Substituted pyrazole and imidazole compositions as orexin receptor antagonists, methods of treating neurological and psychiatric disorders

Abstract

The present disclosure relates to substituted imidazole and pyrazole ring derivatives of compounds that are orexin receptor antagonists that are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which or involving orexin receptors. The disclosure also relates to pharmaceutical compositions comprising these compounds, and the use of these compounds and compositions in the prevention or treatment of diseases in which orexin receptors are involved.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority of U.S. Provisional Application Serial No. 63 / 400,894, filed Aug. 25, 2022, the entire contents of which are incorporated herein by reference.

[0003] Federally Sponsored Research

[0004] This invention was made with government support under Cooperative Agreement UF1DA054817 awarded by the National Institute on Drug Abuse. The government has certain rights in the invention. Technical Field

[0005] The present disclosure relates to and provides compounds, compositions, and methods for preparing and using orexin antagonists as therapeutic agents for treating or ameliorating diseases in humans and animals. In particular, any pathological disorder in which two types of orexin receptors are pharmacologically involved or implicated. These important therapeutic uses include, but are not limited to, treating central nervous system (CNS) disorders and neurological diseases involving orexin receptors or regulated by orexin receptors, including but not limited to disorders responsive to orexin receptor antagonists, such as substance addiction and dependence, cognitive impairment, Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety, autism, pain, and depression. Background Art

[0006] Orexin (also known as hypocretin) consists of two excitatory hypothalamic neuropeptides: orexin A (OX-A; a 33-amino acid peptide) and orexin B (OX-B; a 28-amino acid peptide). They were discovered simultaneously in 1998 by two research groups searching for novel signaling molecules: (1) Sakurai and colleagues (who named them orexin-A and orexin-B) (Sakurai, T. et al, Cell 1998, 92, 573) and (2) de Lecea and colleagues (who named them hypocretin 1 and hypocretin 2, respectively) (de Lecea, L. et al, Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 322). These neuropeptides are the endogenous ligands of two G protein-coupled receptors (GPCRs) named OX1R and OX2R (also known as Hcrt1 and Hcrt2, respectively) and are derived by proteolysis from the same precursor peptide called pre-pro-orexin polypeptide (Sakurai T., et al. The Journal of biological chemistry. 1999;274, 17771–17776). Although structurally related, these endogenous ligands have different binding affinities for the two GPCRs. Orexin A binds to OX1R with an affinity approximately 100-fold higher than that of orexin B, while orexin A and orexin B bind to OX2R with the same affinity (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). Soon after the discovery of orexin, the regulation of orexin signaling was initially considered a potential new treatment for patients with narcolepsy or insomnia because the role of orexin in sleep and wake regulation had been well studied and understood, and the discovery of small molecule modulators of orexin signaling facilitated the development of such compounds. The activity of hypothalamic orexin neurons is reduced in patients with narcolepsy, resulting in a decrease in the amount of circulating orexin in the cerebrospinal fluid. Conversely, the activation of orexin neurons maintains wakefulness and arousal. The role of orexin signaling in feeding and energy homeostasis was also established earlier and was found to be coordinated with the sleep-wake cycle (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375).Recent studies have identified the role of orexin signaling in other key physiological pathways such as neuroendocrine function (Inutsuka, A.; Yamanaka, A. Front. Endocrinol. 2013, 4:18. doi:10.3389 / fendo.2013.00018), glucose metabolism (Tsuneki, H., et al., Endocrinology, 2016, 157, 4146–4157), stress adaptive responses (Xiao, F., et al. Neuropharmacology, 2013, 67, 16–24), and addiction / reward seeking (Aston-Jones, G., et al. Brain Res., 2010, 1314, 74–90). Small molecule orexin antagonists are roughly divided into three categories based on their overall receptor selectivity profile: (1) DORA (dual acting or non-selective OX1R / OX2R antagonists), (2) SORA-1 (selective OX1R antagonists), and (3) SORA-2 (selective OX2R antagonists). It has been shown that while both OX2R knockout mice and OX1R / OX2R double knockout mice exhibit the narcolepsy phenotype, this effect is very weak in OX1R knockout (Wang C., et al. Neurosci., 2018, 11, 220. doi:10.3389 / fnmol.2018.00220). In addition, both DORA and SORA-2 compounds inhibit wakefulness, but SORA-1 compounds do not inhibit wakefulness, thus indicating that the narcolepsy effect is mediated through OX2R or a combination of OX1R and OX2R, rather than through OX1R alone. Therefore, it is clear that the discovery and development of selective orexin antagonists are crucial for the development of this field, but most importantly for the development of therapeutic agents for dysregulated biological processes involving orexin receptors; especially for the development of therapeutic agents for non-sleep related indications such as substance addiction). SUMMARY OF THE INVENTION

[0007] The present disclosure solves the above therapeutic and / or other needs by providing compounds of Formula I and Formula II:

[0008]

[0009] Wherein the variables are as defined herein, including any pharmaceutically acceptable salts, solvates, adducts, polymorphs and isomers thereof, as well as compositions comprising said compounds. The compounds of formula I and / or formula II (and / or their preferred embodiments) and compositions comprising said compounds can be used to treat, for example, the disorders as described herein, such as by active treatment as orexin receptor antagonists. The compounds and / or compositions disclosed herein can be antagonists of one or more orexin receptors, such as any one of OX1R or OX2R, or both OX1R and OX2R. Compared with another orexin receptor, the compounds and / or compositions disclosed herein can be selectively more antagonistic to one or more orexin receptors, for example, more or less antagonistic to OX1R or OX2R compared with another orexin receptor. Accordingly, the compounds and / or their compositions can be referred to herein as "orexin receptor antagonists".

[0010] In some embodiments, the present invention also provides compositions comprising the above compounds or their pharmaceutically acceptable salts. In another aspect of the present invention, there is provided a method of treating CNS disorders in a subject in need or at risk of developing a disease, said CNS disorders being, for example, substance addiction and dependence, post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety and depression, pain, cognitive impairment and Alzheimer's disease (AD), said method comprising the step of administering to said subject a therapeutically effective amount of an orexin receptor antagonist or its pharmaceutically acceptable salt. In certain embodiments of the present invention, the orexin receptor antagonist or its pharmaceutically acceptable salt can be formulated for administration at regular intervals, for example, once every 3 hours, 6 hours to 24 hours, depending on the clinical efficacy. As will be understood by those of ordinary skill in the art, other aspects and embodiments are contemplated herein. Detailed Description

[0011] The present disclosure provides fused six (6)- and five (5)-membered ring system derivatives of formula (I) and formula (II), their pharmaceutically acceptable salts, their compositions, and methods for their preparation and use, wherein the fused six (6)- and five (5)-membered rings are as described structurally. In some embodiments, the present disclosure describes pharmaceutical compositions containing one or more compounds of formula (I) and formula (II), their preparation, and their use as pharmaceuticals and therapeutic agents, particularly (i.e., in preferred embodiments) their use as orexin receptor antagonists. These novel pharmaceuticals as described by formula (I) and formula (II) are non-peptide antagonists of the human orexin receptor and may be used to treat disorders associated with orexinergic dysfunction; including but not limited to such disorders as substance addiction (e.g., cocaine, opioids, alcohol, etc.), anxiety, panic, cognitive dysfunction, mood or appetite, sleep, Alzheimer's disease (AD), metabolic syndrome, pain, and / or hypertension. In preferred embodiments, the compounds disclosed herein have significant therapeutic value in treating anxiety disorders, addiction disorders, and / or sleep disorders.

[0012] In some embodiments, the present disclosure provides compounds of formula (I) and formula (II):

[0013]

[0014] wherein:

[0015] R1 includes E, where E is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); or when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0016] R2, R3, and R4 are independently selected from the group consisting of H, halogen (e.g., F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7)A group consisting of cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, and the substituents are independently selected from one, two, or all of R2, R3, and R4;

[0017] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure, and R5 and R6 are joined together to form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl;

[0018] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0019] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0020] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached as an alkyl to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0021] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl;

[0022] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 or R 12 is attached as an alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure, wherein in some embodiments, R 11and R 12 When connected together, they can form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl;

[0023] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, and R 13 or R 14 is connected to R7 or R8 as an alkyl group to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0024] R 15 is aromatic or aryl, such as but not limited to heteroaryl (e.g., preferably a 5- or 6-membered ring), substituted aromatic or aryl, substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a fused two-heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl.

[0025] In some preferred embodiments, the present disclosure provides compounds of Formula I-a and Formula II-a, wherein the ring system fused to the 6-membered ring (illustrated by the A-B-J-E-D variables in Formulas (I) and (II)) is preferably an imidazo ring system, as represented by the embodiments shown in Formulas I-a and II-a herein:

[0026]

[0027] Wherein:

[0028] R1 includes E, where E is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); or when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, or disubstituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl;

[0029] R2, R3 and R4 are independently selected from the group consisting of H, halogen (e.g., F, Cl, Br), alkyl, substituted alkyl, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, said substituents being independently selected from one, two or all of R2, R3 and R4;

[0030] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure, and R5 and R6 are joined together to form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl;

[0031] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0032] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0033] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached as an alkyl to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0034] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3The group consisting of fluoroalkyl and cycloalkyl;

[0035] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 or R 12 is attached to R7 or R8 as an alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure, wherein in some embodiments, R 11 and R 12 connected together can form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl;

[0036] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, and R 13 or R 14 is attached to R7 or R8 as an alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0037] R 15 is aromatic or aryl, such as but not limited to heteroaryl (e.g., preferably a 5- or 6-membered ring), substituted aromatic or aryl, substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a fused two-heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl.

[0038] In some preferred embodiments of Formula I (e.g., preferably Formula Ia) and Formula II (e.g., preferably Formula IIa), W is CH2 and R7, R8, R 13 and R 14 are H; the carbon atoms with substituents R7, R8, R 13 and R 14 are directly connected to provide a 5-5 bridged bicyclic system as shown below:

[0039]

[0040] In some preferred embodiments of Formula I (e.g., preferably Formula Ia) and Formula II (e.g., preferably Formula IIa), W is absent (i.e., not present) to provide the seven-membered ring system shown below, wherein all other groups are as defined herein:

[0041]

[0042] In some preferred embodiments, the present disclosure also provides compounds of Formula I (e.g., preferably Formula Ia) and Formula II (e.g., preferably Formula IIa), including:

[0043] A fused ring system A-B-J-D-E, which is a five-membered heteroaryl (e.g., imidazole (where A, J = nitrogen, and B, E, D = carbon) or pyrazole (where A, B = nitrogen, and D, E, J = carbon)), fused or unfused to another ring system;

[0044] A fused ring system B-J-M-G-K-L, which is a six (6)-membered aromatic or aryl, substituted aromatic or aryl, substituted or unsubstituted heteroaryl, cycloalkyl or heterocycloalkyl;

[0045] Wherein A, B, J, D, E, M, G, K and L are preferably as shown below:

[0046] A is nitrogen or carbon;

[0047] B is carbon or nitrogen;

[0048] J is carbon or nitrogen;

[0049] D is carbon;

[0050] E is carbon, where R4 is as defined above;

[0051] M is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O or N;

[0052] G is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4 or O;

[0053] K is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4 or O; and

[0054] L is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O or N.

[0055] In some preferred embodiments, the present disclosure provides compounds of Formula I-b or Formula II-b, wherein the ring system fused to the 6-membered ring (illustrated by the A-B-J-D-E variables in Formulas (I) and (II)), preferably a pyrazolo ring system, is represented as in the embodiments shown in Formula I-b or Formula II-b herein:

[0056]

[0057] Wherein:

[0058] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (such as phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, and substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0059] R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position by up to three (3) substituents, and the substituents are independently selected from one or two or all of R2, R3, and R4;

[0060] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl. R6 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0061] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0062] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0063] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0064] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl;

[0065] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R 11 and R 12 are attached to R7 or R8 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0066] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, R 13 and R 14 are attached to R7 or R8 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0067] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring), or a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl.

[0068] In some preferred embodiments, the present disclosure provides compounds of Formula I-b or Formula II-b, wherein W is CH2 and R7, R8, R 13 , R 14 are H, and the carbons having substituents R7, R8, R 13 and R 14 (as described above) can be directly connected to provide a 5-5 bridged bicyclic system as shown below:

[0069]

[0070] In some preferred embodiments, the present disclosure provides compounds of Formula I-b or Formula II-b, wherein W is absent (i.e., not present), to provide a seven-membered ring system as shown below, wherein all other groups are as defined herein;

[0071]

[0072] In other preferred embodiments, the present disclosure provides compounds wherein the imidazole-fused six-membered ring is as shown in the embodiments according to Formula (I-a1) and Formula (II-a1) herein:

[0073]

[0074] Wherein:

[0075] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (such as phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the 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;

[0076] R2, R3 and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7)The group consisting of cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, said substituents being independently selected from one or two or all of R2, R3 and R4;

[0077] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure, and R5 and R6 may be joined together to form a spiro moiety, such as cyclopropyl or cyclobutyl;

[0078] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0079] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0080] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R9 is attached as an alkyl to R6 or R 11 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0081] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl and cycloalkyl;

[0082] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, R 11 and R 12 are attached as an alkyl to R7 or R8 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0083] R13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, R 13 and R 14 is attached to R7 or R8 as alkyl to form a (C 1-3 )alkyl-bridged cyclic structure;

[0084] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a fused two heteroaryl ring system; wherein said aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, 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, (C 3-7 )cycloalkyl and (C 3-7 )heterocycloalkyl;

[0085] In some preferred embodiments, the present disclosure provides a compound of formula I-a or formula II-a1, wherein W is CH2, and R7, R8, R 13 , R 14 are H, and the carbon atoms having substituents R7, R8, R 13 and R 14 can be directly connected to provide a 5-5 bridged bicyclic system as shown below:

[0086]

[0087] In some preferred embodiments, the present disclosure provides a compound of formula I-b or formula II-b, wherein W is absent (i.e., not present) (to provide a seven-membered ring system as shown below), and all other groups are as defined herein;

[0088]

[0089] In some preferred embodiments, the present disclosure provides a compound wherein the imidazole-fused six-membered ring is preferred, as shown in the embodiments according to formula (I-a2) and formula (II-a2) herein:

[0090]

[0091] wherein:

[0092] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (such as phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, and substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0093] R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position by up to three (3) substituents, and the substituents are independently selected from one or two or all of R2, R3, and R4;

[0094] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0095] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0096] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R8 is connected to R 10 or R 11 or R 13to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0097] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 11 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0098] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl;

[0099] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 and R 12 are attached to R7 or R8 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0100] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (e.g., fluoroalkyl), cycloalkyl, and R 13 and R 14 are attached to R7 or R8 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0101] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring), or a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, mono-substituted, di-substituted, or tri-substituted, 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, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl.

[0102] In some preferred embodiments, the present disclosure provides a compound of formula I-a2 or formula II-a2, wherein W is CH2, and R7, R8, R 13 , R 14 are each H, having substituents R7, R8, R 13 and R 14The carbons are directly connected to provide a 5-5 bridge bicyclic system as shown below:

[0103]

[0104] In some preferred embodiments, the present disclosure provides compounds of formula I-a2 or formula II-a2, wherein W is absent (to provide a seven-membered ring system as shown below), and all other groups are as defined herein:

[0105]

[0106] In some preferred embodiments, the present disclosure provides compounds wherein the imidazole-fused six-membered ring is preferred, as shown in the embodiments according to formula (I-a3) and formula (II-a3) herein:

[0107]

[0108] Wherein:

[0109] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (such as phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the 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;

[0110] R2, R3 and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position by up to three (3) substituents, and the substituents are independently selected from one or two or all of R2, R3 and R4;

[0111] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C1-3 ) a group consisting of a fluoroalkyl group and a cycloalkyl group, and R6 is linked to R as an alkyl group 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0112] R7 is selected from the group consisting of H, CH3, an alkyl group, a substituted alkyl group, a (C 1-3 ) fluoroalkyl group, and a cycloalkyl group, and R7 is linked to R as an alkyl group 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0113] R8 is selected from the group consisting of H, CH3, an alkyl group, a substituted alkyl group, a (C 1-3 ) fluoroalkyl group, and a cycloalkyl group, and R8 is linked to R as an alkyl group 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0114] R9 is selected from the group consisting of H, CH3, an alkyl group, a substituted alkyl group, a (C 1-3 ) fluoroalkyl group, and a cycloalkyl group, and R9 is linked to R6 or R as an alkyl group 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0115] R 10 is selected from the group consisting of H, CH3, an alkyl group, a substituted alkyl group, a (C 1-3 ) fluoroalkyl group and a cycloalkyl group;

[0116] R 11 and R 12 are independently selected from the group consisting of H, CH3, an alkyl group, a substituted alkyl group, a (C 1-3 ) fluoroalkyl group, and a cycloalkyl group, R 11 and R 12 are linked to R7 or R8 as an alkyl group to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0117] R 13 and R 14 are independently selected from the group consisting of H, CH3, an alkyl group, a substituted alkyl group (such as a fluoroalkyl group), and a cycloalkyl group, R 13 and R 14 are linked to R7 or R8 as an alkyl group to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0118] R15 Selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a fused two heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, 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, (C 3-7 )cycloalkyl and (C 3-7 )heterocycloalkyl.

[0119] In some preferred embodiments, the present disclosure provides a compound of formula (I-a3) or formula (II-a3), wherein W is CH2, and R7, R8, R 13 , R 14 are H, and the carbon having substituents R7, R8, R 13 and R 14 can be directly connected to provide a 5-5 bridged bicyclic system as shown below:

[0120]

[0121] In some preferred embodiments, the present disclosure provides a compound of formula I-a3 or formula II-a3, wherein W is absent (i.e., not present) (to provide a seven-membered ring system as shown below), and all other groups are as defined herein;

[0122]

[0123] In another preferred embodiment, the present disclosure provides a compound, wherein the pyrazole-fused six-membered ring is preferred, as shown in the embodiments according to formula (I-b1) and formula (II-b1) herein:

[0124]

[0125] Wherein:

[0126] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (such as phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from the group consisting of (C1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7 ) cycloalkyl;

[0127] R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7 ) cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, said substituents being independently selected from one or two or all of R2, R3, and R4;

[0128] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R6 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure, and R5 and R6 may be joined together to form a spiro moiety, such as cyclopropyl or cyclobutyl;

[0129] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0130] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0131] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0132] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl;

[0133] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 and R 12 are linked as alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0134] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, and R 13 and R 14 are linked as alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0135] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring), or a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl.

[0136] In some preferred embodiments, the present disclosure provides a compound of formula (I-b1) or formula (II-b1), wherein W is CH2, and R7, R8, R 13 , R 14 are each H, and the carbon having substituents R7, R8, R 13 and R 14 can be directly linked to provide a 5-5 bridged bicyclic system as shown below:

[0137]

[0138] In some preferred embodiments, the present disclosure provides a compound of formula (I-b1) or formula (II-b1), wherein W is absent (i.e., not present) (to provide a seven-membered ring system as shown below), and all other groups are as defined herein:

[0139]

[0140] In some preferred embodiments, the present disclosure provides compounds wherein the pyrazole-fused six-membered ring is as shown in the embodiments according to Formula (I-b2) and Formula (II-b2) herein:

[0141]

[0142] Wherein:

[0143] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (such as phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the 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;

[0144] R2, R3 and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position by up to three (3) substituents, and the substituents are independently selected from one or two or all of R2, R3 and R4;

[0145] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure, and R5 and R6 can be connected together to form a spiro moiety, such as cyclopropyl or cyclobutyl;

[0146] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0147] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0148] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0149] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl and cycloalkyl;

[0150] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R 11 and R 12 are attached to R7 or R8 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0151] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, R 13 and R 14 are attached to R7 or R8 as alkyl to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0152] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a fused two heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, wherein the substituents are independently selected from (C 1-4 ) alkyl, (C1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, and (C 3-7 )heterocycloalkyl.

[0153] In some preferred embodiments, the present disclosure provides a compound of formula Ib2 or formula IIb2, wherein W is CH2, and R7, R8, R 13 , R 14 are each H, and the carbon atoms bearing the substituents R7, R8, R 13 and R 14 can be directly linked to provide a 5-5 bridged bicyclic system as shown below:

[0154]

[0155] In some preferred embodiments, the present disclosure provides a compound of formula Ib2 or formula IIb2, wherein W is absent (i.e., not present) (to provide a seven-membered ring system as shown below), and all other groups are as defined herein;

[0156]

[0157] In some preferred embodiments, the present disclosure provides a compound wherein the pyrazole-fused six-membered ring is as shown in the embodiments according to formula (I-b3) and formula (II-b3) herein:

[0158]

[0159] Wherein:

[0160] E in R1 is carbon (C) but not nitrogen (N), and E is linked to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0161] R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as but not limited to F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, said substituents being independently selected from one or two or all of R2, R3, and R4;

[0162] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is attached as an alkyl group to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure, and R5 and R6 may be joined together to form a spiro moiety, such as cyclopropyl or cyclobutyl;

[0163] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is attached as an alkyl group to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0164] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl group to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0165] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R9 is attached as an alkyl group to R6 or R 11 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0166] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, and cycloalkyl;

[0167] R 11 and R 12Independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R 11 and R 12 are attached as alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0168] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, R 13 and R 14 are attached as alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0169] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a fused two heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, 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, (C 3-7 ) cycloalkyl and (C 3-7 ) heterocycloalkyl.

