g, 0.12 mmol) was dissolved in a dry THF:DMF mixture (2.0 mL, 1:1). HATU (0.046 g, 0.12 mmol) was added, followed by DIPEA (0.062 g, 0.5 mmol). Intermediate C (0.03 g, 0.12 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 3 hours. LCMS data showed the formation of a product with an m / z of 427. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (25:75 v / v mL)). The desired product band was isolated, yielding 0.032 g of the product (yield 62.0%). 25 H 26 The calculated MS(ESI) mass for N6O is 426.5; m / z = 427.0 [M+H]. + , 1 H NMR(400MHz,DMSO-d6)δ ppm 1.01-1.38(m,3H)1.52-1.93(m,4H)2.20-2.43(m,2H)2.55-2.89(m,2H)3.47-3.89(m,2H)4.43-4.60(m,1H)6.65-6.84(m,1H)6 .84-7.06(m,1H)7.08-7.29(m,1H)7.29-7.47(m,4H)7.47-7.54(m,2H)7.55-7.76(m,1H)8.15(s,1H)8.26(brd,J=6.82Hz,1H).

[0156] O. Example 15:

[0157] [ka]

[0158] Synthesis of Compound Example 15: Intermediate J (0.024 g, 0.1 mmol) was dissolved in dry THF (2.5 mL). HATU (0.038 g, 0.1 mmol) was added, followed by DIPEA (0.052 g, 0.4 mmol). Intermediate C (0.024 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 427. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (75:25 v / v mL)). The desired product band was isolated to obtain 0.034 g of product (yield 76.0%). C 25 H 26 The calculated MS(ESI) mass for N6O is 426.5; m / z = 426.9 [M+H]. + , 1 H NMR(400MHz,DMSO‐d6)δ ppm 1.14‐1.29(t,3H)1.40‐1.95(m,4H)2.21‐2.45(m,2H)2.65‐3.21(m,2H)3.43‐3.72(m,2H)4.47(br s,1H)6.67-6.95(m,1H)7.00(br d,J=6.24Hz,1H)7.12-7.29(m,1H)7.30-7.45(m,4H)7.46-7.62(m,1H)7.72(br s,2H)8.14(br s,1H)8.51‐8.81(br d,J=8.0Hz,1H).

[0159] P. Example 16:

[0160] [ka]

[0161] Synthesis of Compound Example 16: Intermediate A (0.025 g, 0.1 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.039 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added, followed by Et3N (0.14 mL, 1.0 mmol). Compound G (0.03 g, 0.1 mmol) was added, dissolved in dry DCM (2.0 mL), and added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 434.2. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (60:40 v / v mL)). 31.3 mg of pure product was obtained (yield 70.1%). 24 H 27 The calculated MS(ESI) mass for N5O3 is 433.5; m / z = 434.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.20(t,J=7.63Hz,3H)1.48-1.75(m,2H)1.85-2.08(m,2H)2.55(q,J=7.58Hz,2H)2.68-2.77(m,1H)3.1 3(ddd, J=10.60, 6.97, 4.07Hz,1H)3.49-3.99(m,1H)4.00-4.27(m,4H)4.45-4.54(m,1H)4.58-4.65(br d,J=7.70Hz,1H)4.82-5.01(m,2H)7.23-7.36(m,3H)7.43-7.55(m,1H)7.58(br d,J=6.97Hz,1H)8.18-8.29(m,1H)8.34(s,1H).

[0162] Q. Example 17:

[0163] [ka]

[0164] Synthesis of Compound Example 17: Intermediate A (0.025 g, 0.1 mmol) was dissolved in dry DCM (3.0 mL). EDC.HCl (0.039 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added, followed by Et3N (0.14 mL, 1.0 mmol). Intermediate H (0.033 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 473.2. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: Â:hexane (40:60 v / v mL)). 0.045 g of product was obtained (yield 92.5%). 24 H 23 The calculated MS(ESI) mass for F3N4O3 is 472.5; m / z = 473.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.43-1.61(m,1H)1.60-1.71(m,1H)1.71-1.91(m,1H)1.91-2.24(m,1H)2.48-2.81(m,1H)3.01-3.26(m,1H)3.45-3.93(m,1H)3.95-4.2 3(m,4H)4.39-4.71(m,2H)4.71-5.06(m,2H)6.49-6.87(m,1H)7.12-7.39(m,3H)7.39-7.63(m,2H)7.63-7.84(m,1H)8.19-8.54(m,1H).

