Pyrazole and imidazole derivatives as dual modulators of orexin and kappa-opioid receptors, compositions, methods for treating neurological and psychiatric patients

Abstract

The present disclosure relates to substituted pyrazole and imidazole derivatives of compounds that are antagonists and / or modulators of orexin and kappa-opioid receptors that are useful in the treatment or prevention of neurological, psychiatric, cardiovascular and cancer conditions and diseases in which orexin and kappa-opioid receptors are involved or implicated. 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 associated with orexin and kappa-opioid receptors.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Application No. 63 / 403,019, filed Sep. 1, 2022, the entire content of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to and provides compounds, compositions, and methods for using dual-acting orexin and κ-opioid receptor antagonists and / or modulators as therapeutic agents for treating or improving human and animal diseases. In particular, any pathological disease in which both orexin and κ-opioid receptor types are pharmacologically involved or implicated. These important therapeutic applications include, but are not limited to, treating central nervous system (CNS) disorders, neurological diseases, cardiovascular diseases, including various cancers that are involved or regulated by orexin and / or κ-opioid receptors, including but not limited to patients responsive to orexin and / or κ-opioid 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.

[0004] Statement Regarding Federal Support

[0005] This disclosure was made with government support in part under federal award UF1DA054817, awarded by the U.S. NIH National Institute on Drug Abuse. The government has certain rights in this disclosure. 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 new signaling molecules, namely (1) Sakurai and his colleagues (who named them orexin A and orexin B) (Sakurai, T. et al, Cell 1998, 92, 573) and (2) de Lecea and his 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 endogenous ligands for two G protein-coupled receptors (GPCRs), namely OX1R and OX2R (also known as HctR1 and HctR2), and are derived by proteolysis from the same precursor peptide, called the pre-pro-orexin polypeptide (Sakurai T., et al. The Journal of biological chemistry. 1999; 274, 17771–17776). Although structurally related, the binding affinities of these endogenous ligands for the two GPCRs are different. Orexin A has a binding affinity for OX1R that is approximately 100 times higher than that of orexin B, while orexin A and orexin B have the same binding affinity for OX2R (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). Soon after the discovery of orexin, orexin signaling regulation was initially considered a potential new treatment for patients with narcolepsy or insomnia, because the role of orexin in regulating sleep and wakefulness had been well studied and understood, and the discovery of small molecule modulators of orexin signaling promoted the development of such compounds. Patients with narcolepsy show reduced hypothalamic orexin neuron activity, resulting in decreased levels of orexin circulating in the cerebrospinal fluid. In contrast, activation of orexin neurons maintains wakefulness and arousal. The effects of orexin signaling on feeding and energy homeostasis were also established earlier and were found to be coordinated with the sleep-wake cycle (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375).Recent studies have established the role of orexin and / or κ-opioid 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 antagonist), (2) SORA-1 (selective OX1R antagonist), and (3) SORA-2 (selective OX2R antagonist). Studies have shown that while both OX2R knockout mice and OX1R / OX2R double knockout mice exhibit a narcolepsy phenotype, the effect in OX1R knockout mice is very weak (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, suggesting that the narcolepsy effect is mediated through OX2R or a combination of OX1R and OX2R, rather than through OX1R alone. Thus, it is clear that the discovery and development of differentiated orexin antagonists is crucial for the advancement of this field, but most importantly for the development of therapeutic agents for dysregulated biological processes involving orexin receptors; especially for non-sleep related indications such as substance addiction, anxiety, panic, and PTSD.

[0007] κ-opioid receptor (κOR): By modulating the endogenous opioid system, such as the μ, κ, and δ opioid receptors (MOR, κOR, DOR) and their endogenous ligand peptides (β-endorphin, dynorphin, and enkephalin), opioid research has become the focus of many drug development efforts targeting CNS or neuropsychiatric disorders. More specifically (i.e., preferably), κOR antagonists have shown potential utility in treating stress-related mood disorders, including depression, anxiety, and drug abuse. Stress stimuli, especially those occurring during the withdrawal phase, lead to the activation of κOR by the endogenous ligand dynorphin. This stress-induced depression in patients contributes to the relapse of drug-seeking behavior, and κOR antagonists have been shown to reduce this relapse. Conversely, stimulation of κOR by its endogenous ligand dynorphin or synthetic agonists (such as opioids) is known to have anti-nociceptive and analgesic effects.

[0008] Compared to administering a single pill formulated with a drug mixture or a multi-component pharmaceutical agent, synchronously modulating different molecular targets or receptors that are commonly involved in a common disease pathway or patient condition using a single molecular entity can provide better overall efficacy. The potential advantages of the dual-target modulation approach over drug combinations or mixtures include, but are not limited to: improved dosing regimens and compliance, reduced drug-drug interactions, simplified and predictable PK / PD relationships, one-dimensional DMPK and safety profiles, potential synergistic efficacy, reduced tolerance potential, and reduced regulatory hurdles. This network pharmacology approach can provide superior efficacy compared to single-target agents in treating multi-factorial and multi-etiological disease states, such as CNS and / or neurological disorders, cancer, metabolic syndrome, cardiovascular diseases, and more specifically (i.e., preferably) conditions such as addiction disorders. Therefore, the measured but balanced synchronous modulation of orexin and κ-opioid receptors (OXR and κOR) (such as an antagonist of OXR and a partial antagonist or inverse agonist or agonist of κOR) can provide unique, first-in-class, and highly effective new molecular entities as therapeutic agents for many dysregulated biological processes involving orexin and / or κ-opioid receptors. These compounds, compositions, and methods provide solutions to these problems in the prior art. Summary of the Invention

[0009] The present disclosure addresses the above therapeutic needs by providing compounds of Formula I or II in different embodiments:

[0010]

[0011] Wherein the variables are as defined herein and include any pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers. The compounds of Formula I or II can be used, respectively, for treating the disorders described herein, for example, by modulating orexin and / or κ-opioid receptors. In some embodiments, these compounds provide a balanced and simultaneous modulation of orexin and κ-opioid receptors (OXR and κOR) (e.g., an antagonist of OXR and a partial antagonist or inverse agonist or agonist of κOR).

[0012] The present disclosure also provides a composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof. In another aspect of the present disclosure, there is provided a method for treating a CNS disorder (wherein, for example, substance addiction and dependence, post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety, pain, depression, cognitive impairment, and Alzheimer's disease (AD)) in a subject in need or at risk of developing the disease, the method comprising the step of administering to the subject a therapeutically effective amount of an orexin and / or κ-opioid receptor antagonist and / or modulator or a pharmaceutically acceptable salt thereof. In certain embodiments of the present disclosure, the antagonist and / or modulator or a pharmaceutically acceptable salt thereof can be formulated for administration at regular intervals, for example, every 3 hours, 6 hours to 24 hours, or once a week, depending on the clinical benefit. Detailed Description

[0013] The present disclosure relates to fused 6- and 5-membered ring system derivatives of formula (I) and / or (II), wherein the fused 6- and 5-membered rings are as described in the structure in the full disclosure, to their pharmaceutically acceptable salts, their preparation, pharmaceutical compositions comprising one or more compounds of formula (I) and / or (II), and their use as medicaments and therapeutic agents, particularly their use as orexin and / or κ-opioid receptor antagonists and / or modulators. These novel agents, as described by formula (I) and / or (II), are non-peptide modulators of human orexin and / or κ-opioid receptors and may be used to treat disorders associated with orexinergic and κ-opioid receptor dysfunctions; including but not limited to substance addiction, anxiety, panic, cognitive dysfunction, mood, or appetite, sleep, Alzheimer's disease (AD), metabolic syndrome, and hypertension, etc.; in particular, these compounds may have important therapeutic value in treating anxiety disorders, pain, addiction disorders, and sleep disorders.

[0014] The first aspect of the present disclosure relates to and provides a compound of formula (I) or (II):

[0015]

[0016] Wherein:

[0017] R1, including E, wherein E is carbon (C) rather than nitrogen (N), and E is connected to J or D by a double bond, R1 is selected from 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-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted or disubstituted, wherein 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 ) a group consisting of cycloalkyl;

[0018] R2, R3 and R4 are independently selected from 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 each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two or all of R2, R3 and R4;

[0019] R5=H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R5 is substituted by carbon with Y, Z1 and Z2, wherein R 5’ As defined herein;

[0020] R 5’ = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or two heteroaryl ring systems (5-6 membered ring) fused together; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, (C 3-7 ) a group consisting of heterocycloalkyl;

[0021] R6=H, F, CH3, alkyl, substituted alkyl, (C 1-3) fluoroalkyl, cycloalkyl, R6 is linked to R as an alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged-ring structure;

[0022] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R7 is substituted by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein;

[0023] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R8 is linked to R as an alkyl 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged-ring structure;

[0024] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R9 is linked to R6 or R 12 to form a (C 1-3 ) alkyl bridged-ring structure;

[0025] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is linked to R6 or R 11 to form a (C 1-3 ) alkyl bridged-ring structure;

[0026] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is linked to R6 to form a (C 1-3 ) alkyl bridged-ring structure;

[0027] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 to form a (C 1-3 ) alkyl bridged-ring structure;

[0028] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b= alkyl, cycloalkyl, fluoroalkyl); wherein the carbon atom at the 2-position of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the carbon atom at the 2-position of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0029] Y = O, NH, none (R 5’ directly attached to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (wherein R a = alkyl, cycloalkyl, heteroalkyl), or Y can be selected as a preferred linking group, as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0030] Z1, Z2 = H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 2-7 )cycloalkyl or independently selected from one of these groups;

[0031] In addition, wherein:

[0032] The fused or unfused ring system A-B-J-D-E is a 5-membered heteroaryl, such as imidazole (wherein A, J = nitrogen, and B, E, D = carbon), pyrazole (when A, B = nitrogen, and D, E, J = carbon) fused or unfused with another ring system;

[0033] The fused ring system B-J-M-G-K-L is an arrangement of these listed variables, providing a group consisting of a 6-membered aromatic group, a 6-membered aryl group, a 6-membered substituted aromatic group, a 6-membered substituted aryl group, a 6-membered substituted heteroaryl group, a 6-membered unsubstituted heteroaryl group, a 5- or 6-membered cycloalkyl group, and a 5- or 6-membered heterocycloalkyl group;

[0034] Among them, the preferred groups are:

[0035] A = nitrogen, such as an imidazole or pyrazole ring system;

[0036] B = carbon or nitrogen;

[0037] J = carbon or nitrogen;

[0038] D = carbon;

[0039] E = carbon, wherein R1 is as defined above;

[0040] M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N;

[0041] G = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O;

[0042] K = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and

[0043] L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O and N.

[0044] In more specific (i.e., preferred) embodiments, the present disclosure provides compounds having Formulas I-a and II-a, wherein the ring system fused to the 6-membered ring (illustrated by the A-B-J-D-E variables in Formulas (I) or (II)) is preferably an imidazo ring system, as shown herein according to Embodiment Formulas I-a or II-a, respectively:

[0045]

[0046] wherein:

[0047] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, 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 said aryl, aromatic group 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;

[0048] 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 each of R2, R3 and R4 is 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;

[0049] R5 = H, F, CH3, alkyl, substituted alkyl, (C 1-3)The fluoroalkyl group, cycloalkyl group, and R5 is substituted by a carbon atom bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0050] R 5’ = aryl group or aryl, heteroaryl (5-6 membered ring), substituted aryl group or aryl, substituted heteroaryl or a fused bicyclic heteroaryl ring system (5-6 membered ring); wherein the aryl group, 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, (C 3-7 )heterocycloalkyl;

[0051] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is attached to R 10 or R 11 to form a (C 1-3 )alkyl bridged ring structure;

[0052] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is substituted by a carbon atom bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0053] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 )alkyl bridged ring structure;

[0054] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 )alkyl bridged ring structure;

[0055] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, or R 10 is attached to R6 or R 11 to form a (C 1-3 )alkyl bridged ring structure;

[0056] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is linked to R6 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure;

[0057] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure;

[0058] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b = alkyl, cycloalkyl, fluoroalkyl); the carbon atom at the 2-position of the piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the carbon atom at the 2-position of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0059] Y = O, NH, none (R 5’ is directly linked to the carbon atom bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be a preferred linking group, a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0060] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7 ) cycloalkyl or independently selected from one of these groups;

[0061] In addition, where:

[0062] The fused ring system B-J-M-G-K-L is an arrangement of these listed variables to provide a group consisting of a 6-membered aryl, 6-membered aromatic group, 6-membered substituted aryl, 6-membered substituted aromatic group, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl;

[0063] The preferred groups are:

[0064] M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N;

[0065] G = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O;

[0066] K = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and

[0067] L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O and N.

[0068] In more specific (i.e., preferred) embodiments, the present disclosure provides compounds having Formulae I-b and II-b, wherein the ring system fused to the 6-membered ring (illustrated by the A-B-J-D-E variables in Formula (I) or (II)) is preferably a pyrazolo ring system, as shown herein according to Embodiment Formulae I-b or II-b, respectively:

[0069]

[0070] wherein:

[0071] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5- or 6-membered ring), substituted aryl or aromatic group, substituted heteroaryl (5- or 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 aryl, aromatic group 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;

[0072] 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 each of R2, R3 and R4 is 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;

[0073] R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3 ) fluoroalkyl, cycloalkyl, R5 is substituted by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein;

[0074] R 5’ = aryl, aryl, heteroaryl (5-6 membered ring), substituted aryl or aryl, substituted heteroaryl or a fused two heteroaryl ring system (5-6 membered ring); wherein the aryl, 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;

[0075] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R6 is attached to R as an alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0076] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R7 is substituted by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein;

[0077] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0078] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0079] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is attached to R6 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0080] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is linked to R6 as alkyl to form a (C 1-3 ) alkyl bridged-ring structure;

[0081] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 as alkyl to form a (C 1-3 ) alkyl bridged-ring structure;

[0082] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the 2-position carbon atom of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the 2-position carbon atom of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0083] Y = O, NH, none (R 5’ is directly linked to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y may alternatively be a preferred linking group, a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0084] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7 ) cycloalkyl or independently selected from one of these groups;

[0085] Furthermore, wherein:

[0086] The fused ring system B-J-M-G-K-L is an arrangement of these listed variables to provide a group consisting of 6-membered aryl, 6-membered aromatic group, 6-membered substituted aryl, 6-membered substituted aromatic group, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl and 5- or 6-membered heterocycloalkyl;

[0087] Among them, the preferred groups are:

[0088] M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N;

[0089] G = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O;

[0090] K = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and

[0091] L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O and N.

[0092] Another embodiment of the present disclosure relates to preferred compounds, wherein the imidazole-fused six-membered ring is preferred, as shown herein according to Embodiment Formulas I-a1 or II-a1, respectively:

[0093]

[0094] wherein:

[0095] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, 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 aryl, aromatic group 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;

[0096] 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 each of R2, R3 and R4 is 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;

[0097] R5 = H, F, CH3, alkyl, substituted alkyl, (C 1-3) fluoroalkyl, cycloalkyl, R5 is substituted by carbon with Y, Z1 and Z2, wherein R 5’ As defined herein;

[0098] R 5’ = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or two heteroaryl ring systems (5-6 membered ring) fused together; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, (C 3-7 ) a group consisting of heterocycloalkyl;

[0099] R6=H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R6 as an alkyl group connected to R 10 or R 11 Formation (C 1-3 ) an alkyl bridged ring structure;

[0100] R7=H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R7 is substituted by carbon with Y, Z1 and Z2, wherein R 5’ As defined herein;

[0101] R8=H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R8 as an alkyl group connected to R 10 、R 11 or R 12 Formation (C 1-3 ) an alkyl bridged ring structure;

[0102] R9=H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R9 as an alkyl group connected to R6 or R 12 Formation (C 1-3 ) an alkyl bridged ring structure;

[0103] R 10 =H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 As an alkyl group connected to R6 or R 11 Formation (C 1-3 ) an alkyl bridged ring structure;

[0104] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is linked to R6 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure;

[0105] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure;

[0106] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the 2-position carbon atom of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the 2-position carbon atom of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0107] Y = O, NH, none (R 5’ is directly linked to the carbon atom bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be a preferred linking group, a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0108] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 [[ID=S]] 1-3 ) fluoroalkoxy, (C 2-7 ) cycloalkyl or independently selected from one of these groups;

[0109] wherein the preferred groups are:

[0110] L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N.

[0111] Another embodiment of the present disclosure relates to compounds wherein the imidazole-fused six-membered ring is preferred, as shown herein according to Embodiment Formulas I-a2 or II-a2 respectively:

[0112] [[ID=G6]](

[0113] Wherein:​

[0114] 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-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted or disubstituted, wherein 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 ) a group consisting of cycloalkyl;

[0115] R2, R3 and R4 are independently selected from 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 each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two or all of R2, R3 and R4;

[0116] R5=H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R5 is substituted by carbon with Y, Z1 and Z2, wherein R 5’ As defined herein;

[0117] R 5’ = aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or two heteroaryl ring systems (5-6 membered ring) fused together; wherein the aromatic, aryl or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, (C 3-7 ) a group consisting of heterocycloalkyl;

[0118] R6=H, F, CH3, alkyl, substituted alkyl, (C 1-3Fluoroalkyl, cycloalkyl, and R6 is connected to R as an alkyl group 10 or R 11 forms a (C 1-3 ) alkyl bridged-ring structure;

[0119] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is substituted by a carbon atom bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0120] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is connected to R as an alkyl group 10 , R 11 or R 12 forms a (C 1-3 ) alkyl bridged-ring structure;

[0121] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is connected to R6 or R 12 forms a (C 1-3 ) alkyl bridged-ring structure;

[0122] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is connected to R6 or R 11 forms a (C 1-3 ) alkyl bridged-ring structure;

[0123] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is connected to R6 to form a (C 1-3 ) alkyl bridged-ring structure;

[0124] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is connected to R9 to form a (C 1-3 ) alkyl bridged-ring structure;

[0125] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b= alkyl, cycloalkyl, fluoroalkyl); wherein the carbon atom at the 2-position of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the carbon atom at the 2-position of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0126] Y = O, NH, none (R 5’ directly attached to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (wherein R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be selected as a preferred linking group as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0127] Z1, Z2 = H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 2-7 )cycloalkyl or independently selected from one of these groups.

[0128] Another embodiment of the present disclosure relates to preferred compounds, wherein the imidazole-fused six-membered ring is preferred, as shown herein according to Scheme I-a3 or II-a3 respectively:

[0129]

[0130] Wherein:

[0131] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, 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 aryl, aromatic group 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;

[0132] 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)A fluoroalkoxy group and a (C 3-7 ) cycloalkyl group; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4;

[0133] R5 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R5 is substituted by a carbon bearing Y, Z1, and Z2, wherein R 5’ is as defined herein;

[0134] R 5’ = aryl or aromatic group, heteroaryl (5- to 6-membered ring), substituted aryl or aromatic group, substituted heteroaryl or a fused bicyclic heteroaryl ring system (5- to 6-membered ring); wherein the aryl, aromatic group, 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, (C 3-7 ) heterocycloalkyl;

[0135] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R6 is attached as an alkyl group to R 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0136] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R7 is substituted by a carbon bearing Y, Z1, and Z2, wherein R 5’ is as defined herein;

[0137] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R8 is attached as an alkyl group to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0138] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, R9 is attached as an alkyl group to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0139] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is linked to R6 or R as an alkyl group to form a (C 11 ) alkyl bridged-ring structure; 1-3 ) alkyl bridged-ring structure;

[0140] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is linked to R6 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure;

[0141] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure;

[0142] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the 2-position carbon atom of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the 2-position carbon atom of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0143] Y = O, NH, none (R 5’ is directly linked to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be a preferred linking group, a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0144] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7 ) cycloalkyl or independently selected from one of these groups.

[0145] Another embodiment of the present disclosure relates to preferred compounds, wherein the pyrazole-fused six-membered ring is preferred, as shown herein in the embodiments according to Formula I-b1 or II-b1 respectively:

[0146]

[0147] Wherein:

[0148] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, 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 aryl, aromatic group 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;

[0149] 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 each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with at most three (3) substituents, and the substituents are independently selected from one, two or all of R2, R3 and R4;

[0150] R5 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R5 is substituted by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein;

[0151] R 5’ = aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, substituted heteroaryl or a fused two-heteroaryl ring system (5-6 membered ring); wherein the aryl, aromatic group 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, (C 3-7 )heterocycloalkyl;

[0152] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached to R as an alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0153] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0154] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0155] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0156] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is attached to R6 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0157] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is attached to R6 to form a (C 1-3 ) alkyl bridged ring structure;

[0158] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is attached to R9 to form a (C 1-3 ) alkyl bridged ring structure;

[0159] X = CH2, O, none (e.g., to provide a five - membered pyrrolidine ring), CR a R b (where Ra and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the carbon atom at the 2-position of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the carbon atom at the 2-position of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0160] Y = O, NH, none (R 5’ directly attached to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (wherein R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be selected as a preferred linking group as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0161] Z1, Z2 = H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 2-7 )cycloalkyl or independently;

[0162] Among which the preferred groups are:

[0163] M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4 and N.

[0164] Another embodiment of the present disclosure relates to preferred compounds, wherein the pyrazole-fused six-membered ring is preferred, as shown in the embodiments according to Formula I-b2 or II-b2 herein respectively:

[0165]

[0166] Wherein:

[0167] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, substituted heteroaryl (5-6 membered ring); or, when R1 is a 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 aryl, aromatic group 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;

[0168] 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 each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4;

[0169] R5 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, R5 is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0170] R 5’ = aryl or aromatic group, heteroaryl (5 - 6 membered ring), substituted aryl or aromatic group, substituted heteroaryl or fused two heteroaryl ring system (5 - 6 membered ring); wherein the aryl, aromatic group, 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, (C 3-7 )heterocycloalkyl;

[0171] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, R6 is attached as an alkyl to R 10 or R 11 to form a (C 1-3 )alkyl bridged ring structure;

[0172] R7 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, R7 is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0173] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, R8 is attached as an alkyl to R 10 , R 11 or R 12 to form a (C 1-3 )alkyl bridged ring structure;

[0174] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is connected to R6 or R 12 to form a (C 1-3 ) alkyl bridged-ring structure;

[0175] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is connected to R6 or R 11 to form a (C 1-3 ) alkyl bridged-ring structure;

[0176] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is connected to R6 to form a (C 1-3 ) alkyl bridged-ring structure;

[0177] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is connected to R9 to form a (C 1-3 ) alkyl bridged-ring structure;

[0178] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a [[ID=5i]]and R b = alkyl, cycloalkyl, fluoroalkyl); where the 2-position carbon atom of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the 2-position carbon atom of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0179] Y = O, NH, none (R 5’ is directly connected to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be a preferred linking group, a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0180] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7)cycloalkyl or independently selected from one of these groups.

[0181] Another embodiment of the present disclosure relates to preferred compounds, wherein the pyrazole-fused six-membered ring is preferred, as shown in the embodiments of Formula I-b3 or II-b3 herein respectively:

[0182]

[0183] wherein:

[0184] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, 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 aryl, aromatic group 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;

[0185] 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 each of R2, R3 and R4 is 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;

[0186] R5 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R5 is substituted by carbon bearing Y, Z1 and Z2, where R 5’ is defined as herein;

[0187] R 5’ = aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, substituted heteroaryl or fused two-heteroaryl ring system (5-6 membered ring); wherein the aryl, aromatic group or heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted, and the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C1-4 ) an alkoxy group, a halogen, (C 1-3 ) a fluoroalkyl group, (C 1-3 ) a fluoroalkoxy group, (C 3-7 ) a cycloalkyl group, (C 3-7 ) a heterocycloalkyl group;

[0188] R6 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, and R6 is attached to R as an alkyl group 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0189] R7 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, and R7 is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0190] R8 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0191] R9 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0192] R 10 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, or R 10 is attached to R6 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0193] R 11 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, or R 11 is attached to R6 to form a (C 1-3 ) alkyl bridged ring structure;

[0194] R 12 = H, F, CH3, an alkyl group, a substituted alkyl group, (C 1-3 ) a fluoroalkyl group, a cycloalkyl group, or R 12As an alkyl group is linked to R9 to form a (C 1-3 ) alkyl bridged-ring structure;

[0195] X = CH2, O, none (e.g., providing a five-membered pyrrolidine ring), CR a R b (wherein R a and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the carbon atom at the 2-position of the piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the carbon atom at the 2-position of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0196] Y = O, NH, none (R 5’ is directly linked to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (wherein R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be selected as a preferred linking group as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0197] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7 ) cycloalkyl or independently selected from one of these groups.