[0170] In some preferred embodiments, the present disclosure provides a compound of formula (I-b3) or formula (II-b3), wherein W is CH2, and R7, R8, R 13 , R 14 are each H, and the carbon having substituents R7, R8, R 13 and R 14 will be directly connected to provide a 5-5 bridged bicyclic system as shown below:

[0171]

[0172] In some preferred embodiments, the present disclosure provides a compound of formula (I-b3) or formula (II-b3), wherein W is absent (i.e., not present) (to provide a seven-membered ring system as shown below), and all other groups are defined herein;

[0173]

[0174] In some preferred embodiments, the present disclosure provides a compound wherein the pyrazole-fused six-membered ring is as shown in the embodiments according to formula (I-b4) and formula (II-b4) herein:

[0175]

[0176] Wherein:

[0177] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, R1 = H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the 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;

[0178] R2, R3 and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position by at most 3 substituents, and the substituents are independently selected from one or two or all of R2, R3 and R4;

[0179] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure, and R5 and R6 can be connected together to form a spiro moiety, such as cyclopropyl or cyclobutyl;

[0180] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is connected to R 10 or R 11 or R 13 to form a (C 1-3 )alkyl-bridged cyclic structure;

[0181] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is linked as alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0182] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is linked as alkyl to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0183] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl;

[0184] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 and R 12 are linked as alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0185] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, and R 13 or R 14 is linked as alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure; and

[0186] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring), or a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl;

[0187] In some preferred embodiments, the present disclosure provides a compound of formula (I-b4) or formula (II-b4), wherein W is CH2, and R7, R8, R 13 , R 14 are each H, and the carbon atoms having substituents R7, R8, R 13 and R 14 will be directly connected to provide a 5-5 bridged bicyclic system as shown below:

[0188]

[0189] In some preferred embodiments, the present disclosure provides a compound of formula (I-b4) or formula (II-b4), wherein W is absent (e.g., not present) (to provide a seven-membered ring system as shown below), and all other groups are as defined herein;

[0190]

[0191] In some particularly preferred embodiments, the present disclosure provides a compound wherein the stereocenters and the main backbone rings are as shown in the embodiments represented by formula (I-a5), formula (I-b5), formula (II-a5), and formula (II-b5):

[0192]

[0193] Wherein:

[0194] All variables or substituents described (i.e., R1-R 15 ) are as defined above.

[0195] In some preferred embodiments, the present disclosure provides a compound wherein the stereocenters and the main backbone rings are preferred, as exemplified by the embodiments represented by formula (I-a6), formula (I-b6), formula (II-a6), and formula (II-b6) as shown herein:

[0196]

[0197] Wherein:

[0198] All variables or substituents described (i.e., R1-R 15 ) are as defined above.

[0199] In some preferred embodiments, the present disclosure provides a compound having any one of formula I-a7, formula I-a8, formula I-a9, formula II-a7, formula II-a8, or formula II-a9, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof,

[0200]

[0201] Wherein:

[0202] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, and substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0203] R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position by at most 3 substituents, and the substituents are independently selected from one or two or all of R2, R3, and R4; and

[0204] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted 5-6 membered heteroaryl, or a fused two heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, 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, (C 3-7 )cycloalkyl, and (C 3-7 )heterocycloalkyl;

[0205] In some preferred embodiments, the present disclosure provides a compound having any one of Formula I-b7, Formula I-b8, Formula I-b9, Formula I-b10, Formula II-b7, Formula II-b8, Formula II-b9 and Formula II-b10, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof

[0206]

[0207] wherein:

[0208] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl; when R1 is heteroaryl, it is optionally a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the 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;

[0209] R2, R3, R4 are each independently selected from the group consisting of H, halogen which is optionally F, Cl or Br, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 3-7 )cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position with up to 3 substituents, and the substituents are independently selected from one or two or all of R2, R3 and R4; and

[0210] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl and a fused two-heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, 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, (C3-7 )cycloalkyl, (C 3-7 )heterocycloalkyl.

[0211] In some preferred embodiments, the present disclosure provides a compound having any one of Formula I-b11, Formula I-b12, Formula I-b13, Formula I-b14, Formula II-b11, Formula II-b12, Formula II-b13, and Formula II-b14 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof,

[0212]

[0213] wherein:

[0214] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl; when R1 is heteroaryl, it is optionally a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0215] R2, R3, and R4 are each independently selected from the group consisting of H, halogen, F, Cl, or Br, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position by up to 3 substituents, and the substituents are independently selected from one or two or all of R2, R3, and R4;

[0216] R 12 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, and cycloalkyl; and

[0217] R 15Selected from the group consisting of aromatic, aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic, substituted aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl or fused two heteroaryl ring systems; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, di-substituted or tri-substituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 3-7 ) cycloalkyl and (C 3-7 ) heterocycloalkyl.

[0218] In a most preferred embodiment, the present disclosure provides examples of compounds of Formula I and / or Formula II in Table 1.

[0219] Unless otherwise indicated, any embodiment presented herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I. The present disclosure also includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as 3 H, 13 C and 14 C are present. Such isotopically labeled compounds can be used for metabolic studies (preferably with 14 C), reaction kinetics studies (e.g., with 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for radioactive treatment of patients. In particular, for PET or SPECT studies, 18Compounds that are F or labeled may be particularly preferred. The isotopically labeled compounds and prodrugs of the present invention can generally be prepared by replacing the non-isotopically labeled reagents with readily available isotopically labeled reagents and carrying out the procedures disclosed in the following schemes or examples and preparations.

[0220] Many of the compounds disclosed herein and useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. The stereocenter can exist in the R or S configuration, and the R and S symbols are consistent with the rules described in Pure Appl. Chem. (1976), 45, 11-30. Accordingly, the compounds of the present disclosure also include any and all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compound or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726. In addition, in some embodiments, multiple substituents on the piperidinyl or pyrrolidinyl ring can also be cis or trans to each other relative to the plane of the piperidinyl or pyrrolidinyl ring. Such forms or geometric isomers, although not explicitly depicted in the formulas described herein, are intended to be included within the scope of the present disclosure. With respect to the methods and compositions of the present disclosure, reference to one or more compounds is intended to include each possible isomeric form of the compound and mixtures thereof, unless a specific isomeric form is specifically recited.

[0221] As used herein, a pharmaceutically acceptable salt refers to a therapeutically active, non-toxic base or acid salt form of a pharmaceutical agent or compound according to the present disclosure. The acid addition salt form of a compound that occurs as a base in free form can be obtained by treating the free base form with a suitable acid such as an inorganic acid (e.g., a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or an organic acid (e.g., acetic acid, glycolic acid, propionic 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 acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.) (see, e.g., WO 01 / 062726, U.S. Patent No. 8,492,416 B2, US2017 / 0022208 A1, and US2017 / 0253603 A2).

[0222] By treatment with suitable organic and inorganic bases, the compounds of the present disclosure containing acidic protons can be converted into their therapeutically active, non-toxic base addition salt forms, such as metal salts or amine salts. Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts (such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc.), salts with organic bases, and salts with amino acids (such as arginine, lysine, etc.). Conversely, the salt forms can be converted into the free form by treatment with a suitable base or acid. The compounds of the present disclosure and their salts can be in the form of solvates, which are included within the scope herein (e.g., hydrates, alcoholates, etc.).

[0223] As used herein, the term "aryl" refers to a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is a non-limiting example of a monocyclic aromatic or aryl ring system (unless otherwise specified).

[0224] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic or aryl ring system having 1-3 heteroatoms or heteroatom groups in each ring, the heteroatoms or heteroatom groups being selected from O, N, NH, or S and being present in a chemically stable arrangement. In such embodiments of the bicyclic aromatic or aryl ring system of "heteroaryl": both rings can be aromatic or aryl; and one or both rings can contain the heteroatoms or heteroatom groups. Non-limiting examples of heteroaryl rings (unless otherwise specified) include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), pyrazolyl (such as 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, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0225] As used herein, the term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused or (C 1-3)An alkyl-bridged bicyclic carbocyclic system. The cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl, and decalinyl.

[0226] In some embodiments, the compounds of the present disclosure may be in the form of prodrugs, analogs, and / or derivatives. The term "prodrug" is a term recognized by those of ordinary skill in the art and is intended to include compounds or agents that are converted to orexin antagonists under physiological conditions. A common method of preparing a prodrug is to select a moiety that hydrolyzes or metabolizes under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is converted to an orexin antagonist by enzymes or chemical activity of the host animal.

[0227] The compounds of the present disclosure also include isotopically labeled, especially 2 H (deuterium)-labeled compounds of all formulas that are identical to the compounds of all formulas described herein, except that one or more atoms are each replaced with an atom having the same atomic number but an atomic mass different from the atomic mass found commonly in nature. Isotopically labeled, especially 2 H (deuterium)-labeled compounds of all formulas and their salts are within the scope of the present invention. Substitution of hydrogen with a heavier isotope 2 H (deuterium) can result in greater metabolic stability, which can result in, for example, an increased in vivo half-life or a reduced dose requirement, and / or can result in a reduced inhibition of cytochrome P450 enzymes, which can result in, for example, improved safety. In another aspect of the embodiments of the present invention, the compounds of all formulas are not isotopically labeled. However, any person skilled in the art can prepare the isotopically labeled compounds of all formulas disclosed herein in a manner similar to the methods described below, but using appropriate isotopic variants of suitable reagents or starting materials.

[0228] In some embodiments, the present disclosure provides a composition comprising any one or more of such compounds and / or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a therapeutically effective amount of such a compound or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the present disclosure provides such a pharmaceutical composition further comprising at least one second therapeutic agent. The present disclosure also provides a pharmaceutical composition comprising one or more compounds (or analogs, e.g., their pharmaceutically acceptable salts) of the present disclosure (i.e., as an active agent, as a therapeutic agent), and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition contains a therapeutically effective amount of one or more such compounds, etc. (i.e., the active agent) or a suitable moiety thereof. The composition may optionally contain additional active agents. 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 excipient types include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, solvents, isotonic agents, buffers, pH regulators, absorption delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, coloring agents, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include, but are not limited to, oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents (e.g., saline, buffered saline (e.g., phosphate buffered saline [PBS]), and isotonic solutions (e.g., Ringer's solution)), and organic solvents (e.g., dimethyl sulfoxide and alcohols [e.g., ethanol, glycerol, and propylene glycol]). Except to the extent that any conventional excipient or carrier is incompatible with the peptide product, the present disclosure encompasses the use of conventional excipients and carriers in formulations containing the peptide product.See, for example, Remington: The Science and Practice of Pharmacy, 21st 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 suitability of a particular formulation depends on a variety of factors, such as the route of administration selected. Potential routes of administration of a pharmaceutical composition comprising a compound disclosed herein, etc. may include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intra-vascular, intravenous, intra-arterial, intraperitoneal, intracavitary, and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drops), ocular (e.g., by eye drops), pulmonary (e.g., by oral or nasal inhalation), oral, sublingual, rectal (e.g., by suppository), vaginal (e.g., by suppository), and / or other suitable routes known to those of ordinary skill in the art.

[0229] In some embodiments, the compounds and compositions of the present disclosure can be used as orexin receptor antagonists. In preferred embodiments, the compounds and / or compositions disclosed herein can be antagonists of one or more orexin receptor antagonists, such as one of OX1R or OX2R, or both OX1R or OX2R. Compared to another orexin receptor, the compounds and / or compositions disclosed herein can be selectively more antagonistic to one or more orexin receptors, for example, more or less antagonistic to OX1R or OX2R compared to another orexin receptor. Thus, the compounds and / or their compositions can be referred to herein as "orexin receptor antagonists". In some embodiments, the compound can be an antagonist of the κ-opioid receptor (or kappa opioid receptor, abbreviated as KOR or KOP, whose ligand is ketazocine, a G protein-coupled receptor encoded by the OPRK1 gene in humans). In some embodiments, the compounds and / or compositions of the present disclosure can be antagonists of one or more types of orexin receptors (i.e., orexin receptor antagonists), but not KOR. In some embodiments, for example, one or more compounds of the present disclosure and / or their combinations are designed and preferably provide the following characteristics measured using standard in vitro cell assays (e.g., those described in the examples herein) for achieving effective therapeutic efficacy: 1) OX1R Kb < 30 nM, OX2R Kb > 1000 nM, KOR Ki < 500 nM; 2) OX1R Kb < 30 nM, OX2R Kb > 30 nM, KOR Ki < 500 nM; or 3) OX1R Kb < 30 nM, OX2R Kb > 1000 nM, KOR Ki > 1000 nM. In some embodiments, the present disclosure provides methods for preventing or treating conditions associated with orexin receptors (i.e., as orexin receptor antagonists) and / or one or more κ-opioid receptors. For in vivo testing, the compounds and / or compositions of the present disclosure can be tested using animal models (such as rats) by measuring primary dependent measurements (e.g., for example but not limited to the time to obtain the first drug injection, total drug injections administered, drug intake rate, and total ineffective lever presses), progressive ratio (e.g., for example but not limited to the time to obtain the first drug injection, break point, final ratio completed, and total effective and ineffective lever presses), and reinstatement (e.g., for example but not limited to the time of the first lever press and total effective and ineffective lever presses).These tests and in vivo evaluations are designed, planned, and expected to demonstrate the therapeutic utility and in vivo efficacy of the compounds using techniques known to those of ordinary skill in the art - reducing the intake and motivation of illicit drug abuse (e.g., Brain Research 1731 (2020), edited by James, et al. (see, e.g., Brodnik, et al. Article 145894); Gentile, et al. Addict Biol 2018, 23(1):247 - 255; Brodnik, et al. Behav Brain Res. 2015 September 15; 291:377 - 384, doi:10.1016 / j.bbr.2015.05.051). As will be understood by those of ordinary skill in the art, other test methods may also be appropriate.)

[0230] In some embodiments, the present disclosure provides methods of preventing or treating a disorder in a subject in need thereof, the disorder selected from the group consisting of central nervous system (CNS) disorders, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD), the method by administering to the subject one or more such compounds and / or a composition comprising one or more such compounds, or any one of its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In some embodiments, the method may comprise administering a composition comprising a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the composition comprises a pharmaceutically acceptable salt or isotope of such a compound. In some embodiments, the composition may comprise an unlabeled form of the compound or an isotopically labeled form of the compound, wherein the compound has a structure depicted by a formula in which one or more atoms are replaced by atoms having a selected atomic mass or mass number. In some embodiments, the present disclosure provides the use of a compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, disclosed herein, in the manufacture of a medicament for preventing and / or treating a disorder in a subject in need thereof, the disorder selected from the group consisting of central nervous system (CNS) disorders, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD). For example, substance addiction may include a human's addiction to one or more opioid drugs (e.g., for example but not limited to heroin, morphine, oxycodone (e.g., OxyContin, Percocet), fentanyl, and / or hydrocodone (e.g., Vicodin)), one or more stimulants (e.g., amphetamine (e.g., Adderall, Ritalin), cocaine, crack cocaine, methamphetamine, one or more sedatives and / or tranquilizers (e.g., for example but not limited to benzodiazepines (e.g., diazepam, Xanax, Klonopin) or barbiturates (e.g., pentobarbital (Nembutal), luminal, phenobarbital)) or other addictive substances that may be known to one of ordinary skill in the art. In some embodiments, the use may comprise a composition comprising a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, such use may comprise a composition of a pharmaceutically acceptable salt or isotope of the compound.In some embodiments, such uses can include compositions comprising an unlabeled form of a compound or an isotopically labeled form of the compound, wherein the compound has a structure described by a formula in which one or more atoms are replaced by atoms having a selected atomic mass or mass number. The present disclosure also provides intermediates of the compounds disclosed herein and methods for their preparation. In some embodiments, such a preparation method can include using any of the intermediates disclosed herein. As will be understood by those of ordinary skill in the art, other embodiments are also contemplated herein.

[0231] The present disclosure provides various aspects and embodiments of compounds, compositions, and methods for their preparation and use. In preferred embodiments, the present disclosure provides the following aspects:

[0232] Aspect 1. A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof;

[0233]

[0234] Wherein:

[0235] Wherein:

[0236] R1 includes E, where E is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); or when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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;

[0237] R2, R3, and R4 are independently selected from the group consisting of H, halogen (e.g., F, Cl, Br), alkyl, substituted alkyl, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7) A group consisting of cycloalkyl; wherein R2, R3 and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, said substituents being independently selected from one, two or all of R2, R3 and R4;

[0238] R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure, and R5 and R6 are joined together to form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl;

[0239] R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0240] R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0241] R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached as an alkyl to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure;

[0242] R 10 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl and cycloalkyl;

[0243] R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 or R 12 is attached as an alkyl to R7 or R8 to form a (C 1-3 ) alkyl-bridged cyclic structure, wherein in some embodiments, R 11and R 12 When joined together, they can form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl;

[0244] R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, and R 13 or R 14 is attached to R7 or R8 as an alkyl group to form a (C 1-3 )alkyl bridge cyclic structure;

[0245] R 15 is aromatic or aryl, such as but not limited to heteroaryl (e.g., preferably a 5- or 6-membered ring), substituted aromatic or aryl, substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, and (C 3-7 )heterocycloalkyl;

[0246] W is:

[0247] a) selected from the group consisting of CH2, and R7, R8, R 13 , R 14 =H, and the carbon having substituents R7, R8, R 13 and R 14 will be directly connected to provide a 5-5 bridge bicyclic system as shown below:

[0248] or

[0249] b) absent to provide a seven-membered ring system as shown below:

[0250]

[0251] Wherein:

[0252] The fused ring system A-B-J-D-E is a five (5)-membered heteroaryl, optionally imidazole (where A and J are nitrogen, and B, E, and D are carbon) or pyrazole (where A and B are nitrogen, D, E, and J are carbon); the five (5)-membered heteroaryl is fused or unfused with another ring system;

[0253] The fused ring system B-J-M-G-K-L is a six (6)-membered aromatic or aryl, substituted aromatic or aryl, substituted or unsubstituted heteroaryl, cycloalkyl, heterocycloalkyl;

[0254] A is nitrogen or carbon;

[0255] B is carbon or nitrogen;

[0256] J is carbon or nitrogen;

[0257] D is carbon;

[0258] E is carbon;

[0259] M is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N;

[0260] G is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O;

[0261] K is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O;

[0262] L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0263] Aspect 2. The compound according to aspect 1, which is of formula I-a7, formula I-a8, formula I-a9, formula II-a7, formula II-a8 or formula II-a9 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or a combination thereof,

[0264]

[0265] wherein:

[0266] In R1, E is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); when R1 is heteroaryl, it is preferably a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7A group consisting of cycloalkyl;

[0267] R2, R3, and R4 are independently selected from the group consisting of H, halogen (e.g., F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to 3 substituents, and the substituents are independently selected from one or two or all of R2, R3, and R4; and

[0268] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted 5-6 membered heteroaryl, or a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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, (C 3-7 )cycloalkyl, and (C 3-7 )heterocycloalkyl.

[0269] Aspect 3. The compound according to aspect 1, which has formula I-b7, formula I-b8, formula I-b9, formula I-b10, formula II-b7, formula II-b8, formula II-b9, and formula II-b10, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or a combination thereof,

[0270]

[0271] wherein:

[0272] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, and substituted 5-6 membered heteroaryl; when R1 is heteroaryl, it is optionally a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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, (C1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl;

[0273] R2, R3, and R4 are each independently selected from the group consisting of H, a halogen which is optionally F, Cl, or Br, alkyl, substituted alkyl, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7 ) cycloalkyl; where R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to 3 substituents, said substituents being independently selected from one or two or all of R2, R3, and R4; and,

[0274] R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl, and fused two heteroaryl ring systems; where said aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, where 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, (C 3-7 ) cycloalkyl, (C 3-7 ) heterocycloalkyl.

[0275] Aspect 4. The compound according to aspect 1, which has formula I-b11, formula I-b12, formula I-b13, formula I-b14, formula II-b11, formula II-b12, formula II-b13, and formula II-b14 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or a combination thereof,

[0276]

[0277] wherein:

[0278] E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, and substituted 5-6 membered heteroaryl; when R1 is heteroaryl, it is optionally a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the 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.

[0279] R2, R3, and R4 are each independently selected from the group consisting of H, halogen, F, Cl, or Br, alkyl, substituted alkyl, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7 ) cycloalkyl; wherein R2, R3, and R4 are each independently and optionally substituted at each substitutable position by at most 3 substituents, and the substituents are independently selected from one or two or all of R2, R3, and R4.

[0280] R 12 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl; and

[0281] R 15 is selected from the group consisting of aromatic, aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic, substituted aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl, or a fused two heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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, (C 3-7 ) cycloalkyl, and (C 3-7 ) heterocycloalkyl.

[0282] Aspect 5. The compound according to aspect 1, which is selected from the group consisting of the following or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof:

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290] Aspect 6 (particularly preferred embodiment). The compound according to aspect 5, which is selected from the group consisting of the following or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof:

[0291]

[0292]

[0293] Aspect 7. A pharmaceutical composition comprising the compound according to any one of the preceding claims or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof; and an acceptable carrier, adjuvant or vehicle.

[0294] Aspect 8. The pharmaceutical composition according to aspect 6, comprising a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0295] Aspect 9. The pharmaceutical composition according to aspect 7 or 8, wherein the composition further comprises at least one second therapeutic agent.

[0296] Aspect 10. A method of antagonizing at least one orexin receptor in a cell, comprising the step of exposing the cell to the compound and / or composition according to any one of the preceding claims, optionally, wherein the method is in vitro.