[0165] R. Example 18:

[0166] [ka]

[0167] Synthesis of Compound Example 18: 2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I) (0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by Et3N (0.15 mL, 1.1 mmol). Intermediate H (0.034 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 467. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: siRNA:hexane (40:60 v / v mL)). 0.023 g of product was obtained (yield 46.5%). 25 H 21 The calculated MS(ESI) mass for F3N4O2 is 466.5; m / z = 467.2 [M+H]. + , 1 H NMR (400MHz, chloroform-d) δ ppm 1.24-1.52(m,1H)1.52-1.74(m,1H)1.76-2.11(m,2H)2.58-3.21(br s,1H)3.64-3.92(m,1H)3.92-4.18(m,1H)4.49-4.72(m,1H)4.72-4.92(m,1H)6.7-6.91(br d,J=8.80Hz,2H)7.17-7.30(m,2H)7.31-7.49(m,3H)7.53-7.88(m,3H)8.01-8.42(br,1H)8.42-8.7(br,1H).

[0168] S. Example 19:

[0169] [ka]

[0170] Synthesis of Compound Example 19: 2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (intermediate I) (0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by Et3N (0.15 mL, 1.1 mmol). Intermediate G (0.033 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 428. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified using a preparative TLC plate (mobile phase: siRNA:hexane (75:25 v / v mL)). 0.017 g of product was obtained (yield 37.4%). 25 H 25 The calculated MS(ESI) mass for N5O2 is 427.5; m / z = 428.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.18-1.39(t,3H)1.47-1.67(m,1H)1.67-1.85(m,1H)1.85-2.13(m,2H)2.39- 2.61(m,2H)2.77-3.3(br,1H)3.58-3.87(m,1H)3.88-4.15(m,1H)4.59-4.6(br d,J=7.41Hz,1H)4.71-4.74(br d,J=7.56Hz,1H)6.83-6.86(br t,J=6.64Hz,1H)7.18-7.28(m,1H)7.33-7.42(m,3H)7.54-7.70(m,1H)7.78-7.80(br d,J=7.26Hz,1H)7.92(s,1H)8.33-8.40(s,1H)8.41-8.65(brd,J=6.31Hz,1H).

[0171] T. Example 20:

[0172] [ka]

[0173] Synthesis of Compound Example 20: Intermediate J (0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by Et3N (0.15 mL, 1.1 mmol). Intermediate G (0.034 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 467. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (40:60 v / v mL)). 0.042 g of product was obtained (yield 84.9%). 25 H 21 The calculated MS(ESI) mass for F3N4O2 is 466.5; m / z = 467.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.51-1.69(m,1H)1.70-1.82(m,1H)1.82-2.02(m,1H)2.03-2.16(m,1H)2.73-3.28(m,2H)3.69-4.11(m,2H) 4.55-4.90(m,2H)6.77-6.93(m,2H)7.13-7.26(m,1H)7.32-7.53(m,3H)7.56-7.92(m,4H)8.05-8.59(m,2H).

[0174] U. Example 21:

[0175] [ka]

[0176] Synthesis of Compound Example 21: Intermediate J (0.025 g, 0.11 mmol) was dissolved in dry DCM (2.0 mL). EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by Et3N (0.15 mL, 1.1 mmol). Intermediate G (0.033 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of a product with an m / z of 428. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried on anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified on a preparative TLC plate (mobile phase: siRNA:hexane (60:40 v / v mL)). 0.029 g of product was obtained (yield 63.8%). 25 H 25 The calculated MS(ESI) mass for N5O2 is 427.5; m / z = 428.2 [M+H]. + , 1 H NMR(400MHz,chloroform-d)δ ppm 1.1-1.23(t,3H)1.48-1.68(m,1H)1.68-1.80(m,1H)1.93-2.17(m,2H)2.43-2.60(m,2H)2.82-3.22(m,1H)3.75-4.0(br,2H)4.53 -4.75(m,2H)6.76-6.85(m,1H)7.13-7.26(m,1H)7.28-7.43(m,3H)7.60-7.83(m,3H)8.03(s,1H)8.31-8.39(m,2H)8.43-8.45(br d, J = 6.90 Hz, 1 H).

[0177] III. Experimental Biological Assays The antagonist activity for both orexin receptors was measured for each compound in the examples using the following procedure: In vitro assay: Measurement of intracellular calcium Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor and human orexin-2 receptor, respectively, are grown in a culture medium (Ham F-12 containing L-glutamine) containing 300 μg / mL G418, 100 U / mL penicillin, 100 μg / mL streptomycin, and 10% thermoinactivated fetal bovine serum (FCS). The cells are seeded at a rate of 20,000 cells / well in 384-well black transparent-bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2. Human orexin-A, as an agonist, is prepared as a 1 mM stock solution in MeOH:water (1:1) and diluted in HBSS containing 0.1% bovine serum albumin (BSA), 0.375 g / L NaHCO3, and 20 mM HEPES for use in the assay at a final concentration of 3 nM.