[0198] In a more specific (i.e., preferred) embodiment of the present disclosure, when referring to compounds, wherein the stereocenters and the main backbone ring are preferred, as shown by the exemplary formulas as shown in the embodiments according to Formulas I-a4, I-a5, I-a6, II-a4, II-a5 or II-a6 herein:

[0199]

[0200] Wherein:

[0201] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, 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 aryl, aromatic group or heteroaryl is unsubstituted, monosubstituted or disubstituted, wherein 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;

[0202] 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 each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4;

[0203] R5 is H or is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0204] R 5’ = aryl or aromatic group, heteroaryl (5-6 membered ring), substituted aryl or aromatic group, substituted heteroaryl, or a fused two heteroaryl ring system (5-6 membered ring); wherein the aryl, aromatic group, 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, (C 3-7 ) heterocycloalkyl;

[0205] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached as an alkyl to R 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0206] R7 is H or is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein;

[0207] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached as an alkyl to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0208] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is linked to R6 or R 12 to form a (C 1-3 ) alkyl bridged-ring structure;

[0209] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is linked to R6 or R 11 to form a (C 1-3 ) alkyl bridged-ring structure;

[0210] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is linked to R6 to form a (C 1-3 ) alkyl bridged-ring structure;

[0211] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 to form a (C 1-3 ) alkyl bridged-ring structure;

[0212] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the 2-position carbon atom of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the 2-position carbon atom of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0213] Y = O, NH, none (R 5’ is directly linked to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be selected as a preferred linking group as a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl;

[0214] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7) a cycloalkyl group or independently selected from one of these groups; and

[0215] L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N.

[0216] In a more specific (i.e., preferred) embodiment of the present disclosure, when referring to a compound, where the stereocenter and the main backbone ring are preferred, as shown by the exemplary formulas in the embodiments according to Formulas I-b4, I-b5, I-b6, II-b4, II-b5, or II-b6 herein:

[0217]

[0218] Where:

[0219] R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl, heteroaryl (5-6 membered ring), substituted aryl 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 aryl, 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;

[0220] 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 each of R2, R3, and R4 is 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;

[0221] R5 is H or substituted by carbon bearing Y, Z1, and Z2, where R 5’ as defined herein;

[0222] R 5’= an aryl group or aryl, heteroaryl (5-6 membered ring), substituted aryl group or aryl, substituted heteroaryl or fused two heteroaryl ring system (5-6 membered ring); wherein said aryl group, 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, (C 3-7 ) heterocycloalkyl;

[0223] R6 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached to R 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0224] R7 is H or substituted by carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein;

[0225] R8 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0226] R9 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure;

[0227] R 10 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 10 is attached to R6 or R 11 to form a (C 1-3 ) alkyl bridged ring structure;

[0228] R 11 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 11 is attached to R6 to form a (C 1-3 ) alkyl bridged ring structure;

[0229] R 12 = H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, or R 12 is linked to R9 as alkyl to form a (C 1-3 ) alkyl bridged ring structure;

[0230] X = CH2, O, none (e.g., to provide a five-membered pyrrolidine ring), CR a R b (where R a and R b = alkyl, cycloalkyl, fluoroalkyl); wherein the 2-position carbon atom of piperidine or pyrrolidine is preferably in the absolute (S)-configuration; conversely, the 2-position carbon atom of the morpholine ring (when X = O, oxygen) is preferably in the absolute (R)-configuration;

[0231] Y = O, NH, none (R 5’ is directly linked to the carbon bearing the Z1 and Z2 groups), CH2OR 5’ , CH2, NR a (where R a = alkyl, cycloalkyl, heteroalkyl), or Y can alternatively be a preferred linking group, a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and

[0232] Z1, Z2 = H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, (C 2-7 ) cycloalkyl or independently selected from one of these groups;

[0233] wherein the preferred groups are:

[0234] M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4 and N.

[0235] The exemplary preferred compounds of Formulas I, II, II-a and / or II-b and also the sub-formulas included in the main formula and in the preferred embodiments are shown in Table 1 below.

[0236] The preferred compounds of the present disclosure are the compounds given below as Examples 1 - 263. These compounds are shown in the Examples section of the present disclosure and are shown below. If any of the example numbers and / or structures of the compounds shown in Table 1 conflict with those given in the Working Examples section (Table 3), the numbers and / or structures given in Table 3 shall prevail.

[0237] Table 1

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] More preferred compounds in the present disclosure are those compounds in the examples listed below: 4, 6, 7, 8, 10, 12, 13, 20, 22, 24, 25 - 29, 34, 40, 42 - 50, 53 - 64, 66 - 69, 73, 75, 78, 80, 89, 90, 92, 94, 95, 97, 107, 111, 112, 117 - 119, 122 - 142, 147 - 151, 156, 158, 171 - 183, 185 - 198, 201 - 203, 205, 207, 208, 210 - 214, 223 and 224.

[0260] The most preferred compounds in the present disclosure are those compounds in the examples listed below: 53, 55, 66, 95, 112, 118, 119, 122, 123, 124, 129, 130, 131, 134, 135, 138, 139, 140, 141, 142, 147, 148, 156, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 191, 195, 203, 205, 211, 223 and 224.

[0261] Unless otherwise indicated, any embodiment given herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structure of the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, 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 includes various isotopically labeled compounds as defined herein, such as those that are radioactive isotopes (such as 3 H, 13 C, and 14 C). These isotopically labeled compounds are useful in metabolic studies (preferably using 14 C), reaction kinetics studies (e.g., using 2 H or 3H), very useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution, or for radioactive treatment of patients. In particular, 18 F or labeled compounds may be particularly suitable for PET or SPECT studies. The isotopically labeled compounds and prodrugs of the present disclosure can generally be prepared by substituting non-isotopically labeled reagents with readily available isotopically labeled reagents in the following schemes or examples and preparation processes.

[0262] Many of the compounds used in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter can exist in the R or S configuration, and the use of the R and S symbols is consistent with the rules described in Pure Appl.Chem. 1976, 45, 11-30. The present disclosure also relates to all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compound or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0263] In addition, multiple substituents on the piperidine ring or pyrrolidine ring can also be in a cis or trans relationship with respect to the plane of the piperidine ring or pyrrolidine ring. Although the forms or geometric isomers are not explicitly shown in the structural formulas described herein, these forms or geometric isomers are intended to be included within the scope of the present disclosure. With respect to the methods and compositions of the present disclosure, the mention of one or more compounds is intended to cover all possible isomeric forms of the compound and mixtures thereof, unless a specific isomeric form is specifically mentioned.

[0264] The pharmaceutically acceptable salts used herein refer to the pharmaceutically active and non-toxic base salts and acid salts of the compounds according to the present disclosure. The acid addition salt forms of compounds that exist as bases in free form can be obtained by treating the free base form with an appropriate acid, such as inorganic acids, such as hydrohalic acids (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as 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, for example, WO 01 / 062726, U.S. Patent No. 8,492,416B2, US2017 / 0022208A1, and US2017 / 0253603A2).

[0265] Compounds containing acidic protons can be converted into their therapeutically active, non-toxic base addition salt forms, such as metal salts or amine salts, by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts (such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc.), organic base salts, and salts formed with amino acids (such as arginine, lysine, etc.). Conversely, these salt forms can be converted back to the free form by treatment with an appropriate base or acid. The compounds and their salts can exist in solvated forms, which are also included within the scope of this disclosure. Such solvates include, for example, hydrates, alcoholates, etc.

[0266] In this specification, the word "comprise" or its variants (such as "comprises" or "comprising") shall be understood to imply the inclusion of the stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components). The singular forms "a", "an", and "the" include plural forms unless the context clearly dictates otherwise. The term "including" is used to mean "including but not limited to", and "including" and "including but not limited to" can be used interchangeably. The term "substance use disorder" or "substance use disorder" (SUD) can include addiction to a variety of stimulants (e.g., including but not limited to cocaine, methamphetamine, nicotine, etc.) or depressants (e.g., including but not limited to opioids, alcohol, etc.). The term "agent" is used herein to denote a chemical compound (such as an organic compound or a mixture of chemical compounds). Agents include, for example, agents of known structure whose orexin and / or κ-opioid receptor antagonist / modulator activity may render them suitable as "therapeutic agents" in the methods and compositions of this disclosure. When the term "=" is used to describe a substituent (such as R1), it shall be understood to mean "selected from the group consisting of". When the term "=" is used to describe multiple possible substituents, it shall be understood that each possible substituent can be independently selected from the listed group (e.g., "Z1,Z2 =" means "Z1 and Z2 are independently selected from the group consisting of the following groups").

[0267] The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is a non-limiting (unless otherwise stated) example of a monocyclic aromatic or aryl ring system.

[0268] The term "heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic or aryl ring system having from 1 to 3 heteroatoms or heteroatom groups, wherein the heteroatom or heteroatom group in each ring is selected from O, N, NH or S and is present in a chemically stable arrangement. In "heteroaryl" embodiments of such bicyclic aromatic or aryl ring systems: both rings can be aromatic or aryl; one or both rings can contain said heteroatom or heteroatom group. Examples of heteroaryl rings 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 (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

[0269] The term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused or (C 1-3 ) alkyl-bridged bicyclic carbocyclic system that is not aromatic or aryl. A cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantly and decalinyl.

[0270] The compounds of the present disclosure also include prodrugs, analogs or derivatives. The term "prodrug" is a term well recognized in the art and is intended to cover compounds or agents that are converted to orexins and κ-opioid receptor antagonists under physiological conditions. A common method of preparing a prodrug is to select a group that hydrolyzes or metabolizes under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is converted to orexins and / or κ-opioid receptor antagonists (i.e., as its antagonist and / or modulator) by the enzymatic activity of the host animal.

[0271] The present disclosure also includes isotopically labeled compounds, particularly 2Compounds of all structural formulas labeled with H (deuterium), which are identical to the compounds of any structural formula described herein, except that one or more atoms are replaced with atoms having the same atomic number but an atomic mass different from the atomic mass commonly found in nature. Isotopically labeled compounds, particularly 2 All structural formula compounds labeled with H (deuterium) and their salts are within the scope of this disclosure. Replacing hydrogen with a heavier isotope 2 H (deuterium) may result in higher metabolic stability, such as increased in vivo half-life or reduced dose requirements, or may reduce inhibition of cytochrome P450 enzymes, thereby improving safety, for example. In another aspect of the embodiments of this disclosure, the compounds of all structural formulas are not isotopically labeled. However, isotopically labeled compounds of all structural formulas can be prepared by those skilled in the art according to the methods described below, but using appropriate isotopic variants of the appropriate reagents or starting materials.

[0272] In some embodiments, the present disclosure provides compositions that comprise any one or more such compounds, and / or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. The present disclosure also provides pharmaceutical compositions that comprise one or more compounds of the present disclosure and a pharmaceutically acceptable carrier or excipient. In some embodiments, the present disclosure provides pharmaceutical compositions that comprise a compound, a 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 a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the present disclosure provides such pharmaceutical compositions that further comprise at least one second therapeutic agent. The present disclosure also provides pharmaceutical compositions that comprise one or more compounds of the present disclosure (or their pharmaceutically acceptable salts, etc.) (i.e., as active agents, therapeutic agents) and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions comprise a therapeutically effective amount of one or more such compounds or analogs thereof (i.e., active agents) or suitable moieties thereof. The compositions may optionally comprise 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 excipients 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, antimicrobials, 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)). Unless 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, 21 stEd, Lippincott Williams and Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5 th Ed, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3 rd 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 chosen. Potential routes of administration of a pharmaceutical composition comprising a compound or an analogue thereof disclosed herein may include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drops), ophthalmic (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, which are known to those of ordinary skill in the art.

[0273] In some embodiments, the compounds and compositions of the present disclosure can be used as antagonists and / or modulators of orexin receptors and / or κ-opioid receptors (or κ-opioid receptor, abbreviated as KOR or KOP, whose ligand is Ketazocine, a G protein-coupled receptor encoded by the OPRK1 gene in humans). In a preferred embodiment, the compounds and / or compositions disclosed herein can be antagonists of one or more orexin receptors (such as one or both of OX1R or OX2R) and antagonists and / or modulators of KOR. 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 antagonize OX1R or OX2R compared with another orexin receptor. Therefore, these compounds and / or compositions can be referred to herein as "orexin receptor antagonists". In some embodiments, these compounds can be antagonists and / or modulators of the κ-opioid receptor. In some embodiments, the compounds and / or compositions of the present disclosure can be antagonists of one or more orexin receptors (i.e., orexin receptor antagonists), but not antagonists of KOR. In some embodiments, for example, one or more compounds and / or their combinations of the present disclosure are designed and preferably provide the following properties (measured by standard in vitro cell assays, such as those described in the examples herein) to achieve an effective therapeutic effect: 1) OX1R Kb < 100 nM, OX2R Kb > 500 nM, KOR Ki < 1000 nM; 2) OX1R Kb < 100 nM, OX2R Kb < 1000 nM, KOR Ki < 1000 nM; or 3) OX1R Kb < 100 nM, OX2R Kb > 10000 nM, KOR Ki < 1000 nM; 4) OX1R Kb < 100 nM, OX2R Kb < 1000 nM, KOR Ki < 10000 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 assays, the compounds and / or compositions of the present disclosure can be tested using animal models (such as rats) by measuring primary dependence indices (such as but not limited to time to first drug injection, total number of drug injections, drug intake rate, and total number of inactive lever presses), progressive ratio (such as but not limited to time to first drug injection, break point, final completion ratio, and total active and inactive lever presses), and reinstatement (such as but not limited to time to first lever press and total active and inactive lever presses).These trials and in vivo evaluations were designed, planned, and expected to demonstrate the therapeutic utility and in vivo efficacy of the compounds - reducing the intake and motivation of illicit drug abuse - using techniques known to those of ordinary skill in the art (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 would be understood by those of ordinary skill in the art, other test methods may also be appropriate.

[0274] In some embodiments, the present disclosure provides a method for preventing or treating a disorder in a subject in need thereof selected from the group consisting of: central nervous system (CNS) disorders, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegenerative diseases, autism, schizophrenia, and Alzheimer's disease (AD), the method comprising administering to the subject any such one or more compounds and / or a composition comprising one or more such compounds, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the method may comprise administering a composition comprising a therapeutically effective amount of a compound, 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 the compound in an unlabeled form or an isotope-labeled form, wherein the structure of the compound is as shown in the formula, and wherein 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, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof disclosed herein to prepare a medicament for preventing and / or treating a disorder in a subject in need thereof selected from the group consisting of: central nervous system (CNS) disorders, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegenerative diseases, autism, schizophrenia, and Alzheimer's disease (AD). Substance addiction, for example, may include a person's addiction to one or more opioids (such as, but not limited to, heroin, morphine, oxycodone (such as OxyContin, Percocet), fentanyl, and / or hydrocodone (such as Vicodin)), one or more stimulants (such as amphetamine (such as Adderall, Ritalin), cocaine, crack cocaine, methamphetamine), one or more sedatives and / or tranquilizers (such as, but not limited to, benzodiazepines (such as Valium, alprazolam, clonazepam) or barbiturates (such as pentobarbital, luminal, phenobarbital)), or other addictive substances known to one of ordinary skill in the art. In some embodiments, the use may comprise a composition comprising a therapeutically effective amount of a compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the use may comprise a composition comprising a pharmaceutically acceptable salt or isotope-labeled form of the compound. In some embodiments, the use may comprise a composition comprising the compound in an unlabeled form or an isotope-labeled form, wherein the structure of the compound is as shown in the formula, and wherein 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 may include using any intermediate disclosed herein. As would be understood by one of ordinary skill in the art, other embodiments are also contemplated herein.

[0275] The term "therapeutically effective amount" means 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 to be treated, or at least to alleviate to some extent the medical condition or one or more symptoms or complications of the condition, in at least some portion of the subjects to which the compound is administered. The term "therapeutically effective amount" also means an amount of a compound sufficient to elicit a biological or medical response in a cell, tissue, organ, or person 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 preventing the condition. The terms "prevent", "preventing", and "prevention" include precluding a medical condition, reducing the risk of development of a medical condition, and delaying the 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" may be used interchangeably herein.

[0276] In this specification, the word "comprise" or its variants (such as "comprises" or "comprising") shall be understood to imply the inclusion of the stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components). The singular forms "a", "an", and "the" include plural forms unless the context clearly dictates otherwise. The symbol "=" means "is" when describing a structural formula. The term "including" is used to mean "including but not limited to", and "including" and "including but not limited to" may be used interchangeably. The term "agent" is used herein to denote a chemical compound (such as an organic compound or a mixture of chemical compounds). Agents include, for example, agents of known structure whose orexin antagonist activity may render them suitable as "therapeutic agents" in the methods and compositions disclosed herein. In addition, those of ordinary skill in the art recognize that the following abbreviations are commonly used:

[0277] Me: Methyl

[0278] Et: Ethyl

[0279] t-Bu: tert-Butyl

[0280] Ar: Aryl

[0281] Ph: Phenyl

[0282] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0283] Bn: Benzyl

[0284] Ac: Acetyl

[0285] Boc: tert-Butyloxycarbonyl

[0286] BSA: Bovine serum albumin

[0287] CbzCl: Benzyl chloroformate

[0288] CDI: Carbonyl diimidazole

[0289] DCM: Dichloromethane

[0290] DCE: Dichloroethane

[0291] DEAD: Diethyl azodicarboxylate

[0292] DIPEA: N,N-Diisopropylethylamine

[0293] DMF: N,N-Dimethylformamide

[0294] DMSO: Dimethyl sulfoxide

[0295] CH2Cl2: Dichloromethane

[0296] EDC: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide

[0297] Et3N: Triethylamine

[0298] EtOAc: Ethyl acetate

[0299] EtOH: Ethanol

[0300] HCl: Hydrogen chloride

[0301] HOAt: 1-Hydroxy-7-azabenzotriazole

[0302] HOBT: Hydroxybenzotriazole hydrate

[0303] LCMS: Liquid chromatography mass spectrometry

[0304] HPLC: High performance liquid chromatography

[0305] Hunig's base: N,N - Diisopropylethylamine

[0306] MeOH: Methanol

[0307] MgSO4: Magnesium sulfate

[0308] MTBE: Methyl tert - butyl ether

[0309] NaHCO3: Sodium bicarbonate

[0310] Na2CO3: Sodium carbonate

[0311] K2CO3: Potassium carbonate

[0312] NaOH: Sodium hydroxide

[0313] NMM: N - Methylmorpholine

[0314] PtO2: Platinum(IV) oxide

[0315] Pd: Palladium

[0316] Pd / C: Palladium on carbon

[0317] PyCIu: 1-(Chloro - 1 - pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate

[0318] RT or rt: Room temperature

[0319] SOCl2: Thionyl chloride

[0320] THF: Tetrahydrofuran

[0321] TFA: Trifluoroacetic acid

[0322] X - Phos: 2 - Dicyclohexylphosphino - 2',4',6' - triisopropylbiphenyl

[0323] HATU: (1 - [Bis(dimethylamino)methylene] - 1H - 1,2,3 - triazolo[4,5 - b]pyridinium 3 - oxid hexafluorophosphate

[0324] NMR: Nuclear magnetic resonance

[0325] ESI: Electrospray ionization

[0326] MS: Mass spectrometry reaction

[0327] Thus, in some embodiments, the present disclosure provides compounds of the formula shown below, compositions comprising the compounds, methods of preparation (e.g., in the Examples section), and methods of use (e.g., treating disease symptoms):

[0328]

[0329]

[0330]

[0331] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein, if present:

[0332] R1 includes E as carbon (C) rather than nitrogen (N), and in Formula I, E is connected to J or D by a double bond, or in Formula II, E is connected to A or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl (optionally a 5 - or 6 - membered heteroaryl), substituted aryl or aromatic group, and substituted heteroaryl (optionally a 5 - or 6 - membered heteroaryl); wherein, if R1 is a heteroaryl, R1 is optionally a 5 - or 6 - membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the aryl, aromatic group, 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;

[0333] R2, R3, and R4 are independently selected from the group consisting of H, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 3-7 )cycloalkyl, and halogen (optionally F, Cl, or Br); wherein each of R2, R3, and R4 is 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;

[0334] R5 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3)The group consisting of fluoroalkyl and cycloalkyl, where R5 is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ as defined herein;

[0335] R 5’ is selected from the group consisting of aryl, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aryl or aryl, substituted heteroaryl or a fused bicyclic heteroaryl ring system (optionally containing a 5- or 6-membered ring); where the aryl, 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;

[0336] R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R6 is attached to R 10 or R 11 to form a (C 1-3 )alkyl bridged ring structure;

[0337] R7 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R7 is substituted by a carbon bearing Y, Z1, and Z2, where R 5’ as defined herein;

[0338] R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 )alkyl bridged ring structure;

[0339] R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 )alkyl bridged ring structure;

[0340] R 10 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 )fluoroalkyl, cycloalkyl, and R 10 is attached to R6 or R 11Form (C 1-3 ) an alkyl bridged-ring structure;

[0341] R 11 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 is connected as an alkyl to R6 to form (C 1-3 ) an alkyl bridged-ring structure;

[0342] R 12 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 12 is connected as an alkyl to R9 to form (C 1-3 ) an alkyl bridged-ring structure;

[0343] X is selected from the group consisting of none (optionally providing a five-membered pyrrolidine ring), CH2, O, and CR a R b wherein R a and R b are selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and wherein:

[0344] The carbon atom at the 2-position of the piperidine or pyrrolidine ring is optionally in the absolute (S)-configuration; or,

[0345] The carbon atom at the 2-position of the morpholine ring (when X is oxygen) is optionally in the absolute (R)-configuration;

[0346] Y is selected from the group consisting of none (to provide R 5’ directly connected to the carbon bearing the Z1 and Z2 groups); O; NH; CH2OR 5’ ; CH2; NR a and a 5- or 6-membered heteroaryl, wherein R a is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and,

[0347] Z1 and Z2 are independently selected from the group consisting of H, F, (C 1-4 ) alkyl, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 2-7 ) cycloalkyl;

[0348] And wherein:

[0349] The fused or unfused ring system A-B-J-D-E is a five-membered heteroaryl, optionally imidazole (where A and J are nitrogen, and B, E, and D are carbon); pyrazole (where A and B are nitrogen, and D, E, and J are carbon); optionally fused or unfused with one or more additional ring systems;

[0350] The fused ring system B-J-M-G-K-L is an arrangement of these listed variables, providing a group consisting of a 6-membered aromatic group, a 6-membered aryl group, a 6-membered substituted aromatic group, a 6-membered substituted aryl group, a 6-membered substituted heteroaryl group, a 6-membered unsubstituted heteroaryl group, a 5- or 6-membered cycloalkyl group, and a 5- or 6-membered heterocycloalkyl group;

[0351] And wherein, optionally:

[0352] A is nitrogen, optionally imidazole or pyrazole;

[0353] B is carbon or nitrogen;

[0354] J is carbon or nitrogen;

[0355] D is carbon;

[0356] E is carbon, where R1 is as defined above;

[0357] M is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N;

[0358] G is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O;

[0359] K is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; and,

[0360] L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N;

[0361] Or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or a combination thereof.

[0362] In a preferred embodiment, the intermediates, reaction conditions, etc. for preparing the compounds are described in detail in the Examples section and will not be elaborated here. However, those skilled in the art can understand, as in the description of this preferred aspect (i.e., introduced herein). The present disclosure also provides a method for manufacturing a pharmaceutical composition, including combining at least one compound of the present disclosure with at least one pharmaceutically acceptable excipient. Methods for preparing such combinations (i.e., at least one compound or its analogs with at least one pharmaceutical composition) are generally known in the art and are not described in detail herein but are incorporated herein.

[0363] Accordingly, in a preferred embodiment, the present disclosure provides any one of the compounds in Examples 1-263 (see Tables 1 and 3), and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. In some preferred embodiments, the compound is selected from the group consisting of the compounds in Example 4, Example 6, Example 7, Example 8, Example 10, Example 12, Example 13, Example 20, Example 22, Example 24, Examples 25-29, Example 34, Example 40, Examples 42-50, Examples 53-64, Examples 66-69, Example 73, Example 75, Example 78, Example 80, Example 89, Example 90, Example 92, Example 94, Example 95, Example 97, Example 107, Example 111, Example 112, Examples 117-119, Examples 122-142, Examples 147-151, Example 156, Example 158, Examples 171-183, Examples 185-198, Examples 201-203, Example 205, Example 207, Example 208, Examples 210-214, Example 223 and Example 224; and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. In a most preferred embodiment, the present disclosure provides a group consisting of the compounds in Example 53, Example 55, Example 66, Example 95, Example 112, Example 118, Example 119, Example 122, Example 123, Example 124, Example 129, Example 130, Example 131, Example 134, Example 135, Example 138, Example 139, Example 140, Example 141, Example 142, Example 147, Example 148, Example 156, Example 171, Example 172, Example 173, Example 174, Example 175, Example 176, Example 177, Example 178, Example 179, Example 180, Example 181, Example 182, Example 191, Example 195, Example 203, Example 205, Example 211, Example 223 and Example 224; and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. In some embodiments, the compound is unlabeled or isotopically labeled. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof; and at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle.In a preferred embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, and / or a combination thereof. In some embodiments, the composition further comprises at least one second therapeutic agent. In some preferred embodiments, the present disclosure provides a method of antagonizing and / or modulating at least one orexin receptor and / or at least one κ-opioid receptor in a cell, comprising the step of exposing the cell to a compound and / or composition of the present disclosure. Optionally, the method is carried out in vitro. In some preferred embodiments, a method of modulating at least one orexin receptor and / or at least one κ-opioid receptor in a subject in need thereof comprises the step of administering to the subject a compound and / or composition of the present disclosure. In some preferred embodiments, a method of treating a disorder in a subject in need thereof selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegenerative diseases, autism, schizophrenia, pain, Alzheimer's disease (AD), and central nervous system (CNS) disorders comprises the step of administering to the subject a compound and / or composition of the present disclosure. In some preferred embodiments, substances associated with substance addiction or substance dependence are 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 tranquilizers, benzodiazepines, and barbiturates. In some embodiments, the compound antagonizes at least one orexin receptor and / or antagonizes or modulates at least one κ-opioid receptor. In some preferred embodiments, the present disclosure provides a method of making a compound or composition of any of the foregoing claims using at least one suitable combination of the acid intermediates, amine intermediates, and methods shown in Table 2.