[0297] Aspect 11. A method of antagonizing at least one orexin receptor in a subject in need thereof, comprising the step of administering the compound and / or composition according to any one of the preceding claims.

[0298] Aspect 12. A method of treating a disorder in a subject in need thereof, said disorder being selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer's disease (AD), and central nervous system (CNS) disorders, said method comprising the step of administering a compound and / or composition according to any one of the preceding claims.

[0299] Aspect 13. The method according to aspect 12, wherein the substance corresponding to substance addiction or substance dependence is selected from the group consisting of: one or more opioids, optionally heroin, morphine, oxycodone, fentanyl, and hydrocodone; one or more stimulants, optionally selected from the group consisting of amphetamine, cocaine, crack cocaine, and methamphetamine; one or more sedatives and / or tranquillizers, benzodiazepines, and barbiturates.

[0300] Aspect 14. The method according to any one of aspects 10-13, wherein the compound is an orexin receptor antagonist.

[0301] Aspect 15. The method according to any one of aspects 10-14, wherein the compound is an antagonist of orexin receptor 1 (OX1R) or orexin receptor 2 (OX2R), or an antagonist of both OX1R and OX2R; optionally, wherein the compound is an antagonist of the κ-opioid receptor; and / or exhibits the following characteristics when measured in an in vitro cell assay: 1) OX1R Kb < 30 nM, OX2R Kb > 1000 nM, KOR Ki < 500 nM; 2) OX1R Kb < 30 nM, OX2R Kb > 30 nM, KOR Ki < 500 nM; or 3) OX1R Kb < 30 nM, OX2R Kb > 1000 nM, KOR Ki > 1000 nM.

[0302] Aspect 16. The method according to any one of aspects 10-15, comprising administering to a patient a therapeutically effective amount of a compound and / or composition according to any one of the preceding claims.

[0303] Aspect 17. The method according to any one of aspects 10-16, comprising administering at least one unlabeled form and / or at least one isotopically labeled form of a compound according to any one of the preceding claims, and / or a composition comprising the compound.

[0304] Aspect 18. A method for preparing the compound described in Aspect 1, comprising combining at least two intermediates to produce the compound. In a preferred embodiment, the intermediates, reaction conditions, etc. for producing the compound are described in detail in the Examples section and will not be elaborated here, but those skilled in the art will understand that this section is the same as when describing this preferred aspect (i.e., introduced herein).

[0305] Aspect 19. A method for preparing the pharmaceutical composition described in Aspect 1, comprising combining at least one compound described in Aspect 1 with at least one pharmaceutically acceptable excipient. Methods for preparing such combinations (i.e., at least one compound, etc. and at least one pharmaceutical composition) are well known in the art and thus are not described in detail in this regard, but are introduced herein.

[0306] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of development of, delay the onset of, slow the progression of, or cause regression of a medical condition being treated, or to alleviate, to some extent, the medical condition or one or more symptoms or complications of the condition, at least in some portion of the subject taking the compound. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit a biological or medical response in a cell, tissue, organ, or human being that is sought by a physician or clinician. The terms "treat", "treating", and "treatment" include alleviating, ameliorating, inhibiting the development of, reversing, or eliminating a medical condition or one or more symptoms or complications associated with the condition, as well as alleviating, ameliorating, or eradicating one or more causes of the condition. Reference to "treatment" of a medical condition includes prevention of the condition. The terms "prevent", "preventing", and "prevention" include precluding, reducing the development of, and delaying the risk of onset of a medical condition or one or more symptoms or complications associated with the condition. The term "medical condition" (or simply "condition") includes diseases and disorders. The terms "disease" and "disorder" are used interchangeably herein.

[0307] Throughout the specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of the stated integer (or element) or group of integers (or elements), but not the exclusion of any other integer (or element) or group of integers (or elements). The singular forms "a", "an" and "the" include plural forms unless the context clearly dictates otherwise. The symbol "=" means "is" when used in a descriptive sense. The term "including" is used to mean "including but not limited to", and "including" and "including but not limited to" are used interchangeably. The term "agent" is used herein to denote a chemical compound (e.g., an organic compound or a mixture of chemical compounds). Agents include, for example, agents of known structure whose orexin antagonist activity renders them suitable as "therapeutic agents" in the methods and compositions disclosed herein. In addition, those of ordinary skill in the art will recognize the following abbreviations commonly used:

[0308] Me: Methyl

[0309] Et: Ethyl

[0310] t-Bu: tert-Butyl

[0311] Ar: Aryl

[0312] Ph: Phenyl

[0313] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0314] Bn: Benzyl

[0315] Ac: Acetyl

[0316] Boc: tert-Butoxycarbonyl

[0317] BSA: Bovine serum albumin

[0318] CbzCl: Benzyl chloroformate

[0319] CDI: Carbonyldiimidazole

[0320] DCM: Dichloromethane

[0321] DCE: Dichloroethane

[0322] DEAD: Diethyl azodicarboxylate

[0323] DIPEA: N,N-Diisopropylethylamine

[0324] DMF: N,N-Dimethylformamide

[0325] DMSO: Dimethyl sulfoxide

[0326] CH2Cl2: Dichloromethane

[0327] EDC: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide

[0328] Et3N: Triethylamine

[0329] EtOAc: Ethyl acetate

[0330] EtOH: Ethanol

[0331] HCl: Hydrochloric acid

[0332] HOAt: 1-Hydroxy-7-azabenzotriazole

[0333] HOBT: Hydroxybenzotriazole hydrate

[0334] LCMS: Liquid chromatography-mass spectrometry

[0335] HPLC: High performance liquid chromatography

[0336] Hunig's base: N,N-Diisopropylethylamine

[0337] MeOH: Methanol

[0338] MgSO4: Magnesium sulfate

[0339] MTBE: Methyl tert-butyl ether

[0340] NaHCO3: Sodium bicarbonate

[0341] Na2CO3: Sodium carbonate

[0342] K2CO3: Potassium carbonate

[0343] NaOH: Sodium hydroxide

[0344] NMM: N-Methylmorpholine

[0345] PtO2: Platinum oxide

[0346] Pd: Palladium

[0347] Pd / C: Palladium on carbon

[0348] PyClu: 1-(Chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate

[0349] RT or rt: Room temperature

[0350] Rxn: Reaction

[0351] SOCl2: Thionyl chloride

[0352] THF: Tetrahydrofuran

[0353] TFA: Trifluoroacetic acid

[0354] X-Phos: 2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl

[0355] HATU: (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0356] NMR: Nuclear magnetic resonance

[0357] ESI: Electrospray ionization

[0358] MS: Mass spectrometry

[0359] All references cited in this disclosure are incorporated herein by reference in their entirety. Certain embodiments are further described in the following examples. These embodiments are provided by way of example only and are not intended to limit the scope of the claims in any way.

[0360] Example

[0361] Example 1

[0362] For this disclosure, the following intermediates were prepared and used in the synthesis of the embodiments claimed herein:

[0363] 1. Prepared carboxyl-containing intermediate - carboxylic acid group

[0364]

[0365] 2. Prepared secondary amine-containing intermediate - amino group

[0366]

[0367] I. General synthetic methods, procedures, and experiments

[0368] A. General:

[0369] All temperatures are expressed in °C. Commercially available starting materials were used as received without further purification. Unless otherwise stated, all reactions were carried out in a nitrogen atmosphere in dried glassware. Compounds were purified by flash column chromatography on silica gel or preparative HPLC. The compounds described in this disclosure were characterized by LC-MS data (retention time t R given in min; molecular weight obtained from mass spectrometry given in g / mol) using the following conditions.

[0370] LC-MS under acidic conditions

[0371] 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 for 5 min (flow rate: 0.8 mL / min). Detection: UV 280 / 254 nm + MS.

[0372] 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 for 5 min (flow rate: 0.8 mL / min). Detection: UV 280 / 254 nm + MS.

[0373] Generally, the compounds of the present disclosure can be prepared by methods known to those skilled in the art and contemporary techniques in the art. Schemes 1-4 below illustrate the synthetic routes of the compounds of the present disclosure. Other equivalent schemes that are obvious to an ordinary skilled synthetic organic or medicinal chemist can alternatively be used to synthesize different parts of the molecule, as shown in the general schemes described herein.

[0374] B. Intermediate synthesis

[0375] 1. Synthesis of intermediate HBS-037-054:

[0376]

[0377] Step 1: Synthesis of compound HBS-037-036: Dissolve ethyl 3-phenyl-1H-pyrazole-5-carboxylate (0.5 g, 2.31 mmol) in acetone (10.0 mL). Add K2CO3 (0.96 g, 6.9 mmol), then add 1-bromo-2-chloroethane (0.1 mL, 11.6 mmol). Heat the reaction mixture at 55 °C for 16 hours (h). LCMS data shows the formation of the desired product with m / z of 279.0 and the formation of a small amount of by-products. Filter the reaction mixture and wash the solid with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography with the mobile phase: EtOAc: hexane, gradient. Obtain the compound as a liquid (0.6 g) (yield: 93.2%). C 14 H 15 The MS (ESI) mass of ClN2O2 is calculated to be 278.7; m / z is 279.0 [M + H] + .

[0378] Step 2: Synthesis of compound HBS-037-040: Dissolve compound HBS-037-036 (0.55 g, 1.97 mmol) in dry THF (6.0 mL). Add DIBAL (12.0 mL, 1.0 M solution, 11.8 mmol) under an ice-cooling bath. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data shows the formation of the desired product with m / z of 237.0. Quench the reaction mixture with 1.0 N aqueous NaOH and dilute with ethyl acetate (10.0 mL). Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate (10.0 mL × 3). Separate the EtOAc layer, wash with water, and then with brine. Dry the organic layer with anhydrous sodium sulfate. Evaporate the solvent to obtain 0.4 g of the crude product (yield 85.6%). C 12 H 13 The MS (ESI) mass of ClN2O is calculated to be 236.7; m / z is 237.0 [M+H] + 。

[0379] Step 3: Synthesis of compound HBS-037-043: Dissolve compound HBS-037-040 (0.47 g, 1.97 mmol) in dry DMF (12.0 mL). Add NaH (0.12 g, 2.96 mmol) under ice-cooling. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data shows the formation of the desired product with m / z of 201.1. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry with anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc: hexane, gradient. Obtain the compound in solid form (0.26 g) (yield 65.3%). C 12 H 12 The MS (ESI) mass of N2O is calculated to be 200.2; m / z is 201.1 [M+H] + 。

[0380] Step 4: Synthesis of compound HBS-037-043: Dissolve compound HBS-037-042 (0.25 g, 1.25 mmol) in DCM (5.0 mL). Add NBS (0.24 g, 1.37 mmol) and stir the reaction mixture at room temperature for 16 h. LCMS data shows the formation of the desired product with m / z of 280.9. Evaporate the solvent to obtain the crude product. Purify it by column chromatography with mobile phase: EtOAc: hexane, gradient. Obtain compound HBS-037-043 (0.29 g) as a liquid (yield 81.7%). C 12 H 11The MS (ESI) mass of BrN2O was calculated to be 279.1; m / z was 280.9 [M+H] + 。

[0381] Step 5: Synthesis of intermediate HBS-037-054: Dissolve compound HBS-037-043 (0.025 g, 0.09 mmol) in anhydrous THF (1.0 mL) under N2 atmosphere. Cool the reaction mixture to -78.0 °C and add n-BuLi (0.12 mL, 1.6 M) to the reaction mixture. Stir the reaction mixture at -78.0 °C for 30.0 min. Bubble dry CO2 gas through the reaction mixture at -65 °C and gradually warm the reaction mixture to room temperature. LCMS data showed the formation of the desired product, m / z 245, a debrominated by-product (m / z 201), and some unknown products. Quench the reaction mixture with water and extract with ethyl acetate. Separate the ethyl acetate layer and recover the debrominated product. Acidify the aqueous layer with 1 M HCl solution, evaporate to dryness, and obtain 0.022 g of solid product. C 13 H 12 The MS (ESI) mass of N2O3 was calculated to be 244.3; m / z was 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).

[0382] 2. Synthesis of intermediate HBS-037-193:

[0383]

[0384] Step 1: Synthesis of compound HBS-037-191: Dissolve ethyl benzoylacetate (0.5 g, 2.6 mmol) in DMSO (5.0 mL). Add NBS (0.51 g, 2.86 mmol) and stir the reaction mixture at ambient temperature for 24 h. LCMS showed the formation of the product, m / z 270.9. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the ethyl acetate layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product, which was purified by a combi-flash system with mobile phase: EtOAc: hexane, gradient. Obtain 0.42 g of product (yield 59.7%). C 11 H 11 The MS (ESI) mass of BrO3 was calculated to be 271.1; m / z was 270.9 [M+H] + 。

[0385] Step 2: Synthesis of compound HBS-037-192: Dissolve compound HBS-037-191 (0.42 g, 1.55 mmol) in anhydrous acetonitrile (5.0 mL). Add 2-amino-pyridine (0.15 g, 1.55 mmol), and stir the reaction mixture at 80 °C for 1 h. LCMS shows the formation of the product with m / z of 267.1. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product through a combi-flash system with mobile phase: EtOAc: hexane, gradient. Obtain compound HBS-037-192 (0.24 g) (yield 58.0%). C 16 H 14 The MS (ESI) mass of N2O2 is calculated to be 266.3; m / z is 267.1 [M+H] + 。

[0386] Step 3: Synthesis of intermediate HBS-037-193: Dissolve compound HBS-037-192 (0.24 g, 0.9 mmol) in MeOH (5.0 mL). Add 1.0 N aqueous NaOH solution (4.51 mL, 4.51 mmol), and stir the reaction mixture at 60 °C for 3 h. LCMS shows the formation of the product with m / z of 239. Concentrate the reaction mixture under reduced pressure, dissolve the solid in water, and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate (ppts) and wash with water (10.0 mL × 3) to obtain 0.2 g of solid product. C 14 H 10 The MS (ESI) mass of N2O2 is calculated to be 238.2; m / z is 239.1 [M+H] + , 1 H NMR (400 MHz, chloroform-d) δ ppm 7.04 (t, J = 6.93 Hz, 1H) 7.33 - 7.48 (m, 4H) 7.70 - 7.78 (m, 3H) 9.41 (d, J = 7.04 Hz, 1H).

[0387] 3. Synthesis of intermediate HBS-037-163:

[0388]

[0389] Step 1: Synthesis of Intermediate HBS-037-163: Dissolve compound C1 (synthesized as reported in Journal of Medicinal Chemistry; 2011, 54(13), 4752 - 4772) (0.2 g, 0.75 mmol) in MeOH (6.0 mL). Add 1.0 N aqueous NaOH solution (3.8 mL, 3.8 mmol), and stir the reaction mixture at 60 °C for 24 h. LCMS shows the formation of the product, with m / z of 239.1. Concentrate the reaction mixture under reduced pressure, dissolve the solid in water, and acidify with 1.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash it with water (10.0 mL × 3) to obtain 0.18 g of the solid product. C 14 H 10 The MS (ESI) mass of N2O2 is calculated to be 238.2; m / z is 239.1 [M+H] + , 1 H NMR (400 MHz, 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, 1.54 Hz, 2H) 8.18 - 8.28 (dd, J = 8.99, 0.70 Hz, 1H) 8.49–8.56 (dd, J = 6.90, 0.73 Hz, 1H).

[0390] 4. Synthesis of Intermediate HBS-037-188:

[0391]

[0392] Step 1: Synthesis of Compound HBS-037-187: Dissolve 1,4-diazabicyclo[2.2.2]octane-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) and 2,5-dichlorobenzoxazole (0.47 g, 2.5 mmol) in anhydrous DMF (10.0 mL). Add triethylamine (1.0 mL, 7.5 mmol), and heat the reaction mixture at 70 °C for 16 h. LCMS data shows the formation of the product, with m / z of 352.1. Dilute the reaction mixture with water and extract the product with ethyl acetate. Wash the combined ethyl acetate layers with water and then with brine. Separate the organic layer and dry it over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product, which is purified by column chromatography with the mobile phase: EtOAc:hexane, gradient. 0.88 g of the product is isolated (quantitative yield (Yield Quant.)). C 17 H 22 The MS (ESI) mass of ClN3O3 is calculated to be 351.8; m / z is 352.1 [M+H] + .

[0393] Step 2: Synthesis of Intermediate HBS-037-188: Dissolve compound HBS-037-187 (0.88 g, 2.5 mmol) in anhydrous dioxane (10.0 mL). Add a solution of 4.0 M HCl in dioxane (6.2 mL, 25.0 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 252. Concentrate the reaction mixture under reduced pressure to obtain the product (0.9 g, quantitative yield). C 12 H 14 The MS (ESI) mass of ClN3O was calculated to be 251.7; m / z was 252.0 [M+H] + 。

[0394] 5. Synthesis of Intermediate HBS-039-002:

[0395]

[0396] Step 1: Synthesis of Compound HBS-037-198: Dissolve Intermediate C (0.029 g, 0.12 mmol) in anhydrous DCM (2.5 mL). Add EDC.HCl (0.046 g, 0.24 mmol) and HOBt (0.032 g, 0.24 mmol), then add Et3N (0.17 mL, 1.21 mmol). Stir the reaction mixture at ambient temperature for 10.0 min. Add a solution of (5R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester (0.03 g, 0.12 mmol) in DCM (2.0 mL) to the reaction mixture. Stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 469.2. Dilute the reaction mixture with saturated NaHCO3 solution and extract the product with DCM. Separate the combined DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Obtain the product in solid form (0.055 g) (yield 97.1%). C 28 H 28 The MS (ESI) mass of N4O3 was calculated to be 468.55; m / z was 469.2 [M+H] + 。

[0397] Step 2: Synthesis of Intermediate HBS-039-002: Dissolve compound HBS-037-198 (0.055 g, 0.11 mmol) in ethyl acetate (3.0 mL). Add 20.0% Pd-OH / C (10.0 mg), and stir the reaction mixture under a hydrogen atmosphere at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 335.2. Filter the reaction mixture through a diatomaceous earth bed and wash with ethyl acetate. Evaporate the filtrate under reduced pressure to obtain 37.1 mg of the crude product, which is used in the next step without purification. C 20 H 22 The MS (ESI) mass of N4O is calculated to be 334.4; m / z is 335.2 [M+H] + 。

[0398] 6. Synthesis of Intermediate HBS-039-011A / B:

[0399]

[0400] Step 1: Synthesis of Compound HBS-039-007: Dissolve Intermediate HBS-039-193 (0.029 g, 0.12 mmol) in anhydrous DCM (2.0 mL). Add EDC.HCl (0.046 g, 0.24 mmol) and HOBt (0.032 g, 0.24 mmol), then add Et3N (0.17 mL, 1.21 mmol). Stir the reaction mixture at ambient temperature for 10.0 min. Add a solution of (5R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester (0.03 g, 0.12 mmol) in DCM (2.0 mL) to the reaction mixture and stir at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 469.2. Dilute the reaction mixture with saturated NaHCO3 solution and extract the product with DCM. Separate the combined DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product, which is purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Obtain product HBS-039-007 (0.033 g) (yield 58.3%). C 28 H 28 The MS (ESI) mass of N4O3 is calculated to be 468.55; m / z is 469.2 [M+H] + 。

[0401] Step 2: Synthesis of Intermediate HBS-039-011A / B: Dissolve compound HBS-039-007 (0.033 g, 0.07 mmol) in ethyl acetate (5.0 mL). Add 20.0% Pd-OH / C (10.0 mg) and stir the reaction mixture under a hydrogen atmosphere at ambient temperature for 16 h. LCMS data shows the formation of the product, m / z 335.2, and the formation of an over-reduced byproduct, m / z 339.2. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Evaporate the filtrate under reduced pressure to obtain 22.0 mg of the crude product, which is used in the next step without purification. C 20 H 22 The MS (ESI) mass of N4O is calculated to be 334.4; m / z 335.2 [M+H] + 。

[0402] 7. Synthesis of Intermediate HBS-039-010:

[0403]

[0404] Step 1: Synthesis of Compound HBS-039-008: Dissolve intermediate HBS-037-071 (0.044 g, 0.18 mmol) in anhydrous DCM (2.0 mL). Add EDC.HCl (0.046 g, 0.24 mmol) and HOBt (0.032 g, 0.24 mmol), then add Et3N (0.17 mL, 1.21 mmol). Stir the reaction mixture at ambient temperature for 10.0 min, then add a solution of (5R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester (0.03 g, 0.12 mmol) in DCM (2.0 mL) to the reaction mixture and stir at ambient temperature for 16 h. LCMS data shows the formation of the product, m / z 475.2. Dilute the reaction mixture with saturated NaHCO3 solution and extract the product with DCM. Separate the combined DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product, which is purified by an ISCO combi-flash system with a mobile phase: EtOAc: hexane, gradient. Obtain compound HBS-039-008 (0.023 g) (yield 26.7%). C 27 H 30 The MS (ESI) mass of N4O4 is calculated to be 474.55; m / z 475.2 [M+H] + 。

[0405] Step 2: Synthesis of intermediate HBS-039-010: Dissolve compound HBS-039-008 (0.023 g, 0.048 mmol) in ethyl acetate (5.0 mL). Add 20.0% Pd-OH / C (5.0 mg), and stir the reaction mixture at ambient temperature for 16 h under a hydrogen atmosphere. LCMS data shows the formation of the product, with m / z of 341.2. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Evaporate the filtrate under reduced pressure to obtain 14.0 mg of the crude product, which is used in the next step without purification. C 19 H 24 The MS (ESI) mass of N4O2 is calculated to be 340.4; m / z is 341.2 [M+H] + 。