[0178] The antagonist was prepared as a 10 mM stock solution in DMSO, diluted in a 384-well plate with DMSO, and then transferred to an HBSS containing 0.1% bovine serum albumin (BSA), 0.375 g / L NaHCO3, and 20 mM HEPES. On the day of the assay, 50 μL of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, 0.375 g / L NaHCO3, 5 mM probenecid (Sigma), and 3 μM fluorescent calcium indicator Fluo-4 AM) (1 mM stock solution in DMSO containing 10% Pluronic®) was added to each well. The 384-well cell plate was incubated in 5% CO2 at 37°C for 50 minutes, followed by equilibration at room temperature for 30 minutes, and then measured.

[0179] In a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices), the antagonist was added to the plate in a volume of 10 μL / well, incubated for 120 minutes, and finally, 10 μL / well of the agonist was added. Fluorescence was measured for each well at 1-second intervals, and the height of each fluorescence peak was compared to the height of the fluorescence peak induced by 3 nM orexin-A with a vehicle instead of the antagonist. The IC50 value (the concentration of the compound required to inhibit 50% of the agonist response) was determined and can be normalized using the obtained IC50 value of the on-plate reference compound. Optimized conditions were achieved by adjusting the pipette drop rate and cell division regime. The calculated IC50 values ​​may vary depending on the performance of the daily cell assay. This type of variation is known to those skilled in the art. If the IC50 value was determined multiple times for the same compound, the geometric mean is given. The antagonist activities of the compounds in the examples are shown in Tables 1 and 2.

[0180] [Table 1]

[0181] [Table 2]

[0182] While specific embodiments have been described as preferred embodiments, it will be understood that those skilled in the art will be able to conceive of variations and modifications. Accordingly, the appended claims are: the It is intended to encompass all such equivalent variations within the scope of the claims. The following describes preferred embodiments of the present invention in separate sections. Embodiment 1 Equation (I): [ka] A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination of the said compound: R 1 The group consists of aromatic, aryl, 5- or 6-membered heteroaryl, substituted aromatic, substituted aryl, and substituted 5- or 6-membered heteroaryl; optionally, the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyradadinyl; the aromatic, aryl, or heteroaryl may be unsubstituted, or have one R 1 Monosubstituted by substituents, or two R 1 It is a disubstituted product due to substituents, and each R 1 The substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyls; halogens are arbitrarily selected from the group consisting of F, Cl, Br, and I; R 2 and R 3 H, halogen, alkyl, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) Independently selected from the group consisting of cycloalkyl; R 2 and R 3 Each of these can independently and arbitrarily have up to 3 R's at their respective replaceable positions. 2 ‐R 3 Substituting with substituents, each R 2 ‐R 3 The substituents are H, halogen, alkyl, substituted alkyl, (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 ) independently selected from the group consisting of cycloalkyls; halogens are optionally selected from the group consisting of F, Cl, Br, and I; R 4 is selected from the group consisting of aromatic, aryl, 5- or 6-membered heteroaryl, substituted aromatic, substituted aryl, and substituted 5- or 6-membered heteroaryl; the aromatic, aryl, or heteroaryl may be unsubstituted, or have one R 4 Monosubstituted by substituents, 2 R 4 Disubstituted derivatives by substituents, or three R 4 It is a trisubstituted product due to substituents, and each R 4 The substituent is (C 1‐4 ) alkyl, (C 1‐4 )alkoxy, halogen, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 3‐7 )Cycloalkyl, (C 3‐7 ) independently selected from the group consisting of heterocycloalkyls; the halogen is optionally selected from the group consisting of F, Cl, Br, and I; R 5 CH 3 Selected from the group consisting of alkyl and substituted alkyl; R 6 The halogen is selected from the group consisting of H, halogens, alkyls, and substituted alkyls; the halogen is selected from the group consisting of F, Cl, Br, and I; Arbitrarily R 5 and R 6 (C 1‐3 ) It can form an alkyl crosslinked cyclic structure; X is absent in order to provide a pyrrolidine ring, and CH is absent in order to provide a piperidine ring. 2 or to provide a morpholine ring, it is O; the carbon atom at position 2 of the piperidine ring or pyrrolidine ring is optionally in (S) absolute configuration; the carbon atom at position 2 of the morpholine ring is optionally in (R) absolute configuration; Y is absent, or NH, O, CH 2 Ure 4 CH 2 , and NR 4 R 7 A group consisting of R is selected, where R 7 is H or alkyl; Z 1 and Z 2 These are H, F, and (C respectively). 1‐4 ) alkyl, (C 1‐3 ) Fluoroalkyl, (C 1‐3 ) fluoroalkoxy, and (C 2‐7 ) Independently selected from the group consisting of cycloalkyl groups; Here again: A-B-J-D-E is a five-membered heteroaryl; B-J-M-G-K-L is a six-membered ring selected from the group consisting of aromatic, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl compounds; Also, optionally here: A is N; and / or B is C or N; and / or J is C or N; and / or D is C; and / or E is C; and / or M stands for C, CH, CR 2 R 3 CR 2 CR 3 Selected from the group consisting of , O; and / or G is C, CH, CR 2 R 3 , CR 2 , CR 3 Selected from the group consisting of , and O; and / or K is C, CH, CR 2 R 3 CR 2 CR 3 Selected from the group consisting of , and O; and / or L stands for C, CH, CR 2 R 3 CR 2 CR 3 A compound selected from the group consisting of , and O, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination of said compound. Embodiment 2 Formula (II):