[0364] All references cited in the present disclosure are incorporated herein by reference in their entirety. Certain embodiments are further described in the following examples. These embodiments are provided only as examples and are not intended to limit the scope of the claims in any way.

[0365] Example

[0366] In the present disclosure, the following intermediates were prepared and used to synthesize the exemplary compounds claimed herein:

[0367] 1. Preparation of a carboxyl-containing intermediate - carboxyl group

[0368]

[0369] 2. Preparation of a secondary amine-containing intermediate - amino group

[0370]

[0371]

[0372] I. General synthetic methods and procedures

[0373] Overview:

[0374] All temperatures are expressed in degrees Celsius (°C). Commercially available starting materials are used directly without further purification. Unless otherwise stated, all reactions are carried out in dried glassware under a nitrogen atmosphere. Compounds are purified by flash column chromatography on silica gel or preparative HPLC. The compounds described in this disclosure are characterized by LC-MS data (retention time t R expressed in min; molecular weights obtained in the mass spectrum are expressed in g / mol) using the following conditions.

[0375] LC-MS under acidic conditions

[0376] Method A: Agilent 1100 series, equipped with mass spectrometry detection (MS: Agilent single quadrupole). Column: Zorbax SB (3.5 μm, 4.6 x 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.

[0377] Method B: Agilent 1100 series, equipped with mass spectrometry detection (MS: Agilent single quadrupole). Column: X-Bridge C18 (3.5 μm, 4.6 x 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.

[0378] 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. The following Schemes 1-4 illustrate the synthetic routes of the compounds of the present disclosure. Other equivalent schemes that are obvious to ordinary synthetic organic chemists or medicinal chemists can alternatively be used to synthesize different parts of the molecule, as shown in the general schemes described herein.

[0379] Synthesis of carboxyl-containing intermediates - carboxyl groups

[0380]

[0381] Step 1: Synthesis of HBS-037-036: Ethyl 3-phenyl-1H-pyrazole-5-carboxylate (0.5 g, 2.31 mmol) was dissolved in acetone (10.0 mL). K2CO3 (0.96 g, 6.9 mmol) was added, followed by 1-bromo-2-chloroethane (0.1 mL, 11.6 mmol). The reaction mixture was heated at 55 °C for 16 h. LCMS data showed the formation of the target product (m / z 279.0) and the formation of a small amount of by-products. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography with the mobile phase: EtOAc:hexane, gradient elution. 0.6 g of the liquid product was isolated (yield 93.2%). C 14 H 15 Calculated MS (ESI) mass for ClN2O2: 278.7; m / z found 279.0 [M+H] + .

[0382] Step 2: Synthesis of HBS-037-040: Compound HBS-037-036 (0.55 g, 1.97 mmol) was dissolved in dry THF (6.0 mL). DIBAL (12.0 mL, 1.0 M solution, 11.8 mmol) was added under ice bath cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data showed the formation of the target product (m / z 237.0). The reaction mixture was quenched with 1.0 N aqueous NaOH and diluted with ethyl acetate (10.0 mL). The reaction mixture was filtered through a bed of celite and washed with ethyl acetate (10.0 mL x 3). The EtOAc layer was separated, washed with water, and then with brine. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent gave 0.4 g of the crude product (yield 85.6%). C 12 H 13 Calculated MS (ESI) mass for ClN2O: 236.7; m / z found 237.0 [M+H] + .

[0383] Step 3: Synthesis of HBS-037-042: 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-bath cooling. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed the formation of the target product (m / z 201.1). Dilute the reaction mixture with water and extract the product with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product was obtained. The crude product was purified by column chromatography with the mobile phase: EtOAc: hexane, gradient elution. 0.26 g of solid product was obtained (yield 65.3%). C 12 H 12 MS (ESI) mass calculated for N2O: 200.2; m / z 201.1 [M+H] + 。

[0384] Step 4: Synthesis of 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 showed the formation of the target product (m / z 280.9). After evaporation of the solvent, a crude product was obtained. The crude product was purified by column chromatography with the mobile phase: EtOAc: hexane, gradient elution. 0.29 g of liquid product was obtained (yield 81.7%). C 12 H 11 MS (ESI) mass calculated for BrN2O: 279.1; m / z 280.9 [M+H] + 。

[0385] Step 5: Synthesis of HBS-037-054: Under N2 atmosphere, dissolve compound HBS-037-043 (0.025 g, 0.09 mmol) in anhydrous THF (1.0 mL), 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 min. Pass dry CO2 gas into the reaction mixture at -65 °C and gradually warm the reaction mixture to room temperature. LCMS data showed the formation of the target product (m / z 245), the formation of a debromination by-product (m / z 201), and the formation of some unknown products. Quench the reaction mixture with water and extract with ethyl acetate. The debromination product was recovered after separation of the ethyl acetate layer. Acidify the aqueous layer with 1 M HCl solution and evaporate to dryness to obtain 0.022 g of solid product. C 13 H 12MS(ESI) mass calculated value of N2O3: 244.3; m / z is 245.0 [M+H] + , 1 H 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)

[0386]

[0387] Step 1: Synthesis of 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 hours. LCMS shows the formation of the product (m / z 270.9). Dilute the reaction mixture with water, and extract the product with ethyl acetate. After separating the ethyl acetate layer, dry it over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product through a Combi-Flash system, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.42 g of the product (yield 59.7%). C 11 H 11 MS(ESI) mass calculated value of BrO3: 271.1; m / z is 270.9 [M+H] + 。

[0388] Step 2: Synthesis of HBS-037-192: Dissolve compound HBS-037-191 (0.42 g, 1.55 mmol) in anhydrous acetonitrile (5.0 mL). Add 2-aminopyridine (0.15 g, 1.55 mmol), and stir the reaction mixture at 80 °C for 1 hour. LCMS shows the formation of the product (m / z 267.1). 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 elution. Obtain 0.24 g of the product (yield 58.0%). C 16 H 14 MS(ESI) mass calculated value of N2O2: 266.3; m / z is 267.1 [M+H] + 。

[0389] Step 3: Synthesis of 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 hours. LCMS shows the formation of the product (m / z 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 (ppt) and wash with water (10.0 mL x 3) to obtain 0.2 g of solid product. C 14 H 10 MS (ESI) mass calculated for N2O2: 238.2; m / z 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).

[0390]

[0391] Step 1: Synthesis of HBS-037-163: Dissolve ethyl 2-phenyl-pyrazolo[1,5-a]pyridine-3-carboxylate (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 hours. LCMS shows the formation of the product (m / z 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 with water (10.0 mL x 3) to obtain 0.18 g of solid product. C 14 H 10 MS (ESI) mass calculated for N2O2: 238.2; m / z 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) 8.4 - 8.56 (dd, J = 6.90, 0.73 Hz, 1H).

[0392]

[0393] Step 1: Synthesis of HBS-039-013: Pyrazolo[1,5-a]pyridine-2-carboxylic acid (1.0 g, 6.17 mmol) was dissolved in ethanol (20.0 mL). A catalytic amount of concentrated sulfuric acid (0.5 mL) was added and the reaction mixture was refluxed for 16 h. LCMS data showed the formation of the product (m / z 191.1). The reaction mixture was concentrated under reduced pressure and neutralized with saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained. 1.2 g of the product was obtained (quantitative yield). C 10 H 10 Calculated mass of MS (ESI) of N2O2: 190.2; m / z 191.1 [M+H] + 。

[0394] Step 2: Synthesis of HBS-039-014: HBS-039-013 (1.17 g, 6.17 mmol) was dissolved in DCM (25.0 mL). NBS (1.1 g, 6.17 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 271.0). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 1.5 g of the product was obtained (yield 90.4%). C 10 Calculated mass of MS (ESI) of H9BrN2O2: 269.1; m / z 271.0 [M+H] + 。

[0395] Step 3: Synthesis of HBS-039-015: HBS-039-014 (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, followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.07 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 5 h. LCMS data showed the formation of the product (m / z 267). The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 0.2 g of the product was obtained (quantitative yield). C 16 H 14 Calculated mass of MS (ESI) of N2O2: 266.3; m / z 267.1 [M+H] + 。

[0396] Step 4: Synthesis of HBS-039-018: Dissolve HBS-039-015 (0.2 g, 0.74 mmol) in MeOH (6.0 mL). Add 1.0 N aqueous NaOH solution (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 (m / z 239.1). Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 1.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (5.0 mL x 3) to obtain 0.16 g of the solid product (yield 92.6%). C 14 H 10 MS (ESI) mass calculated for N2O2: 238.2; m / z 239.1 [M+H] + 。

[0397]

[0398] Step 1: Synthesis of HBS-039-016: Dissolve imidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g, 5.26 mmol) in DCM (20.0 mL). Add NBS (1.0 g, 5.78 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product (m / z 271.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by ISCO Combi-Flash chromatography system, mobile phase: EtOAc: hexane, gradient elution. Obtain 1.4 g of the product (yield 98.9%). C 10 MS (ESI) mass calculated for H9BrN2O2: 269.1; m / z 271.0 [M+H] + 。

[0399] Step 2: Synthesis of HBS-039-017: Dissolve compound HBS-039-016 (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 under a N2 atmosphere for 5 h. LCMS data shows the formation of the product (m / z 267.1). 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 elution. Obtain 0.2 g of the product (yield quantitative). C 16 H 14 MS (ESI) mass calculated for N2O2: 266.3; m / z 267.1 [M+H] + 。

[0400] Step 3: Synthesis of HBS-039-019: Dissolve compound HBS-039-017 (0.2 g, 0.74 mmol) in MeOH (6.0 mL). Add 1.0 N aqueous NaOH solution (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 (m / z 239.1). Concentrate the reaction mixture under reduced pressure and dilute with water. Acidify the aqueous layer with 1.0 M HCl solution (pH = 5). Filter the precipitate and wash with water (5.0 mL x 3) to obtain 0.11 g of the solid product (yield 62.1%). C 14 H 10 MS (ESI) mass calculated for N2O2: 238.2; m / z 239.1 [M+H] + 。

[0401]

[0402] Step 1: Synthesis of HBS-039-130: Ethyl benzoylacetate (3.0 g, 15.61 mmol) was dissolved in DCM (20.0 mL). NBS (3.1 g, 17.17 mmol) was added and the reaction mixture was stirred at 35 °C for 48 h. LCMS showed the formation of the product (m / z 272.0). The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product was obtained. The crude product was purified by Combi-Flash system with mobile phase: EtOAc: hexane, gradient elution. 3.75 g of the product was obtained (yield 88.6%). C 11 H 11 The calculated MS (ESI) mass of BrO3: 271.1; m / z 272.0 [M+H]+.

[0403] Step two: Synthesis of HBS-039-135: Compound HBS-039-130 (0.25 g, 0.92 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). Pyrazin-2-amine (0.088 g, 0.92 mmol) was added and the reaction mixture was stirred at 80 °C for 24 h. LCMS showed the formation of the product (m / z 268.1). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Combi-Flash system with mobile phase: EtOAc: hexane, gradient elution. 0.13 g of the product was obtained (yield 51.5%). C 15 H 13 The calculated MS (ESI) mass of N3O2: 267.28; m / z 268.1 is [M+H] + 。

[0404] Step 3: Synthesis of HBS-039-139: Compound HBS-039-135 (0.12 g, 0.45 mmol) was dissolved in MeOH (2.5 mL). 1.0 N aqueous NaOH solution (2.24 mL, 2.24 mmol) was added and the reaction mixture was stirred at 60 °C for 3 h. LCMS showed the formation of the product (m / z 240.0). 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 (1.0 mL x 3) to obtain 0.11 g of solid product. C 13 The calculated MS (ESI) mass of H9N3O2: 239.23; m / z is 240.0 [M+H] + 。

[0405]

[0406] 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 hour. Add ethyl chloroformate (1.59 mL, 16.7 mmol) at -78 °C, and gradually warm the reaction mixture to ambient temperature. LCMS data shows the formation of the product (m / z 193.0). Dilute the reaction mixture with aqueous NH4Cl solution, and extract the product with ethyl acetate. The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. 0.8 g of crude product is obtained (yield quantitative). C 11 Calculated mass for MS (ESI) of H9FO2: 192.19; m / z 193.0 [M+H] + 。

[0407] Step 2: Synthesis of HBS-039-148: Dissolve compound HBS-039-147 (0.4 g, 2.08 mmol) and 1-aminopyridinium 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 hours. LCMS data shows the formation of the product (m / z 285.1). Dilute the reaction mixture with water, and filter the precipitate. Dry the precipitate to obtain a crude product. The crude product is purified by a Combi-Flash system, mobile phase: EtOAc: hexane, gradient elution. 0.4 g of product is obtained (yield 67.6%). C 16 H 13 Calculated mass for MS (ESI) of HFN2O2: 284.29; m / z 285.1 [M+H] + 。

[0408] 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 hours. LCMS shows the formation of the product (m / z 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 x 3) to obtain 0.35 g of solid product (yield 97.5%). C 14 Calculated mass for MS (ESI) of H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0409]

[0410] Step 1: Synthesis of HBS-039-188: Dissolve 1-ethynyl-2-fluorobenzene (1.0 g, 8.33 mmol) in anhydrous THF (10.0 mL). Add n-BuLi (10.4 mL, 16.65 mmol) at -78 °C, and stir the reaction mixture at -78 °C for 1 hour. Add ethyl chloroformate (3.8 mL, 40.0 mmol) at -78 °C, and gradually warm the reaction mixture to ambient temperature. LCMS data shows the formation of the product (m / z 193.0). Dilute the reaction mixture with an aqueous NH4Cl solution, and extract the product with ethyl acetate. The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. 1.6 g of the crude product is obtained (yield quantitative). C 11 MS (ESI) mass calculated for C9FO2: 192.19; m / z found 193.0 [M+H] + 。

[0411] Step 2: Synthesis of HBS-039-189: Dissolve compound HBS-039-188 (1.6 g, 8.33 mmol) and 1-aminopyridinium iodide (I.85 g, 8.33 mmol) in anhydrous DMF (15.0 mL). Add anhydrous K2CO3 (2.88 g, 20.81 mmol), and stir the reaction mixture at ambient temperature for 16 hours. LCMS data shows the formation of the product (m / z 285.1). Dilute the reaction mixture with water, and extract the product with ethyl acetate, The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. The crude product is purified by column chromatography, eluting with a gradient of EtOAc:hexane. 1.56 g of the product is obtained (yield 66.0%). C 16 H 13 MS (ESI) mass calculated for C11FN2O2: 284.29; m / z found 285.1 [M+H] + 。

[0412] Step 3: Synthesis of HBS-039-192: Dissolve compound HBS-039-189 (1.56 g, 5.5 mmol) in MeOH (10.0 mL). Add 1.0 N aqueous NaOH (16.5 mL, 16.5 mmol), and reflux the reaction mixture for 12 hours. LCMS shows the formation of the product (m / z 257.0). Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water, and acidify with 2.0 M aqueous HCl (pH = 5). The precipitate is filtered and washed with water (5.0 mL x 3) to give 1.3 g of the solid product (yield 92.3%). C14 MS (ESI) mass calculated value of H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0413]

[0414] 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 (m / z 272.0). Dilute the reaction mixture with water, and extract the product with ethyl acetate. After separation of the ethyl acetate layer, dry it over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by Combi-Flash system, mobile phase: EtOAc: hexane, gradient elution. Obtain 2.1 g of the product (yield 70.0%). C 11 H 11 MS (ESI) mass calculated value of BrO3: 271.1; m / z 272.0 [M+H] + 。

[0415] 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 shows the formation of the product (m / z 285.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by Combi-Flash system, mobile phase: EtOAc: hexane, gradient elution. Obtain 1.2 g of the product (yield 75.0%). C 16 H 13 MS (ESI) mass calculated value of FN2O2: 284.29; m / z 285.0 [M+H] + 。

[0416] 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 hours. LCMS shows the formation of the product (m / z 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 x 3) to obtain 0.92 g of the solid product (yield 84.0%). C 14 Calculated mass for MS(ESI) of H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0417]

[0418] 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 hours. LCMS shows the formation of the product (m / z 285.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by Combi-Flash system, mobile phase: EtOAc: hexane, gradient elution. Obtain 1.9 g of the product (yield 95.0%). C 16 H 13 Calculated mass for MS(ESI) of HFN2O2: 284.29; m / z 285.0 [M+H] + 。

[0419] 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 hours. LCMS shows the formation of the product (m / z 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 x 3) to obtain 1.07 g of the solid product (yield 79.0%). C 14 Calculated mass for MS(ESI) of H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0420]

[0421] Step 1: Synthesis of HBS-054-012: Ethyl 3-(2-fluorophenyl)-3-oxopropionate (1.5 g, 7.14 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Aminopyridine (2.0 g, 21.4 mmol) was added, followed by CBr4 (4.7 g, 14.27 mmol), and the reaction mixture was stirred at 80 °C for 4 h. LCMS showed the formation of the product (m / z 285.0). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by a Combi-Flash system with the mobile phase: EtOAc:hexane, gradient elution. 1.83 g of the product was obtained (yield 90.0%). C 16 H 13 MS (ESI) mass calculated for FN2O2: 284.29; m / z 285.0 [M+H] + .

[0422] Step 2: Synthesis of HBS-054-016: Compound HBS-054-012 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol) was added, and the reaction mixture was stirred at 60 °C for 12 h. LCMS showed the formation of the product (m / z 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 x 3) to give 1.1 g of the solid product (yield 81.0%). C 14 MS (ESI) mass calculated for H9FN2O2: 256.23; m / z 257.0 [M+H] + .

[0423]

[0424] 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, followed by CBr4 (5.2 g, 15.6 mmol), and the reaction mixture was stirred at 80 °C for 16 h. LCMS showed the formation of the product (m / z 285.0). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by a Combi-Flash system with the mobile phase: EtOAc:hexane, gradient elution. 0.9 g of the product was obtained (yield 41.0%). C16 H 13 MS(ESI) mass calculated for FN2O2: 284.29; m / z 285.0 [M+H] + 。

[0425] Step 2: Synthesis of HBS-054-021: Dissolve compound HBS-054-020 (0.9 g, 3.17 mmol) in MeOH (10.0 mL). Add 1.0 N aqueous NaOH solution (6.3 mL, 6.34 mmol), and stir the reaction mixture at 60 °C for 12 h. LCMS shows the formation of the product (m / z 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 x 3) to obtain 0.37 g of the solid product (yield 41.0%). C 14 MS(ESI) mass calculated for H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0426]

[0427] Step 1: Synthesis of HBS-054-028: Dissolve ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) in DCM (80.0 mL). Add NBS (3.4 g, 18.94 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product (m / z 270.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by ISCO Combi-Flash chromatography system, mobile phase: EtOAc: hexane, gradient elution. Obtain 5.1 g of the product (quantitative yield). C 10 MS(ESI) mass calculated for H9BrN2O2: 269.1; m / z 270.0 [M+H] + 。

[0428] Step 2: Synthesis of HBS-054-035: Dissolve compound HBS-054-028 (1.5 g, 5.6 mmol) and 4-fluorobenzeneboronic acid (1.2 g, 8.4 mmol) in a mixture of dioxane / water (24.0:6.0 v / v mL). Add anhydrous Cs2CO3 (3.8 g, 11.75 mmol), then add Pd2(dba)3 (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). Stir the reaction mixture at 80 °C under a N2 atmosphere for 12 h. LCMS data showed the formation of the product (m / z 285.0). 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 elution. Obtain 1.4 g of the product (yield 85.0%). C 16 H 13 MS (ESI) mass calculated for FN2O2: 284.29; m / z 285.0 [M+H]+.

[0429] Step 3: Synthesis of HBS-054-039: Dissolve compound HBS-054-035 (1.4 g, 4.93 mmol) in MeOH (15.0 mL). Add 1.0 N aqueous NaOH solution (10.0 mL, 9.86 mmol) and reflux the reaction mixture for 12 h. LCMS data showed the formation of the product (m / z 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 x 3) to obtain 0.56 g of the solid product (yield 45.0%). C 14 MS (ESI) mass calculated for H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0430]

[0431] Step 1: Synthesis of HBS-054-028: Dissolve ethyl imidazo[1,2-a]pyridine-`2-carboxylate (3.6 g, 18.94 mmol) in DCM (80.0 mL). Add NBS (3.4 g, 18.94 mmol) and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product (m / z 270.0). Concentrate the reaction mixture 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 elution. Obtain 5.1 g of the product (quantitative yield). C10 MS (ESI) mass calculated for H9BrN2O2: 269.1; m / z 270.0 [M+H] + 。

[0432] Step 2: Synthesis of HBS-054-036: Dissolve compound HBS-054-028 (1.5 g, 5.6 mmol) and 2-fluorophenylboronic acid (1.2 g, 8.4 mmol) in a mixture of dioxane / water (24.0:6.0 v / v mL). Add anhydrous Cs2CO3 (3.8 g, 11.75 mmol), then add Pd2(dba)3 (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). Stir the reaction mixture at 80 °C under N2 atmosphere for 12 h. LCMS data showed formation of the product (m / z 285.0). Filter the reaction mixture through a bed of Celite and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. Obtain 1.2 g of the product (yield 75.0%). C 16 H 13 MS (ESI) mass calculated for HFN2O2: 284.29; m / z 285.0 [M+H] + 。

[0433] 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 formation of the product (m / z 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 x 3) to obtain 0.7 g of the solid product (yield 65.0%). C 14 MS (ESI) mass calculated for H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0434]

[0435] Step 1: Synthesis of HBS-054-033: Methyl pyrazolo[1,5-a]pyridine-2-carboxylate (2.4 g, 13.6 mmol) was dissolved in DCM (54.0 mL). NBS (2.5 g, 14.3 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 256.0). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 3.5 g of the product was obtained (quantitative yield). MS (ESI) mass calculated for C9H7BrN2O2: 255.07; m / z 256.0 [M+H] + .

[0436] Step 2: Synthesis of HBS-054-037: Compound HBS-054-033 (1.5 g, 5.9 mmol) and 4-fluorophenylboronic acid (1.2 g, 8.86 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous Cs2CO3 (4.0 g, 12.39 mmol) was added, followed by Pd2(dba)3 (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The reaction mixture was stirred at 80 °C under a N2 atmosphere for 12 h. LCMS data showed the formation of the product (m / z 271.0). The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 1.24 g of the product was obtained (78.0% yield). MS (ESI) mass calculated for C 15 H 11 FN2O2: 270.26; m / z 271.0 [M+H] + .

[0437] Step 3: Synthesis of HBS-054-041: Compound HBS-054-037 (1.2 g, 4.59 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (9.2 mL, 9.18 mmol) was added, and the reaction mixture was refluxed for 12 h. LCMS data showed the formation of the product (m / z 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 x 3) to give 1.0 g of the solid product (85.0% yield). C 14Calculated MS(ESI) mass for H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0438]

[0439] Step 1: Synthesis of HBS-054-033: Methyl pyrazolo[1,5-a]pyridine-2-carboxylate (2.4 g, 13.6 mmol) was dissolved in DCM (54.0 mL). NBS (2.5 g, 14.3 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 h. LCMS data showed formation of the product (m / z 256.0). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 3.5 g of the product was obtained (quantitative yield). Calculated MS(ESI) mass for C9H7BrN2O2: 255.07; m / z 256.0 [M+H] + 。

[0440] Step 2: Synthesis of HBS-054-038: Compound HBS-054-033 (1.5 g, 5.9 mmol) and 2-fluorophenylboronic acid (1.2 g, 8.86 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous Cs2CO3 (4.0 g, 12.39 mmol) was added, followed by Pd2(dba)3 (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 12 h. LCMS data showed formation of the product (m / z 271.0). The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 1.4 g of the product was obtained (86.0% yield). C 15 H 11 Calculated MS(ESI) mass for HFN2O2: 270.26; m / z 271.0 [M+H] + 。

[0441] Step 3: Synthesis of HBS-054-042: Dissolve compound HBS-054-038 (1.4 g, 5.18 mmol) in MeOH (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 showed the formation of the product (m / z 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 x 3) to obtain 1.0 g of the solid product (yield 85.0%). C 14 Calculated MS (ESI) mass for H9FN2O2: 256.23; m / z 257.0 [M+H] + 。

[0442]

[0443] 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 showed the formation of the product (m / z 335.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by Combi-Flash system, mobile phase: EtOAc: hexane, gradient elution. Obtain 1.0 g of the product (yield 38.0%). C 17 H 13 Calculated MS (ESI) mass for H F3N2O2: 334.29; m / z 335.0 [M+H] + 。

[0444] 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 showed the formation of the product (m / z 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 with water (5.0 mL x 3) to obtain 0.3 g of the solid product (yield 33.0%). C 15 Calculated MS (ESI) mass for H9F3N2O2: 306.24; m / z 307.0 [M+H] + 。

[0445]

[0446] 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 hydrate (0.56 g, 11.21 mmol). Heat the reaction mixture under reflux for 3 hours. LCMS data shows the formation of the target product (m / z 221.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is purified by column chromatography with the mobile phase: EtOAc:hexane, gradient elution. 1.2 g of the product is isolated (yield 51.0%). C 11 MS (ESI) mass calculated for C9FN2O2: 220.2; m / z 221.0 [M+H] + .