[0406] 8. Synthesis of intermediate HBS-039-024:

[0407]

[0408] Step 1: Synthesis of compound HBS-039-013: Dissolve pyrazolo[1,5-a]pyridine-2-carboxylic acid (1.0 g, 6.17 mmol) in ethanol (20.0 mL). Add a catalytic amount of concentrated sulfuric acid (0.5 mL), and reflux the reaction mixture for 16 h. LCMS data shows the formation of the product, with m / z of 191.1. Concentrate the reaction mixture under reduced pressure and neutralize with saturated aqueous sodium bicarbonate. Extract the product with ethyl acetate. Separate the ethyl acetate layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the product (1.2 g) (quantitative yield). C 10 H 10 The MS (ESI) mass of N2O2 is calculated to be 190.2; m / z is 191.1 [M+H] + 。

[0409] Step 2: Synthesis of compound HBS-039-014: Dissolve compound HBS-039-013 (1.17 g, 6.17 mmol) in DCM (25.0 mL). Add NBS (1.1 g, 6.17 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 271.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify it by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Obtain compound HBS-039-013 (1.5 g) (yield 90.4%). C 10 The MS (ESI) mass of H9BrN2O2 is calculated to be 269.1; m / z is 271.0 [M+H] + 。

[0410] Step 3: Synthesis of compound HBS-039-015: Dissolve compound HBS-039-014 (0.2 g, 0.74 mmol) in a mixture of dioxane / water (8.0:2.0 v / v mL). Add phenylboronic acid (0.11 g, 0.89 mmol) and K2CO3 (0.3 g, 2.23 mmol), and then add Pd(dppf)Cl2.DCM2 (0.06 g, 0.07 mmol). Stir the reaction mixture at 80 °C for 5 h under a N2 atmosphere. LCMS data shows the formation of the product with an m / z of 267. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product, which is purified by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Compound HBS-039-015 is obtained (quantitative yield). C 16 H 14 The MS (ESI) mass of N2O2 is calculated to be 266.3; m / z is 267.1 [M+H] + 。

[0411] Step 4: Synthesis of compound HBS-039-018: Dissolve compound HBS-039-015 (0.2 g, 0.74 mmol) in MeOH (6.0 mL). Add 1.0 N aqueous NaOH (3.7 mL, 3.7 mmol), and stir the reaction mixture at 60 °C for 16 h. LCMS data shows the formation of the product with an m / z of 239.1. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 1.0 M aqueous HCl (pH = 5), filter the precipitate, and wash with water (5.0 mL × 3) to obtain 0.16 g of the solid product HBS-039-018 (yield 92.6%). C 14 H 10 The MS (ESI) mass of N2O2 is calculated to be 238.2; m / z is 239.1 [M+H] + 。

[0412] Step 5: Synthesis of Compound HBS-039-022: Dissolve Compound HBS-039-018 (0.025 g, 0.11 mmol) in anhydrous DCM (2.0 mL). Add EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol), then add Et3N (0.15 mL, 1.1 mmol). Stir the reaction mixture at ambient temperature for 10.0 min. Add a solution of (5R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester (0.03 g, 0.11 mmol) in DCM (2.0 mL) to the reaction mixture, and then stir at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 469.2. Dilute the reaction mixture with saturated NaHCO3 solution and extract the product with DCM. Separate the combined DCM layers, dry over anhydrous Na2SO4, and then evaporate to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. 0.049 g of the product was obtained (quantitative yield). C 28 H 28 The MS (ESI) mass of N4O3 was calculated to be 468.6; m / z was 469.2 [M+H] + 。

[0413] Step 6: Synthesis of Intermediate HBS-039-024: Dissolve Compound HBS-039-022 (0.05 g, 0.11 mmol) in EtOAc (3.0 mL). Add 20.0% Pd-OH / C (10.0 mg), and stir the reaction mixture at ambient temperature for 16 h under a H2 atmosphere. LCMS data showed the formation of the product, with m / z of 335.2. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain 0.03 g of crude product HBS-039-024, which was used directly in the next step without purification. C 20 H 22 The MS (ESI) mass of N4O was calculated to be 334.4; m / z was 335.2 [M+H] + 。

[0414] 9. Synthesis of Intermediate HBS-039-025:

[0415]

[0416] Step 1: Synthesis of Compound HBS-039-016: Imidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g, 5.26 mmol) was dissolved in DCM (20.0 mL). NBS (1.0 g, 5.78 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 271.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Pure HBS-039-016 (1.4 g) was obtained (yield 98.9%). C 10 The MS (ESI) mass of C9BrN2O2 was calculated to be 269.1; m / z was 271.0 [M+H] + .

[0417] Step 2: Synthesis of Compound HBS-039-017: Compound HBS-039-016 (0.2 g, 0.74 mmol) was dissolved in a mixture of dioxane / water (8.0:2.0 v / v mL). Phenylboronic acid (0.11 g, 0.89 mmol) and K2CO3 (0.3 g, 2.23 mmol) were added, and then Pd(dppf)Cl2.DCM2 (0.06 g, 0.07 mmol) was added. The reaction mixture was stirred at 80 °C for 5 h under a N2 atmosphere. LCMS data showed the formation of the product with m / z of 267.1. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Compound HBS-039-017 (0.2 g) was obtained (quantitative yield). C 16 H 14 The MS (ESI) mass of C9H9N2O2 was calculated to be 266.3; m / z was 267.1 [M+H] + .

[0418] Step 3: Synthesis of Compound HBS-039-019: Compound HBS-039-017 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL), and 1.0 N aqueous NaOH solution (3.7 mL, 3.7 mmol) was added, and the reaction mixture was stirred at 60 °C for 16 h. LCMS data showed the formation of the product with m / z of 239.1. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 1.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (5.0 mL × 3) to obtain 0.11 g of the solid product (yield 62.1%). C 14 H 10The MS(ESI) mass of N2O2 was calculated to be 238.2; m / z was 239.1 [M+H] + 。

[0419] Step 4: Synthesis of compound HBS-039-023: Dissolve compound HBS-039-017 (0.025 g, 0.11 mmol) in anhydrous DCM (2.0 mL). Add EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol), then add Et3N (0.15 mL, 1.1 mmol). Stir the reaction mixture at ambient temperature for 10.0 min. Add a solution of (5R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester (0.03 g, 0.11 mmol) in DCM (2.0 mL) to the reaction mixture, and then stir at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 469.2. Dilute the reaction mixture with saturated NaHCO3 solution. Extract the product with DCM. Separate the combined DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product, which was purified by an ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain the product compound HBS-039-023 (0.049 g) (quantitative yield). C 28 H 28 The MS(ESI) mass of C14H16N4O3 was calculated to be 468.6; m / z was 469.2 [M+H] + 。

[0420] Step 5: Synthesis of intermediate HBS-039-025: Dissolve compound HBS-039-023 (0.05 g, 0.11 mmol) in EtOAc (3.0 mL). Add 20.0% Pd-OH / C (10.0 mg), and stir the reaction mixture at ambient temperature for 16 h under H2 atmosphere. LCMS data showed the formation of the product, with m / z of 339.2. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain 0.03 g of the crude product, which was used in the next step without purification. C 20 H 26 The MS(ESI) mass of C12H16N4O was calculated to be 338.5; m / z was 339.2 [M+H] + 。

[0421] 10. Synthesis of intermediate HBS-039-055:

[0422]

[0423] Compound HBS-037-198 (0.11 g, 0.24 mmol) was dissolved in ethyl acetate (5.0 mL). 20.0% Pd-OH / C (25.0 mg) was added, and the reaction mixture was stirred at ambient temperature for 16 h under a hydrogen atmosphere. LCMS data showed the formation of the product, m / z 335.2, and the formation of an over-reduced byproduct, m / z 339.2. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to afford 72.0 mg of the crude product, which was used in the next step without purification as a mixture. C 20 H 22 The MS (ESI) mass of N4O was calculated to be 334.4; m / z 335.2 [M+H] + 。

[0424] 11. Synthesis of Intermediate HBS-039-080:

[0425]

[0426] Step 1: Synthesis of Intermediate HBS-039-080: Compound HBS-039-007 (0.4 g, 0.84 mmol) was dissolved in ethyl acetate (10.0 mL). 20.0% Pd-OH / C (20.0 mg) was added, and the reaction mixture was stirred at ambient temperature for 16 h under a hydrogen atmosphere. LCMS data showed the formation of the major product, m / z 335.2. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to afford 0.25 g of the crude product, which was used in the next step without purification. C 20 H 22 The MS (ESI) mass of N4O was calculated to be 334.4; m / z 335.2 [M+H] + 。

[0427]

[0428] Step 1: Synthesis of HBS-039-170: 2-Boc-hexahydro-pyrrolo[3,4-c]pyrrole (1.0 g, 4.71 mmol) was dissolved in IPA (15.0 mL). Anhydrous K2CO3 (0.97 g, 7.07 mmol) was added, followed by 2-chloro-4,6-dimethylpyrimidine (0.067 g, 4.71 mmol). The reaction mixture was stirred at 80 °C for 12 h. LCMS data showed the formation of the product, m / z 319.3. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated to afford the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. 1.16 g of the product was obtained (yield 77.3%). C 17H 26 The MS(ESI) mass of N4O2 was calculated to be 318.41; m / z was 319.3 [M+H] + 。

[0429] Step 2: Synthesis of HBS-039-171: Dissolve compound HBS-039-170 (1.16 g, 3.64 mmol) in anhydrous dioxane (15.0 mL). Add a solution of 2.0 M HCl in diethyl ether (7.3 mL, 14.6 mmol), and stir the reaction mixture at 55 °C for 6 h. LCMS data showed the formation of the product, with m / z of 219.1. Cool the reaction mixture to ambient temperature and filter to obtain the product (0.8 g, quantitative yield). C 12 H 18 The MS(ESI) mass of N4 was calculated to be 218.3; m / z was 219.1 [M+H] + 。

[0430]

[0431] Step 1: Synthesis of HBS-039-147: Dissolve 1-ethynyl-4-fluorobenzene (0.5 g, 4.16 mmol) in anhydrous THF (5.0 mL). Add n-BuLi (5.2 mL, 8.32 mmol) at -78 °C, and stir the reaction mixture at -78 °C for 1 h. Add ethyl chloroformate (1.59 mL, 16.7 mmol) at -78 °C, and gradually warm the reaction mixture to ambient temperature. LCMS data showed the formation of the product, with m / z of 193.0. Dilute the reaction mixture with aqueous NH4Cl solution, and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. 0.8 g of crude product was obtained (quantitative yield). C 11 The MS(ESI) mass of H9FO2 was calculated to be 192.19; m / z was 193.0 [M+H] + 。

[0432] Step 2: Synthesis of HBS-039-148: Dissolve compound HBS-039-147 (0.4 g, 2.08 mmol) and 1-aminopyridine iodide (0.46 g, 2.08 mmol) in anhydrous DMF (5.0 mL). Add anhydrous K2CO3 (0.72 g, 5.2 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 285.1. Dilute the reaction mixture with water, filter the precipitate, and dry the precipitate to obtain the crude product. Purify the crude product through a combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.4 g of the product (yield 67.6%). C 16 H 13 The MS (ESI) mass of FN2O2 is calculated to be 284.29; m / z is 285.1 [M+H] + 。

[0433] Step 3: Synthesis of HBS-039-150: Dissolve compound HBS-039-148 (0.4 g, 1.41 mmol) in MeOH (7.0 mL). Add 1.0 N aqueous NaOH solution (7.0 mL, 7.0 mmol), and reflux the reaction mixture for 8 h. LCMS shows the formation of the product, with m / z of 257.0. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (5.0 mL × 3) to obtain 0.35 g of the solid product (yield 97.5%). C 14 The MS (ESI) mass of H9FN2O2 is calculated to be 256.23; m / z is 257.0 [M+H] + 。

[0434]

[0435] Step 1: Synthesis of HBS-054-005: Dissolve ethyl benzoylacetate (2.13 g, 11.1 mmol) in DCM (20.0 mL). Add NBS (1.8 g, 11.1 mmol) and TsOH.H2O (0.38 g, 2.0 mmol), and stir the reaction mixture at ambient temperature for 24 h. LCMS shows the formation of the product, with m / z of 272.0. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the ethyl acetate layer and dry with anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product through a combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 2.1 g of the product (yield 70.0%). C 11 H 11The MS (ESI) mass of BrO3 was calculated to be 271.1; m / z was 272.0 [M+H] + 。

[0436] Step 2: Synthesis of HBS-054-010: Dissolve compound HBS-054-005 (1.5 g, 5.56 mmol) in anhydrous acetonitrile (20.0 mL). Add 2-amino-5-fluoropyridine (1.9 g, 16.67 mmol), and stir the reaction mixture at 80 °C for 16 h. LCMS showed the formation of the product, with m / z of 285.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product through a combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 1.2 g of the product (yield 75.0%). C 16 H 13 The MS (ESI) mass of FN2O2 was calculated to be 284.29; m / z was 285.0 [M+H] + 。

[0437] Step 3: Synthesis of HBS-054-014: Dissolve compound HBS-054-010 (1.2 g, 4.22 mmol) in MeOH (12.0 mL). Add 1.0 N aqueous NaOH solution (8.44 mL, 8.5 mmol), and stir the reaction mixture at 60 °C for 12 h. LCMS showed the formation of the product, with m / z of 257.0. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash it with water (5.0 mL × 3) to obtain 0.92 g of the solid product (yield 84.0%). C 14 The MS (ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + 。

[0438]

[0439] Step 1: Synthesis of HBS-054-011: Dissolve ethyl 3-(4-fluorophenyl)-3-oxopropionate (1.5 g, 7.14 mmol) in anhydrous acetonitrile (20.0 mL). Add 2-aminopyridine (2.0 g, 21.4 mmol), then add CBr4 (4.7 g, 14.27 mmol), and stir the reaction mixture at 80 °C for 16 h. LCMS showed the formation of the product, with m / z of 285.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product through a combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 1.9 g of the product (yield 95.0%). C 16 H 13The MS(ESI) mass of FN2O2 was calculated to be 284.29; m / z was 285.0 [M+H] + 。

[0440] Step 2: Synthesis of HBS-054-015: Dissolve compound HBS-054-011 (1.5 g, 5.28 mmol) in MeOH (15.0 mL). Add 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol), and stir the reaction mixture at 60 °C for 12 h. LCMS showed the formation of the product, with m / z of 257.0. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify it with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash it with water (5.0 mL × 3) to obtain 1.07 g of solid product (yield 79.0%). C 14 The MS(ESI) mass of C9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + 。

[0441]

[0442] Step 1: Synthesis of HBS-054-012: Dissolve ethyl 3-(2-fluorophenyl)-3-oxopropionate (1.5 g, 7.14 mmol) in anhydrous acetonitrile (20.0 mL). Add 2-aminopyridine (2.0 g, 21.4 mmol), then add CBr4 (4.7 g, 14.27 mmol), and stir the reaction mixture at 80 °C for 4 h. LCMS showed the formation of the product, with m / z of 285.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by a combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 1.83 g of product (yield 90.0%). C 16 H 13 The MS(ESI) mass of FN2O2 was calculated to be 284.29; m / z was 285.0 [M+H] + 。

[0443] Step 2: Synthesis of HBS-054-016: Dissolve compound HBS-054-012 (1.5 g, 5.28 mmol) in methanol (15.0 mL). Add 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol), and stir the reaction mixture at 60 °C for 12 h. LCMS showed the formation of the product, with m / z of 257.0. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify it with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash it with water (5.0 mL × 3) to obtain 1.1 g of solid product (yield 81.0%). C 14The MS(ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + 。

[0444]

[0445] Step 1: Synthesis of HBS-054-020: Ethyl benzoylacetate (1.5 g, 7.81 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-4-fluoropyridine (2.6 g, 23.4 mmol) was added, then CBr4 (5.2 g, 15.6 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. LCMS showed the formation of the product, m / z was 285.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by a combi-flash system, mobile phase: EtOAc: hexane, gradient. 0.9 g of the product was obtained (yield 41.0%). C 16 H 13 The MS(ESI) mass of HFN2O2 was calculated to be 284.29; m / z was 285.0 [M+H] + 。

[0446] Step 2: Synthesis of HBS-054-021: Compound HBS-054-020 (0.9 g, 3.17 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (6.3 mL, 6.34 mmol) was added, and the reaction mixture was stirred at 60 °C for 12 h. LCMS showed the formation of the product, m / z was 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (5.0 mL × 3) to obtain 0.37 g of the solid product (yield 41.0%). C 14 The MS(ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + 。

[0447]

[0448] Step 1: Synthesis of HBS-054-028: Ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) was dissolved in DCM (80.0 mL). NBS (3.4 g, 18.94 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 270.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 5.1 g of the product was obtained (quantitative yield). C 10 The MS (ESI) mass of H9BrN2O2 was calculated to be 269.1; m / z was 270.0 [M+H] + .

[0449] Step 2: Synthesis of HBS-054-035: Compound HBS-054-028 (1.5 g, 5.6 mmol) and 4-fluorophenylboronic acid (1.2 g, 8.4 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous Cs2CO3 (3.8 g, 11.75 mmol) was added, followed by Pd2(dba)3 (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The reaction mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS data showed the formation of the product, with m / z of 285.0. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 1.4 g of the product was obtained (yield 85.0%). C 16 H 13 The MS (ESI) mass of FN2O2 was calculated to be 284.29; m / z was 285.0 [M+H] + .

[0450] Step 3: Synthesis of HBS-054-039: Compound HBS-054-035 (1.4 g, 4.93 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (10.0 mL, 9.86 mmol) was added and the reaction mixture was refluxed for 12 h. LCMS data showed the formation of the product, with m / z of 257.0. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL × 3) to obtain 0.56 g of the solid product (yield 45.0%). C 14The MS(ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + 。

[0451]

[0452] Step 1: Synthesis of HBS-054-028: Ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) was dissolved in DCM (80.0 mL). NBS (3.4 g, 18.94 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 270.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 5.1 g of the product was obtained (quantitative yield). C 10 The MS(ESI) mass of H9BrN2O2 was calculated to be 269.1; m / z was 270.0 [M+H] + 。

[0453] Step 2: Synthesis of HBS-054-036: Compound HBS-054-028 (1.5 g, 5.6 mmol) and 2-fluorophenylboronic acid (1.2 g, 8.4 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous Cs2CO3 (3.8 g, 11.75 mmol) was added, followed by Pd2(dba)3 (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The reaction mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS data showed the formation of the product, with m / z of 285.0. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 1.2 g of the product was obtained (yield 75.0%). C 16 H 13 The MS(ESI) mass of FN2O2 was calculated to be 284.29; m / z was 285.0 [M+H] + 。

[0454] Step 3: Synthesis of HBS-054-040: Dissolve compound HBS-054-036 (1.2 g, 4.22 mmol) in MeOH (15.0 mL). Add 1.0 N aqueous NaOH solution (8.4 mL, 8.44 mmol), and reflux the reaction mixture for 12 h. LCMS data showed the formation of the product, with m / z of 257.0. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (5.0 mL × 3) to obtain 0.7 g of the solid product (yield 65.0%). C 14 The MS (ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + .

[0455]

[0456] Step 1: Synthesis of HBS-054-033: Dissolve methyl pyrazolo[1,5-a]pyridine-2-carboxylate (2.4 g, 13.6 mmol) in DCM (54.0 mL). Add NBS (2.5 g, 14.3 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 256.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. Obtain 3.5 g of the product (quantitative yield). The MS (ESI) mass of C9H7BrN2O2 was calculated to be 255.07; m / z was 256.0 [M+H] + .