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Claims

1. Equation (I): 【Chemistry 1】 Compounds thereof, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, stereoisomers thereof, or combinations thereof: R １ R is selected from the group consisting of aryl, 5- or 6-membered heteroaryls, which may be substituted; optionally, the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; the aryl or heteroaryl may be unsubstituted, or one R １a Monosubstituted by substituents, or two R １a It is a disubstituted compound by substituents, and each R １a The substituent is (C １‐４ ) alkyl, (C １‐４ ) Alkoxy, Ha A halogen, (C １‐３ ) fluoroalkyl, (C １‐３ ) fluoroalkoxy, and (C ３‐７ ) cycloalkyl, independently selected from the group consisting of; the halogen is optionally selected from the group consisting of F, Cl, Br, and I; R ２ and R ３ H, halogen, (C １‐４ ) alkyl, substituted alkyl, (C １‐４ ) Alkoxy, (C １‐３ ) Fluoroalkyl, (C １‐３ ) Fluoroalkoxy, and (C ３‐７ ) Independently selected from the group consisting of cycloalkyl; R ２ and R ３ Each of these can independently and arbitrarily have up to three R's at their respective replaceable positions. ２a -R ３a Substituting with a substituent, each R ２a -R ３a The substituents are H, halogen, (C １‐４ ) alkyl, substituted alkyl, (C １‐４ ) Alkoxy, (C １‐３ ) Fluoroalkyl, (C １‐３ ) Fluoroal Coxy and (C ３‐７ ) independently selected from the group consisting of cycloalkyls; the halogen is optionally selected from the group consisting of F, Cl, Br, and I; R ４ is selected from the group consisting of aryl, 5-membered or 6-membered heteroaryls, which may be substituted; the aryl or heteroaryl may be unsubstituted, or one R ４a by substituents Monosubstituted compound, 2 R ４a Disubstituted derivatives by substituents, or three R ４a It is a trisubstituted compound by substituents, and each R ４a The substituent is (C １‐４ ) alkyl, (C １‐４ ) Alkyl, halogen, (C １‐３ ) Fluoroalkyl, (C １‐３ ) Fluoroalkoxy, and (C ３‐７ ) Cycloalkyl, (C ３‐７ ) independently selected from the group consisting of heterocycloalkyls; the halogen is optionally selected from the group consisting of F, Cl, Br, and I; R ５ is selected from the group consisting of alkyl and substituted alkyl; R ６ is selected from the group consisting of H, halogens, alkyls, and substituted alkyls; the halogen is selected from the group consisting of F, Cl, Br, and I; Arbitrarily R ５ and R ６ (C) is achieved by connecting as an alkyl group. １‐３ ) It can form an alkyl crosslinked cyclic structure; X is absent in order to provide a pyrrolidine ring, and CH is absent in order to provide a piperidine ring. ２ or to provide a morpholine ring, it is O; the carbon atom at position 2 of the piperidine ring or pyrrolidine ring is optionally in (S) absolute configuration; the carbon atom at position 2 of the morpholine ring is optionally in (R) absolute configuration; Y is absent, or NH, O and CH ２ A group consisting of R is selected, where R ７ is H or alkyl; Z １ and Z ２ These are H, F, and (C) respectively. １‐４ ) alkyl, (C １‐３ ) Fluoroalkyl, (C １‐３ ) Fluoroalkoxy, and (C ３‐７ ) independently selected from the group consisting of cycloalkyl; Here again: A-B-J-D-E is a five-membered heteroaryl; B-J-M-G-K-L is a six-membered ring selected from the group consisting of heteroaryl and heterocycloalkyl groups; Also, optionally here: A is N; and / or B and J are either C or N, and either B or J is N; and / or D is C; and / or E is C; and / or M stands for C, CH, CR ２ R ３ CR ２ CR ３ Selected from the group consisting of , O; and / or G is C, CH, CR ２ R ３ CR ２ CR ３ Selected from the group consisting of , and O; and / or K is C, CH, CR ２ R ３ CR ２ CR ３ Selected from the group consisting of , and O; and / or L stands for C, CH, CR ２ R ３ CR ２ CR ３ A compound selected from the group consisting of , and O, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer, or combination thereof of the compound.