[0447] 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 hours. LCMS data shows the formation of the target product (m / z 283.0) and a small amount of by-products. The reaction mixture is filtered, and the solid is washed with ethyl acetate. The filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is purified by column chromatography with the mobile phase: EtOAc:hexane, gradient elution. 0.7 g of the product is obtained (yield 85.0%). C 13 H 12 MS (ESI) mass calculated for C10H10ClFN2O2: 282.7; m / z 283.0 [M+H] + .

[0448] Step 3: Synthesis of HBS-054-064: Dissolve compound HBS-054-062 (0.7 g, 2.48 mmol) in dry THF (10.0 mL). Add a 2.0 M solution of LAH in THF (1.24 mL, 2.48 mmol) under ice-bath cooling. Gradually warm the reaction mixture to room temperature and stir for 16 hours. LCMS data shows the formation of the target product (m / z 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 x 3). Separate the organic layer and wash with water, 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%). C12 H 12 MS (ESI) mass calculated for ClFN2O: 254.69; m / z 255.0 [M+H] + 。

[0449] 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-bath cooling. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data shows the formation of the target product (m / z 219.0). Dilute the reaction mixture with water and extract the product with ethyl acetate. The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. The crude product is purified by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.46 g of solid product is obtained (yield 88.0%). C 12 H 11 MS (ESI) mass calculated for FN2O: 218.23; m / z 219.0 [M+H]+.

[0450] 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 target product (m / z 298.0). After evaporation of the solvent, a crude product is obtained. The crude product is purified by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.25 g of product is obtained (yield 40.0%). C 12 H 10 MS (ESI) mass calculated for BrFN2O: 297.12; m / z 298.0 [M+H] + 。

[0451] Step 6: Synthesis of HBS-054-088: Under a N2 atmosphere, compound HBS-054-071 (1.15 g, 3.85 mmol) was dissolved in anhydrous THF (20.0 mL). The reaction mixture was cooled to -78.0 °C, and a 1.6 M n-BuLi hexane solution (4.81 mL, 7.7 mmol) was added to the reaction mixture. The reaction mixture was stirred at -78.0 °C for 30 minutes. Dry CO2 gas was bubbled into the reaction mixture at -65 °C, and the reaction mixture was gradually warmed to room temperature. LCMS data showed the formation of the target product (m / z 263.0), the formation of a debrominated byproduct, and some unknown products. The reaction mixture was quenched with water and extracted with ethyl acetate. The debrominated product was recovered after separation of the ethyl acetate layer. The aqueous layer was acidified with 2 M HCl solution to give a precipitate. The precipitate was filtered and dried to give 0.6 g of a solid product (yield 60.0%). C 13 H 11 MS (ESI) mass calculated for FN2O3: 262.24; m / z 263.0 [M+H] + 。

[0452]

[0453] 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 dissolved in 25.0 mL of methanol). The reaction mixture was stirred at ambient temperature for 30 minutes. 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 hours. LCMS data showed the formation of the target product (m / z 225.0). The reaction mixture was concentrated under reduced pressure to give a 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 give 8.62 g of a crude product. C 11 MS (ESI) mass calculated for H9FO4: 224.19; m / z 225.0 [M+H] + 。

[0454] Step 2: Synthesis of HBS-039-200: Dissolve compound HBS-039-198 (8.62 g, 36.19 mmol) in IPA (100.0 mL). Add hydrazine hydrate (2.1 mL, 43.4 mmol), and heat the reaction mixture under reflux for 3 hours. LCMS data showed the formation of the target product (m / z 221.0), as well as the formation of hydrolysis by-products (m / z 207.0). Cool the reaction mixture to ambient temperature to obtain a precipitate. The precipitate was filtered to obtain 7.19 g of crude product (yield 90.2%). C 11 Calculated mass of MS (ESI) for H9FN2O2: 220.2; m / z 221.0 [M+H] + , and C 10 Calculated mass of H7FN2O2: 206.17; m / z 207.0 [M+H] + .

[0455] Step 3: Synthesis of HBS-055-002: Dissolve the crude product of compound HBS-039-200 (7.19 g, 32.65 mmol) in anhydrous methanol (100.0 mL). Add concentrated sulfuric acid (4.0 mL), and heat the reaction mixture under reflux for 24 hours. LCMS data showed the formation of the target product (m / z 221.0). Cool the reaction mixture to ambient temperature, neutralize it with saturated aqueous sodium bicarbonate to obtain a precipitate, and the precipitate was filtered and dried to obtain 7.19 g of solid product (quantitative yield). C 11 Calculated mass of MS (ESI) for H9FN2O2: 220.2; m / z 221.0 [M+H] + .

[0456] 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 hours. LCMS data showed the formation of the target product (m / z 283.0). Filter the reaction mixture, and wash the solid with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography, mobile phase: EtOAc: hexane, gradient elution. 2.85 g of product was isolated (yield 30.9%). C 13 H 12 Calculated mass of MS (ESI) for HClFN2O2: 282.7; m / z 283.0 [M+H] + .

[0457] 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 to 0 °C. Add a 1.0 M solution of DIBAL in hexanes (25.2 mL, 25.2 mmol). Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed formation of the target 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. Evaporation of the solvent gave 2.57 g of crude product (yield quantitative). C 12 H 12 MS (ESI) mass calculated for ClFN2O: 254.69; m / z found 255.0 [M+H] + 。

[0458] 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 (0.81 g, 20.2 mmol) in mineral oil under ice cooling. Gradually warm the reaction mixture to room temperature and stir for 16 h. LCMS data showed formation of the target 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. Evaporation of the solvent gave a crude product. Purify the crude product by column chromatography, eluting with a gradient of EtOAc:hexanes. 1.17 g of solid product was obtained (yield 53.2%). C 12 H 11 MS (ESI) mass calculated for FN2O: 218.23; m / z found 219.1 [M+H] + 。

[0459] 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 formation of the target product (m / z 299.0). Evaporation of the solvent gave a crude product. Purify the crude product by column chromatography, eluting with a gradient of EtOAc:hexanes. 1.27 g of product was obtained (yield 79.7%). C 12 H 10MS (ESI) mass calculated value of BrFN2O: 297.12; m / z 299.0 [M+H] + 。

[0460] Step 8: Synthesis of HBS-055-013: Under N2 atmosphere, dissolve compound HBS-055-010 (1.27 g, 4.27 mmol) in anhydrous THF (15.0 mL). Cool the reaction mixture to -78.0 °C. Add 1.6 M n-BuLi in hexane solution (5.33 mL, 8.54 mmol), and stir the reaction mixture at -78.0 °C for 30 minutes. Pass dry CO2 gas into the reaction mixture at -65 °C, and gradually warm up the reaction mixture to room temperature. LCMS data shows the formation of the target product (m / z 263.1), the formation of debrominated by-products 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. The precipitate is filtered and dried to obtain 0.84 g of solid product (yield 75.0%). C 13 H 11 MS (ESI) mass calculated value of FN2O3: 262.24; m / z 263.1 [M+H] + 。

[0461]

[0462] Step 1: Synthesis of HBS-055-191: Dissolve ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1.0 g, 6.40 mmol) in anhydrous acetonitrile (15.0 mL). Add anhydrous K2CO3 (3.54 g, 25.62 mmol), and stir the reaction mixture at ambient temperature for 15 minutes. Add 1,3-dibromopropane (0.72 mL, 7.05 mmol), and reflux the reaction mixture for 6 hours. LCMS data shows the formation of the product (m / z 197.1). Cool the reaction mixture to ambient temperature and filter. Concentrate the filtrate under reduced pressure to obtain a crude product. Purify the crude product by ISCO Combi-Flash chromatography system, mobile phase: EtOAc: hexane, gradient elution. Obtain 1.03 g of product (yield 81.97%). C9H 12 MS (ESI) mass calculated value of N2O3: 196.20; m / z 197.1 [M+H] + 。

[0463] Step 2: Synthesis of HBS-055-192: Dissolve compound HBS-055-191 (1.03 g, 5.25 mmol) in DCM (15.0 mL). Add NBS (0.93 g, 5.25 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data showed the formation of the product (m / z 275.0). Dilute the reaction mixture with water, and extract the product with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was obtained. The crude product was purified by an ISCO Combi-Flash system with mobile phase: EtOAc: hexane, gradient elution. 1.44 g of the product was obtained (yield quantitative). C9H 11 Calculated MS (ESI) mass for C9HBrN2O3: 275.1; m / z found 275.0 [M+H] + .

[0464] 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), followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.073 mmol). Stir the reaction mixture at 100 °C under N2 atmosphere for 6 h. LCMS data showed the formation of the product (m / z 273.1). Filter the reaction mixture through a bed of Celite and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc: hexane, gradient elution. 0.37 g of the product was obtained (yield 94.7%). C 15 H 16 Calculated MS (ESI) mass for C9H9N2O3: 272.3; m / z found 273.1 [M+H] + .

[0465] 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 (m / z 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). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.26 g of the solid product (yield 77.3%). C 13 H 12MS (ESI) mass calculated value of N2O3: 244.25; m / z is 245.1 [M+H] + 。

[0466]

[0467] 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 hours. LCMS data shows the formation of the product (m / z 161.1). Extract the reaction mixture with ethyl acetate. The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. The solvent is evaporated to obtain the crude product. 1.22 g of the product is obtained (quantitative yield). MS (ESI) mass calculated value of C5H8N2O4: 160.13; m / z is 161.1 [M+H] + 。

[0468] 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 hours. LCMS data shows the formation of the product (m / z 143.1). Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is purified by an ISCO Combi-Flash chromatography system, mobile phase: EtOAc: hexane, gradient elution. 1.02 g of the product is obtained (yield 94.1%). MS (ESI) mass calculated value of C5H6N2O3: 142.11; m / z is 143.1 [M+H] + 。

[0469] 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 hours. LCMS data shows the formation of the product (m / z 197.1). Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is purified by an ISCO Combi-Flash chromatography system, mobile phase: EtOAc: hexane, gradient elution. 1.0 g of the product is obtained (yield 71.0%). C9H 12MS(ESI) mass calculated value of N2O3: 196.20; m / z is 197.1 [M+H] + 。

[0470] 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 hours. LCMS data shows the formation of the product (m / z 275.0). Dilute the reaction mixture with water, and extract the product with DCM. Combine the DCM layers, separate, and dry over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. The crude product is purified by an ISCO Combi-Flash system, mobile phase: EtOAc: hexane, gradient elution. 1.4 g of the product is obtained (yield 99.7%). C9H 11 MS(ESI) mass calculated value of BrN2O3: 275.1; m / z is 275.0 [M+H] + 。

[0471] Step 5: Synthesis of HBS-062-011: 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 under a N2 atmosphere for 6 hours. LCMS data shows the formation of the product (m / z 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 a crude product. The crude product is purified by an ISCO Combi-Flash chromatographic system, mobile phase: EtOAc: hexane, gradient elution. 0.39 g of the product is obtained (yield 95.5%). C 15 H 16 MS(ESI) mass calculated value of H + 。

[0472] 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 hours. LCMS data shows the formation of the product (m / z 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). The precipitate is filtered and washed with water (2.0 mL x 3) to give 0.23 g of the solid product (yield 65.8%). C 13 H 12 MS (ESI) mass calculated for N2O3: 244.25; m / z 245.1 [M+H] + 。

[0473]

[0474] 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 hours. LCMS data shows the formation of the product (m / z 236.0). Dilute the reaction mixture with saturated aqueous NaHCO3 solution. Extract the product with DCM. Combine the DCM layers, separate, 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 mobile phase: DCM:methanol, gradient elution. Obtain 0.62 g of the product (yield 41.1%). MS (ESI) mass calculated for C6H8BrN3O2: 234.05; m / z 236.0 [M+H] + 。

[0475] 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 hours. LCMS data shows the formation of the product (m / z 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%). MS (ESI) mass calculated for C9H8BrN3O2: 270.08; m / z 272.0 [M+H] + 。

[0476] 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 under a N2 atmosphere for 4 hours. LCMS data shows the formation of the product (m / z 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 elution. Obtain 0.25 g of the product (yield 84.2%). C 15 H 13 MS (ESI) mass calculated value for N3O2: 267.28; m / z is 268.1 [M+H] + 。

[0477] 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 hours. LCMS data shows the formation of the product (m / z 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 x 3) to obtain 0.11 g of the solid product (yield 49.2%). C 13 MS (ESI) mass calculated value for H9N3O2: 239.23; m / z is 240.1 [M+H] + 。

[0478]

[0479] 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 minutes. Add ethyl chloroformate (1.4 mL, 14.41 mmol) at -78 °C and gradually warm the reaction mixture to ambient temperature over 3 hours. LCMS data showed the formation of the product (m / z 177.1). Dilute the reaction mixture with aqueous NH4Cl solution and extract the product with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was obtained. The crude product was purified by an ISCO Combi-Flash system with mobile phase: DCM:MeOH, gradient elution. 0.78 g of the product was obtained (yield 46.1%). MS (ESI) mass calculated for C9H8N2O2: 176.17; m / z 177.1 [M+H] + .

[0480] Step 2: Synthesis of HBS-062-023: Dissolve compound HBS-062-020 (0.75 g, 4.25 mmol) and 1-aminopyridinium 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 hours. LCMS data showed the formation of the product (m / z 269.1). Dilute the reaction mixture with water and extract the product with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was obtained. The crude product was purified by an ISCO Combi-Flash system with mobile phase: ethyl acetate:hexane, gradient elution. 0.48 g of the product was obtained (yield 42.1%). MS (ESI) mass calculated for C 14 H 12 N4O2: 268.27; m / z 269.1 [M+H] + .

[0481] 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 (2.1 mL, 2.09 mmol) and reflux the reaction mixture for 6 hours. LCMS data showed the formation of the product (m / z 241.1). Concentrate the reaction mixture under reduced pressure. Dissolve the solid in water and acidify with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.22 g of the solid product (yield 87.5%). C12 Calculated MS(ESI) mass of H8N4O2: 240.22; m / z 241.1 [M+H] + 。

[0482]

[0483] 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 -78 °C, and stir the reaction mixture at -78 °C for 30 minutes. Add ethyl chloroformate (2.2 mL, 23.3 mmol) at -78 °C, and gradually warm the reaction mixture to ambient temperature over 3 hours. LCMS data showed the formation of the product (m / z 176.1). Dilute the reaction mixture with aqueous NH4Cl solution, and extract the product with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product was obtained. The crude product was purified by an ISCO Combi-Flash system with mobile phase: ethyl acetate:hexane, gradient elution. 1.29 g of the product was obtained (yield 38.0%). C 10 Calculated MS(ESI) mass of H9NO2: 175.18; m / z 176.1 [M+H] + 。

[0484] Step 2: Synthesis of HBS-062-025: Dissolve compound HBS-062-022 (0.5 g, 2.85 mmol) and 1-aminopyridinium 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 hours. LCMS data showed the formation of the product (m / z 268.1). 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 a crude product. The crude product was purified by an ISCO Combi-Flash system with mobile phases: ethyl acetate:hexane and DCM:methanol, gradient elution. 0.57 g of the product was obtained (yield 74.6%). C 15 H 13 Calculated MS(ESI) mass of H N3O2: 267.28; m / z 268.1 [M+H] + 。

[0485] 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 hours. LCMS data showed the formation of the product (m / z 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 x 3) to obtain 0.26 g of the solid product (yield 50.9%). C 13 Calculated mass of MS (ESI) for H9N3O2: 239.23; m / z 240.1 [M+H] + .

[0486]

[0487] Step 1: Synthesis of HBS-062-033: Dissolve 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) in anhydrous acetic acid (8.0 mL). Heat the reaction mixture at 70 °C for 24 hours. LCMS data showed the formation of the product (m / z 192.1). 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. Extract the product with DCM. Combine the DCM layers, separate, and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by ISCO Combi-Flash system with mobile phase: DCM:methanol, gradient elution. Obtain 0.98 g of the product (yield 79.7%). Calculated mass of MS (ESI) for C9H9N3O2: 191.19; m / z 192.1 [M+H] + .

[0488] Step 2: Synthesis of HBS-062-037: Dissolve compound HBS-062-033 (0.98 g, 5.13 mmol) in DCM (15.0 mL). Cool the reaction mixture in an ice bath at 0 °C. Add NBS (1.0 g, 5.64 mmol), and stir the reaction mixture at ambient temperature for 16 hours. LCMS data showed the formation of the product (m / z 272.0). Dilute the reaction mixture with saturated aqueous NaHCO3 solution and extract the product with DCM. Combine the DCM layers, separate, and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain 1.38 g of the crude product (yield quantitative). Calculated mass of MS (ESI) for C9H8BrN3O2: 270.08; m / z 272.0 [M+H] + .

[0489] Step 3: Synthesis of HBS-062-038: Dissolve compound HBS-062-037 (0.4 g, 1.48 mmol) and phenylboronic acid (0.27 g, 2.22 mmol) in a mixture of dioxane / water (8:1 v / v mL). Add anhydrous K2CO3 (0.61 g, 4.44 mmol), and then add Pd(dppf)Cl2.DCM2 (0.06 g, 0.074 mmol). Stir the reaction mixture at 100 °C under a N2 atmosphere for 6 hours. LCMS data shows the formation of the product (m / z 268.1). 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 mobile phase: EtOAc:hexane, gradient elution. Obtain 0.32 g of the product (yield 80.1%). C 15 H 13 MS (ESI) mass calculated for H + N3O2: 267.28; m / z 268.1 [M+H]

[0490] 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 hours. LCMS data shows the formation of the product (m / z 240.1). 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 x 3) to obtain 0.18 g of the solid product (yield 65.9%). C 13 MS (ESI) mass calculated for H + 9N3O2: 239.23; m / z 240.1 [M+H]

[0491]

[0492] Step 1: Synthesis of 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 hours. LCMS data shows the formation of the product (m / z 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. Obtain 1.2 g of the product (quantitative yield). C10 H 10 MS (ESI) mass calculated value of N2O2: 190.2; m / z 191.1 [M+H] + 。

[0493] Step 2: Synthesis of HBS-039-014: Dissolve 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 (m / z 271.0). Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 1.5 g of the product is obtained (yield 90.4%). C 10 MS (ESI) mass calculated value of C9H9BrN2O2: 269.1; m / z 271.0 [M+H] + 。

[0494] Step 3: Synthesis of HBS-062-179: Dissolve compound HBS-039-014 (0.5 g, 1.86 mmol) and 2-(tributylstannyl)pyridine (1.36 g, 3.72 mmol) in 1,4-dioxane (10.0 mL). Add Pd(PPh3)4 (0.214 g, 0.18 mmol), and heat the reaction mixture at 115 °C under N2 atmosphere for 18 h. LCMS data shows the formation of the product (m / z 268.0). 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. The crude product is purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 0.35 g of the product is obtained (yield 70.5%). C 15 H 13 MS (ESI) mass calculated value of C12H11N3O2: 267.28; m / z 268.0 [M+H] + 。

[0495] Step 4: Synthesis of HBS-062-182: Dissolve compound HBS-062-179 (0.35 g, 1.31 mmol) in MeOH (5.0 mL). Add 1.0 N aqueous NaOH solution (2.62 mL, 2.62 mmol), and reflux the reaction mixture for 8 hours. LCMS data showed the formation of the product (m / z 240.1). The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.31 g of the product (quantitative yield). C 13 Calculated mass for MS (ESI) of H9N3O2: 239.23; m / z 240.1 [M+H] + .

[0496]

[0497] Step 1: Synthesis of HBS-062-033: Dissolve 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) in anhydrous acetic acid (8.0 mL). Heat the reaction mixture at 70 °C for 24 hours. LCMS data showed the formation of the product (m / z 192.1). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was diluted with water and neutralized with saturated aqueous NaHCO3 solution. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was obtained. The crude product was purified by an ISCO Combi-Flash system with mobile phase: DCM:methanol, gradient elution. 0.98 g of the product was obtained (yield 79.7%). Calculated mass for MS (ESI) of C9H9N3O2: 191.19; m / z 192.1 [M+H] + .

[0498] Step 2: Synthesis of HBS-062-037: Dissolve compound HBS-062-033 (0.98 g, 5.13 mmol) in DCM (15.0 mL). Cool the reaction mixture in an ice bath at 0 °C. Add NBS (1.0 g, 5.64 mmol), and stir the reaction mixture at ambient temperature for 16 hours. LCMS data showed the formation of the product (m / z 272.0). Dilute the reaction mixture with saturated aqueous NaHCO3 solution. Extract the product with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, 1.38 g of the crude product was obtained (quantitative yield). Calculated mass for MS (ESI) of C9H8BrN3O2: 270.08; m / z 272.0 [M+H] + .

[0499] Step 3: Synthesis of HBS-062-183: Dissolve compound HBS-062-037 (0.95 g, 3.52 mmol) and 2-(tributylstannyl)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 under a N2 atmosphere for 18 h. Add 0.05 equivalent of Pd(PPh3)4 to consume the starting materials. LCMS data showed the formation of the product (m / z 269.0). Filter the reaction mixture through a bed of Celite 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 elution. Obtain 0.725 g of the product (yield 76.8%). C 14 H 12 Calculated MS (ESI) mass for C11H12N4O2: 268.27; m / z found 269.0 [M+H] + .

[0500] 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 showed the formation of the product (m / z 241.1). 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 x 3) to obtain 0.52 g of the product (yield 80.2%). C 12 Calculated MS (ESI) mass for C10H10N4O2: 240.22; m / z found 241.1 [M+H] + .

[0501]

[0502] Step 1: Synthesis of HBS-062-173: Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (2.0 g, 12.81 mmol) was dissolved in anhydrous acetonitrile (40.0 mL). Anhydrous K2CO3 (7.1 g, 51.24 mmol) was added, and the reaction mixture was stirred at ambient temperature for 10 minutes. 1,3-Dibromopropane (1.43 mL, 14.1 mmol) was added, and the reaction mixture was heated to reflux for 12 hours. LCMS data showed the formation of the product (m / z 197.1). The reaction mixture was cooled to ambient temperature and filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. 1.93 g of the product was obtained (yield 76.8%). C9H 12 MS (ESI) mass calculated for C9H + N2O3: 196.20; m / z found 197.1 [M+H]

[0503] Step 2: Synthesis of HBS-062-178: Compound HBS-062-173 (1.9 g, 9.68 mmol) was dissolved in DCM (30.0 mL). NIS (2.61 g, 11.62 mmol) was added, and the reaction mixture was stirred at ambient temperature for 30 hours. 0.6 equivalent of NIS was added to consume the starting material. LCMS data showed the formation of the product (m / z 323.0). The reaction mixture was diluted with water, and the product was extracted with DCM. The DCM layer was separated and washed with an aqueous solution of sodium thiosulfate. The combined DCM layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was obtained. The crude product was purified by an ISCO Combi-Flash system with mobile phase: EtOAc:hexane, gradient elution. 3.12 g of the product was obtained (yield quantitative). C9H 11 MS (ESI) mass calculated for C9H + IN2O3: 322.1; m / z found 323.0 [M+H]

[0504] Step 3: Synthesis of HBS-062-189: Dissolve compound HBS-062-178 (1.0 g, 3.11 mmol) and 2-(tributylstannyl)pyridine (1.14 g, 3.11 mmol) in 1,4-dioxane (12.0 mL). Add Pd(PPh3)4 (0.36 g, 0.31 mmol), and heat the reaction mixture at 120 °C under a N2 atmosphere for 30 h. LCMS data showed the formation of the product (m / z 274.0). 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 mobile phases: EtOAc:hexane gradient elution and EtOAc:methanol (95:05, v / v mL) gradient elution. Obtain 0.44 g of the product (yield 51.9%). C 14 H 15 Calculated MS (ESI) mass for N3O3: 273.3; m / z 274.0 [M+H] + 。

[0505] Step 4: Synthesis of HBS-062-192: Dissolve compound HBS-062-189 (0.44 g, 1.61 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH solution (3.22 mL, 3.22 mmol), and reflux the reaction mixture for 8 h. LCMS data showed the formation of the product (m / z 246.1). 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 x 3) to obtain 0.31 g of the product (yield 78.5%). C 12 H 11 Calculated MS (ESI) mass for N3O3: 245.23; m / z 246.1 [M+H] + 。

[0506]

[0507] Step 1: Synthesis of HBS-062-199: Ethyl 3-bromoimidazo[1,2-a]pyridine-2-carboxylate (1.0 g, 3.72 mmol) and 2-(tributylstannyl)pyridine (1.5 g, 4.1 mmol) were dissolved in dry DMF (12.0 mL). Pd(PPh3)4 (0.43 g, 0.37 mmol) was added, and the reaction mixture was heated at 115 - 120 °C under a N2 atmosphere for 36 h. 0.05 equivalent of Pd(PPh3)4 was added to consume the starting materials in the reaction. LCMS data showed the formation of the product (m / z 268.1), as well as the formation of an acidic by-product (m / z 240.1). The reaction mixture was diluted with water, and the product was extracted with DCM. The DCM layer was separated and washed with an aqueous sodium thiosulfate solution. The combined DCM layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product was obtained. The crude product was purified by an ISCO Combi-Flash chromatography system with mobile phases: EtOAc:hexane gradient elution and EtOAc:methanol (95:05, v / v mL) gradient elution. 0.61 g of the product was obtained (yield 61.4%). C 15 H 13 Calculated MS (ESI) mass for C13H9N3O2: 267.28; m / z 268.1 [M + H] + , and 0.1 g of the acidic by-product (yield 11.2%). C 13 Calculated MS (ESI) mass for C11H9N3O2: 239.23; m / z 240.1 [M + H] + .