[0457] Step 2: Synthesis of HBS-054-037: Dissolve compound HBS-054-033 (1.5 g, 5.9 mmol) and 4-fluorophenylboronic acid (1.2 g, 8.86 mmol) in a mixture of dioxane / water (24.0:6.0 v / v mL). Add anhydrous Cs2CO3 (4.0 g, 12.39 mmol), then add Pd2(dba)3 (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). Stir the reaction mixture at 80 °C for 12 h under a N2 atmosphere. LCMS data showed the formation of the product, with m / z of 271.0. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. Obtain 1.24 g of the product (yield 78.0%). C 15 H 11The MS (ESI) mass of FN2O2 was calculated to be 270.26; m / z was 271.0 [M+H] + 。

[0458] Step 3: Synthesis of HBS-054-041: Dissolve compound HBS-054-037 (1.2 g, 4.59 mmol) in MeOH (15.0 mL). Add 1.0 N aqueous NaOH solution (9.2 mL, 9.18 mmol), and reflux the reaction mixture for 12 h. LCMS data showed the formation of the product, with m / z of 257.0. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (5.0 mL × 3) to obtain 1.0 g of solid product (yield: 85.0%). C 14 The MS (ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H] + 。

[0459]

[0460] Step 1: Synthesis of HBS-054-033: Dissolve methyl pyrazolo[1,5-a]pyridine-2-carboxylate (2.4 g, 13.6 mmol) in DCM (54.0 mL). Add NBS (2.5 g, 14.3 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 256.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. Obtain 3.5 g of product (quantitative yield). The MS (ESI) mass of C9H7BrN2O2 was calculated to be 255.07; m / z was 256.0 [M+H] + 。

[0461] Step 2: Synthesis of HBS-054-038: Dissolve compound HBS-054-033 (1.5 g, 5.9 mmol) and 2-fluorophenylboronic acid (1.2 g, 8.86 mmol) in a mixture of dioxane / water (24.0:6.0 v / v mL). Add anhydrous Cs2CO3 (4.0 g, 12.39 mmol), then add Pd2(dba)3 (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). Stir the reaction mixture at 80 °C for 12 h under a N2 atmosphere. LCMS data shows the formation of the product with m / z of 271.0. Filter the reaction mixture through a diatomaceous earth bed and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with mobile phase: EtOAc:hexane, gradient. Obtain 1.4 g of the product (yield 86.0%). C 15 H 11 The MS (ESI) mass of FN2O2 is calculated to be 270.26; m / z is 271.0 [M+H] + 。

[0462] Step 3: Synthesis of HBS-054-042: Dissolve compound HBS-054-038 (1.4 g, 5.18 mmol) in methanol (15.0 mL). Add 1.0 N aqueous NaOH solution (10.4 mL, 10.36 mmol) and reflux the reaction mixture for 12 h. LCMS data shows the formation of the product with m / z of 257.0. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl (pH = 5). Filter the precipitate and wash with water (5.0 mL × 3) to obtain 1.0 g of the solid product (yield 85.0%). C 14 The MS (ESI) mass of H9FN2O2 is calculated to be 256.23; m / z is 257.0 [M+H] + 。

[0463]

[0464] Step 1: Synthesis of HBS-055-001: Dissolve 2-Boc-hexahydro-pyrrolo[3,4-c]pyrrole (0.2 g, 0.94 mmol) in IPA (5.0 mL). Add anhydrous K2CO3 (0.2 g, 1.41 mmol), and then add 2-chloro-5-(trifluoromethyl)pyridine (0.21 g, 1.13 mmol). Reflux the reaction mixture for 16 h. LCMS data shows the formation of the product, with m / z of 319.3. Cool the reaction mixture and filter it through a Buchner funnel. Concentrate the filtrate to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.22 g of the product (yield 65.4%). C 17 H 22 The MS (ESI) mass of F3N3O2 is calculated to be 357.37; m / z is 358.3 [M+H] + 。

[0465] Step 2: Synthesis of HBS-055-003: Dissolve compound HBS-055-001 (0.22 g, 0.62 mmol) in anhydrous dioxane (10.0 mL). Add a solution of 2.0 M HCl in diethyl ether (1.63 mL, 3.27 mmol), and stir the reaction mixture at 55 °C for 8 h. LCMS data shows the formation of the product, with m / z of 258.1. Cool the reaction mixture to ambient temperature and filter to obtain the solid product (0.2 g, yield 88.5%). C 12 H 14 The MS (ESI) mass of F3N3 is calculated to be 257.25; m / z is 258.1 [M+H] + 。

[0466]

[0467] Step 1: Synthesis of HBS-054-076: Dissolve ethyl benzoylacetate (1.5 g, 7.81 mmol) in anhydrous acetonitrile (20.0 mL). Add 2-amino-4-(trifluoromethyl)pyridine (3.8 g, 23.4 mmol), then add CBr4 (5.2 g, 15.6 mmol), and stir the reaction mixture at 80 °C for 16 h. LCMS shows the formation of the product, with m / z of 335.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by a combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 1.0 g of the product (yield 38.0%). C 17 H 13 The MS (ESI) mass of F3N2O2 is calculated to be 334.29; m / z is 335.0 [M+H] + 。

[0468] Step 2: Synthesis of HBS-054-080: Dissolve compound HBS-054-076 (1.0 g, 2.99 mmol) in MeOH (10.0 mL). Add 1.0 N aqueous NaOH solution (6.0 mL, 6.0 mmol), and reflux the reaction mixture for 12 h. LCMS shows the formation of the product with m / z of 307.0. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash it with water (5.0 mL × 3) to obtain 0.3 g of the solid product (yield: 33.0%). C 15 The MS (ESI) mass of H9F3N2O2 is calculated to be 306.24; m / z is 307.0 [M+H] + .

[0469]

[0470] Step 1: Synthesis of HBS-054-061: Dissolve methyl 4-(4-fluorophenyl)-2,4-dioxobutyrate (2.2 g, 10.68 mmol) in anhydrous THF (40.0 mL). Add hydrazine monohydrate (0.56 g, 11.21 mmol). Heat the reaction mixture under reflux for 3 h. LCMS data shows the formation of the desired product with m / z of 221.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by column chromatography with the mobile phase: EtOAc: hexane, gradient. Isolate 1.2 g of the product (yield: 51.0%). C 11 The MS (ESI) mass of H9FN2O2 is calculated to be 220.2; m / z is 221.0 [M+H] + .

[0471] Step 2: Synthesis of HBS-054-062: Dissolve compound HBS-054-061 (0.64 g, 2.91 mmol) in acetone (15.0 mL). Add K2CO3 (0.8 g, 5.82 mmol), and then add 1-bromo-2-chloroethane (0.5 g, 3.49 mmol). Heat the reaction mixture at 55 °C for 16 h. LCMS data shows the formation of the desired product with m / z of 283.0 and a small amount of by-products. Filter the reaction mixture and wash the solid with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography with the mobile phase: EtOAc: hexane, gradient. Isolate 0.7 g of the product (yield: 85.0%). C 13 H 12The MS(ESI) mass of ClFN2O2 was calculated to be 282.7; m / z was 283.0 [M+H] + .

[0472] Step 3: Synthesis of HBS-054-064: Dissolve compound HBS-054-062 (0.7 g, 2.48 mmol) in dry THF (10.0 mL). Under an ice-cooling bath, add a solution of 2.0 M LAH in THF (1.24 mL, 2.48 mmol). Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed the formation of the desired product, with m / z of 255.0. Quench the reaction mixture with 1.0 N aqueous NaOH and dilute with ethyl acetate (10.0 mL). Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate (10.0 mL × 3). Separate the organic layer, wash with water, and then with brine. Dry the organic layer over anhydrous sodium sulfate. Evaporate the solvent to obtain 0.6 g of the crude product (yield 95.0%). C 12 H 12 The MS(ESI) mass of ClFN2O was calculated to be 254.69; m / z was 255.0 [M+H] + .

[0473] Step 4: Synthesis of HBS-054-065: Dissolve compound HBS-054-064 (0.6 g, 2.36 mmol) in dry DMF (5.0 mL). Add NaH (0.11 g, 4.72 mmol) under ice-cooling. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed the formation of the desired product, with m / z of 219.0. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc: hexane, gradient. Obtain 0.46 g of the solid product (yield 88.0%). C 12 H 11 The MS(ESI) mass of FN2O was calculated to be 218.23; m / z was 219.0 [M+H] + .

[0474] Step 5: Synthesis of HBS-054-071: Dissolve compound HBS-054-065 (0.46 g, 2.11 mmol) in DCM (7.0 mL). Add NBS (0.41 g, 2.32 mmol), and stir the reaction mixture at room temperature for 16 h. LCMS data shows the formation of the desired product with m / z of 298.0. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc: hexane, gradient. Obtain 0.25 g of the product (yield 40.0%). C 12 H 10 The MS (ESI) mass of BrFN2O is calculated to be 297.12; m / z is 298.0 [M+H] + 。

[0475] Step 6: Synthesis of HBS-054-088: Dissolve compound HBS-054-071 (1.15 g, 3.85 mmol) in anhydrous THF (20.0 mL) under N2 atmosphere. Cool the reaction mixture to -78.0 °C, and add a solution of 1.6 M n-BuLi in hexane (4.81 mL, 7.7 mmol) to the reaction mixture. Stir the reaction mixture at -78.0 °C for 30.0 min. Bubble dry CO2 gas through the reaction mixture at -65 °C, and gradually warm the reaction mixture to room temperature. LCMS data shows the formation of the desired product with m / z of 263.0, a debrominated byproduct, and some unknown products. Quench the reaction mixture with water and extract with ethyl acetate. Separate the ethyl acetate layer and recover the debrominated product. Acidify the aqueous layer with 2 M HCl solution to obtain a precipitate. Filter and dry the precipitate to obtain 0.6 g of the solid product (yield 60.0%). C 13 H 11 The MS (ESI) mass of FN2O3 is calculated to be 262.24; m / z is 263.0 [M+H] + 。

[0476]

[0477] Step 1: Synthesis of HBS-039-188: 1-Ethynyl-2-fluorobenzene (1.0 g, 8.33 mmol) was dissolved in anhydrous THF (10.0 mL). n-BuLi (10.4 mL, 16.65 mmol) was added at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h. Ethyl chloroformate (3.8 mL, 40.0 mmol) was added at -78 °C, and the reaction mixture was gradually warmed to ambient temperature. LCMS data showed the formation of the product, with m / z of 193.0. The reaction mixture was diluted with aqueous NH4Cl solution, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product. 1.6 g of the crude product was obtained (quantitative yield). C 11 The MS (ESI) mass of H9FO2 was calculated to be 192.19; m / z was 193.0 [M+H] + .

[0478] Step 2: Synthesis of HBS-039-189: Compound HBS-039-188 (1.6 g, 8.33 mmol) and 1-aminopyridine iodide (1.85 g, 8.33 mmol) were dissolved in anhydrous DMF (15.0 mL). Anhydrous K2CO3 (2.88 g, 20.81 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 285.1. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product. The crude product was purified by column chromatography, mobile phase: EtOAc: hexane, gradient. 1.56 g of the product was obtained (yield 66.0%). C 16 H 13 The MS (ESI) mass of HFN2O2 was calculated to be 284.29; m / z was 285.1 [M+H] + .

[0479] Step 3: Synthesis of HBS-039-192: Compound HBS-039-189 (1.56 g, 5.5 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (16.5 mL, 16.5 mmol) was added, and the reaction mixture was refluxed for 12 h. LCMS showed the formation of the product, with m / z of 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL × 3) to obtain 1.3 g of the solid product (yield 92.3%). C 14 The MS (ESI) mass of H9FN2O2 was calculated to be 256.23; m / z was 257.0 [M+H]+ .

[0480]

[0481] Step 1: Synthesis of HBS-055-009: Dissolve 2-Boc-hexahydro-pyrrolo[3,4-c]pyrrole (0.3 g, 1.41 mmol) in IPA (10.0 mL). Add anhydrous K2CO3 (0.97 g, 7.07 mmol), and then add 2,5-dichlorobenzoxazole (0.38 g, 1.99 mmol). Stir the reaction mixture at 80 °C for 16 h. LCMS data showed the formation of the product, with m / z of 364.2. Filter the reaction mixture at room temperature and wash with ethyl acetate. Concentrate the filtrate to obtain the crude product. Purify the crude product through an ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.27 g of the product (yield 52.5%). C 18 H 22 The MS (ESI) mass of ClN3O3 was calculated to be 363.84; m / z was 364.2 [M+H] + .

[0482] Step 2: Synthesis of HBS-055-011: Dissolve compound HBS-055-009 (0.27 g, 0.74 mmol) in anhydrous dioxane (15.0 mL). Add a solution of 2.0 M HCl in diethyl ether (1.5 mL, 2.97 mmol), and stir the reaction mixture at 55 °C for 6 h. LCMS data showed the formation of the product, with m / z of 264.1. Cool the reaction mixture to ambient temperature and filter to obtain the solid product (0.25 g, quantitative yield). C 13 H 14 The MS (ESI) mass of ClN3O was calculated to be 263.7; m / z was 264.1 [M+H] + .

[0483]

[0484] Step 1: Synthesis of HBS-039-198: 2-Fluoroacetophenone (5.0 g, 36.19 mmol) was added dropwise to a solution of NaOMe (1.25 g of Na in 25.0 mL of methanol). The reaction mixture was stirred at ambient temperature for 30.0 min. A solution of diethyl oxalate (5.81 g, 39.81 mmol) in anhydrous methanol (25.0 mL) was added, and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the desired product, with m / z of 225.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in cold water and acidified with 2.0 M aqueous HCl. The precipitate was filtered and dried to obtain 8.62 g of the crude product. C 11 The MS (ESI) mass of H9FO4 was calculated to be 224.19; m / z was 225.0 [M+H] + .

[0485] Step 2: Synthesis of HBS-039-200: Compound HBS-039-198 (8.62 g, 36.19 mmol) was dissolved in IPA (100.0 mL). Hydrazine monohydrate (2.1 mL, 43.4 mmol) was added, and the reaction mixture was heated to reflux for 3 h. LCMS data showed the formation of the desired product, with m / z of 221.0, and the formation of a hydrolysis by-product, with m / z of 207.0. The reaction mixture was cooled to ambient temperature to obtain a precipitate. The precipitate was filtered to obtain 7.19 g of the crude product (yield 90.2%). C 11 The MS (ESI) mass of H9FN2O2 was calculated to be 220.2; m / z was 221.0 [M+H] + . C 10 The MS (ESI) mass of H7FN2O2 was calculated to be 206.17; m / z was 207.0 [M+H] + .

[0486] Step 3: Synthesis of HBS-055-002: The crude product of compound HBS-039-200 (7.19 g, 32.65 mmol) was dissolved in anhydrous methanol (100.0 mL). Concentrated sulfuric acid (4.0 mL) was added, and the reaction mixture was heated to reflux for 24 h. LCMS data showed the formation of the desired product, with m / z of 221.0. The reaction mixture was cooled to ambient temperature and neutralized with saturated aqueous sodium bicarbonate to obtain a precipitate. The precipitate was filtered and dried to obtain 7.19 g of the solid product (quantitative yield). C 11 The MS (ESI) mass of H9FN2O2 was calculated to be 220.2; m / z was 221.0 [M+H] + .

[0487] Step 4: Synthesis of HBS-055-004: Dissolve compound HBS-055-002 (7.19 g, 32.65 mmol) in acetone (100.0 mL). Add K2CO3 (13.53 g, 97.95 mmol), and then add 1-bromo-2-chloroethane (13.5 mL, 163.3 mmol). Heat the reaction mixture at 65 °C for 24 h. LCMS data showed the formation of the desired product, m / z 283.0. Filter the reaction mixture and wash the solid with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc: hexane, gradient. Isolate 2.85 g of the product (yield 30.9%). C 13 H 12 The MS (ESI) mass of ClFN2O2 was calculated to be 282.7; m / z 283.0 [M+H] + 。

[0488] Step 5: Synthesis of HBS-055-007: Dissolve compound HBS-055-004 (2.85 g, 10.1 mmol) in dry THF (25.0 mL). Cool the reaction mixture in an ice bath at 0 °C. Add a 1.0 M solution of DIBAL in hexane (25.2 mL, 25.2 mmol). Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed the formation of the desired product, m / z 255.1. Quench the reaction mixture with aqueous NH4Cl and dilute with ethyl acetate (100.0 mL). Filter the reaction mixture through a bed of celite and wash with ethyl acetate. Separate the organic layer and wash with brine. Dry the organic layer over anhydrous sodium sulfate. Evaporate the solvent to obtain 2.57 g of the crude product (quantitative yield). C 12 H 12 The MS (ESI) mass of ClFN2O was calculated to be 254.69; m / z 255.0 [M+H] + 。

[0489] Step 6: Synthesis of HBS-055-008: Dissolve compound HBS-055-007 (2.57 g, 10.1 mmol) in dry DMF (20.0 mL). Add 60.0% NaH in mineral oil (0.81 g, 20.2 mmol) under ice cooling. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed the formation of the desired product, m / z 219.1. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc: hexane, gradient. Obtain 1.17 g of the solid product (yield 53.2%). C 12H 11 The MS (ESI) mass of FN2O was calculated to be 218.23; m / z was 219.1 [M+H] + 。

[0490] Step 7: Synthesis of HBS-055-010: Dissolve compound HBS-055-008 (1.17 g, 5.36 mmol) in DCM (15.0 mL). Add NBS (1.05 g, 5.9 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the desired product, m / z 299.0. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc: hexane, gradient. Obtain 1.27 g of the product (yield 79.7%). C 12 H 10 The MS (ESI) mass of BrFN2O was calculated to be 297.12; m / z was 299.0 [M+H] + 。

[0491] Step 8: Synthesis of HBS-055-013: Dissolve compound HBS-055-010 (1.27 g, 4.27 mmol) in anhydrous THF (15.0 mL) under N2 atmosphere. Cool the reaction mixture to -78.0 °C. Add a solution of 1.6 M n-BuLi in hexane (5.33 mL, 8.54 mmol), and stir the reaction mixture at -78.0 °C for 30.0 min. Bubble dry CO2 gas through the reaction mixture at -65 °C, and gradually warm the reaction mixture to room temperature. LCMS data showed the formation of the desired product, m / z 263.1, and the formation of a debrominated byproduct and some unknown products. Quench the reaction mixture with water and extract with ethyl acetate. Separate the ethyl acetate layer and recover the debrominated product. Acidify the aqueous layer with 2 M HCl solution to obtain a precipitate. Filter and dry the precipitate to obtain 0.84 g of a solid product (yield 75.0%). C 13 H 11 The MS (ESI) mass of FN2O3 was calculated to be 262.24; m / z was 263.1 [M+H] + 。

[0492]

[0493] Step 1: Synthesis of HBS-055-027: Dissolve intermediate HBS-039-192 (0.1 g, 0.39 mmol) in anhydrous DCM (4.0 mL). Add EDC.HCl (0.11 g, 0.59 mmol) and HOBt (0.079 g, 0.59 mmol), then add DIPEA (0.34 mL, 1.95 mmol). Stir the reaction mixture at ambient temperature for 10.0 min. Add a solution of (5R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester (0.097 g, 0.39 mmol) in DCM (1.0 mL) to the reaction mixture. Stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 487.2. Dilute the reaction mixture with saturated NaHCO3 solution. Extract the product with DCM. Separate the combined DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by the ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.1 g of the product (yield 52.7%). C 28 H 27 The MS (ESI) mass of FN4O3 is calculated to be 486.54; m / z is 487.2 [M+H] + 。

[0494] Step 2: Synthesis of HBS-055-028: Dissolve compound HBS-055-027 (0.1 g, 0.21 mmol) in ethyl acetate (5.0 mL). Add 20.0% Pd-OH / C (10.0 mg) and stir the reaction mixture at ambient temperature for 16 h under a hydrogen atmosphere. LCMS data shows the formation of the product, with m / z of 353.2. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Evaporate the filtrate under reduced pressure to obtain 72.0 mg of the crude product. The crude product is used in the next step without purification. C 20 H 21 The MS (ESI) mass of FN4O is calculated to be 352.41; m / z is 353.2 [M+H] + 。

[0495]

[0496] Step 1: Synthesis of HBS-055-113: (7R)-7-Methyl-1,4-diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 2.33 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (0.47 g, 2.57 mmol) were dissolved in anhydrous DMF (10.0 mL). Anhydrous K2CO3 (0.64 g, 4.66 mmol) was added, and the reaction mixture was stirred at 100 °C for 8 h. LCMS data showed the formation of the product with m / z of 360.1. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: EtOAc: hexane, gradient. 0.84 g of the product was obtained (quantitative yield). C 17 H 24 The MS (ESI) mass of F3N3O2 was calculated to be 359.39; m / z was 360.1 [M+H] + 。

[0497] Step 2: Synthesis of HBS-055-117: Compound HBS-055-113 (0.84 g, 2.33 mmol) was dissolved in anhydrous dioxane (10.0 mL). A solution of 4.0 M HCl in dioxane (2.33 mL, 9.32 mmol) was added, and the reaction mixture was stirred at 50 °C for 12 h. LCMS data showed the formation of the product with m / z of 259.27. The reaction mixture was cooled to ambient temperature and concentrated to obtain a solid product (0.75 g, yield 87.3%). C 12 H 16 The MS (ESI) mass of F3N3 was calculated to be 259.27; m / z was 260.1 [M+H] + 。

[0498]

[0499] Step 1: Synthesis of HBS-062-029: Dissolve (7R)-7-methyl-1,4-diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 2.33 mmol) and 2,5-dichlorobenzoxazole (0.53 g, 2.79 mmol) in anhydrous DMF (8.0 mL). Add anhydrous K2CO3 (0.64 g, 4.66 mmol), and stir the reaction mixture at 100 °C for 16 h. LCMS data shows the formation of the product, with m / z of 366.1. Dilute the reaction mixture with water, and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by the ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.4 g of the product (yield 46.9%). C 18 H 24 The MS (ESI) mass of ClN3O3 is calculated to be 365.85; m / z is 366.1 [M+H] + 。

[0500] Step 2: Synthesis of HBS-062-031: Dissolve compound HBS-062-029 (0.4 g, 1.09 mmol) in anhydrous dioxane (10.0 mL). Add a solution of 4.0 M HCl in dioxane (0.82 mL, 3.28 mmol), and stir the reaction mixture at 50 °C for 8 h. LCMS data shows the formation of the product, with m / z of 266.1. Cool the reaction mixture to ambient temperature and concentrate to obtain the solid product (0.32 g, yield 86.4%). C 13 H 16 The MS (ESI) mass of ClN3O is calculated to be 265.74; m / z is 266.1 [M+H] + 。

[0501]

[0502] Step 1: Synthesis of HBS-062-005: Dissolve morpholine-3-carboxylic acid (1.0 g, 7.63 mmol) in water (6.0 mL). Add anhydrous NaNO2 (0.79 g, 11.44 mmol), and cool the reaction mixture in an ice bath at 0 °C. Add 12.0 M HCl aqueous solution (1.27 mL, 15.26 mmol), and gradually warm the reaction mixture to ambient temperature over 16 h. LCMS data shows the formation of the product, with m / z of 161.1. Extract the reaction mixture with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Obtain 1.22 g of the product (quantitative yield). The MS (ESI) mass of C5H8N2O4 is calculated to be 160.13; m / z is 161.1 [M+H]+ .