2. Formula (II): 【Chemistry 2】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

3. Formula III: 【Transformation 3】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

4. Formula II-a: 【Chemistry 4】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

5. Formula II-b: 【Transformation 5】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

6. Formula II-c: 【Transformation 6】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

7. Formula III-a: 【Transformation 7】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

8. Formula III-b: 【Transformation 8】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

9. Formula III-c: 【Chemistry 9】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

10. Formula III-d: 【Chemistry 10】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

11. Formula II-aa, II-ab, II-ac, II-ba, II-bb, II-bc, II -ca, II-cb, or II-cc: 【Chemistry 11】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof.

12. Formulas III-aa, III-ab, III-ac, III-ba, III-bb, III-bc, and III-ca, III-cb, or III-cc: 【Chemistry 12】 The compound according to claim 1, represented by (wherein the formula, the same symbol as in formula I indicates the same atom or group as in formula I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or combination thereof. 【Request Item 13】 【Chemistry 13】 Compounds selected from the group consisting of, or pharmaceutically acceptable salts, hydrates, or solvates thereof. Polymorphs, stereoisomers, or combinations thereof.

14. A composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or a combination thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer, or combination thereof; and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

16. The pharmaceutical composition according to claim 15, comprising a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or a combination thereof.

17. The pharmaceutical composition according to claim 15 or 16, further comprising at least one second therapeutic agent.

18. Use of any one of the compounds described in claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer, or combination thereof, in the preparation of agents for the prevention and / or treatment of a condition selected from the group consisting of central nervous system (CNS) disorders, drug addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD), in patients in need.

19. The use according to claim 18, wherein the agent comprises a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, stereoisomer thereof, or a combination thereof.

20. The use according to claim 18 or 19, wherein the agent comprises a pharmaceutically acceptable salt or isotope of the compound.

21. The use according to any one of claims 18 to 20, wherein the agent comprises an unlabeled form of the compound or an isotope-labeled form of the compound, wherein in the isotope-labeled form, one or more atoms are replaced with atoms having a selected atomic weight or mass number.

22. A method for preparing a compound, The step of reacting the following intermediate A with the following intermediate F to produce the following compound (1); The following step involves reacting intermediate A with intermediate B to produce compound (2); The step of reacting the following intermediate A with the following intermediate C to produce the following compound (3); The following step involves reacting intermediate J with intermediate D to produce compound (4); The step of reacting the following intermediate A with the following intermediate D to produce the following compound (5); The following step involves reacting the following intermediate J with the following intermediate E to produce the following compound (6); The step of reacting the following intermediate A with the following intermediate E to produce the following compound (7); The step of reacting the following intermediate I with the following intermediate E to produce the following compound (8); The step of reacting the following intermediate I with the following intermediate D to produce the following compound (9); The step of reacting the following intermediate J with the following intermediate B to produce the following compound (10); The step of reacting the following intermediate I with the following intermediate B to produce the following compound (11); The step of reacting the following intermediate I with the following intermediate F to produce the following compound (12); The following step involves reacting the following intermediate J with the following intermediate F to produce the following compound (13); The step of reacting the following intermediate I with the following intermediate C to produce the following compound (14); The following step involves reacting the following intermediate J with the following intermediate C to produce the following compound (15); The step of reacting the following intermediate A with the following intermediate G to produce the following compound (16); The step of reacting the following intermediate A with the following intermediate H to produce the following compound (17); The step of reacting the following intermediate I with the following intermediate H to produce the following compound (18); The step of reacting the following intermediate I with the following intermediate G to produce the following compound (19); The steps of reacting the following intermediate J with the following intermediate H to produce the following compound (20); and The following step involves reacting the following intermediate J with the following intermediate G to produce the following compound (21). A method comprising a reaction selected from the group consisting of the following. 【Chemistry 14】 【Chemistry 15】

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