[0508] Step 2: Synthesis of HBS-065-004: Compound HBS-062-199A (0.61 g, 2.28 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (4.6 mL, 4.56 mmol) was added, and the reaction mixture was refluxed for 8 h. LCMS data showed the formation of the product (m / z 240.9). 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). After concentration of the aqueous layer, 0.55 g of the product was obtained (quantitative yield). C 13 Calculated MS (ESI) mass for C11H9N3O2: 239.23; m / z 240.9 [M + H] + .

[0509]

[0510] Step 1: Synthesis of HBS-065-011: Dissolve HBS-062-010 (1.0 g, 3.64 mmol) and 2-(tributylstannyl)pyridine (1.6 g, 4.36 mmol) in dry DMF (12.0 mL). Add Pd(PPh3)4 (0.42 g, 0.36 mmol), and heat the reaction mixture at 120 °C under a N2 atmosphere for 30 h. Add 0.05 equivalent of Pd(PPh3)4 to consume the starting materials in the reaction. LCMS data shows the formation of the product (m / z 274.0), as well as the formation of acidic by-products (m / z 246.0). Dilute the reaction mixture with water, and extract the product with DCM. Separate the DCM layer and wash it with an aqueous sodium thiosulfate solution. Combine the DCM layers, separate, and dry over anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO Combi-Flash chromatography system with mobile phases: gradient elution of EtOAc:hexane and gradient elution of DCM:methanol. Obtain 0.26 g of the product (yield 26.3%). C 14 H 15 Calculated MS (ESI) mass for C H N3O3: 273.29; m / z 274.0 [M+H] + , and obtain 0.15 g of acidic by-products (yield 16.8%). C 12 H 11 Calculated MS (ESI) mass for C H N3O3: 245.23; m / z 246.0 [M+H] + ,

[0511] Step 2: Synthesis of HBS-065-019: Dissolve compound HBS-065-011A (0.26 g, 0.96 mmol) in MeOH (5.0 mL). Add 1.0 N aqueous NaOH solution (1.9 mL, 1.91 mmol), and reflux the reaction mixture for 3 h. LCMS data shows the formation of the product (m / z 246.1). Concentrate the reaction mixture under reduced pressure and dilute it with water. Acidify the aqueous layer with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate, and after concentrating the aqueous layer, obtain 0.23 g of the total product (yield 92.0%). C 12 H 11 Calculated MS (ESI) mass for C H N3O3: 245.23; m / z 246.1 [M+H] + .

[0512]

[0513] Step 1: Synthesis of HBS-065-050: Ethyl pyridinecarboxylate acetate (0.5 g, 2.59 mmol) was dissolved in chloroform (12.0 mL). A solution of bromine (0.13 mL, 2.59 mmol) in chloroform (1.0 mL) was added, and the reaction mixture was stirred at ambient temperature for 2 hours. LCMS showed the formation of the product (m / z 274.0). The reaction mixture was diluted with saturated aqueous NaHCO3, and the product was extracted with chloroform. The chloroform layer was separated and dried over anhydrous Na2SO4. After evaporation of the solvent, 0.7 g of the crude product was obtained (yield quantitative). C 10 H 10 Calculated mass for BrNO3 by MS (ESI): 272.1; m / z 274.0 [M+H] + 。

[0514] Step 2: Synthesis of HBS-065-051: Compound HBS-065-050 (0.7 g, 2.59 mmol) was dissolved in anhydrous acetonitrile (8.0 mL). 2-Amino-5-fluoropyridine (0.29 g, 2.59 mmol) was added, and the reaction mixture was heated to reflux for 16 hours. LCMS data showed the formation of the product (m / z 286.1). The reaction mixture was diluted with saturated aqueous NaHCO3, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product was obtained. The crude product was purified by a Combi-Flash system with mobile phase: DCM:methanol, gradient elution. 0.39 g of the product was obtained (yield 52.8%). C 15 H 12 Calculated mass for FN3O2 by MS (ESI): 285.27; m / z 286.1 [M+H] + 。

[0515] Step 3: Synthesis of HBS-065-055: Compound HBS-065-051 (0.39 g, 1.37 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (2.7 mL, 2.73 mmol) was added, and the reaction mixture was heated to reflux for 12 hours. LCMS showed the formation of the product (m / z 258.2). 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 (2.0 mL x 3) to give 0.33 g of the solid product (yield 93.8%). C 13 Calculated mass for H8FN3O2 by MS (ESI): 257.22; m / z 258.2 [M+H] + 。

[0516]

[0517] Step 1: Synthesis of HBS-065-062: Dissolve compound HBS-065-050 (1.41 g, 5.18 mmol) in anhydrous acetonitrile (10.0 mL). Add 2-amino-4-chloropyridine (0.67 g, 5.18 mmol), and heat the reaction mixture under reflux for 16 hours. LCMS data shows the formation of the product (m / z 302.0). Dilute the reaction mixture with saturated aqueous NaHCO3, and extract the product with ethyl acetate. The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. The crude product is purified by a Combi-Flash system with the mobile phase: DCM: methanol, gradient elution. 0.8 g of the product is obtained (yield 51.2%). C 15 H 12 MS (ESI) mass calculated value for ClN3O2H: 301.73; m / z 302.0 [M+H] + .

[0518] Step 2: Synthesis of HBS-065-064: Dissolve compound HBS-065-062 (0.8 g, 2.65 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH (5.3 mL, 5.30 mmol), and heat the reaction mixture under reflux for 8 hours. LCMS shows the formation of the product (m / z 274.0). Concentrate the reaction mixture under reduced pressure. Dissolve the crude product in water and acidify with 2.0 M aqueous HCl (pH = 5). The precipitate is filtered and washed with water (3.0 mL x 3) to obtain 0.46 g of the solid product (yield 63.4%). C 13 MS (ESI) mass calculated value for ClN3O2H8: 273.67; m / z 274.0 [M+H] + .

[0519]

[0520] Step 1: Synthesis of HBS-065-073: Dissolve compound HBS-065-050 (1.41 g, 5.18 mmol) in anhydrous acetonitrile (12.0 mL). Add 2-aminopyridine (0.49 g, 5.18 mmol), and heat the reaction mixture under reflux for 16 hours. LCMS shows the formation of the product (m / z 268.0). Dilute the reaction mixture with saturated aqueous NaHCO3, and extract the product with ethyl acetate. The combined ethyl acetate layers are separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product is obtained. The crude product is purified by a Combi-Flash system with the mobile phase: DCM: methanol, gradient elution. 0.7 g of the product is obtained (yield 50.6%). C 15H 13 Calculated MS(ESI) mass of N3O2: 267.28; m / z 268.0 [M+H] + .

[0521] Step 2: Synthesis of HBS-065-076: Dissolve compound HBS-065-073 (0.7 g, 2.62 mmol) in MeOH (6.0 mL). Add 1.0 N aqueous NaOH solution (5.2 mL, 5.24 mmol), and heat the reaction mixture under reflux for 4 h. LCMS shows the formation of the product (m / z 240.0). Concentrate the reaction mixture under reduced pressure. Dissolve the crude product in water, and acidify with 2.0 M aqueous HCl solution (pH = 5). Filter the precipitate and wash with water (3.0 mL x 3) to obtain 0.52 g of the solid product (yield 83.0%). C 13 Calculated MS(ESI) mass of H9N3O2: 239.23; m / z 240.0 [M+H] + .

[0522]

[0523] Step 1: Synthesis of HBS-065-106: Dissolve pyrazolo[1,5-a]pyridine-2-carboxylic acid (2.0 g, 12.34 mmol) in ethanol (40.0 mL). Add a catalytic amount of concentrated sulfuric acid (0.1 mL), and reflux the reaction mixture for 8 h. LCMS data shows the formation of the product (m / z 191.1). Concentrate the reaction mixture under reduced pressure, and neutralize with saturated aqueous sodium bicarbonate solution. Extract the product with ethyl acetate. Separate the ethyl acetate layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the product. 2.2 g of the product is obtained (yield 93.7%). C 10 H 10 Calculated MS(ESI) mass of N2O2: 190.2; m / z 191.1 [M+H] + .

[0524] Step 2: Synthesis of HBS-065-108: Dissolve compound HBS-065-106 (2.2 g, 11.57 mmol) in DCM (40.0 mL). Add NBS (2.27 g, 12.73 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product (m / z 270.9). Dilute the reaction mixture with saturated aqueous sodium bicarbonate solution. Extract the product with DCM. Combine the DCM layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the product. Purify the crude product by a normal-phase chromatography system, mobile phase: EtOAc: hexane, gradient elution. 3.11 g of the product is obtained (quantitative yield). C10 MS (ESI) mass calculated for H9BrN2O2: 269.1; m / z 270.9 [M+H] + 。

[0525] Step 3: Synthesis of HBS-065-125: Dissolve compound HBS-065-108 (0.4 g, 1.49 mmol) and 5-chlorothiophene-2-boronic acid (0.48 g, 2.97 mmol) in a mixture of dioxane / water (12:1 v / v mL). Add anhydrous K2CO3 (0.41 g, 2.97 mmol), and then add Pd(dppf)Cl2.DCM2 (0.06 g, 0.074 mmol). Stir the reaction mixture at 100 °C under N2 atmosphere for 24 h. Add 5-chlorothiophene-2-boronic acid and the catalyst to consume the starting materials in the reaction. LCMS data shows the formation of the product (m / z 307.0). 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 elution. Obtain 0.31 g of the product (yield 67.9%). C 14 H 11 MS (ESI) mass calculated for CIN2O2S: 306.77; m / z 307.0 [M+H] + 。

[0526] Step 4: Synthesis of HBS-065-127: Dissolve compound HBS-065-125 (0.31 g, 1.01 mmol) in MeOH (5.0 mL). Add 1.0 N aqueous NaOH solution (2.0 mL, 2.0 mmol), and stir the reaction mixture at ambient temperature for 16 h. LCMS data shows the formation of the product (m / z 278.9). 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 x 3) to obtain 0.24 g of the solid product (yield 83.4%). C 12 MS (ESI) mass calculated for H7ClN2O2S: 278.71; m / z 278.9 [M+H] + 。

[0527]

[0528] Step 1: Synthesis of HBS-065-156: Dissolve compound HBS-065-108 (0.5 g, 1.86 mmol) and 2-(tributylstannyl)-pyrimidine (0.69 g, 1.86 mmol) in anhydrous DMF (6.0 mL). Add anhydrous CsF (0.85 g, 5.57 mmol) and CuCl (0.024 g, 0.24 mmol), and then add Pd(PPh3)4 (0.11 g, 0.093 mmol). Microwave irradiate the reaction mixture in a microwave reactor at 120 °C for 50 minutes. LCMS data shows the formation of the product (m / z 269.2). Filter the reaction mixture through a bed of celite and wash with ethyl acetate. Dilute the filtrate with water and extract with ethyl acetate. Combine the ethyl acetate layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.37 g of the product (yield 73.6%). C 14 H 12 Calculated MS (ESI) mass for C10H12N4O2: 268.27; m / z 269.2 [M+H] + .

[0529] Step 2: Synthesis of HBS-065-159: Dissolve compound HBS-065-156 (0.37 g, 1.37 mmol) in MeOH (8.0 mL). Add 1.0 N aqueous NaOH solution (2.74 mL, 2.74 mmol), and reflux the reaction mixture for 4 hours. LCMS data shows the formation of the product (m / z 241.1). 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 x 3) to obtain 0.25 g of the solid product (yield 76.7%). C 12 Calculated MS (ESI) mass for C8H10N4O2: 240.22; m / z 241.1 [M+H] + .

[0530]

[0531] Step 1: Synthesis of HBS-039-126: Ethyl benzoylacetate (0.5 g, 2.6 mmol) was dissolved in anhydrous acetonitrile (10.0 mL). 2-Aminopyrimidine (0.55 g, 5.76 mmol) was added, followed by CBr4 (1.27 g, 3.84 mmol), and the reaction mixture was stirred at 80 °C for 48 h. Reagents were added to consume the starting materials. LCMS data showed the formation of the product (m / z 268.1). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by a Combi-Flash system with the mobile phase: EtOAc: hexane, gradient elution. 0.15 g of the product was obtained (yield 21.3%). C 15 H 13 Calculated MS (ESI) mass for C11H9N3O2: 267.28; m / z found 268.1 [M+H] + 。

[0532] Step 2: Synthesis of HBS-039-132: Compound HBS-039-126 (0.15 g, 0.55 mmol) was dissolved in MeOH (2.5 mL). 1.0 N aqueous NaOH (2.77 mL, 2.76 mmol) was added, and the reaction mixture was refluxed for 3 h. LCMS data showed the formation of the product (m / z 240.1). 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 (2.0 mL x 3) to give 0.11 g of the solid product (yield 82.7%). C 13 Calculated MS (ESI) mass for C9H9N3O2: 239.23; m / z found 240.1 [M+H] + 。

[0533] Synthesis of the secondary amine intermediate - amino

[0534]

[0535] Step 1: Synthesis of HBS-061-186: Carboxylic acid (1.540 g, 6.72 mmol) was dissolved in THF (30 mL). The solution was cooled in an ice bath for 1 hour. CDI (1.09 g, 6.72 mmol) was added, the ice bath was removed after 30 minutes, and the reaction was stirred at room temperature for 18 hours. Hydroxyl amidine (0.694 g, 4.48 mmol) was added and continued to stir at room temperature. After 24 hours, only 36% conversion to the acyl intermediate was observed by LCMS. HOBT (0.908 g, 6.72 mmol), EDC (1.09 g, 6.72 mmol), TEA (3.11 mL, 22.3 mmol) and CHCl (30 mL) were added in sequence and stirred at room temperature. LCMS showed complete conversion to the acyl intermediate (m / z 367) after 22 hours. The acyl intermediate was isolated by extractive workup between EtOAc and water to give a viscous yellow oil (2.40 g). The oil was dissolved in DCM (15 mL), toluene (25 mL) was added, and the reaction was heated to 100-120° C. in an open flask. LCMS showed product formation (m / z 349). The reaction mixture was dissolved in saturated aqueous NaHCO 3 and extracted with EtOAc. The EtOAc layer was dried over Na 2 SO 4 , filtered, and evaporated. The crude product was purified by column chromatography with a mobile phase of hexane:EtOAc gradient elution. 1.14 g of a white solid was obtained (yield 73.3%). 17 H 21 MS (ESI) mass calculated for FN4O3: 348.2; m / z: 349.1 [M+H] + .

[0536] Step 2: Synthesis of HBS-061-199: Compound HBS-061-186 (1.142 g, 3.28 mmol) was dissolved in anhydrous dioxane (20 mL). A 4.0 M HCl solution in dioxane (4.1 mL, 16.4 mmol) was added and the reaction was vigorously stirred at 60 ° C for 42 hours to form a suspension. LCMS showed complete conversion to the product (m / z 249). The reaction mixture was cooled to room temperature, filtered and washed with hexane to obtain a paste adhering to the filter paper. The sample was dissolved in MeOH, concentrated and dried in a vacuum oven to obtain 0.807 g of a powdery off-white solid (yield 76.7%). 12 H 13 MS (ESI) mass calculated for FN4O: 248.1; m / z: 249.1 [M+H] + .

[0537]

[0538] Step 1: Synthesis of HBS-061-180: Dissolve carboxylic acid (1.993 g, 8.69 mmol) in THF (40 mL). Cool the solution in an ice bath for 1 hour. Add CDI (1.42 g, 8.76 mmol). Remove the ice bath after 15 minutes and stir the reaction at room temperature for 6 hours. Add hydroxyamidine (0.795 g, 5.80 mmol) and continue stirring at room temperature. After 72 hours, only 50% conversion to the acyl intermediate was observed by LCMS. Add HOBT (1.17 g, 8.66 mmol), EDC (1.67 g, 8.71 mmol), TEA (4.0 mL, 28.7 mmol) and CH2Cl2 (40 mL) successively and stir at room temperature. LCMS showed complete conversion to the acyl intermediate (m / z 349) after 22 hours. Separate the acyl intermediate by extraction between EtOAc and water to obtain a light yellow oil (2.87 g). Dissolve the oil in CH2Cl2 (25 mL), add toluene (30 mL), and heat the reaction in an open flask to 100 °C. LCMS showed formation of the product (m / z 331). Dissolve the reaction mixture in saturated aqueous NaHCO3 and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. Obtain 1.65 g of colorless oil (yield 85.9%). C 17 H 22 Calculated mass of MS (ESI) of N4O3: 330.2; m / z is 331.1 [M+H] + 。

[0539] Step 2: Synthesis of HBS-061-198: Dissolve compound HBS-061-180 (1.645 g, 4.98 mmol) in anhydrous dioxane (30 mL). Add a dioxane solution of 4.0 M HCl (6.2 mL, 24.8 mmol) and stir the reaction vigorously at 60 °C for 42 hours. LCMS showed complete conversion to the product (m / z 231). Cool the reaction mixture to room temperature, filter, wash with hexane to obtain a paste adhering to the filter paper. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 1.47 g of a shell-like beige solid (yield 97.1%). C 12 H 14 Calculated mass of MS (ESI) of N4O: 230.1; m / z is 231.1 [M+H] + 。

[0540]

[0541] General synthesis of HBS-061-129: Dissolve alcohol (3.09 g, 14.3 mmol) in anhydrous DCM (30 mL). Add DIPEA (3.75 mL, 21.5 mmol) and DMAP (2.63 g, 21.5 mmol) successively, and stir the mixture in an ice bath for 1 hour. Add p-TsCl (3.01 g, 15.8 mmol) in portions over 20 minutes, and allow the ice bath to warm slowly to room temperature over 24 hours. Add reagents to consume the starting materials in the reaction. LCMS data showed the formation of the product (m / z 314, 270). Treat the reaction mixture with water, and extract the product with DCM. Dry the DCM layer over Na2SO4, filter and evaporate. Purify the crude product by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtain 3.21 g of a crystalline white solid (yield 60.4%). C 18 H 27 MS (ESI) mass calculated for NO5S: 369.2; m / z at 314.1, 270.1 [M+H] + 。

[0542] Step 1: Synthesis of HBS-061-132: Dissolve HBS-061-129 (1.034 g, 2.80 mmol) and pyrazole (0.716 g, 3.36 mmol) in anhydrous dioxane (20 mL). Add Cs2CO3 (1.82 g, 5.58 mmol), and heat the reaction mixture to 70 °C with vigorous stirring. After 40 hours, LCMS showed the formation of a mixture of 82:18 isomer products (m / z at 411) with high conversion. Cool the reaction mixture to room temperature, treat with water, and extract with EtOAc. Dry the EtOAc layer over Na2SO4, filter and evaporate. Purify the crude product by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtain 0.39 g of the major isomer as a colorless oil (yield 33.7%). C 20 H 25 MS (ESI) mass calculated for F3N4O2: 410.2; m / z at 411.2 [M+H] + 。

[0543] Step 2: Synthesis of HBS-061-140: Dissolve compound HBS-061-132 (0.387 g, 0.943 mmol) in anhydrous dioxane (7 mL). Add a dioxane solution of 4.0 M HCl (1.2 mL, 4.8 mmol), and stir the reaction vigorously at 50 °C for 21 h. LCMS shows complete conversion to the product (m / z 311). Cool the reaction mixture to room temperature and concentrate to obtain a glassy material. Dissolve the sample in MeOH, concentrate, and dry in a vacuum oven to obtain 0.38 g of a glassy material (quantitative yield). C 15 H 17 Calculated MS (ESI) mass for F3N4: 310.2; m / z 311.2 [M+H] + 。

[0544]

[0545] Step 1: Synthesis of HBS-061-133: Dissolve compound HBS-061-129 (1.050 g, 2.84 mmol) and pyrazole (0.612 g, 3.41 mmol) in anhydrous dioxane (20 mL). Add Cs2CO3 (1.85 g, 5.68 mmol), and heat the reaction mixture to 70 °C with vigorous stirring. After 40 h, LCMS shows formation of an 80:20 isomer mixture product (m / z 377) with high conversion. Cool the reaction mixture to room temperature, treat with water, and extract with EtOAc. Dry the EtOAc layer over Na2SO4, filter, and evaporate. Purify the crude product by column chromatography with mobile phase: hexane:EtOAc, gradient elution. Obtain 0.35 g of the major isomer as a colorless oil (yield: 32.3%). C 19 H 25 Calculated MS (ESI) mass for ClN4O2: 376.2; m / z 377.2 [M+H] + 。

[0546] Step 2: Synthesis of HBS-061-141: Dissolve compound HBS-061-133 (0.346 g, 0.918 mmol) in anhydrous dioxane (7 mL). Add a dioxane solution of 4.0 M HCl (1.15 mL, 4.6 mmol), and stir the reaction vigorously at 50 °C for 24 h, then stir at 60 °C for 3 h. LCMS shows complete conversion to the product (m / z 277). Cool the reaction mixture to room temperature, filter, and wash with hexane to obtain 0.27 g of a white powdery solid (yield: 85.3%). C 14 H 17Calculated MS(ESI) mass of ClN4: 276.1; m / z 277.1 [M+H] + 。

[0547]

[0548] Step 1: Synthesis of HBS-061-134: Dissolve compound HBS-061-129 (1.011 g, 2.74 mmol) and pyrazole (0.612 g, 3.41 mmol) in anhydrous dioxane (20 mL). Add Cs2CO3 (1.78 g, 5.46 mmol), and heat the reaction mixture to 70 °C with vigorous stirring. After 40 h, LCMS showed formation of an 88:12 isomer mixture product (m / z 412) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. Obtained 0.30 g of the major isomer as a colorless oil (yield 26.9%). C 19 H 24 Calculated MS(ESI) mass of F3N5O2: 411.2; m / z 412.1 [M+H] + 。

[0549] Step 2: Synthesis of HBS-061-142: Dissolve compound HBS-061-134 (0.303 g, 0.736 mmol) in anhydrous dioxane (7 mL). Add a dioxane solution of 4.0 M HCl (0.92 mL, 3.7 mmol), and stir the reaction vigorously at 50 °C for 24 h, then at 60 °C for 3 h. LCMS showed complete conversion to the product (m / z 312). A precipitate formed upon cooling. Filter the reaction mixture and wash with hexane to obtain 0.23 g of a powdery white solid (yield 79.9%). C 14 H 16 Calculated MS(ESI) mass of F3N5: 311.1; m / z 312.2 [M+H] + 。

[0550]

[0551] Synthesis of HBS-061-169: Dissolve alcohol (3.02 g, 15.0 mmol) in anhydrous CH2Cl2 (32 mL). Add DIPEA (3.92 mL, 22.5 mmol) and DMAP (2.75 g, 22.5 mmol) successively, and stir the mixture in an ice bath for 1 hour. Add p-TsCl (3.43 g, 15.8 mmol) portionwise over 10 minutes, and slowly warm the ice bath to room temperature. After 24 hours, at room temperature, LCMS shows complete conversion to the product (m / z 300, 256). Treat the reaction mixture with water, and extract the product with DCM. Dry the DCM layer over Na2SO4, filter and evaporate. Purify the crude product by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtain 4.91 g of a colorless oil (yield 92.0%). C 17 H 25 Calculated MS (ESI) mass for NO5S: 355.2; m / z at 300.0, 256.0 [M+H] + 。

[0552]

[0553] Step 1: Synthesis of HBS-061-146: Dissolve compound HBS-061-169 (1.533 g, 4.31 mmol) and pyrazole (0.750 g, 5.17 mmol) in anhydrous dioxane (30 mL). Add Cs2CO3 (2.81 g, 5.17 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 24 hours, LCMS shows formation of an 83:17 isomer mixture product with high conversion (m / z at 329). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. Dry the EtOAc layer over Na2SO4, filter and evaporate. Purify the crude product by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtain 1.06 g of the major isomer as a colorless oil (yield 75.0%). C 18 H 24 Calculated MS (ESI) mass for N4O2: 328.2; m / z at 329.2 [M+H] + 。

[0554] Step 2: Synthesis of HBS-061-153: Dissolve compound HBS-061-146 (1.061 g, 3.23 mmol) in anhydrous dioxane (12 mL). Add a dioxane solution of 4.0 M HCl (4.04 mL, 16.2 mmol), and stir the reaction vigorously at 60 °C for 18 h. LCMS showed complete conversion to the product (m / z 229). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.97 g of a white solid powder (yield 100%). C 13 H 16 Calculated mass of N4 by MS (ESI): 228.1; m / z 229.1 [M+H] + .