[0503] Step 2: Synthesis of HBS-062-007: Dissolve compound HBS-062-005 (1.22 g, 7.63 mmol) in anhydrous toluene (10.0 mL). Cool the reaction mixture in an ice bath at 0 °C. Add anhydrous TFA (1.6 mL, 11.44 mmol), and gradually warm the reaction mixture to ambient temperature over 16 h. LCMS data shows the formation of the product with m / z of 143.1. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Obtain 1.02 g of the product (yield 94.1%). The MS (ESI) mass of C5H6N2O3 is calculated to be 142.11; m / z is 143.1 [M+H] + .

[0504] Step 3: Synthesis of HBS-062-009: Dissolve compound HBS-062-007 (1.0 g, 7.18 mmol) in xylene (10.0 mL). Add ethyl propiolate (0.95 mL, 9.33 mmol), and heat the reaction mixture at 120 °C for 6 h. LCMS data shows the formation of the product with m / z of 197.1. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Obtain 1.0 g of the product (yield 71.0%). The MS (ESI) mass of C9H 12 N2O3 is calculated to be 196.20; m / z is 197.1 [M+H] + .

[0505] Step 4: Synthesis of HBS-062-010: Dissolve compound HBS-062-009 (1.0 g, 5.1 mmol) in DCM (15.0 mL). Add NBS (1.0 g, 5.61 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product with m / z of 275.0. Dilute the reaction mixture with water and extract the product with DCM. Separate the combined DCM layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Obtain 1.4 g of the product (yield 99.7%). The MS (ESI) mass of C9H 11 BrN2O3 is calculated to be 275.1; m / z is 275.0 [M+H] + .

[0506] Step 5: Synthesis of HBS-052-011: Dissolve compound HBS-062-010 (0.4 g, 1.45 mmol) and phenylboronic acid (0.27 g, 2.18 mmol) in a mixture of dioxane / water (9:1 v / v mL). Add anhydrous K2CO3 (0.6 g, 4.36 mmol), and then add Pd(dppf)Cl2.DCM2 (0.06 g, 0.073 mmol). Stir the reaction mixture at 100 °C for 6 h under a N2 atmosphere. LCMS data shows the formation of the product with m / z of 273.1. Filter the reaction mixture through a celite bed and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Obtain 0.39 g of the product (yield 95.5%). C 15 H 16 The MS(ESI) mass of N2O3 is calculated to be 272.3; m / z is 273.1 [M+H] + 。

[0507] Step 6: Synthesis of HBS-062-013: Dissolve compound HBS-062-011 (0.39 g, 1.43 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH solution (4.3 mL, 4.3 mmol), and reflux the reaction mixture for 6 h. LCMS data shows the formation of the product with m / z of 245.1. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.23 g of the solid product (yield 65.8%). C 13 H 12 The MS(ESI) mass of N2O3 is calculated to be 244.25; m / z is 245.1 [M+H] + 。

[0508]

[0509] Step 1: Synthesis of HBS-055-191: Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1.0 g, 6.40 mmol) was dissolved in anhydrous acetonitrile (15.0 mL). Anhydrous K2CO3 (3.54 g, 25.62 mmol) was added, and the reaction mixture was stirred at ambient temperature for 15.0 min. 1,3-Dibromopropane (0.72 mL, 7.05 mmol) was added, and the reaction mixture was heated to reflux for 6 h. LCMS data showed the formation of the product, with m / z of 197.1. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 1.03 g of the product was obtained (yield 81.97%). The MS (ESI) mass of C9H 12 N2O3 was calculated to be 196.20; m / z was 197.1 [M+H] + .

[0510] Step 2: Synthesis of HBS-055-192: Compound HBS-055-191 (1.03 g, 5.25 mmol) was dissolved in DCM (15.0 mL). NBS (0.93 g, 5.25 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 275.0. The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. 1.44 g of the product was obtained (quantitative yield). The MS (ESI) mass of C9H 11 BrN2O3 was calculated to be 275.1; m / z was 275.0 [M+H] + .

[0511] Step 3: Synthesis of HBS-055-194: Dissolve compound HBS-055-192 (0.4 g, 1.45 mmol) and phenylboronic acid (0.27 g, 2.18 mmol) in a mixture of dioxane / water (9:1 v / v mL). Add anhydrous K2CO3 (0.6 g, 4.36 mmol), and then add Pd(dppf)Cl2.DCM2 (0.06 g, 0.073 mmol). Stir the reaction mixture at 100 °C for 6 h under a N2 atmosphere. LCMS data showed the formation of the product with m / z of 273.1. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with mobile phase: EtOAc: hexane, gradient. Obtain 0.37 g of the product (yield 94.7%). C 15 H 16 The MS (ESI) mass of N2O3 was calculated to be 272.3; m / z was 273.1 [M+H] + 。

[0512] Step 4: Synthesis of HBS-055-197: Dissolve compound HBS-055-194 (0.37 g, 1.38 mmol) in MeOH (5.0 mL). Add 1.0 N aqueous NaOH solution (4.1 mL, 4.1 mmol), and reflux the reaction mixture for 6 h. LCMS data showed the formation of the product with m / z of 245.1. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.26 g of the solid product (yield 77.3%). C 13 H 12 The MS (ESI) mass of N2O3 was calculated to be 244.25; m / z was 245.1 [M+H] + 。

[0513]

[0514] Step 1: Synthesis of HBS-062-020: Dissolve 1-ethynylpyrimidine (1.0 g, 9.61 mmol) in anhydrous THF (12.0 mL). Add n-BuLi (7.2 mL, 11.53 mmol) at -78 °C, and stir the reaction mixture at -78 °C for 30.0 min. Add ethyl chloroformate (1.4 mL, 14.41 mmol) at -78 °C, and gradually warm the reaction mixture to ambient temperature within 3 h. LCMS data shows the formation of the product, with m / z of 177.1. Dilute the reaction mixture with aqueous NH4Cl solution, and extract the product with ethyl acetate. Separate the combined ethyl acetate layers, and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. Obtain 0.78 g of the product (yield 46.1%). The MS (ESI) mass of C9H8N2O2 is calculated as 176.17; m / z is 177.1 [M+H] + 。

[0515] Step 2: Synthesis of HBS-062-023: Dissolve compound HBS-062-020 (0.75 g, 4.25 mmol) and 1-aminopyridine iodide (1.13 g, 5.11 mmol) in anhydrous DMF (10.0 mL). Add anhydrous K2CO3 (1.47 g, 10.63 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 269.1. Dilute the reaction mixture with water, and extract the product with ethyl acetate. Separate the combined ethyl acetate layers, and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: EtOAc:hexane, gradient. Obtain 0.48 g of the product (yield 42.1%). The MS (ESI) mass of C 14 H 12 N4O2 is calculated as 268.27; m / z is 269.1 [M+H] + 。

[0516] Step 3: Synthesis of HBS-062-028: Dissolve compound HBS-062-023 (0.28 g, 1.04 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH solution (2.1 mL, 2.09 mmol), and reflux the reaction mixture for 6 h. LCMS shows the formation of the product, with m / z of 241.1. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water, and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.22 g of the solid product (yield 87.5%). C12 The MS(ESI) mass of H8N4O2 was calculated to be 240.22; m / z was 241.1 [M+H] + 。

[0517]

[0518] Step 1: Synthesis of HBS-062-022: Dissolve 1-ethynylpyridine (2.0 g, 19.4 mmol) in anhydrous THF (15.0 mL). Add n-BuLi (14.6 mL, 23.3 mmol) at a temperature of -78 °C, and stir the reaction mixture at -78 °C for 30.0 min. Add ethyl chloroformate (2.2 mL, 23.3 mmol) at a temperature of -78 °C, and gradually warm the reaction mixture to ambient temperature within 3 h. LCMS data showed the formation of the product, with m / z of 176.1. Dilute the reaction mixture with an aqueous NH4Cl solution, and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: ethyl acetate: hexane, gradient. Obtain 1.29 g of the product (yield 38.0%). C 10 The MS(ESI) mass of H9NO2 was calculated to be 175.18; m / z was 176.1 [M+H] + 。

[0519] Step 2: Synthesis of HBS-062-025: Dissolve compound HBS-062-022 (0.5 g, 2.85 mmol) and 1-aminopyridine iodide (0.76 g, 3.43 mmol) in anhydrous DMF (8.0 mL). Add anhydrous K2CO3 (0.79 g, 5.71 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 268.1. Dilute the reaction mixture with water, and extract the product with ethyl acetate. Separate the combined ethyl acetate layers, dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: ethyl acetate: hexane and DCM: methanol, gradient. Obtain 0.57 g of the product (yield 74.6%). C 15 H 13 The MS(ESI) mass of H N3O2 was calculated to be 267.28; m / z was 268.1 [M+H] + 。

[0520] Step 3: Synthesis of HBS-062-030: Dissolve compound HBS-062-025 (0.56 g, 2.1 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH solution (4.2 mL, 4.19 mmol), and reflux the reaction mixture for 4 h. LCMS shows the formation of the product, with m / z of 240.1. Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.26 g of the solid product (yield 50.9%). C 13 The MS (ESI) mass of H9N3O2 is calculated to be 239.23; m / z is 240.1 [M+H] + .

[0521]

[0522] Step 1: Synthesis of HBS-062-019: Dissolve ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.44 mmol) in DCM (15.0 mL). Cool the reaction mixture in an ice bath at 0 °C. Add NBS (1.38 g, 7.73 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product, with m / z of 236.0. Dilute the reaction mixture with saturated aqueous NaHCO3 solution. Extract the product with DCM. Separate the combined DCM layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by the ISCO combi-flash system, mobile phase: DCM: methanol, gradient. Obtain 0.62 g of the product (yield 41.1%). The MS (ESI) mass of C6H8BrN3O2 is calculated to be 234.05; m / z is 236.0 [M+H] + .

[0523] Step 2: Synthesis of HBS-062-021: Dissolve compound HBS-062-019 (0.62 g, 2.65 mmol) and 1,1,3,3-tetraethoxypropane (0.76 mL, 3.18 mmol) in anhydrous acetic acid (10.0 mL). Heat the reaction mixture at 70 °C for 24 h. LCMS data shows the formation of the product, with m / z of 272.0. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Dilute the crude product with water and neutralize with saturated aqueous NaHCO3 solution. Filter and dry the precipitate to obtain 0.3 g of the product (yield 41.9%). The MS (ESI) mass of C9H8BrN3O2 is calculated to be 270.08; m / z is 272.0 [M+H] + .

[0524] Step 3: Synthesis of HBS-062-024: Dissolve compound HBS-062-021 (0.3 g, 1.11 mmol) and phenylboronic acid (0.2 g, 1.67 mmol) in a mixture of dioxane / water (7:1 v / v mL). Add anhydrous K2CO3 (0.46 g, 3.33 mmol), and then add Pd(dppf)Cl2.DCM2 (0.045 g, 0.056 mmol). Stir the reaction mixture at 100 °C for 4 h under a N2 atmosphere. LCMS data shows the formation of the product with m / z of 268.1. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Obtain 0.25 g of the product (yield 84.2%). C 15 H 13 The MS (ESI) mass of N3O2 is calculated to be 267.28; m / z is 268.1 [M+H] + .

[0525] Step 4: Synthesis of HBS-062-027: Dissolve compound HBS-062-024 (0.25 g, 0.94 mmol) in MeOH (6.0 mL). Add 1.0 N aqueous NaOH solution (1.9 mL, 1.87 mmol), and reflux the reaction mixture for 8 h. LCMS data shows the formation of the product with m / z of 240.1. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.11 g of the solid product (yield 49.2%). C 13 The MS (ESI) mass of H9N3O2 is calculated to be 239.23; m / z is 240.1 [M+H] + .

[0526]

[0527] Step 1: Synthesis of HBS-062-033: Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.43 mmol) and 1,1,3,3-tetraethoxypropane (1.85 mL, 7.72 mmol) were dissolved in anhydrous acetic acid (8.0 mL). The reaction mixture was heated at 70 °C for 24 h. LCMS data showed the formation of the product, m / z 192.1.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM: methanol, gradient. 0.98 g of the product was obtained (yield 79.7%). The MS (ESI) mass of C9H9N3O2 was calculated as 191.19; m / z 192.1 [M+H] + .

[0528] Step 2: Synthesis of HBS-062-037: Compound HBS-062-033 (0.98 g, 5.13 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled to 0 °C in an ice bath. NBS (1.0 g, 5.64 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, m / z 272.0. The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give 1.38 g of the crude product (quantitative yield). The MS (ESI) mass of C9H8BrN3O2 was calculated as 270.08; m / z 272.0 [M+H] + .

[0529] Step 3: Synthesis of HBS-062-038: Compound HBS-062-037 (0.4 g, 1.48 mmol) and phenylboronic acid (0.27 g, 2.22 mmol) were dissolved in a mixture of dioxane / water (8:1 v / v mL). Anhydrous K2CO3 (0.61 g, 4.44 mmol) was added, followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.074 mmol). The reaction mixture was stirred at 100 °C for 6 h under a N2 atmosphere. LCMS data showed the formation of the product, m / z 268.1. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 0.32 g of the product was obtained (yield 80.1%). C 15 H 13The MS(ESI) mass of N3O2 was calculated to be 267.28; m / z was 268.1 [M+H] + 。

[0530] Step 4: Synthesis of HBS-062-041: Dissolve compound HBS-062-038 (0.32 g, 1.19 mmol) in MeOH (5.0 mL). Add 1.0 N aqueous NaOH solution (2.4 mL, 2.37 mmol), and reflux the reaction mixture for 6 h. LCMS data showed the formation of the product, with m / z of 240.1. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.18 g of the solid product (yield: 65.9%). C 13 The MS(ESI) mass of C9H9N3O2 was calculated to be 239.23; m / z was 240.1 [M+H] + 。

[0531]

[0532] Step 1: Synthesis of HBS-062-091: Dissolve (7R)-7-methyl-1,4-diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 2.33 mmol) and 2-chloro-4,6-dimethylpyrimidine (0.4 g, 2.8 mmol) in anhydrous DMF (8.0 mL). Add anhydrous K2CO3 (0.64 g, 4.66 mmol), and stir the reaction mixture at 90 °C for 16 h. LCMS data showed the formation of the product, with m / z of 321.1. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by the ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.75 g of the product (quantitative yield). C 17 H 28 The MS(ESI) mass of C12H12N4O2 was calculated to be 320.43; m / z was 321.2 [M+H] + 。

[0533] Step 2: Synthesis of HBS-062-092: Dissolve compound HBS-062-091 (0.75 g, 2.33 mmol) in anhydrous dioxane (6.0 mL). Add a solution of 4.0 M HCl in dioxane (2.91 mL, 11.65 mmol), and stir the reaction mixture at 50 °C for 8 h. LCMS data showed the formation of the product, with m / z of 221.2. Cool the reaction mixture to ambient temperature and concentrate to obtain the solid product (0.69 g, yield: 89.8%). C10 H 20 The MS (ESI) mass of N4 was calculated to be 220.31; m / z was 221.2 [M+H] + 。

[0534]

[0535] Step 1: Synthesis of HBS-062-111: Dissolve (7R)-7-methyl-1,4-diazepane-1-carboxylic acid tert-butyl ester (0.73 g, 3.4 mmol) and 2-iodo-5-methoxypyridine (0.8 g, 3.4 mmol) in anhydrous 1,4-dioxane (2.0 mL). Add anhydrous t-BuOK (0.95 g, 8.5 mmol), and stir the reaction mixture under N2 atmosphere. Add Pd2(dba)3 (0.16 g, 0.17 mmol) and X-Phos (0.16 g, 0.34 mmol), and heat the reaction mixture to reflux for 24 h. Add reagents to consume the starting materials and drive the reaction to completion. LCMS data showed the formation of the product, with m / z of 322.1. Filter the reaction mixture through diatomaceous earth. Concentrate the filtrate to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: DCM: methanol, gradient. Obtain 0.18 g of the product (yield 16.5%). C 17 H 27 The MS (ESI) mass of N3O3 was calculated to be 321.41; m / z was 322.2 [M+H] + 。

[0536] Step 2: Synthesis of HBS-062-119: Dissolve compound HBS-062-111 (0.18 g, 0.56 mmol) in anhydrous dioxane (4.0 mL). Add a solution of 4.0 M HCl in dioxane (0.7 mL, 2.8 mmol), and stir the reaction mixture at 50 °C for 8 h. LCMS data showed the formation of the product, with m / z of 222.2. Cool the reaction mixture to ambient temperature and concentrate to obtain the product (0.18 g, quantitative yield). C 12 H 19 The MS (ESI) mass of N3O was calculated to be 221.30; m / z was 222.2 [M+H] + 。

[0537]

[0538] Step 1: Synthesis of HBS-062-135: Dissolve (7R)-7-methyl-1,4-diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 2.33 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (0.35 mL, 2.8 mmol) in anhydrous DMF (8.0 mL). Add anhydrous K2CO3 (0.64 g, 4.66 mmol), and heat the reaction mixture at 90 °C for 12 h. LCMS data shows the formation of the product, with m / z of 305.0. Dilute the reaction mixture with water and extract the product with ethyl acetate. Separate the combined ethyl acetate layers and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO combi-flash system, mobile phase: EtOAc: hexane, gradient. Obtain 0.74 g of the product (yield 88.1%). C 16 H 23 The MS (ESI) mass of F3N4O2 is calculated to be 360.37; m / z is 305.0 [M-tButyl]+

[0539] Step 2: Synthesis of HBS-062-136: Dissolve compound HBS-062-135 (0.74 g, 2.05 mmol) in anhydrous dioxane (10.0 mL). Add a solution of 4.0 M HCl in dioxane (2.6 mL, 10.25 mmol), and stir the reaction mixture at 50 °C for 8 h. LCMS data shows the formation of the product, with m / z of 261.0. Cool the reaction mixture to ambient temperature and concentrate to obtain the solid product (0.76 g, yield 91.3%). C 11 H 15 The MS (ESI) mass of F3N4 is calculated to be 260.26; m / z is 261.0 [M+H] + 。

[0540]

[0541] Step 1: Synthesis of HBS-062-033: Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.43 mmol) and 1,1,3,3-tetraethoxypropane (1.85 mL, 7.72 mmol) were dissolved in anhydrous acetic acid (8.0 mL). The reaction mixture was heated at 70 °C for 24 h. LCMS data showed the formation of the product, m / z 192.1.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM: methanol, gradient. 0.98 g of the product was obtained (yield 79.7%). The MS (ESI) mass of C9H9N3O2 was calculated as 191.19; m / z 192.1 [M+H] + .

[0542] Step 2: Synthesis of HBS-062-037: Compound HBS-062-033 (0.98 g, 5.13 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled to 0 °C in an ice bath. NBS (1.0 g, 5.64 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, m / z 272.0. The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give 1.38 g of the crude product (quantitative yield). The MS (ESI) mass of C9H8BrN3O2 was calculated as 270.08; m / z 272.0 [M+H] + .

[0543] Step 3: Synthesis of HBS-062-183: Dissolve compound HBS-062-037 (0.95 g, 3.52 mmol) and 2-(tributyl stannyl)-pyridine (1.94 g, 5.28 mmol) in 1,4-dioxane (12.0 mL). Add Pd(PPh3)4 (0.41 g, 0.35 mmol), and heat the reaction mixture at 115 °C for 18 h under a N2 atmosphere. Add 0.05 equivalent of Pd(PPh3)4 to consume the starting materials. LCMS data shows the formation of the product with m / z of 269.0. Filter the reaction mixture through a bed of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by an ISCO combi-flash chromatography system with mobile phase: EtOAc: hexane, gradient. Obtain 0.725 g of the product (yield 76.8%). C 14 H 12 The MS (ESI) mass of C10H8N4O2 is calculated to be 268.27; m / z is 269.0 [M+H] + .

[0544] Step 4: Synthesis of HBS-062-186: Dissolve compound HBS-062-183 (0.73 g, 2.7 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH solution (5.4 mL, 5.4 mmol), and reflux the reaction mixture for 6 h. LCMS data shows the formation of the product with m / z of 241.1. Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (2.0 mL × 3) to obtain 0.52 g of the product (yield 80.2%). C 12 The MS (ESI) mass of C8H8N4O2 is calculated to be 240.22; m / z is 241.1 [M+H] + .

[0545] IV. Synthesis of Example Compounds

[0546] A. Example 1:

[0547]

[0548] Synthesis of Compound Example 1: Intermediate HBS-037-163 (0.025 g, 0.1 mmol) was dissolved in anhydrous DCM (2.5 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). The reaction mixture was stirred at ambient temperature for 10.0 min. Intermediate HBS-037-188 (0.038 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 472.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product, which was purified by an ISCO combi-flash system with mobile phase: EtOAc: hexane, gradient. 0.05 g of the product was obtained (quantitative yield). C 26 H 22 The MS (ESI) mass of ClN5O2 was calculated to be 471.9; m / z was 472.2 [M+H] + 。

[0549] B. Example 2:

[0550]

[0551] Synthesis of Compound Example 2: HBS-037-054 (0.026 g, 0.1 mmol) was dissolved in anhydrous DCM (2.5 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). The reaction mixture was stirred at ambient temperature for 10.0 min. HBS-037-188 (0.038 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 478.2. The reaction mixture was diluted with saturated NaHCO3 solution and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product, which was purified by an ISCO combi-flash system with mobile phase: EtOAc: hexane, gradient. Pure Example 2 (0.019 g, 37.9% yield) was obtained. C 25 H 24 The MS (ESI) mass of ClN5O3 was calculated to be 477.9; m / z was 478.2 [M+H] + 。

[0552] C. Example 3:

[0553]

[0554] Synthesis of Compound Example 3: Dissolve intermediate HBS-037-193 (0.025 g, 0.1 mmol) in anhydrous DCM (2.5 mL). Add EDC.HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol), then add Et3N (0.15 mL, 1.0 mmol). Stir the reaction mixture at ambient temperature for 10.0 min. Add HBS-037-188 (0.038 g, 0.1 mmol) to the reaction mixture. Stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product with m / z of 472.2. Dilute the reaction mixture with saturated NaHCO3 solution and extract the product with DCM. Separate the combined DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product, which is purified by an ISCO combi-flash system with mobile phase: EtOAc: hexane, gradient. Obtain pure Example 3 (0.034 g, yield 68.6%). C 26 H 22 The MS (ESI) mass of ClN5O2 is calculated to be 471.9; m / z is 472.2 [M+H] + 。

[0555] D. Example 4:

[0556]

[0557] Synthesis of Compound Example 4: Dissolve HBS-039-002 (0.037 g, 0.11 mmol) in anhydrous DMF (2.5 mL). Add triethylamine (0.046 mL, 0.33 mmol), then add 2,5-dichloro-1,3-benzoxazole (0.021 g, 0.11 mmol). Stir the reaction mixture at 60 °C for 16 h. LCMS data shows the formation of the product with m / z of 486. Dilute the reaction mixture with water and extract the product with ethyl acetate. Wash the combined ethyl acetate layers with water and then with brine. Separate the organic layer and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product, which is purified by an ISCO combi-flash chromatography system with mobile phase: EtOAc: hexane, gradient. Obtain pure Example 4 (0.038 g, yield 69.9%). C 27 H 24 The MS (ESI) mass of ClN5O2 is calculated to be 485.96; m / z is 486.0 [M+H] + 。

[0558] E. Example 5 and Example 6:

[0559]

[0560] Synthesis of Compound Example 5 and Example 6: Intermediate HBS-039-011A / B (0.022 g, 0.07 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.03 mL, 0.2 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.012 g, 0.07 mmol). The reaction mixture was stirred at 60 °C for 16 h. LCMS data showed the formation of a mixture of two products with m / z 486 and m / z 490. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a crude product mixture of Example 5 and Example 6. The mixture was purified by an ISCO combi-flash chromatography system with mobile phase: EtOAc: hexane, gradient, and then by prep-TLC plates with mobile phase: EtOAc: hexane (60:40, v / v mL). 0.0053 g of product Example 5 with m / z 486.2 (yield 16.7%) and 0.014 g of product Example 6 with m / z 490.2 (yield 44.1%) were obtained. C 27 H 24 The MS (ESI) mass of ClN5O2 was calculated as 485.96; m / z 486.2 [M+H] + C 27 H 28 The MS (ESI) mass of ClN5O2 was calculated as 490.0; m / z 490.2 [M+H] + .

[0561] F. Example 7:

[0562]

[0563] Synthesis of Compound Example 7: Dissolve HBS-039-010 (0.014 g, 0.04 mmol) in anhydrous DMF (2.5 mL). Add triethylamine (0.017 mL, 0.12 mmol), and then add 2,5-dichloro-1,3-benzoxazole (0.008 g, 0.042 mmol). Stir the reaction mixture at 60 °C for 16 h. LCMS data showed the formation of the product, with m / z of 492.2. Dilute the reaction mixture with water and extract the product with ethyl acetate. Wash the combined ethyl acetate layers with water and then with brine. Separate the organic layer and dry it over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product, which was purified by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient. Obtain pure Example 7 (12.4 mg, yield 60.4%). C 26 H 26 The MS (ESI) mass of ClN5O3 is calculated to be 491.97; m / z is 492.2 [M+H] + 。

[0564] G. Example 8:

[0565]

[0566] Synthesis of Compound Example 8: Dissolve intermediate HBS-039-024 (0.032 g, 0.1 mmol) in anhydrous DMF (2.5 mL). Add triethylamine (0.04 mL, 0.29 mmol), and then add 2,5-dichloro-1,3-benzoxazole (0.018 g, 0.1 mmol). Stir the reaction mixture at 60 °C for 16 h. LCMS data showed the formation of the product, with m / z of 486.2. Dilute the reaction mixture with water and extract the product with ethyl acetate. Wash the combined ethyl acetate layers with water and then with brine. Separate the organic layer and dry it over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product, which was purified by a prep-TLC plate with the mobile phase: EtOAc: hexane (50:50 v / v mL). Obtain pure Example 8 (0.032 g, yield 68.8%). C 27 H 24 The MS (ESI) mass of ClN5O2 is calculated to be 485.96; m / z is 486.2 [M+H] + 。

[0567] H. Example 9:

[0568]

[0569] Synthesis of Compound Example 9: Intermediate HBS-039-025 (0.017 g, 0.05 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.021 mL, 0.15 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.009 g, 0.05 mmol). The reaction mixture was stirred at 60 °C for 16 h. LCMS data showed the formation of the product with m / z 490.2. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then with brine. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product, which was purified by prep-TLC plate with mobile phase: EtOAc: hexane (80:20 v / v mL). Example 9 (0.009 g, yield 35.7%) was obtained. C 27 H 28 The MS (ESI) mass of ClN5O2 was calculated to be 490.0; m / z 490.2 [M+H] + 。

[0570] I. Example 10:

[0571]

[0572] Synthesis of Compound Example 10: Intermediate HBS-039-055 (0.07 g, 0.22 mmol) was dissolved in anhydrous DMF (3.0 mL). DIPEA (0.11 mL, 0.65 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.049 g, 0.26 mmol). The reaction mixture was stirred at 60 °C for 8 h. LCMS data showed the formation of two products: m / z 486.2 (major) and m / z 490.2 (minor). The reaction mixture was diluted with water and the products were extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then with brine. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give a crude product mixture, which was purified by ISCO combi-flash chromatography system with mobile phase: EtOAc: hexane, gradient. 0.054 g of the product of Example 4 (yield 51.6%) and 0.015 g of the product of Example 10 (yield 14.1%) were obtained. C 27 H 24 The MS (ESI) mass of ClN5O2 was calculated to be 485.96; m / z 486.2 [M+H] + ,C 27 H 28 The MS (ESI) mass of ClN5O2 was calculated to be 490.0; m / z 490.2 [M+H] + 。

[0573] J. Example 11:

[0574]

[0575] Synthesis of Compound Example 11: HBS-039-010 (0.02 g, 0.06 mmol), 3-bromo-6-methoxypyridazine (0.024 g, 0.13 mmol) and Cs2CO3 (0.058 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc)2 (0.003 g, 0.012 mmol) and BINAP (0.015 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 16 h. LCMS data showed the formation of the product with m / z of 449.3. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by prep-TLC plate with the mobile phase: EtOAc: hexane (70:30 v / v mL). Example 11 (0.004 g, yield 18.2%) was obtained. C 24 H 28 The MS (ESI) mass of N6O3 was calculated to be 448.5; m / z was 449.3 [M+H] + 。

[0576] K. Example 12:

[0577]

[0578] Synthesis of Compound Example 12: HBS-039-010 (0.02 g, 0.06 mmol), 2-bromo-5-methoxypyridine (0.022 g, 0.12 mmol) and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc)2 (0.003 g, 0.012 mmol) and BINAP (0.015 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 5 h. LCMS data showed the formation of the product with m / z of 448.3. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product. The crude product was purified by prep-TLC plate with the mobile phase: EtOAc: hexane (50:50 v / v mL). Example 12 (0.005 g, yield 19.8%) was obtained. C 25 H 29 The MS (ESI) mass of N5O3 was calculated to be 447.5; m / z was 448.3 [M+H] + 。

[0579] L. Example 13:

[0580]

[0581] Synthesis of Compound Example 13: HBS-039-002 (0.02 g, 0.06 mmol), 3-bromo-6-methoxypyridazine (0.023 g, 0.12 mmol) and t-BuOK (0.017 g, 0.15 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc)2 (0.003 g, 0.012 mmol) and X-Phos (0.011 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by LCMS, and the reagents were added twice to consume the starting materials. LCMS data showed the formation of the product with m / z of 443.3. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product. The crude product was purified by prep-TLC plate with the mobile phase: EtOAc: hexane (35:65 v / v mL). Example 13 (0.011 g, yield 42.6%) was obtained. C 25 H 26 The MS (ESI) mass of C19H17N6O2 was calculated to be 442.5; m / z was 443.3 [M+H] + 。

[0582] M. Example 14:

[0583]

[0584] Synthesis of Compound Example 14: HBS-039-002 (0.02 g, 0.06 mmol), 2-bromo-5-methoxypyridine (0.022 g, 0.12 mmol) and t-BuOK (0.017 g, 0.15 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc)2 (0.003 g, 0.012 mmol) and X-Phos (0.011 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 6 h. LCMS data showed the formation of the product with m / z of 442.3. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by prep-TLC plate with the mobile phase: EtOAc: hexane (40:60 v / v mL). Example 14 (0.009 g, yield 33.3%) was obtained. C 26 H 27 The MS (ESI) mass of C19H17N5O2 was calculated to be 441.5; m / z was 442.3 [M+H] + 。

[0585] N. Example 15:

[0586]

[0587] Synthesis of Compound Example 15: HBS-039-002 (0.02 g, 0.06 mmol), 5-iodo-2-methoxypyridine (0.028 g, 0.12 mmol) and Cs2CO3 (0.058 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.011 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 6 h. The reaction progress was monitored by LCMS, and the reagents were added twice to consume the starting materials. LCMS data showed the formation of the product with m / z of 442.3. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 15 (0.01 g, yield 37.8%) was obtained. C 26 H 27 The MS (ESI) mass of N5O2 was calculated to be 441.5; m / z was 442.3 [M+H] + 。

[0588] O. Example 16:

[0589]

[0590] Synthesis of Compound Example 16: HBS-039-010 (0.02 g, 0.06 mmol), 5-iodo-2-methoxypyridine (0.04 g, 0.18 mmol) and Cs2CO3 (0.057 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.011 g, 0.011 mmol) and X-Phos (0.011 g, 0.023 mmol) were added. The reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by LCMS, and the reagents were added twice to consume the starting materials. LCMS data showed the formation of the product with m / z of 448.3. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 16 (0.005 g, yield 19.3%) was obtained. C 25 H 29 The MS (ESI) mass of N5O3 was calculated to be 447.5; m / z was 448.3 [M+H] + 。

[0591] P. Example 17:

[0592]

[0593] Synthesis of Compound Example 17: HBS-039-002 (0.02 g, 0.06 mmol), 2-chloro-5-trifluoromethyl-pyridine (0.022 g, 0.12 mmol) and Cs2CO3 (0.058 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.006 g, 0.012 mmol) and X-Phos (0.006 g, 0.012 mmol) were added. The reaction mixture was stirred at 100 °C for 24 h. The reaction progress was monitored by LCMS, and the reagents were added twice to consume the starting materials. LCMS data showed the formation of the product with m / z of 480.2. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 17 (0.01 g, yield 36.5%) was obtained. C 26 H 24 The MS (ESI) mass of F3N5O was calculated to be 479.5; m / z was 480.2 [M+H] + 。

[0594] Q. Example 18:

[0595]

[0596] Synthesis of Compound Example 18: HBS-039-010 (0.017 g, 0.05 mmol) and 2-chloro-5-trifluoromethyl-pyridine (0.018 g, 0.1 mmol) were dissolved in anhydrous DMF (2.0 mL). Anhydrous K2CO3 (0.021 g, 0.15 mmol) was added, and the reaction mixture was stirred at 115 °C for 16 h. LCMS data showed the formation of the product with m / z of 486.3. The reaction mixture was concentrated under a stream of air to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 18 (0.014 g, yield 58.5%) was obtained. C 25 H 26 The MS (ESI) mass of F3N5O2 was calculated to be 485.5; m / z was 486.3 [M+H] + 。

[0597] R. Example 19:

[0598]

[0599] Synthesis of Compound Example 19: Dissolve HBS-039-080 (0.02 g, 0.06 mmol) and 2-chloro-5-trifluoromethyl-pyridine (0.022 g, 0.12 mmol) in anhydrous DMF (2.0 mL). Add anhydrous K2CO3 (0.025 g, 0.18 mmol), and stir the reaction mixture at 115 °C for 16 h. LCMS data shows the formation of the product, with m / z of 480.2. Concentrate the reaction mixture under a stream of air to obtain the crude product, which is purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Obtain Example 19 (0.01 g, yield 35.5%). C 25 H 24 The MS (ESI) mass of F3N5O is calculated to be 479.5; m / z is 480.2 [M+H] + 。

[0600] S. Example 20:

[0601]

[0602] Synthesis of Compound Example 20: Suspend HBS-039-080 (0.02 g, 0.06 mmol), 2-bromo-5-methoxy-pyridine (0.034 g, 0.18 mmol) and t-BuOK (0.02 g, 0.18 mmol) in 1,4-dioxane (2.0 mL). Add Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.006 g, 0.01 mmol), and stir the reaction mixture at 110 °C for 24 h. Monitor the reaction progress by LCMS and add the reagents twice to consume the starting materials. LCMS data shows the formation of the product, with m / z of 442.3. Filter the reaction mixture through diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate to obtain the crude product, which is purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Obtain Example 20 (0.007 g, yield 26.8%). C 26 H 27 The MS (ESI) mass of N5O2 is calculated to be 441.5; m / z is 442.3 [M+H] + 。

[0603] T. Example 21:

[0604]

[0605] Synthesis of Compound Example 21: HBS-039-080 (0.02 g, 0.06 mmol), 2-bromo-5-methoxypyridazine (0.034 g, 0.18 mmol) and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.006 g, 0.012 mmol) were added, and the reaction mixture was stirred at 110 °C for 24 h. The reaction progress was monitored by LCMS, and the reagents were added twice to consume the starting materials. The LCMS data showed the formation of the product with m / z of 443.3. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 21 (0.015 g, yield 56.2%) was obtained. C 25 H 26 The MS (ESI) mass of C6H5N6O2 was calculated to be 442.5; m / z was 443.3 [M+H] + .

[0606] U. Example 22:

[0607]

[0608] Synthesis of Compound Example 22: HBS-039-080 (0.02 g, 0.06 mmol), 5-iodo-2-methoxypyridine (0.04 g, 0.18 mmol) and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.006 g, 0.012 mmol) were added, and the reaction mixture was stirred at 110 °C for 24 h. The reaction progress was monitored by LCMS, and the reagents were added twice to consume the starting materials. The LCMS data showed the formation of the product with m / z of 442.3. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 22 (0.02 g, yield 74.6%) was obtained. C 26 H 27 The MS (ESI) mass of C6H4N5O2 was calculated to be 441.5; m / z was 442.3 [M+H] + .

[0609] V. Example 23:

[0610]

[0611] Synthesis of Compound Example 23: HBS-039-080 (0.025 g, 0.075 mmol), 2-chloro-5-fluoropyridine (0.02 g, 0.15 mmol) and t-BuOK (0.025 g, 0.22 mmol) were suspended in 1,4-dioxane (2.5 mL). Pd2(dba)3 (0.014 g, 0.015 mmol) and X-Phos (0.007 g, 0.015 mmol) were added, and the reaction mixture was stirred at 110 °C for 6 h. LCMS data showed the formation of the product with m / z of 430.3. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 23 (0.017 g, yield 51.9%) was obtained. C 25 H 24 The MS (ESI) mass of FN5O was calculated to be 429.5; m / z was 430.3 [M+H] + 。

[0612] W. Example 24:

[0613]

[0614] Synthesis of Compound Example 24: HBS-039-002 (0.025 g, 0.075 mmol), 2-chloro-5-fluoropyridine (0.02 g, 0.15 mmol) and t-BuOK (0.025 g, 0.22 mmol) were suspended in 1,4-dioxane (3.0 mL). Pd2(dba)3 (0.014 g, 0.015 mmol) and X-Phos (0.007 g, 0.015 mmol) were added. The reaction mixture was stirred at 110 °C for 6 h. LCMS data showed the formation of the product with m / z of 430.3. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Example 24 (0.019 g, yield 59.8%) was obtained. C 25 H 24 The MS (ESI) mass of FN5O was calculated to be 429.5; m / z was 430.3 [M+H] + 。

[0615] X. Example 25:

[0616]

[0617] Synthesis of Compound Example 25: HBS-039-010 (0.025 g, 0.073 mmol), 2-bromo-5-fluoropyridine (0.026 g, 0.15 mmol) and t-BuOK (0.021 g, 0.18 mmol) were suspended in 1,4-dioxane (2.5 mL). Pd2(dba)3 (0.007 g, 0.007 mmol) and X-Phos (0.004 g, 0.007 mmol) were added, and the reaction mixture was stirred at 110 °C for 6 h. LCMS data showed the formation of the product with m / z of 436.3. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. Compound Example 25 (0.026 g, yield 83.5%) was obtained. C 24 H 26 The MS (ESI) mass of FN5O2 was calculated to be 435.5; m / z was 436.3 [M+H] + 。

[0618]

[0619] Synthesis of Example 26: Intermediate HBS-054-014 (0.025 g, 0.1 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC.HCl (0.028 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added, followed by DIPEA (0.07 mL, 0.4 mmol). The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-039-171 (0.031 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 457.0. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. 0.045 g of the product (quantitative yield) was obtained. C 26 H 25 The MS (ESI) mass of FN6O was calculated to be 456.5; m / z was 457.0 [M+H] + 。

[0620] Note: Compounds of Example 27 to Example 34 were prepared using the corresponding acid intermediate and amine intermediate HBO-039-171 according to a similar coupling procedure.

[0621]

[0622]

[0623]

[0624] Synthesis of Example 35: Intermediate HBS-054-014 (0.015 g, 0.059 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.017 g, 0.088 mmol) and HOBt (0.012 g, 0.088 mmol) were added, and then DIPEA (0.04 mL, 0.18 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-055-003 (0.019 g, 0.064 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 457.0. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. 0.023 g of the product was obtained (yield 79.0%). C 26 H 21 The MS (ESI) mass of F4N5O was calculated to be 495.47; m / z was 496.0 [M+H] + .

[0625] Note: Compound Example 36 was prepared according to a similar coupling procedure using the corresponding acid intermediate and amine intermediate.

[0626] Acid intermediate Amine intermediate Final product HBS-054-021 HBS-055-003 Example 36

[0627]

[0628] Synthesis of Example 37: Intermediate HBS-054-080 (0.02 g, 0.07 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.019 g, 0.1 mmol) and HOBt (0.013 g, 0.1 mmol) were added, and then DIPEA (0.034 mL, 0.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-039-171 (0.021 g, 0.072 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 507.0. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. 0.02 g of the product was obtained (yield 61.0%). C 27 H 25 The MS (ESI) mass of F3N6O was calculated to be 506.52; m / z was 507.03 [M+H] + 。

[0629]

[0630] Synthesis of Example 39: Intermediate HBS-054-088 (0.025 g, 0.095 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.027 g, 0.14 mmol) and HOBt (0.019 g, 0.14 mmol) were added, and then DIPEA (0.05 mL, 0.29 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-039-171 (0.031 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 463.0. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: EtOAc: hexane, gradient. 0.027 g of the product was obtained (yield 61.0%). C 25 H 27 The MS (ESI) mass of FN6O2 was calculated to be 462.52; m / z was 463.0 [M+H] + 。

[0631] Note: Compounds Example 41, Example 42 and Example 43 were prepared according to a similar coupling procedure using the corresponding acid intermediate and amine intermediate.

[0632]

[0633]

[0634]

[0635] Synthesis of Example 44: Intermediate HBS-039-192 (0.025 g, 0.098 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.025 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added, and then DIPEA (0.17 mL, 0.98 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-039-171 (0.029 g, 0.098 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 457.3. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: DCM:MeOH, gradient. 0.045 g of the product was obtained (quantitative yield). C 26 H 25 The MS (ESI) mass of FN6O was calculated to be 456.51; m / z was 457.3 [M+H] + 。

[0636] Note: Compounds Example 45 and Example 44 were prepared according to a similar coupling procedure using the corresponding acid intermediate and amine intermediate.

[0637] Acid intermediate Amine intermediate Final product HBS-039-192 HBS-055-003 Example 44 HBS-039-150 HBS-055-003 Example 45

[0638]

[0639] Synthesis of Example 47: Intermediate HBS-039-192 (0.02 g, 0.078 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.022 g, 0.12 mmol) and HOBt (0.016 g, 0.12 mmol) were added, followed by DIPEA (0.14 mL, 0.78 mmol). The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-055-011 (0.026 g, 0.078 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed product formation with m / z of 502.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: EtOAc: hexane, gradient. 0.039 g of the product was obtained (quantitative yield). C 27 H 21 The MS (ESI) mass of ClFN5O2 was calculated to be 501.94; m / z was 502.2 [M+H] + 。

[0640] Note: Compound HBO-12240 was prepared according to a similar coupling procedure using the corresponding acid intermediate and amine intermediate.