[0555]

[0556] Step 1: Synthesis of HBS-061-167: Dissolve the alcohol (1.41 g, 7.0 mmol) in anhydrous THF (10 mL). Add 60% NaH (0.42 g, 10.5 mmol) in one portion, and after 15 min, add a DMF (6 mL) solution of chloropyrimidine (1.28 g, 7.0 mmol). Heat the reaction mixture to 70 °C. After 3 h, LCMS showed formation of the product (m / z 292, 248). Cool the reaction mixture to room temperature, treat with water, and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. Obtain 0.13 g of a colorless oily product (yield = 5.3%). C 15 H 20 Calculated mass of F3N3O3 by MS (ESI): 347.2; m / z 292.0, 248.1 [M+H] + .

[0557] Step 2: Synthesis of HBS-061-170: Dissolve compound HBS-061-167 (0.129 g, 0.371 mmol) in anhydrous dioxane (2 mL). Add a dioxane solution of 4.0 M HCl (0.47 mL, 1.88 mmol), and stir the reaction vigorously at room temperature for 96 h to form a suspension. LCMS showed complete conversion to the product (m / z 248). Filter the reaction mixture and wash with hexane to obtain 67 mg of a white solid (yield 63.5%). C 10 H 12 Calculated mass of F3N3O by MS (ESI): 247.1; m / z 248.1 [M+H] + .

[0558]

[0559] Step 1: Synthesis of HBS-061-185: Dissolve compound HBS-061-169 (0.695 g, 1.96 mmol) and pyrazole (0.422 g, 2.35 mmol) in anhydrous dioxane (15 mL). Add Cs2CO3 (1.27 g, 3.90 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 42 h, LCMS showed the formation of a mixture of isomeric products (m / z 363) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography, mobile phase: hexane:EtOAc, gradient elution. 0.18 g of the major isomer as a colorless oil was obtained (yield 24.9%). C 18 H 23 MS (ESI) mass calculated for ClN4O2: 362.2; m / z 363.1 [M+H] + 。

[0560] Step 2: Synthesis of HBS-061-192: Dissolve compound HBS-061-185 (0.177 g, 0.488 mmol) in anhydrous dioxane (10 mL). Add a dioxane solution of 4.0 M HCl (1.22 mL, 4.88 mmol), and stir the reaction vigorously at 60 °C for 64 h. LCMS showed complete conversion to the product (m / z 263). Cool the reaction mixture to room temperature, filter and wash with hexane to give 0.16 g of a white solid (yield 97.7%). C 13 H 15 MS (ESI) mass calculated for ClN4: 262.1; m / z 263.1 [M+H] + 。

[0561]

[0562] Step 1: Synthesis of HBS-061-176: Dissolve compound HBS-061-169 (0.704 g, 1.98 mmol) and pyrazole (0.427 g, 2.38 mmol) in anhydrous dioxane (20 mL). Add Cs2CO3 (1.29 g, 3.96 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 64 h, LCMS showed formation of the product with high conversion (m / z 363). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. 0.64 g of the product as a colorless oil was obtained (yield 89.3%). C 18 H 23 MS (ESI) mass calculated for C1H1ClN4O2: 362.2; m / z 363.1 [M+H] + .

[0563] Step 2: Synthesis of HBS-061-179: Dissolve compound HBS-061-176 (0.642 g, 1.77 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.21 mL, 8.84 mmol), and stir the reaction vigorously at 60 °C for 18 h. LCMS showed complete conversion to the product (m / z 263). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.54 g of a powdery white solid (yield 91.6%). C 13 H 15 MS (ESI) mass calculated for C1H1ClN4: 262.1; m / z 263.1 [M+H] + .

[0564]

[0565] Step 1: Synthesis of HBS-066-001: Dissolve HBS-061-169 (0.614 g, 1.73 mmol) and pyrazole (0.441 g, 2.07 mmol) in anhydrous dioxane (20 mL). Add Cs2CO3 (1.12 g, 3.44 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 64 h, LCMS showed formation of an 88:12 isomer mixture product with high conversion (m / z 397). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. 0.51 g of the major isomer as a waxy white solid was obtained (yield 74.9%). C 19 H23 The calculated MS(ESI) mass of F3N4O2: 396.2; m / z 397.1 [M+H] + 。

[0566] Step 2: Synthesis of HBS-066-005: Dissolve compound HBS-066-001 (0.513 g, 1.29 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (1.62 mL, 6.48 mmol), and stir the reaction vigorously at 60 °C for 90 hours. LCMS shows complete conversion to the product (m / z 297). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.36 g of a white solid powder (yield 76.0%). C 14 H 15 The calculated MS(ESI) mass of F3N4: 296.1; m / z 297.1 [M+H] + 。

[0567] <C

[0568] Step 1: Synthesis of HBS-061-186: Dissolve the carboxylic acid (1.720 g, 7.50 mmol) in CH2Cl2 (40 mL). Add hydroxyamidine (0.771 g, 5.00 mmol), HOBT (1.35 g, 10.0 mmol), EDC (1.917 g, 10.0 mmol) and TEA (3.50 mL, 25.0 mmol) in sequence, and stir at room temperature. After 24 hours, LCMS shows complete conversion to the acyl intermediate (m / z 366). Separate the acyl intermediate by extraction between EtOAc and water to obtain a viscous yellow oil (2.44 g). Dissolve the oil in DCM (20 mL), add toluene (30 mL), and heat the reaction in an open flask to 100 °C. After 21 hours, LCMS shows complete conversion to form the product (m / z 348, 292, 248). After cooling, dissolve the reaction mixture in EtOAc and extract with saturated aqueous NaHCO3. The EtOAc layer is dried over Na2SO4, filtered and evaporated. The crude product is purified by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtain 0.717 g of a colorless oil (yield 41.0%). C 18 H 22 The calculated MS(ESI) mass of FN3O3: 347.2; m / z 348.1, 292.0, 248.0 [M+H] + 。

[0569] Step 2: Synthesis of HBS-066-011 / HBS-066-022: Dissolve compound HBS-066-008 (0.717 g, 2.06 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (3.29 mL, 13.2 mmol), and stir the reaction vigorously at 60 °C for 72 h. LCMS shows complete conversion to the product (m / z 248). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.53 g of a white solid powder (yield 90.2%). C 13 H 14 Calculated MS (ESI) mass for FN3O: 247.1; m / z 248.1 [M+H] + 。

[0570]

[0571] Step 1: Synthesis of HBS-066-010: Dissolve compound HBS-061-169 (0.547 g, 1.54 mmol) and pyrazole (0.392 g, 1.85 mmol) in anhydrous dioxane (20 mL). Add Cs2CO3 (1.00 g, 3.07 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 48 h, LCMS shows formation of the product with high conversion (m / z 396). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer is dried over Na2SO4, filtered and evaporated. The crude product is purified by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtain 0.47 g of a colorless oily product (yield 77.7%). C 20 H 24 Calculated MS (ESI) mass for F3N3O2: 395.2; m / z 396.1 [M+H] + 。

[0572] P120 Step 2: Synthesis of HBS-066-013: Dissolve compound HBS-066-010 (0.473 g, 1.20 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (1.50 mL, 6.00 mmol), and stir the reaction vigorously at 60 °C for 66 h. LCMS shows complete conversion to the product (m / z 296). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.37 g of a white solid powder (yield 84.0%). C 15 H 16 Calculated MS (ESI) mass for F3N3: 295.1; m / z 296.1 [M+H] + 。

[0573]

[0574] Synthesis of HBS-066-019: Dissolve HBS-061-169 (1.179 g, 3.32 mmol) in anhydrous DMF (20 mL). Add NaN3 (0.323 g, 4.97 mmol), and heat the reaction mixture to 70 °C with vigorous stirring. After 24 hours, LCMS showed the formation of the product with high conversion (m / z 171, 127). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography, mobile phase: hexane:EtOAc, gradient elution. 0.630 g of a colorless oily product was obtained (yield 83.9%). C 10 H 18 MS (ESI) mass calculated for C9H10N4O2: 226.2; m / z found 171.1, 127.1 [M+H] + 。

[0575]

[0576] Step 1: Synthesis of HBS-066-017: Dissolve compound HBS-066-019 (0.177 g, 0.782 mmol) in a mixture of toluene and t-BuOH (4:1 v / v mL). Add acetylene (0.103 mL, 0.938 mmol), CuI (15 mg, 0.078 mmol) and DIPEA (0.272 mL, 1.56 mmol) successively. Stir the reaction mixture vigorously at room temperature. After 42 hours, LCMS showed the formation of the product with high conversion (m / z 329.0). Evaporate the reaction mixture, and purify the crude product by column chromatography, mobile phase: hexane:EtOAc, gradient elution. 0.159 g of a white solid product was obtained (yield 62.0%). C 18 H 24 MS (ESI) mass calculated for C16H14N4O2: 328.2; m / z found 329.2 [M+H] + 。

[0577] Step 2: Synthesis of HBS-066-021: Dissolve compound HBS-066-017 (0.159 g, 0.484 mmol) in anhydrous dioxane (10 mL). Add a dioxane solution of 4.0 M HCl (0.81 mL, 3.24 mmol), and stir the reaction vigorously at 60 °C for 72 h to form a suspension. LCMS shows complete conversion to the product (m / z 229). Cool the reaction mixture to room temperature, filter and wash with hexane. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.14 g of an off-white waxy solid (yield 95.3%). C 13 H 16 Calculated mass of MS (ESI) for N4: 228.1; m / z is 229.1 [M+H] + 。

[0578]

[0579] Step 1: Synthesis of HBS-066-024: Dissolve compound HBS-066-019 (0.315 g, 1.39 mmol) in a mixture of toluene and t-BuOH (6:1.5 v / v mL). Add acetylene (0.200 g, 1.66 mmol), CuI (28 mg, 0.147 mmol) and DIPEA (0.485 mL, 2.78 mmol) successively. Stir the reaction mixture vigorously at room temperature. After 42 h, LCMS shows incomplete conversion of the product. Heat to 60 °C, and the product is formed with a high conversion rate after 2.5 h (m / z 347). Evaporate the reaction mixture, and purify the crude product by column chromatography with mobile phase: hexane / EtOAc, gradient elution. Obtain 0.32 g of a white solid product (yield 66.6%). C 18 H 23 Calculated mass of MS (ESI) for FN4O2: 346.2; m / z is 347.1 [M+H] + 。

[0580] Step 2: Synthesis of HBS-066-028: Dissolve compound HBS-066-024 (0.321 g, 0.927 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.32 mL, 9.27 mmol), and stir the reaction vigorously at 60 °C for 42 h. LCMS shows complete conversion to the product (m / z 247). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain a white waxy solid adhering to the filter paper. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.32 g of a white waxy solid (quantitative yield). C 13 H 15Calculated MS (ESI) mass of FN4: 246.1; m / z 247.1 [M+H] + 。

[0581]

[0582] Step 1: Synthesis of HBS-066-025: Dissolve compound HBS-066-019 (0.315 g, 1.39 mmol) in a mixture of toluene and t-BuOH (6:1.5 v / v mL). Sequentially add acetylene (0.228 g, 1.67 mmol), CuI (28 mg, 0.147 mmol), and DIPEA (0.485 mL, 2.78 mmol). Stir the reaction mixture vigorously at room temperature. After 42 h, LCMS shows incomplete conversion of the product. Heat to 60 °C, and after 2.5 h, the product is formed with high conversion (m / z 363). Evaporate the reaction mixture, and purify the crude product by column chromatography with mobile phase: hexane:EtOAc, gradient elution. Obtain 0.312 g of a white solid product (yield 61.8%). C 18 H 23 Calculated MS (ESI) mass of ClN4O2: 362.2; m / z 363.1 [M+H] + 。

[0583] Step 2: Synthesis of HBS-066-029: Dissolve compound HBS-066-025 (0.31 g, 0.860 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.15 mL, 8.60 mmol), and stir the reaction vigorously at 60 °C for 42 h to form a suspension. LCMS shows complete conversion to the product (m / z 263). Cool the reaction mixture to room temperature, filter, and wash with hexane to obtain 0.260 g of a white solid (yield 90.1%). C 13 H 15 Calculated MS (ESI) mass of ClN4: 262.1; m / z 263.1 [M+H] + 。

[0584]

[0585] Step 1: Synthesis of HBS-066-032: Dissolve HBS-061-169 (1.01 g, 2.83 mmol) and pyrazole (0.607 g, 3.40 mmol) in anhydrous dioxane (25 mL). Add Cs2CO3 (1.85 g, 5.68 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 24 h, LCMS showed formation of a 92:8 isomer mixture product (m / z 362) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtained 0.518 g of the major isomer as a colorless oil (yield 50.5%). C 19 H 24 MS (ESI) mass calculated for ClN3O2: 361.2; m / z 362.1 [M+H] + 。

[0586] Step 2: Synthesis of HBS-066-035 / HBS-066-044: Dissolve compound HBS-066-032 (0.518 g, 1.43 mmol) in anhydrous dioxane (30 mL). Add a dioxane solution of 4.0 M HCl (3.58 mL, 14.3 mmol), and stir the reaction vigorously at 60 °C for 66 h to form a suspension. LCMS showed complete conversion to the product (m / z 262). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.395 g of a powdery white solid (yield 82.4%). C 14 H 16 MS (ESI) mass calculated for ClN3: 261.1; m / z 262.1 [M+H] + 。

[0587]

[0588] Step 1: Synthesis of HBS-066-034: Dissolve HBS-061-169 (0.499 g, 1.40 mmol) and pyrazole (0.243 g, 1.68 mmol) in anhydrous dioxane (12 mL). Add Cs2CO3 (0.915 g, 2.81 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 90 h, LCMS showed the formation of a mixture of isomer products (m / z 328) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. TLC (95:5, DCM, MeOH) showed the separation of isomers. The crude product was purified by column chromatography, mobile phase: DCM:MeOH, gradient elution. Obtained 0.253 g of the major isomer as a yellow oil (yield 55.0%). C 19 H 25 MS (ESI) mass calculated for H N3O2: 327.2; m / z 328.2 [M+H] + .

[0589] Step 2: Synthesis of HBS-066-039: Dissolve compound HBS-066-034 (0.253 g, 7.73 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (1.93 mL, 4.88 mmol), and stir the reaction vigorously at 60 °C for 27 h to form a suspension. LCMS showed complete conversion to the product (m / z 228). Cool the reaction mixture to room temperature, filter and wash with hexane. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.168 g of a white crystalline wax (yield 72.4%). C 14 H 17 MS (ESI) mass calculated for H N3: 227.1; m / z 228.1 [M+H] + .

[0590]

[0591] Step 1: Synthesis of HBS-066-036: Dissolve compound HBS-061-169 (0.978 g, 2.75 mmol) and pyrazole (0.545 g, 3.02 mmol) in anhydrous dioxane (25 mL). Add Cs2CO3 (1.79 g, 5.49 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 64 h, LCMS showed the formation of a 96:4 isomer mixture product (m / z 364) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. Obtained 0.682 g of the major isomer as a colorless oil (yield 68.2%). C 19 H 23 Calculated mass for MS (ESI) of F2N3O2: 363.2; m / z 364.2 [M+H] + 。

[0592] Step 2: Synthesis of HBS-066-042: Dissolve compound HBS-066-036 (0.682 g, 1.88 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.35 mL, 9.40 mmol), and stir the reaction vigorously at 60 °C for 66 h to form a suspension. LCMS showed complete conversion to the product (m / z 264). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain a film adhering to the filter paper. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.55 g of an off-white wax (yield 87.2%). C 14 H 15 Calculated mass for MS (ESI) of F2N3: 263.1; m / z 264.2 [M+H] + 。

[0593]

[0594] Step 1: Synthesis of HBS-066-037: Dissolve compound HBS-061-169 (0.963 g, 2.71 mmol) and pyrazole (0.532 g, 2.98 mmol) in anhydrous dioxane (25 mL). Add Cs2CO3 (1.76 g, 5.40 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 64 h, LCMS showed formation of the product with high conversion (m / z 362). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography with mobile phase: hexane:EtOAc, gradient elution. 0.65 g of the major isomer as a yellow oil was obtained (yield 66.4%). C 19 H 24 MS (ESI) mass calculated for ClN3O2: 361.2; m / z 362.1 [M+H] + 。

[0595] Step 2: Synthesis of HBS-066-043: Dissolve compound HBS-066-037 (0.651 g, 1.80 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.25 mL, 9.00 mmol), and stir the reaction vigorously at 60 °C for 66 h to form a suspension. LCMS showed complete conversion to the product (m / z 262). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain a film adhering to the filter paper. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.54 g of a beige wax (yield 88.9%). C 14 H 16 MS (ESI) mass calculated for ClN3: 261.1; m / z 262.1 [M+H] + 。

[0596]

[0597] Step 1: Synthesis of HBS-066-046: Dissolve compound HBS-061-169 (1.355 g, 3.81 mmol) and pyrazole (0.680 g, 4.19 mmol) in anhydrous dioxane (40 mL). Add Cs2CO3 (2.48 g, 7.61 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 48 hours, LCMS showed the formation of a mixture of isomer products with high conversion (m / z 346). Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. TLC (95:5, DCM, MeOH) showed separation of the isomers. The crude product was purified by column chromatography, mobile phase: DCM:MeOH, gradient elution. 0.63 g of the major isomer as a yellow oil was obtained (yield 47.9%). C 19 H 24 Calculated mass for MS (ESI) of FN3O2: 345.2; m / z 346.2 [M+H] + .

[0598] Step 2: Synthesis of HBS-066-050: Dissolve compound HBS-066-046 (0.61 g, 1.78 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.22 mL, 8.88 mmol), and stir the reaction vigorously at 60 °C for 68 hours to form a suspension. LCMS showed complete conversion to the product (m / z 246). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain 0.478 g of a white solid (yield 84.5%). C 14 H 16 Calculated mass for MS (ESI) of FN3: 245.1; m / z 246.2 [M+H] + .

[0599]

[0600] Step 1: Synthesis of HBS-066-047: Dissolve compound HBS-061-169 (0.858 g, 2.41 mmol) and pyrazole (0.564 g, 2.66 mmol) in anhydrous dioxane (25 mL). Add Cs2CO3 (1.57 g, 4.82 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 64 hours, LCMS showed the formation of a 92:8 isomer mixture product (m / z 396) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography, mobile phase: hexane / EtOAc, gradient elution. 0.70 g of the major isomer as a colorless oil was obtained (yield 73.8%). C 20 H 24 Calculated mass for MS (ESI) of F3N3O2: 395.2; m / z 396.2 [M+H] + 。

[0601] Step 2: Synthesis of HBS-066-053: Dissolve compound HBS-066-047 (0.704 g, 1.78 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.20 mL, 8.80 mmol), and stir the reaction vigorously at 60 °C for 72 hours. LCMS showed complete conversion to the product (m / z 296). Cool the reaction mixture to room temperature, filter and wash with hexane. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.59 g of an off-white shell-like solid (yield 90.1%). C 15 H 16 Calculated mass for MS (ESI) of F3N3: 295.1; m / z 296.2 [M+H ]+ 。

[0602]

[0603] Step 1: Synthesis of HBS-066-048: Dissolve HBS-061-169 (0.866 g, 2.44 mmol) and pyrazole (0.495 g, 2.68 mmol) in anhydrous dioxane (25 mL). Add Cs2CO3 (1.59 g, 4.88 mmol), and heat the reaction mixture to 100 °C with vigorous stirring. After 64 h, LCMS showed the formation of a mixture of isomer products (m / z 368) with high conversion. Cool the reaction mixture to room temperature, treat with water and extract with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated. TLC (2:1 hexane:EtOAc) showed separation of the isomers. The crude product was purified by column chromatography, mobile phase: hexane:EtOAc, gradient elution. Obtained 0.670 g of the major isomer as a colorless oil (yield 74.7%). C 17 H 22 MS (ESI) mass calculated for ClN3O2S: 367.1; m / z 368.1 [M+H] + 。

[0604] Step 2: Synthesis of HBS-066-054: Dissolve compound HBS-066-048 (0.670 g, 1.82 mmol) in anhydrous dioxane (20 mL). Add a dioxane solution of 4.0 M HCl (2.30 mL, 9.20 mmol), and stir the reaction vigorously at 60 °C for 72 h. LCMS showed complete conversion to the product (m / z 268). Cool the reaction mixture to room temperature, filter and wash with hexane to obtain a shell-like solid adhering to the filter paper. Dissolve the sample in MeOH, concentrate and dry in a vacuum oven to obtain 0.53 g of a grayish-white shell-like solid (yield 85.9%). C 12 H 14 MS (ESI) mass calculated for ClN3S: 267.1; m / z 268.1 [M+H] + 。

[0605]

[0606] Step 1: Synthesis of HBS-037-067: Dissolve 2-chloro-5-(trifluoromethyl)pyridine (0.33 g, 1.82 mmol) and (S)-1-Boc-2-(aminomethyl)pyrrolidine (0.36 g, 1.81 mmol) in dry DMSO (5.0 mL). Add DIPEA (1.6 mL, 9.1 mmol), and stir the reaction mixture at 100 °C for 4 h. TLC shows the formation of the product. 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. Purify the crude product by ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. Isolate 0.24 g of the target liquid product (yield 39.0%). C 16 H 22 Calculated MS (ESI) mass for F3N3O2: 345.0; m / z 346.1 [M+H] + 。

[0607] Step 2: Synthesis of HBS-037-069: Dissolve HBS-037-067 (0.24 g, 0.71 mmol) in dry dioxane (3.0 mL). Add 4.0 M HCl in dioxane solution (1.77 mL, 7.08 mmol), and stir the reaction mixture at 50 °C for 4 h. LCMS shows the formation of the product (m / z 246). Concentrate the reaction mixture under reduced pressure to obtain the solid product (0.19 g, yield 78.4%). C 11 H 14 Calculated MS (ESI) mass for F3N3: 245.2; m / z 246.0 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ ppm 1.76 - 2.01 (m, 1H) 2.01 - 2.15 (m, 1H) 2.15 - 2.28 (m, 1H) 2.36 (br s, 1H) 3.25 - 3.46 (br s, 1H) 3.48 (br s, 1H) 4.04 (br s, 2H) 4.31 (br s, 1H) 7.47 (br s, 1H) 7.86 (br s, 1H) 8.19 (br s, 1H) 9.41 - 10.42 (br s, 1H).

[0608]

[0609] Step 1: Synthesis of HBS-037-070: Dissolve 2-chloro-5-ethylpyrimidine (0.2 g, 1.37 mmol) and (S)-1-Boc-2-(aminomethyl)pyrrolidine (0.28 g, 1.37 mmol) in dry DMF (5.0 mL). Add Cs2CO3 (0.89 g, 2.75 mmol), and stir the reaction mixture at 120 °C for 24 h. TLC shows the formation of the product. 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. Purify the crude product by ISCO Combi-Flash chromatography system, mobile phase: EtOAc:hexane, gradient elution. Isolate 0.27 g of the target liquid product (yield 64.2%). C 16 H 26 Calculated mass of MS (ESI) for C H N4O2: 306.4; m / z 307.1 [M+H] + 。

[0610] Step 2: Synthesis of HBS-037-074: Dissolve HBS-037-070 (0.27 g, 0.88 mmol) in dry dioxane (3.0 mL). Add a dioxane solution of 4.0 M HCl (2.2 mL, 8.81 mmol), and stir the reaction mixture at 60 °C for 4 h. LCMS shows the formation of the product (m / z 207). Concentrate the reaction mixture under reduced pressure to obtain a solid product (0.31 g, quantitative yield). C 11 H 18 Calculated mass of MS (ESI) for C H N4: 206.3; m / z 207.1 [M+H] + 。

[0611]

[0612] Step 1: Synthesis of HBS-037-095: Dissolve [(2S,3R)-1-[(4-methoxyphenyl)methyl]-3-methylpiperidin-2-yl]methanamine (0.35 g, 1.4 mmol) and 2-chloro-5-ethylpyrimidine (0.2 g, 1.4 mmol) in dry DMF (4.0 mL). Add Cs2CO3 (0.39 g, 2.82 mmol), and stir the reaction mixture at 120 °C for 6 h. TLC shows the formation of the product. Dilute the reaction mixture with water. 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. Purify the crude product by Combiflash chromatography system with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.33 g of the product (yield 65.4%). C 21 H 30 Calculated MS (ESI) mass for C18H25N4O: 354.5; m / z found 355.2 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ ppm 0.85–0.94 (d, J = 8.0 Hz, 3H) 1.16 (t, J = 8.0 Hz, 3H) 1.25 - 1.47 (m, 2H) 1.50 - 1.84 (m, 2H) 2.05–2.25 (m, 1H) 2.35–2.47 (q, J = 8.0 Hz, 2H) 2.47–2.60 (m, 1H) 2.62 - 2.83 (m, 2H) 3.33 - 3.46 (m, 2H) 3.77 (s, 3H) 3.78 - 3.85 (m, 2H) 5.68 (br s, 1H) 6.84 (d, J = 8.66 Hz, 2H) 7.24 - 7.31 (m, 2H) 8.12 (s, 2H).

[0613] Step 2: Synthesis of HBS-037-101: Dissolve HBS-037-095 (0.1 g, 0.3 mmol) in MeOH (3.0 mL). Add 20.0% Pd-OH / C (30.0 mg), and stir the reaction mixture at ambient temperature for 24 h. TLC shows a small amount of starting material and the formation of the product. Further add 20.0% Pd-OH / C (30.0 mg), and stir the reaction mixture at ambient temperature for an additional 24 h. TLC shows the completion of the reaction. LCMS data shows the formation of the product (m / z 235). Filter the reaction mixture through celite and wash with MeOH. Evaporate the filtrate under reduced pressure to obtain 66.0 mg of the crude product. The crude product is used for the next step without purification. C 13 H 22 Calculated MS (ESI) mass for C12H19N4: 234.3; m / z found 235.2 [M+H]+ 。

[0614]

[0615] Step 1: Synthesis of HBS-037-106: Dissolve [(2S,3R)-1-[(4-methoxyphenyl)methyl]-3-methylpiperidin-2-yl]methanamine (0.32 g, 1.29 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (0.23 g, 1.29 mmol) in dry DMF (5.0 mL). Add K2CO3 (0.36 g, 2.58 mmol), and stir the reaction mixture at 120 °C for 4 h. TLC shows the formation of the product, and LCMS shows the formation of the product (m / z 394). Dilute the reaction mixture with water. 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. Purify the crude product by an ISCO Combi-Flash chromatography system, mobile phase: DCM:MeOH (90:10 v / v mL). Collect the product band to obtain 0.41 g of pure product, m / z 394 (yield 81.4%). C 21 H 26 MS (ESI) mass calculated for F3N3O: 393.5; m / z found 394.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ ppm 0.88 (d, J = 7.04 Hz, 3H) 1.19 - 1.46 (m, 2H) 1.54 - 1.65 (m, 1H) 1.65 - 1.83 (m, 1H) 2.07 - 2.22 (m, 1H) 2.50 - 2.65 (m, 1H) 2.65 - 2.80 (m, 2H) 3.20 - 3.38 (m, 2H) 3.78 (s, 3H) 3.79 - 3.84 (m, 2H) 5.67 (br s, 1H) 6.32 (d, J = 8.80 Hz, 1H) 6.80 - 6.89 (m, 2H) 7.15 - 7.29 (m, 2H) 7.49 (dd, J = 8.80, 2.35 Hz, 1H) 8.28 - 8.32 (m, 1H).

[0616] Step 2: Synthesis of HBS-037-110: Dissolve HBS-037-106 (0.02 g, 0.5 mmol) in MeOH (5.0 mL). Add 10.0% Pd / C (60.0 mg), and stir the reaction mixture at ambient temperature under H2 atmosphere for 24 h. TLC showed completion of the reaction. LCMS data showed formation of the product (m / z 274). Filter the reaction mixture through celite and wash with MeOH. Evaporate the filtrate under reduced pressure to give 0.16 g of the crude product. C 13 H 18 MS (ESI) mass calculated for F3N3: 273.3; m / z found 274.1 [M+H] + 。

[0617]

[0618] Step 1: Synthesis of HBS-037-152: Dissolve N-Boc-L-prolinol (0.2 g, 0.99 mmol) in dry DMF (4.0 mL). Add NaH (0.08 g, 2.0 mmol) under ice-cooling. Add 2-chloro-5-ethylpyrimidine (0.2 g, 1.5 mmol) under cooling, and gradually warm the reaction mixture to room temperature with stirring for 3 h. LCMS showed formation of the product (m / z 308.2). Dilute the reaction mixture with water. Extract the product three times with ethyl acetate. Separate the EtOAc layer and dry over anhydrous Na2SO4. Evaporate the solvent to give the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.3 g of the pure product (yield quantitative). C 16 H 25 MS (ESI) mass calculated for N3O3: 307.4; m / z found 308.2 [M+H] + 。

[0619] Step 2: Synthesis of HBS-037-154: Dissolve HBS-037-152 (0.3 g, 0.99 mmol) in dry dioxane (4.0 mL). Add 4.0 M HCl in dioxane solution (2.48 mL, 9.9 mmol), and stir the reaction mixture at 60 °C for 4 h. LCMS showed formation of the product (m / z 208.1). Concentrate the reaction mixture under reduced pressure to give 0.32 g of the liquid product. C 11 H 17 MS (ESI) mass calculated for N3O: 207.3; m / z found 208.1 [M+H] + 。

[0620]

[0621] Step 1: Synthesis of HBS-037-153: Dissolve N-Boc-L-prolinol (0.2 g, 0.99 mmol) in dry DMF (4.0 mL). Add NaH (0.08 g, 2.0 mmol), and then add 2-chloro-5-trifluoromethylpyridine (0.27 g, 1.5 mmol). Heat the reaction mixture at 70 °C for 3 hours. LCMS shows the formation of the product (m / z 347.1). Dilute the reaction mixture with water. Extract the product three times with ethyl acetate. Separate the EtOAc layer and dry it over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with the mobile phase: EtOAc:hexane, gradient elution. Obtain 0.3 g of the pure product (yield 86.0%). C 16 H 21 MS (ESI) mass calculated for F3N2O3: 346.3; m / z 347.1 [M+H] + 。

[0622] Step 1: Synthesis of HBS-037-155: Dissolve HBS-037-153 (0.3 g, 0.86 mmol) in dry dioxane (2.0 mL). Add a dioxane solution of 4.0 M HCl (2.14 mL, 8.6 mmol), and stir the reaction mixture at 60 °C for 4 hours. LCMS shows the formation of the product (m / z 247.1). Filter the reaction mixture and wash it with hexane (5.0 mL x3) to obtain 0.27 g of the solid product (quantitative yield). C 11 H 13 MS (ESI) mass calculated for F3N2O: 246.2; m / z 247.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ ppm 1.87 - 1.99 (m, 1H) 1.99 - 2.08 (m, 1H) 2.08 - 2.17 (m, 1H) 2.17 - 2.29 (m, 1H) 3.32 - 3.49 (m, 2H) 3.96 - 4.09 (m, 1H) 4.60 - 4.77 (m, 2H) 7.00 (d, J = 8.73 Hz, 1H) 7.77 (dd, J = 8.73, 2.35 Hz, 1H) 8.37 - 8.42 (m, 1H) 9.74 (br s, 1H) 10.32 (br s, 1H).

[0623]

[0624] Step 1: Synthesis of HBS-039-033: Dissolve N-Boc-L-prolinol (0.5 g, 2.48 mmol) in DCM (10.0 mL). Add DIPEA (0.9 mL, 4.97 mmol), and then add DMAP (0.61 g, 4.97 mmol). Cool the reaction mixture in an ice bath and add p-TsCl (0.52 g, 2.73 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 256, 300). Dilute the reaction mixture with water and extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.88 g of the product is obtained (quantitative yield). C 17 H 25 Calculated MS (ESI) mass for NO5S: 355.5; m / z at 300.1, 256.1 [M+H] + 。

[0625] Step 2: Synthesis of HBS-039-034: Dissolve HBS-039-033 (0.88 g, 2.48 mmol) and 3-phenyl-1H-pyrazole (0.43 g, 2.98 mmol) in dry DMF (5.0 mL). Add Cs2CO3 (1.61 g, 4.96 mmol) and stir the reaction mixture at 70 °C for 4 hours. LCMS shows the formation of the product (m / z 328). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.73 g of pure product is obtained (yield 89.5%). C 19 H 25 Calculated MS (ESI) mass for N3O2: 327.4; m / z at 328.3 [M+H] + 。

[0626] Step 3: Synthesis of HBS-039-036: Dissolve HBS-039-034 (0.73 g, 2.24 mmol) in dry dioxane (10.0 mL). Add a 4.0 M HCl solution in dioxane (2.8 mL, 11.2 mmol) and stir the reaction mixture at 50 °C for 16 hours. LCMS shows the formation of the product (m / z 228). Filter the reaction mixture and wash it with hexane (5.0 mL x3) to obtain 0.53 g of solid product (quantitative yield). C 14 H 17 Calculated MS (ESI) mass for N3: 227.1; m / z at 228.2 [M+H] +。 1 1H NMR (400 MHz, chloroform-d) δ ppm 1.74 - 1.94 (m, 1H) 1.94 - 2.05 (m, 1H) 2.06 - 2.15 (m, 1H) 2.16–2.35 (m, 1H) 3.21 - 3.45 (m, 2H) 4.33 (br s, 1H) 4.86 (dd, J=14.82, 3.96 Hz, 1H) 5.07 (brdd, J=14.67, 8.66 Hz, 1H) 6.75 (d, J=2.20 Hz, 1H) 7.34 - 7.48 (m, 3H) 7.76 - 7.87 (m, 2H) 8.44 (d, J=2.49 Hz, 1H) 9.51 - 10.12 (br, 1H).

[0627]

[0628] Step 1: Synthesis of HBS-039-118: Dissolve (S)-1-Boc-2-(aminomethyl)pyrrolidine (1.5 g, 5.6 mmol) and 2-chloro-5-fluoropyridine (0.033 g, 0.25 mmol) in dioxane (3.0 mL). Add anhydrous t-BuOK (0.042 g, 0.37 mmol), then add Pd2(dba)3 (0.023 g, 0.025 mmol) and X-Phos (0.012 g, 0.025 mmol). Stir the reaction mixture at 110 °C under N2 atmosphere for 4 hours. LCMS data shows the formation of the product (m / z 296.0). Filter the reaction mixture through a bed of celite 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 elution. Obtain 0.032 g of the product (yield 86.8%). C 15 H 22 MS (ESI) mass calculated for C12H13FN3O2: 295.35; m / z found 296.0 [M+H] + 。

[0629] Step 2: Synthesis of HBS-039-120: Dissolve compound HBS-039-118 (0.032 g, 0.11 mmol) in dry dioxane (1.0 mL). Add a dioxane solution of 4.0 M HCl (0.27 mL, 1.1 mmol) and stir the reaction mixture at ambient temperature for 16 hours. LCMS shows the formation of the product (m / z 196.1). Concentrate the reaction mixture under reduced pressure to obtain 0.033 g of the product (yield quantitative). C 10 H 14Calculated MS(ESI) mass of FN3: 195.24; m / z 196.1 [M+H] + .

[0630]

[0631] Step 1: Synthesis of HBS-039-131: Dissolve N-Boc-L-prolinol (0.2 g, 0.99 mmol) in dry DMF (2.0 mL). Add NaH (0.12 g, 2.98 mmol) at 0 °C. Stir the reaction mixture at 0 °C for 30.0 minutes. Add a solution of 2-bromo-5-fluoropyridine (0.26 g, 1.49 mmol) in DMF (1.0 mL) at 0 °C. Gradually warm the reaction mixture to ambient temperature and heat at 70 °C for 3 hours. LCMS shows formation of the product (m / z 357.1). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.25 g of the product (yield 70.4%). C 15 H 21 Calculated MS(ESI) mass of BrN2O3: 357.24; m / z 357.1 [M+H] + .

[0632] Step 2: Synthesis of HBS-039-137: Dissolve compound HBS-039-131 (0.25 g, 0.7 mmol) in dry dioxane (5.0 mL). Add a solution of 4.0 M HCl in dioxane (1.74 mL, 7.0 mmol) and stir the reaction mixture at 50 °C for 6 hours. LCMS shows formation of the product (m / z 257). Filter and dry the reaction mixture to obtain 0.2 g of the product (yield 86.6%). C 10 H 13 Calculated MS(ESI) mass of BrN2O: 257.13; m / z 257.0 [M+H] + .

[0633]

[0634] Step 1: Synthesis of HBS-039-144: Dissolve (S)-1-Boc-2-(hydroxymethyl)piperidine (0.25 g, 1.16 mmol) in anhydrous DMF (5.0 mL). Add NaH (0.14 g, 3.48 mmol) at 0 °C, and stir the reaction mixture for 15.0 minutes. Add 2-chloro-5-trifluoromethylpyridine (0.32 g, 1.74 mmol), and gradually warm the reaction mixture to ambient temperature. Heat the reaction mixture at 80 °C for 8 hours. LCMS shows the formation of the product (m / z 361.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.2 g of the product (yield 48.0%). C 17 H 23 Calculated mass of MS (ESI) of F3N2O3: 360.37; m / z is 361.2 [M+H] + 。

[0635] Step 2: Synthesis of HBS-039-160: Dissolve compound HBS-039-144 (0.2 g, 0.56 mmol) in anhydrous dioxane (5.0 mL). Add a dioxane solution of 4.0 M HCl (1.39 mL, 5.58 mmol), and heat the reaction at 50 °C for 3 hours. LCMS shows the formation of the product (m / z 261.1). Concentrate the reaction mixture under reduced pressure to obtain 0.16 g of the product (yield 86.1%). C 12 H 15 Calculated mass of MS (ESI) of F3N2O 260.26; m / z is 261.1 [M+H] + 。

[0636]

[0637] Step 1: Synthesis of HBS-039-166: Dissolve N-Boc-L-prolinol (1.0 g, 4.97 mmol) in DCM (15.0 mL). Add DIPEA (1.72 mL, 9.94 mmol), followed by DMAP (1.21 g, 9.94 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (1.04 g, 5.46 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 256). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain 1.76 g of the product (quantitative yield). C17 H 25 Calculated MS(ESI) mass of NO5S: 355.45; m / z 256.0 [M - Boc] + 。

[0638] Step 2: Synthesis of HBS - 039 - 172: Dissolve compound HBS - 039 - 166 (0.84 g, 2.36 mmol) and 3 - [4 - (trifluoromethyl)phenyl]-1H - pyrazole (0.5 g, 2.36 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (1.53 g, 4.71 mmol), and stir the reaction mixture at 70 °C for 12 h. LCMS shows the formation of the product (m / z 396.3). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with the mobile phase: EtOAc:hexane, gradient elution. Obtain 0.8 g of the pure product (yield 85.9%). C 20 H 24 Calculated MS(ESI) mass of F3N3O2: 395.42; m / z 396.3 [M + H] + 。

[0639] Step 3: Synthesis of HBS - 039 - 176: Dissolve compound HBS - 039 - 172 (0.8 g, 2.02 mmol) in dry dioxane (20.0 mL). Add a 2.0 M HCl solution in diethyl ether (4.1 mL, 8.1 mmol), and stir the reaction mixture at 60 °C for 16 h. LCMS shows the formation of the product (m / z 296.1). Cool the reaction mixture and filter the precipitate. Dry the precipitate to obtain 0.6 g of the solid product (yield 89.4%). C 14 H 17 Calculated MS(ESI) mass of N3: 227.1; m / z 228.2 [M + H] + 。

[0640]

[0641] Step 1: Synthesis of HBS-039-177: Dissolve N-Boc-L-prolinol (1.0 g, 4.97 mmol) in DCM (15.0 mL). Add DIPEA (1.72 mL, 9.94 mmol), and then add DMAP (1.21 g, 9.94 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (1.04 g, 5.46 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 256.1, 300.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 1.76 g of the product is obtained (quantitative yield). C 17 H 25 Calculated MS (ESI) mass of NO5S: 355.45; m / z 256.1, 300.1 [M - Boc] + 。

[0642] Step 2: Synthesis of HBS-039-178: Dissolve compound HBS-039-177 (1.0 g, 6.17 mmol) and 3-[4-fluorophenyl]-1H-pyrazole (1.0 g, 6.17 mmol) in dry DMF (20.0 mL). Add anhydrous Cs2CO3 (4.0 g, 12.33 mmol), and stir the reaction mixture at 70 °C for 12 hours. LCMS shows the formation of the product (m / z 346.3). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 2.0 g of the pure product is obtained (yield 93.9%). C 19 H 24 Calculated MS (ESI) mass of FN3O2: 345.41; m / z 346.3 [M + H] + 。

[0643] Step 3: Synthesis of HBS-039-179: Dissolve compound HBS-039-178 (2.0 g, 5.79 mmol) in dry dioxane (20.0 mL). Add a 2.0 M HCl solution in diethyl ether (11.58 mL, 23.16 mmol), and stir the reaction mixture at 60 °C for 16 hours. LCMS shows the formation of the product (m / z 24621). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 1.63 g of the solid product is obtained (quantitative yield). C 14 H 16Calculated MS (ESI) mass of FN3: 245.3; m / z 246.2 [M+H] + .

[0644]

[0645] Step 1: Synthesis of HBS-055-090: Dissolve N-Boc-L-prolinol (0.5 g, 2.48 mmol) in DCM (10.0 mL). Add DIPEA (0.9 mL, 4.97 mmol), and then add DMAP (0.61 g, 4.97 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.52 g, 2.73 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 256.1, 300.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.88 g of the product is obtained (yield quantitative). C 17 H 25 Calculated MS (ESI) mass of NO5S: 355.45; m / z 256.1, 300.1 [M-Boc] + .

[0646] Step 2: Synthesis of HBS-055-091: Dissolve compound HBS-055-090 (0.88 g, 2.48 mmol) and 2-(1H-pyrazol-4-yl)pyridine dihydrochloride (0.6 g, 2.73 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (1.61 g, 4.97 mmol), and stir the reaction mixture at 70 °C for 16 hours. LCMS shows the formation of the product (m / z 329.2). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.82 g of pure product is obtained (yield 81.5%). C 18 H 24 Calculated MS (ESI) mass of N4O2: 328.41; m / z 329.2 [M+H] + .

[0647] Step 3: Synthesis of HBS-055-092: Dissolve compound HBS-055-091 (0.82 g, 2.48 mmol) in dry dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (2.5 mL, 9.94 mmol), and stir the reaction mixture at 50 °C for 12 h. LCMS shows the formation of the product (m / z 229.2). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.75 g of solid product is obtained (yield quantitative). C 13 H 16 Calculated mass of N4 by MS (ESI): 228.29; m / z 229.1 [M+H] + 。

[0648]

[0649] Step 1: Synthesis of HBS-055-093: Dissolve N-Boc-L-prolinol (0.5 g, 2.48 mmol) in DCM (10.0 mL). Add DIPEA (0.9 mL, 4.97 mmol), and then add DMAP (0.61 g, 4.97 mmol). Cool the reaction mixture to 0 °C in an ice bath. Add p-TsCl (0.52 g, 2.73 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 h. LCMS shows the formation of the product (m / z 256.1, 300.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.88 g of product is obtained (yield quantitative). C 17 H 25 Calculated mass of NO5S by MS (ESI): 355.45; m / z 256.1, 300.1 [M-Boc] + 。

[0650] Step 2: Synthesis of HBS-055-094: Dissolve compound HBS-055-093 (0.88 g, 2.48 mmol) and 2-(1H-pyrazol-3-yl)pyridine (0.43 g, 2.98 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (1.62 g, 4.97 mmol), and stir the reaction mixture at 70 °C for 12 h. LCMS shows the formation of the product (m / z 329.2). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.81 g of product is obtained (yield quantitative). C 18 H24 MS (ESI) mass calculated for N4O2: 328.41; m / z 329.2 [M+H] + 。

[0651] Step 3: Synthesis of HBS-055-097: Dissolve compound HBS-055-094 (0.81 g, 2.48 mmol) in dry dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (2.5 mL, 9.93 mmol), and stir the reaction mixture at 50 °C for 12 h. LCMS shows formation of the product (m / z 229.2). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.75 g of solid product is obtained (quantitative yield). C 13 H 16 MS (ESI) mass calculated for N4: 228.29; m / z 229.1 [M+H] + 。

[0652]

[0653] Step 1: Synthesis of HBS-055-095: Dissolve N-Boc-L-prolinol (0.5 g, 2.48 mmol) in DCM (10.0 mL). Add DIPEA (0.9 mL, 4.97 mmol), then add DMAP (0.61 g, 4.97 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.52 g, 2.73 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 h. LCMS shows formation of the product (m / z 256.1, 300.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.88 g of product is obtained (quantitative yield). C 17 H 25 MS (ESI) mass calculated for NO5S: 355.45; m / z 256.1, 300.1 [M-Boc] + 。

[0654] Step 2: Synthesis of HBS-055-096: Dissolve compound HBS-055-095 (0.88 g, 2.48 mmol) and 4-phenyl-1H-pyrazole (0.72 g, 4.97 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (1.62 g, 4.97 mmol), and stir the reaction mixture at 70 °C for 16 h. LCMS shows the formation of the product (m / z 328.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.6 g of the pure product (yield 73.8%). C 19 H 25 Calculated MS (ESI) mass for H N3O2: 327.42; m / z found 328.2 [M+H] + 。

[0655] Step 3: Synthesis of HBS-055-098: Dissolve compound HBS-055-096 (0.6 g, 1.83 mmol) in dry dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (1.83 mL, 7.33 mmol), and stir the reaction mixture at 50 °C for 12 h. LCMS shows the formation of the product (m / z 228.2). Cool the reaction mixture and filter the precipitate. Dry the precipitate to obtain 0.48 g of the solid product (quantitative yield). C 14 H 17 Calculated MS (ESI) mass for H N3: 227.31; m / z found 228.2 [M+H] + 。

[0656]

[0657] Step 1: Synthesis of HBS-055-102: Dissolve N-Boc-L-prolinol (0.5 g, 2.48 mmol) in DCM (10.0 mL). Add DIPEA (0.9 mL, 4.97 mmol), followed by DMAP (0.61 g, 4.97 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.52 g, 2.73 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 h. LCMS shows the formation of the product (m / z 256.1, 300.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain 0.88 g of the product (quantitative yield). C 17 H 25Calculated MS (ESI) mass of NO5S: 355.45; m / z 256.1, 300.1 [M - Boc] + 。

[0658] Step 2: Synthesis of HBS - 055 - 103: Dissolve compound HBS - 055 - 102 (0.88 g, 2.48 mmol) and 5 - fluoro - 2 - (1H - pyrazol - 4 - yl)pyridine (0.7 g, 2.98 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (2.64 g, 8.1 mmol), and stir the reaction mixture at 80 °C for 16 h. LCMS shows the formation of the product (m / z 347.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.45 g of pure product (yield 52.3%). C 18 H 23 Calculated MS (ESI) mass of FN4O2: 346.4; m / z 347.2 [M + H] + 。

[0659] Step 3: Synthesis of HBS - ..... 13 H 15 Calculated MS (ESI) mass of FN4: 246.28; m / z 247.1 [M + H] + 。

[0660]

[0661] It should be noted that there seems to be some incomplete information in the original text for step 3 in item . The translation is done as accurately as possible based on the provided text.Step 1: Synthesis of HBS-055-120: Dissolve (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (0.5 g, 2.1 mmol) in dry THF (10.0 mL). Add 2.0 M BH3·Me2S (2.1 mL, 4.14 mmol) at 0 °C. Gradually warm the reaction mixture to ambient temperature over 16 h. LCMS shows formation of the product (m / z 172.1, 250.1). Quench the reaction mixture with methanol. Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry over anhydrous Na2SO4. Evaporate the solvent to give 0.47 g of crude product (yield quantitative). C 12 H 21 MS (ESI) mass calculated for HNO3: 227.3; m / z 172.1, 250.1 [M+Na] + 。

[0662] Step 2: Synthesis of HBS-055-123: Dissolve compound HBS-055-120 (0.47 g, 2.1 mmol) in dry THF (10.0 mL). Add NaH (0.166 g, 4.14 mmol) at 0 °C. Add 2-chloro-5-(trifluoromethyl)pyridine (0.45 g, 2.48 mmol) and gradually heat the reaction mixture to reflux temperature over 16 h. LCMS shows formation of the product (m / z 373.1). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to give a crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.5 g of pure product (yield 64.9%). C 18 H 23 MS (ESI) mass calculated for C11H7F3N2O3: 372.38; m / z 373.1 [M+H] + 。

[0663] Step 3: Synthesis of HBS-055-127: Dissolve compound HBS-055-123 (0.5 g, 1.34 mmol) in dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (1.34 mL, 5.37 mmol) and stir the reaction mixture at 50 °C for 16 h. LCMS shows formation of the product (m / z 273.1). Cool the reaction mixture and filter the precipitate. Dry the precipitate to give 0.41 g of solid product (yield 88.4%). C 13 H 15 MS (ESI) mass calculated for C10H7F3N2O: 272.27; m / z 273.1 [M+H]+ 。

[0664]

[0665] Step 1: Synthesis of HBS-055-140: Dissolve N-Boc-L-prolinol (0.25 g, 1.24 mmol) in DCM (5.0 mL). Add DIPEA (0.43 mL, 2.48 mmol), and then add DMAP (0.3 g, 2.48 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.26 g, 1.34 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 256.1, 300.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.44 g of the product is obtained (quantitative yield). C 17 H 25 Calculated mass of MS (ESI) of NO5S: 355.45; m / z 256.1, 300.1 [M - Boc] + 。

[0666] Step 2: Synthesis of HBS-055-141: Dissolve compound HBS-055-140 (0.44 g, 1.24 mmol) and 5-fluoro-2-(1H-pyrazol-3-yl)pyridine (0.24 g, 1.49 mmol) in dry DMF (8.0 mL). Add anhydrous Cs2CO3 (1.21 g, 3.73 mmol), and stir the reaction mixture at 70 °C for 16 hours. LCMS shows the formation of the product (m / z 347.2). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.42 g of pure product is obtained (yield 97.2%). C 18 H 23 Calculated mass of MS (ESI) of FN4O2: 346.4; m / z 347.2 [M + H] + 。