[0641] Acid intermediate Amine intermediate Final product HBS-039-150 HBS-055-011 Example 48

[0642]

[0643] Synthesis of Example 49: Intermediate HBS-055-013 (0.02 g, 0.076 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.022 g, 0.11 mmol) and HOBt (0.015 g, 0.11 mmol) were added, followed by DIPEA (0.13 mL, 0.76 mmol). The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-039-171 (0.022 g, 0.076 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed product formation with m / z of 463.3. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: DCM: MeOH, gradient. 0.0168 g of the product was obtained (yield 47.6%). C 25 H 27The MS(ESI) mass of FN6O2 was calculated to be 462.52; m / z was 463.3 [M+H] + 。

[0644] Note: Compounds Example 50 and Example 51 were prepared using the corresponding acid intermediate and amine intermediate according to a similar coupling procedure.

[0645] Acid intermediate Amine intermediate Final product HBS-055-013 HBS-055-003 Example 50 HBS-055-013 HBS-055-011 Example 51

[0646]

[0647] Synthesis of Example 52: Intermediate HBS-055-028 (0.02 g, 0.057 mmol) was dissolved in anhydrous acetonitrile (2.0 mL). Anhydrous Cs2CO3 (0.037 g, 0.11 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.016 g, 0.085 mmol). The reaction mixture was heated under reflux for 6 h. LCMS data showed the formation of the product, with m / z of 504.2. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient. 22.2 g of the product was obtained (yield 77.2%). C 27 H 23 The MS(ESI) mass of ClFN5O2 was calculated to be 503.96; m / z was 504.2 [M+H] + 。

[0648]

[0649] Synthesis of Example 53: Intermediate HBS-055-028 (0.02 g, 0.057 mmol) was dissolved in anhydrous DMF (2.0 mL). Anhydrous Cs2CO3 (0.037 g, 0.11 mmol) was added, followed by 2-chloro-5-trifluoromethylpyridine (0.016 g, 0.089 mmol). The reaction mixture was heated at 100 °C for 16 h. LCMS data showed the formation of the product, with m / z of 498.2. The reaction mixture was diluted with water and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash chromatography system, mobile phase: EtOAc: hexane, gradient, to obtain 17.2 mg of the pure product (yield 60.5%). C 26 H 23 The MS(ESI) mass of F4N5O2 was calculated to be 497.49; m / z was 498.2 [M+H] + 。

[0650]

[0651] Synthesis of Example 54: Intermediate HBS-055-028 (0.02 g, 0.057 mmol) was dissolved in anhydrous DMF (2.0 mL). Anhydrous Cs2CO3 (0.037 g, 0.11 mmol) was added, and then 2-chloro-4,6-dimethylpyrimidine (0.018 g, 0.086 mmol) was added. The reaction mixture was heated at 100 °C for 16 h. LCMS data showed the formation of the product with m / z of 459.3. The reaction mixture was diluted with water and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash chromatography system with the mobile phase: EtOAc: hexane, gradient, to obtain 21.1 mg of the pure product (yield 80.7%). C 26 H 27 The MS (ESI) mass of FN6O was calculated to be 458.53; m / z was 459.3 [M+H] + .

[0652] Note: Examples 54 and 55 were prepared using the corresponding acid intermediate and amine intermediate according to the general EDC.HCl, HOBt.H2O coupling procedure.

[0653] Acid intermediate Amine intermediate Final product HBS-039-023 HBS-055-117 Example 55 HBS-039-023 HBS-062-031 Example 56

[0654]

[0655] Synthesis of Example 57: Intermediate HBS-062-013 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC.HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, and then Et3N (0.06 mL, 0.42 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-031 (0.028 g, 0.082 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 492.1. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: DCM: MeOH, gradient. 0.023 g of the product was obtained (yield 56.1%). C 26 H 26The MS(ESI) mass of ClN5O3 was calculated to be 491.97; m / z was 492.1 [M+H] + 。

[0656] Note: Compound Example 58 was prepared according to a similar coupling procedure.

[0657] Acid intermediate Amine intermediate Final product HBS-062-013 HBS-055-117 Example 58

[0658]

[0659] Synthesis of Example 59: Intermediate HBS-055-197 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC.HCl (0.024 g, 0.12 mmol) and HOBt (0.017 g, 0.13 mmol) were added, and then Et3N (0.06 mL, 0.41 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-031 (0.028 g, 0.082 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 492.1. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. 0.037 g of the product was obtained (yield 91.9%). C 26 H 26 The MS(ESI) mass of ClN5O3 was calculated to be 491.97; m / z was 492.1 [M+H] + 。

[0660] Note: Compound Example 60 was prepared according to a similar coupling procedure.

[0661]

[0662]

[0663]

[0664] Synthesis of Example 61: Intermediate HBS-062-028 (0.02 g, 0.083 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC.HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, and then Et3N (0.06 mL, 0.42 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-031 (0.028 g, 0.083 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 488.1. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: DCM:MeOH, gradient. 0.0347 g of the product was obtained (yield 85.5%). C 25 H 22 The MS (ESI) mass of ClN7O2 was calculated to be 487.94; m / z was 488.1 [M+H] + 。

[0665] Note: According to a similar coupling procedure, Compound Example 62 was prepared using the following intermediates.

[0666] Acid intermediate Amine intermediate Final product HBS-062-028 HBS-055-117 Example 62

[0667]

[0668] Synthesis of Example 63: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.06 mL, 0.33 mmol) was added, and the reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-031 (0.028 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 487.1. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with the mobile phase: DCM:MeOH, gradient. 0.041 g of the product was obtained (quantitative yield). C 26 H 23 The MS (ESI) mass of ClN6O2 was calculated to be 486.95; m / z was 487.1 [M+H]+ 。

[0669] Note: Compound Example 64 was prepared using the following intermediate according to a similar coupling procedure.

[0670] Acid intermediate Amine intermediate Final product HBS-062-030 HBS-055-117 Example 64

[0671]

[0672] Synthesis of Example 65: Intermediate HBS-062-027 (0.02 g, 0.084 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, and then Et3N (0.06 mL, 0.42 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-031 (0.028 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 487.1. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. 0.0375 g of the product was obtained (yield 92.1%). C 26 H 23 The MS (ESI) mass of ClN6O2 was calculated to be 486.95; m / z was 487.1 [M+H] + 。

[0673] Note: Compound Example 66 was prepared using the following intermediate according to a similar coupling procedure.

[0674] Acid intermediate Amine intermediate Final product HBS-062-027 HBS-055-117 Example 66

[0675]

[0676] Synthesis of Example 67: Intermediate HBS-062-041 (0.02 g, 0.084 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by Et3N (0.06 mL, 0.42 mmol). The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-031 (0.028 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 487.1. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. 0.0336 g of the product was obtained (yield 82.5%). C 26 H 23 The MS (ESI) mass of ClN6O2 was calculated to be 486.95; m / z was 487.1 [M+H] + .

[0677] Note: According to a similar coupling procedure, the following intermediates were used to prepare Compound Example 68.

[0678] Acid intermediate Amine intermediate Final product HBS-062-041 HBS-055-117 Example 68

[0679]

[0680] Synthesis of Example 69: HBS-039-019 (0.02 g, 0.084 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by Et3N (0.06 mL, 0.42 mmol). The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-092 (0.028 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 441.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. 0.0343 g of the product was obtained (yield 92.7%). C 26 H 28The MS(ESI) mass of N6O was calculated to be 440.54; m / z was 441.2 [M+H] + 。

[0681] Note: According to a similar coupling procedure, the following intermediates were used to prepare Compound Examples 70, 71, 72, 73 and 74.

[0682] Acid intermediate Amine intermediate Final product HBS-062-013 HBS-062-092 Example 70 HBS-039-018 HBS-062-092 Example 71 HBS-037-054 HBS-062-092 Example 72 HBS-037-093 HBS-062-092 Example 73 HBS-062-041 HBS-062-092 Example 74

[0683]

[0684] Synthesis of Example 75: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.06 mL, 0.33 mmol) was added, and the reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-092 (0.028 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, m / z was 442.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. 0.037 g of the product was obtained (quantitative yield). C 25 H 27 The MS(ESI) mass of N7O was calculated to be 441.53; m / z was 442.2 [M+H] + 。

[0685]

[0686] Synthesis of Example 76: Intermediate HBS-062-013 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, and then Et3N (0.06 mL, 0.41 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-119 (0.027 g, 0.082 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed product formation with m / z of 448.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: DCM:MeOH, gradient. 0.0294 g of the product was obtained (yield 80.2%). C 25 H 29 The MS (ESI) mass calculation for N5O3 is 447.53; m / z is 448.2 [M+H] + 。

[0687] Note: According to a similar coupling procedure, Compounds of Examples 77, 78, 79 and 80 were prepared using the following intermediates.

[0688] Acid intermediate Amine intermediate Final product HBS-039-019 HBS-062-119 Example 77 HBS-039-018 HBS-062-119 Example 78 HBS-055-197 HBS-062-119 Example 79 HBS-062-041 HBS-062-119 Example 80

[0689]

[0690] Synthesis of Example 81: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.06 mL, 0.33 mmol) was added, and the reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-119 (0.028 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed product formation with m / z of 442.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: DCM:MeOH, gradient. 0.0342 g of the product was obtained (yield 92.3%). C 25 H 26The MS (ESI) mass of N6O was calculated to be 442.51; m / z was 443.4 [M+H] + .

[0691]

[0692] Synthesis of Example 82: Intermediate HBS-062-013 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, and then Et3N (0.06 mL, 0.42 mmol) was added. The reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-136 (0.03 g, 0.082 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product, with m / z of 487.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to obtain the crude product. The crude product was purified by an ISCO combi-flash system, mobile phase: DCM:MeOH, gradient. 0.0348 g of the product was obtained (yield 87.4%). C 24 H 25 The MS (ESI) mass of F3N6O2 was calculated to be 486.49; m / z was 487.2 [M+H] + .

[0693] Note: According to a similar coupling procedure, the following intermediates were used to prepare Compound Examples 83, 84, 85, 86, 87, 88, 89, 90 and 91.

[0694] Acid intermediate Amine intermediate Final product HBS-039-019 HBS-062-136 Example 83 HBS-055-197 HBS-062-136 Example 84 HBS-062-041 HBS-062-136 Example 85 HBS-039-018 HBS-062-136 Example 86 HBS-062-030 HBS-062-136 Example 87 HBS-062-028 HBS-062-136 Example 88 HBS-037-054 HBS-062-136 Example 89 HBS-037-163 HBS-062-136 Example 90 HBS-062-027 HBS-062-136 Example 91

[0695]

[0696] Synthesis of Example 87: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.07 mL, 0.4 mmol) was added, and the reaction mixture was stirred at ambient temperature for 5.0 min. Intermediate HBS-062-136 (0.034 g, 0.084 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed the formation of the product with m / z of 482.2. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system with mobile phase: ethyl acetate: hexane, gradient. 0.04 g of the product was obtained (quantitative yield). C 24 H 22 The MS (ESI) mass of F3N7O was calculated to be 481.47; m / z was 482.2 [M+H] + 。

[0697] Note: Compounds of Examples 92, 93, 94, 95, 96, 97, 98, 99, 100 and 101 were prepared using the following intermediates according to the general coupling procedure (EDC.HCl or HATU).

[0698]

[0699] Example 2

[0700] A. Biological Assays

[0701] The antagonistic activity of the compounds of each example against the two orexin receptors (i.e., identification of orexin receptor antagonists) has been measured using the in vitro assay (intracellular calcium measurement) described herein. As will be understood by those of ordinary skill in the art, other assays can also be used to identify orexin receptor antagonists. Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor and human orexin-2 receptor separately were grown in a medium (Ham F-12 containing L-glutamine) containing 300 μg / mL G418, 100 U / mL penicillin, 100 μg / mL streptomycin, and 10% heat-inactivated fetal bovine serum (FCS). The cells were seeded at 20,000 cells / well into a 384-well black clear-bottom sterile plate (Greiner). The seeded plate was incubated overnight at 37 °C in 5% CO2. Human orexin-A as an agonist was prepared as a 1 mM methanol:water (1:1) stock solution and diluted in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g / L, and 20 mM HEPES for the assay, with a final concentration of 3 nM.

[0702] The antagonist was prepared as a 10 mM DMSO stock solution and then diluted in a 384-well plate with DMSO, and then the dilution was transferred into HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g / L, and 20 mM HEPES. On the day of the assay, 50 μL of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, NaHCO3: 0.375 g / L, 5 mM probenecid (Sigma), and 3 μM fluorescent calcium indicator fluo-4AM (1 mM DMSO stock solution containing 10% pluronic)) was added to each well. The 384-well cell plate was incubated at 37 °C in 5% CO2 for 50 min and then equilibrated at room temperature for 30 min before measurement. Inside a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices), the potential orexin receptor antagonist was added to the plate at a volume of 10 μL / well, incubated for 120 min, and finally 10 μL / well of the agonist was added. The fluorescence of each well was measured at 1-second intervals, and the height of each fluorescence peak was compared with the height of the fluorescence peak induced by 3 nM orexin-A with vehicle instead of the antagonist. IC 50 values (the concentration of the compound required to inhibit 50% of the agonist response) were determined and normalized using the IC 50 values of the reference compounds obtained on the plate. Optimized conditions were achieved by adjusting the pipetting speed and cell splitting protocol. As is known to those skilled in the art, the calculated IC 50 values fluctuate according to the daily performance of the cell assay. In multiple determinations of the IC 50In the case of values, the geometric mean is given. The antagonistic activities of the example compounds are shown in Table 1.

[0703] Table 1

[0704] Examples of Compound Data

[0705] (% Inhibition of Orexin Receptor Type 1 and Type 2, @1uM and IC 50 / K b value)

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720] Although certain embodiments have been described in terms of preferred embodiments, it should be understood that various changes and modifications will occur to those skilled in the art. Accordingly, the appended claims are intended to cover all such equivalent changes that fall within the scope of the appended claims.

Claims

1. A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof; Wherein: R1 includes E, where E is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); or when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-substituted or di-substituted, and the substituents are independently selected from (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (e.g., F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; provided that R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to three (3) substituents, said substituents being independently selected from one, two, or all of R2, R3, and R4; R5 and R6 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R6 is attached to R as alkyl 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure, and R5 and R6 are joined together to form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl; R7 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is attached to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure; R8 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl group to R 10 or R 11 or R 13 to form a (C 1-3 ) alkyl-bridged cyclic structure; R9 is selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is linked to R6 or R 11 to form a (C 1-3 ) alkyl-bridged cyclic structure; R 10 selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 or R 12 is attached to R7 or R8 as an alkyl group to form a (C 1-3 ) alkyl-bridged cyclic structure, wherein in some embodiments, R 11 and R 12 connected together can form a spiro moiety, such as but not limited to cyclopropyl or cyclobutyl; R 13 and R 14 are independently selected from the group consisting of H, CH3, alkyl, substituted alkyl (such as fluoroalkyl), cycloalkyl, and R 13 or R 14 is attached to R7 or R8 as alkyl to form a (C 1-3 )alkyl-bridged cyclic structure; R 15 is aromatic or aryl, such as but not limited to heteroaryl (e.g., preferably a 5- or 6-membered ring), substituted aromatic or aryl, substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a fused two-heteroaryl ring system; wherein the aromatic, aryl, or heteroaryl is unsubstituted, mono-substituted, di-substituted, or tri-substituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, and (C 3-7 )heterocycloalkyl; W is: c) is selected from the group consisting of CH2, and R7, R8, R 13 , R 14 = H, and the carbon having substituents R7, R8, R 13 and R 14 will be directly connected to provide the 5-5 bridged bicyclic system shown below: d) There is no provision of a heptacyclic ring system as shown below: The fused ring system A - B - J - D - E is a five (5)-membered heteroaryl, which is optionally imidazole, where A and J are nitrogen, and B, E, and D are carbon, or optionally pyrazole, where A and B are nitrogen, and D, E, and J are carbon; the five (5)-membered heteroaryl is fused or unfused with another ring system; The fused ring system B - J - M - G - K - L is a six (6)-membered aromatic or aryl, substituted aromatic or aryl, substituted or unsubstituted heteroaryl, cycloalkyl, heterocycloalkyl; A is nitrogen or carbon; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon; M is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; G is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; K is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

2. The compound according to claim 1, wherein the compound is of formula I-a7, formula I-a8, formula I-a9, formula II-a7, formula II-a8 or formula II-a9, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, Wherein: E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, and substituted heteroaryl (5-6 membered ring). When R1 is heteroaryl, it is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. The aromatic, aryl, or heteroaryl is unsubstituted, mono-substituted, or di-substituted, 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, R3, and R4 are independently selected from the group consisting of H, halogen (e.g., F, Cl, Br), alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; provided that R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to 3 substituents, said substituents being independently selected from one or two or all of R2, R3, and R4; and R 15 selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted 5-6 membered heteroaryl or fused two heteroaryl ring systems; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl and (C 3-7 )heterocycloalkyl.

3. The compound according to claim 1, wherein the compound has the formula I-b7, formula I-b8, formula I-b9, formula I-b10, formula II-b7, formula II-b8, formula II-b9 and formula II-b10 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or a combination thereof wherein: E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl; when R1 is heteroaryl, it is optionally a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl; R2, R3, and R4 are each independently selected from the group consisting of H, a halogen which is optionally F, Cl, or Br, an alkyl group, a substituted alkyl group, a (C 1-4 )alkyl group, a (C 1-4 )alkoxy group, a (C 1-3 )fluoroalkyl group, a (C 1-3 )fluoroalkoxy group, and a (C 3-7 )cycloalkyl group; provided that R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to 3 substituents, said substituents being independently selected from one or two or all of R2, R3, and R4; and R 15 selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl, and fused two heteroaryl ring systems; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, di-substituted or tri-substituted, and wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, (C 3-7 )heterocycloalkyl.

4. The compound according to claim 1, wherein the compound has the formula I-b11, formula I-b12, formula I-b13, formula I-b14, formula II-b11, formula II-b12, formula II-b13 and formula II-b14 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or a combination thereof wherein: E in R1 is carbon (C) but not nitrogen (N), and E is connected to J or D by a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl; when R1 is heteroaryl, it is optionally a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl; R2, R3, and R4 are each independently selected from the group consisting of H, halogen, F, Cl, or Br, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; provided that R2, R3, and R4 are each independently and optionally substituted at each substitutable position with up to 3 substituents, said substituents being independently selected from one or two or all of R2, R3, and R4; R 12 selected from the group consisting of H, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, and cycloalkyl; and R 15 selected from the group consisting of aromatic, aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic, substituted aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl or fused two heteroaryl ring systems; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl and (C 3-7 )heterocycloalkyl.

5. The compound according to claim 1, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or a combination thereof: Example 22, Example 23, Example 24, 6. The compound according to claim 5, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or a combination thereof:

7. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof according to any one of the preceding claims; and an acceptable carrier, adjuvant or vehicle.

8. The pharmaceutical composition according to claim 7, comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

9. The pharmaceutical composition according to claim 7 or 8, wherein the composition further comprises at least one second therapeutic agent.

10. A method of antagonizing at least one orexin receptor in a cell, comprising the step of exposing the cell to a compound and / or composition according to any one of the preceding claims, optionally, wherein the method is in vitro.

11. A method of antagonizing at least one orexin receptor in a subject in need thereof, comprising the step of administering a compound and / or composition according to any one of the preceding claims.

12. A method of treating a disorder in a subject in need thereof, the disorder selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer's disease (AD) and central nervous system (CNS) disorders, the method comprising the step of administering a compound and / or composition according to any one of the preceding claims.

13. The method of claim 12, wherein the substance corresponding to substance addiction or substance dependence is selected from the group consisting of: one or more opioid drugs, optionally heroin, morphine, oxycodone, fentanyl and hydrocodone; one or more stimulants, optionally selected from the group consisting of amphetamine, cocaine, crack cocaine and methamphetamine; one or more sedatives and / or tranquilizers, benzodiazepines and barbiturates.

14. The method according to any one of claims 10 - 13, wherein the compound is an orexin receptor antagonist.

15. A method according to any one of claims 10 - 14, wherein the compound is an antagonist of orexin receptor 1 (OX1R) or orexin receptor 2 (OX2R), or an antagonist of both OX1R and OX2R; optionally, wherein the compound is an antagonist of the κ - opioid receptor; and / or has the following characteristics when measured in an in vitro cell assay: 1) OX1R Kb < 30 nm, OX2R Kb > 1000 nm, KOR Ki < 500 nm; 2) OX1R Kb < 30 nm, OX2R Kb > 30 nm, KOR Ki < 500 nm; or 3) OX1R Kb < 30 nm, OX2R Kb > 1000 nm, KOR Ki > 1000 nm.

16. A method according to any one of claims 10 - 15, comprising administering to the patient a therapeutically effective amount of the compound and / or composition according to any one of the preceding claims.

17. A method according to any one of claims 10 - 16, comprising administering at least one unlabeled form and / or at least one isotopically labeled form of the compound according to any one of the preceding claims, and / or a composition comprising the compound.

18. A method for making the compound according to claim 1, comprising combining at least two intermediates to produce the compound.

19. A method for making the pharmaceutical composition according to any one of claims 7 - 9, comprising combining at least one compound of claim 1 with at least one pharmaceutically acceptable excipient.

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