[0667] Step 3: Synthesis of HBS-055-143: Dissolve compound HBS-055-141 (0.42 g, 1.21 mmol) in dry dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (1.21 mL, 4.83 mmol), and stir the reaction mixture at 50 °C for 12 h. LCMS shows the formation of the product (m / z 247.1). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.38 g of solid product is obtained (yield 98.6%). C 13 H 15 Calculated MS (ESI) mass of FN4: 246.28; m / z 247.1 [M+H] + 。

[0668]

[0669] Step 1: Synthesis of HBS-055-131: Dissolve (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]heptane-3-carboxylic acid (1.0 g, 4.4 mmol) in dry THF (10.0 mL). Add 2.0 M BH3·Me2S (4.4 mL, 8.8 mmol) at 0 °C. Gradually warm the reaction mixture to ambient temperature over 16 h. LCMS shows the formation of the product (m / z 158.1). Quench the reaction mixture with methanol. Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry over anhydrous Na2SO4. After evaporation of the solvent, 0.94 g of crude product is obtained (quantitative yield). C 11 H 19 Calculated MS (ESI) mass of NO3: 213.27; m / z 158.1 [M-Boc] + 。

[0670] Step 2: Synthesis of HBS-055-139: Dissolve compound HBS-055-131 (0.25 g, 1.17 mmol) in DCM (10.0 mL). Add DIPEA (0.4 mL, 2.34 mmol), followed by DMAP (0.24 g, 2.34 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.25 g, 1.29 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 h. LCMS shows the formation of the product (m / z 268.1, 312.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry over anhydrous Na2SO4. After evaporation of the solvent, 0.4 g of product is obtained (quantitative yield). C 18 H 25Calculated MS (ESI) mass of NO5S: 367.46; m / z 268.1, 312.1 [M-Boc] + 。

[0671] Step 3: Synthesis of HBS-055-142: Dissolve compound HBS-055-139 (0.4 g, 1.1 mmol) and 3-(4-fluorophenyl)-1H-pyrazole (0.2 g, 1.21 mmol) in dry DMF (8.0 mL). Add anhydrous Cs2CO3 (1.1 g, 3.3 mmol), and stir the reaction mixture at 70 °C for 16 h. LCMS shows the formation of the product (m / z 358.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.24 g of pure product (yield 61.5%). C 20 H 24 Calculated MS (ESI) mass of FN3O2: 357.42; m / z 358.2 [M+H] + 。

[0672] Step 4: Synthesis of HBS-055-147: Dissolve compound HBS-055-141 (0.24 g, 0.68 mmol) in dry dioxane (5.0 mL). Add a 4.0 M HCl solution in dioxane (1.35 mL, 2.71 mmol), and stir the reaction mixture at 50 °C for 16 h. LCMS shows the formation of the product (m / z 258.1). Cool the reaction mixture and filter the precipitate. Dry the precipitate to obtain 0.19 g of solid product (yield 95.5%). C 15 H 16 Calculated MS (ESI) mass of FN3: 257.31; m / z 258.1 [M+H] + 。

[0673]

[0674] Step 1: Synthesis of HBS-055-154: Dissolve (S)-1-(tert-butoxycarbonyl)-2-azetidinemethanol (0.5 g, 2.67 mmol) in DCM (10.0 mL). Add DIPEA (0.93 mL, 5.34 mmol), and then add DMAP (0.65 g, 5.34 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.56 g, 2.94 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 242.1, 286.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.91 g of the product is obtained (quantitative yield). C 16 H 23 Calculated MS (ESI) mass for NO5S: 341.42; m / z 242.1, 286.1 [M - Boc] + 。

[0675] Step 2: Synthesis of HBS-055-155: Dissolve compound HBS-055-154 (0.91 g, 2.67 mmol) and 3-(4-fluorophenyl)-1H-pyrazole (0.48 g, 0.48 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (2.61 g, 8.01 mmol), and stir the reaction mixture at 70 °C for 16 hours. LCMS shows the formation of the product (m / z 332.2). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.89 g of pure product is obtained (quantitative yield). C 18 H 22 Calculated MS (ESI) mass for FN3O2: 331.38; m / z 332.2 [M + H] + 。

[0676] Step 3: Synthesis of HBS-055-158: Dissolve compound HBS-055-155 (0.89 g, 2.67 mmol) in dry dioxane (10.0 mL). Add a 4.0 M HCl solution in dioxane (2.7 mL, 10.68 mmol), and stir the reaction mixture at 50 °C for 16 hours. LCMS shows the formation of the product (m / z 232.1). Cool the reaction mixture and concentrate it under reduced pressure to obtain 0.72 g of a solid product (quantitative yield). C 13 H 14Calculated MS (ESI) mass of FN3: 231.27; m / z 232.1 [M+H] + 。

[0677]

[0678] Step 1: Synthesis of HBS-055-156: Dissolve (S)-1-(tert-butoxycarbonyl)-2-azetidinemethanol (0.25 g, 1.33 mmol) in DCM (8.0 mL). Add DIPEA (0.47 mL, 2.67 mmol), and then add DMAP (0.33 g, 2.67 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.28 g, 1.47 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 242.1, 286.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.46 g of the product is obtained (quantitative yield). C 16 H 23 Calculated MS (ESI) mass of NO5S: 341.42; m / z 242.1, 286.1 [M-Boc] + 。

[0679] Step 2: Synthesis of HBS-055-157: Dissolve compound HBS-055-156 (0.46 g, 1.33 mmol) and 5-fluoro-2-(1H-pyrazol-3-yl)pyridine (0.26 g, 1.60 mmol) in dry DMF (10.0 mL). Add anhydrous Cs2CO3 (1.31 g, 4.0 mmol), and stir the reaction mixture at 70 °C for 16 hours. LCMS shows the formation of the product (m / z 333.1). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.44 g of pure product is obtained (quantitative yield). C 17 H 21 Calculated MS (ESI) mass of FN4O2: 332.37; m / z 333.1 [M+H] + 。

[0680] Step 3: Synthesis of HBS-055-162: Dissolve compound HBS-055-157 (0.44 g, 1.34 mmol) in dry dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (1.34 mL, 5.34 mmol), and stir the reaction mixture at 40 °C for 16 h. LCMS shows the formation of the product (m / z 233.1). Cool the reaction mixture and concentrate it under reduced pressure to give 0.41 g of the product (yield quantitative). C 12 H 13 MS (ESI) mass calculated for FN4: 232.26; m / z 233.1 [M+H] + 。

[0681]

[0682] Step 1: Synthesis of HBS-055-168: Dissolve compound HBS-055-131 (0.25 g, 1.17 mmol) in DCM (10.0 mL). Add DIPEA (0.4 mL, 2.34 mmol), followed by DMAP (0.24 g, 2.34 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.25 g, 1.29 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 h. LCMS shows the formation of the product (m / z 268.1, 312.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. Evaporate the solvent to give 0.43 g of the product (yield quantitative). C 18 H 25 MS (ESI) mass calculated for NO5S 367.46; m / z 268.1, 312.1 [M-Boc] + 。

[0683] Step 2: Synthesis of HBS-055-169: Dissolve compound HBS-055-168 (0.43 g, 1.17 mmol) and 5-fluoro-2-(1H-pyrazol-3-yl)pyridine (0.23 g, 1.41 mmol) in dry DMF (8.0 mL). Add anhydrous Cs2CO3 (1.15 g, 3.52 mmol), and stir the reaction mixture at 70 °C for 16 h. LCMS shows the formation of the product (m / z 359.2). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. Evaporate the solvent to give a crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.23 g of the pure product (yield 53.8%). C19 H 23 MS (ESI) mass calculated for FN4O2: 358.41; m / z 359.2 [M+H] + 。

[0684] Step 3: Synthesis of HBS-055-170: Dissolve compound HBS-055-169 (0.23 g, 0.63 mmol) in dry dioxane (6.0 mL). Add a dioxane solution of 4.0 M HCl (0.63 mL, 2.52 mmol), and stir the reaction mixture at 50 °C for 16 h. LCMS shows the formation of the product (m / z 259.1). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.19 g of solid product is obtained (yield 90.95%). C 14 H 15 MS (ESI) mass calculated for FN4: 258.29; m / z 259.1 [M+H] + 。

[0685]

[0686] Step 1: Synthesis of HBS-055-179: Dissolve (R)-3-hydroxymethyl-4-Boc-morpholine (0.5 g, 2.3 mmol) in dry THF (10.0 mL). Add NaH (0.14 g, 3.45 mmol) at 0 °C. Add 2-chloro-5-trifluoromethylpyridine (0.5 g, 2.76 mmol), and gradually heat the reaction mixture to the reflux temperature for 16 h. LCMS shows the formation of two products (m / z 363.1 and m / z 263.1). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography with mobile phases: EtOAc:hexane gradient elution and DCM:MeOH gradient elution. 0.39 g of pure product A (yield 46.8%) and 0.12 g of de-Boc product B (yield 19.9%) are obtained. C 16 H 21 MS (ESI) mass calculated for F3N2O4: 362.34; m / z 363.1 [M+H] + and C 11 H 13 MS (ESI) mass calculated for F3N2O2: 262.23; m / z 263.1 [M+H] + 。

[0687] Step 2: Synthesis of HBS-055-180: Dissolve compound HBS-055-179A (0.39 g, 1.08 mmol) in dioxane (6.0 mL). Add a dioxane solution of 4.0 M HCl (1.1 mL, 4.31 mmol), and stir the reaction mixture at 50 °C for 16 h. LCMS shows the formation of the product (m / z 263.0). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.33 g of the pure product is obtained (yield 91.5%). C 11 H 13 Calculated MS (ESI) mass for F3N2O2: 262.23; m / z 263.0 [M+H] + 。

[0688]

[0689] Step 1: Synthesis of HBS-062-054: Dissolve compound HBS-062-051 (0.9 g, 4.18 mmol) in DCM (15.0 mL). Add DIPEA (1.1 mL, 6.27 mmol), and then add DMAP (0.77 g, 6.27 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.88 g, 4.6 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 h. LCMS shows the formation of the product (m / z 270.1, 314.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 1.54 g of the product is obtained (quantitative yield). C 18 H 27 Calculated MS (ESI) mass for NO5S: 369.48; m / z 270.1, 314.1 [M-Boc] + 。

[0690] Step 2: Synthesis of HBS-062-055: Dissolve compound HBS-062-054 (1.54 g, 4.17 mmol) and 2-(1H-pyrazol-3-yl)pyridine (0.61 g, 4.17 mmol) in dry DMF (12.0 mL). Add anhydrous Cs2CO3 (4.1 g, 12.5 mmol), and stir the reaction mixture at 70 °C for 12 h. LCMS shows the formation of the product (m / z 343.2) and other by-products. Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.12 g of the pure product is obtained (yield 8.41%). C19 H 26 The calculated MS(ESI) mass of HNO4O2 is 342.44; m / z is 343.2 [M+H]+ + 。

[0691] Step 3: Synthesis of HBS-062-063: Dissolve compound HBS-062-055 (0.12 g, 0.35 mmol) in dry dioxane (5.0 mL). Add a dioxane solution of 4.0 M HCl (0.4 mL, 1.75 mmol), and stir the reaction mixture at 50 °C for 6 hours. LCMS shows the formation of the product (m / z 243.1). Cool the reaction mixture and concentrate the solvent to obtain 0.067 g of the solid product (yield 60.7%). C 14 H 18 The calculated MS(ESI) mass of HN4 is 242.32; m / z is 243.1 [M+H]+ + 。

[0692]

[0693] Step 1: Synthesis of HBS-062-051: Dissolve N-Boc-α-methyl-L-proline (4.0 g, 17.44 mmol) in dry THF (20.0 mL). Add 2.0 M BH3·Me2S (17.4 mL, 34.9 mmol) at 0 °C. Gradually warm the reaction mixture to ambient temperature over 16 hours. LCMS shows the formation of the product (m / z 160.1). Quench the reaction mixture with methanol. Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry it over anhydrous Na2SO4. Evaporate the solvent to obtain 3.75 g of the crude product (quantitative yield). C 11 H 21 The calculated MS(ESI) mass of HNO3 is 215.29; m / z is 160.1 [M-Boc]+ + 。

[0694] Step 2: Synthesis of HBS-062-060: Dissolve compound HBS-062-051 (0.9 g, 4.18 mmol) in dry DMF (10.0 mL). Add NaH (0.25 g, 6.27 mmol) at 0 °C. Add 2-chloro-5-(trifluoromethyl)pyridine (0.76 g, 4.18 mmol), and gradually heat the reaction mixture at reflux temperature for 5 h. LCMS shows the formation of the product (m / z 361.1). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.66 g of the product is obtained (yield 43.8%). C 17 H 23 Calculated MS (ESI) mass for F3N2O3: 360.37; m / z 361.1 [M+H] + .

[0695] Step 3: Synthesis of HBS-062-065: Dissolve compound HBS-062-060 (0.66 g, 1.83 mmol) in dioxane (8.0 mL). Add a dioxane solution of 4.0 M HCl (1.83 mL, 7.33 mmol), and stir the reaction mixture at 50 °C for 16 h. LCMS shows the formation of the product (m / z 261.1). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.46 g of the pure product is obtained (yield 75.4%). C 12 H 15 Calculated MS (ESI) mass for F3N2O: 260.26; m / z 261.1 [M+H] + .

[0696]

[0697] Step 1: Synthesis of HBS-062-114: Dissolve tert-butyl 1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (0.2 g, 0.88 mmol) in dry DMF (6.0 mL). Add NaH (0.052 g, 1.32 mmol) at 0 °C. Add 2-chloro-5-(trifluoromethyl)pyridine (0.24 g, 1.32 mmol), and gradually heat the reaction mixture at 75 °C for 8 h. LCMS shows the formation of the product (m / z 373.1). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.33 g of the product is obtained (yield quantitative). C18 H 23 Calculated MS(ESI) mass of F3N2O3: 372.38; m / z 373.1 [M+H] + 。

[0698] Step 2: Synthesis of HBS-062-116: Dissolve compound HBS-062-114 (0.33 g, 0.88 mmol) in dioxane (5.0 mL). Add a dioxane solution of 4.0 M HCl (0.88 mL, 3.52 mmol), and stir the reaction mixture at 50 °C for 8 hours. LCMS shows the formation of the product (m / z 273.1). Cool the reaction mixture and concentrate it under reduced pressure to obtain 0.28 g of the pure product (yield 92.2%). C 13 H 15 Calculated MS(ESI) mass of F3N2O: 272.27; m / z 273.1 [M+H] + 。

[0699]

[0700] Step 1: Synthesis of HBS-062-134: Dissolve N-Boc-α-methyl-L-proline (5.0 g, 21.81 mmol) in dry THF (20.0 mL). Add 2.0 M BH3.Me2S (21.8 mL, 43.62 mmol) at 0 °C. Gradually warm the reaction mixture to ambient temperature over 16 hours. LCMS shows the formation of the product (m / z 160.0). Quench the reaction mixture with methanol. Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry it over anhydrous Na2SO4. Evaporate the solvent to obtain 4.3 g of the crude product (quantitative yield). C 11 H 21 Calculated MS(ESI) mass of NO3: 215.29; m / z 160.1 [M-Boc] + 。

[0701] Step 2: Synthesis of HBS-062-138: Dissolve compound HBS-062-134 (0.5 g, 2.32 mmol) in dry THF (6.0 mL). Add NaH (0.14 g, 3.49 mmol) at 0 °C. Add 2-chloro-5-trifluoromethylpyrazine (0.3 mL, 2.32 mmol), and gradually heat the reaction mixture at reflux temperature for 6 hours. LCMS shows the formation of the product (m / z 262.1, 306.0). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc: hexane, gradient elution. Obtain 0.44 g of the product (yield 52.4%). C 16 H 22 Calculated MS (ESI) mass for F3N3O3: 361.36; m / z at 262.1, 306.0 [M - Boc] + 。

[0702] Step 3: Synthesis of HBS-062-142: Dissolve compound HBS-062-138 (0.44 g, 1.22 mmol) in dioxane (5.0 mL). Add a dioxane solution of 4.0 M HCl (1.52 mL, 6.1 mmol), and stir the reaction mixture at 50 °C for 8 hours. LCMS shows the formation of the product (m / z 262.1). Cool the reaction mixture and concentrate it under reduced pressure to obtain 0.37 g of the pure product (yield 82.4%). C 11 H 14 Calculated MS (ESI) mass for F3N3O: 261.24; m / z at 262.1 [M + H] + 。

[0703]

[0704] Step 1: Synthesis of HBS-062-150: Dissolve L-proline (0.58 g, 5.0 mmol) and NaOH (0.6 g, 15.0 mmol) in D2O (5.0 mL). Add Ru / C, 5 wt.% (0.058 g, 10% w / w), and stir the reaction mixture at 70 °C under a hydrogen atmosphere for 6 hours. LCMS shows the formation of the product (m / z 118.1). Filter the reaction mixture through a bed of diatomaceous earth and wash with D2O. Adjust the pH of the reaction mixture to pH 6.5 with HCl. Add Dowex X-8 [H +The resin was filtered through an aqueous layer and washed with 25% aqueous ammonia solution. The aqueous layer was concentrated under reduced pressure to give 0.59 g of the crude product (quantitative yield). Calculated mass for MS (ESI) of C5H6D3NO2: 118.15; m / z 118.1 [M+H] + .

[0705] Step 2: Synthesis of HBS-062-155: Compound HBS-062-150 (0.59 g, 5.0 mmol) was dissolved in DCM (15.0 mL). Triethylamine (0.76 mL, 5.5 mmol) was added, followed by di-tert-butyl dicarbonate (1.2 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for 16 h. LCMS showed formation of the product (m / z 162.0). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. After evaporation of the solvent, the aqueous layer was extracted to give 0.95 g of the combined product (yield 87.1%). Calculated mass for MS (ESI) of C 10 H 14 D3NO4: 218.26; m / z 162.0 [M-tButyl] + .

[0706] Step 3: Synthesis of HBS-062-156: Compound HBS-062-155 (0.95 g, 4.35 mmol) was dissolved in dry THF (10.0 mL). 2.0 M BH3.Me2S (4.3 mL, 8.70 mmol) was added at 0 °C. The reaction mixture was gradually warmed to ambient temperature over 16 h. LCMS showed formation of the product (m / z 148.1). The reaction mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. The crude product was purified by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.8 g of the product was obtained (yield 90.0%). C 10 H 16 D3NO3: 204.28; m / z 148.1 [M-tButyl] + .

[0707] Step 4: Synthesis of HBS-062-163: Dissolve compound HBS-062-156 (0.4 g, 1.96 mmol) in dry THF (10.0 mL). Add NaH (0.12 g, 2.49 mmol) at 0 °C. Add 2-chloro-5-trifluoromethylpyridine (0.53 g, 2.94 mmol), and gradually heat the reaction mixture to the reflux temperature for 6 hours. LCMS shows the formation of the product (m / z 350.1). Dilute the reaction mixture with water. Extract the product with ethyl acetate. The combined EtOAc layers are separated and dried over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. The crude product is purified by column chromatography with the mobile phase: EtOAc:hexane, gradient elution. 0.6 g of the product is obtained (yield 87.7%). C 16 H 18 MS (ESI) mass calculated for D3F3N2O3: 349.36; m / z 350.1 [M+H] + 。

[0708] Step 5: Synthesis of HBS-062-166: Dissolve compound HBS-062-163 (0.6 g, 1.72 mmol) in dioxane (8.0 mL). Add a dioxane solution of 4.0 M HCl (2.15 mL, 8.59 mmol), and stir the reaction mixture at 55 °C for 8 hours. LCMS shows the formation of the product (m / z 250.1). Cool the reaction mixture to ambient temperature. Filter the precipitate and dry it to obtain 0.49 g of the pure product (yield 88.5%). C 11 H 10 MS (ESI) mass calculated for D3F3N2O: 249.25; m / z 250.1 [M+H] + 。

[0709]

[0710] Step 1: Synthesis of HBS-062-167: Dissolve compound HBS-062-156 (0.4 g, 1.96 mmol) in DCM (15.0 mL). Add DIPEA (0.51 mL, 2.94 mmol), followed by DMAP (0.36 g, 2.94 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.41 g, 2.15 mmol). Stir the reaction mixture and gradually warm it to room temperature over 24 hours. LCMS shows the formation of the product (m / z 258.1, 302.1). Dilute the reaction mixture with water. Extract the product with DCM. The DCM layer is separated and dried over anhydrous Na2SO4. After evaporation of the solvent, 0.7 g of the product is obtained (yield quantitative). C 17 H22 MS (ESI) mass calculated for D3NO5S: 358.47; m / z 258.1, 302.1 [M - Boc] + 。

[0711] Step 2: Synthesis of HBS - 062 - 169: Dissolve compound HBS - 062 - 167 (0.7 g, 1.96 mmol) and 3 - phenyl - 1H - pyrazole (0.34 g, 2.35 mmol) in dry 1,4 - dioxane (10.0 mL). Add anhydrous Cs2CO3 (1.6 g, 4.9 mmol), and stir the reaction mixture at reflux temperature for 24 h. LCMS shows the formation of the product (m / z 331.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. The combined EtOAc layers are separated and dried over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. The crude product is purified by column chromatography with mobile phase: EtOAc: hexane, gradient elution. 0.58 g of pure product is obtained (yield 89.6%). C 19 H 22 MS (ESI) mass calculated for D3N3O2: 330.44; m / z 331.2 [M + H] + 。

[0712] Step 3: Synthesis of HBS - 062 - 172: Dissolve compound HBS - 062 - 169 (0.58 g, 1.76 mmol) in dry dioxane (8.0 mL). Add a 4.0 M HCl solution in dioxane (2.2 mL, 8.78 mmol), and stir the reaction mixture at 55 °C for 8 h. LCMS shows the formation of the product (m / z 231.1). Cool the reaction mixture and concentrate the solvent to obtain 0.47 g of solid product (quantitative yield). C 14 H 14 MS (ESI) mass calculated for D3N3: 230.32; m / z 231.1 [M + H] + 。

[0713]

[0714] Step 1: Synthesis of HBS-062-190: Dissolve compound HBS-062-156 (0.5 g, 2.45 mmol) in DCM (15.0 mL). Add DIPEA (0.64 mL, 3.67 mmol), and then add DMAP (0.45 g, 3.67 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (0.56 g, 2.94 mmol). Stir the reaction mixture and gradually warm it to room temperature within 24 hours. LCMS shows the formation of the product (m / z 259.1, 303.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 0.82 g of the product is obtained (yield 93.7%). C 17 H 22 Calculated mass for MS (ESI) of D3NO5S: 358.47; m / z 259.1, 303.1 [M - Boc] + 。

[0715] Step 2: Synthesis of HBS-062-194: Dissolve compound HBS-062-190 (0.8 g, 2.23 mmol) and 3-(4-fluorophenyl)-1H-pyrazole (0.43 g, 2.68 mmol) in dry 1,4-dioxane (12.0 mL). Add anhydrous Cs2CO3 (1.81 g, 5.58 mmol), and stir the reaction mixture at the reflux temperature for 24 hours. LCMS shows the formation of the product (m / z 349.2). Cool the reaction mixture at ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.62 g of pure product is obtained (yield 79.7%). C 19 H 21 Calculated mass for MS (ESI) of D3FN3O2: 348.43; m / z 349.2 [M + H] + 。

[0716] Step 3: Synthesis of HBS-062-197: Dissolve compound HBS-062-194 (0.62 g, 1.78 mmol) in dry dioxane (8.0 mL). Add a 4.0 M HCl solution in dioxane (1.8 mL, 7.12 mmol), and stir the reaction mixture at 55 °C for 8 hours. LCMS shows the formation of the product (m / z 249.2). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.49 g of solid product is obtained (yield 96.7%). C 14 H 13Calculated MS (ESI) mass of D3FN3: 248.31; m / z 249.2 [M+H] + .

[0717]

[0718] Step 1: Synthesis of HBS-065-037: Dissolve N-Boc-L-prolinol (1.0 g, 4.97 mmol) in DCM (15.0 mL). Add DIPEA (1.3 mL, 7.45 mmol), and then add DMAP (0.91 g, 7.45 mmol). Cool the reaction mixture in an ice bath at 0 °C. Add p-TsCl (1.04 g, 5.46 mmol). Stir the reaction mixture and gradually warm it to room temperature over 16 hours. LCMS shows the formation of the product (m / z 256.0, 300.0). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry it over anhydrous Na2SO4. After evaporation of the solvent, 1.76 g of the product is obtained (quantitative yield). C 17 H 25 Calculated MS (ESI) mass of NO5S: 355.45; m / z 256.0, 300.0 [M-Boc] + .

[0719] Step 2: Synthesis of HBS-065-040: Dissolve compound HBS-065-037 (1.76 g, 4.97 mmol) and 2-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride (1.42 g, 4.97 mmol) in dry 1,4-dioxane (25.0 mL). Add anhydrous Cs2CO3 (3.24 g, 9.94 mmol), and stir the reaction mixture at reflux temperature for 24 hours. LCMS shows the formation of the product (m / z 397.2). Cool the reaction mixture to ambient temperature and dilute it with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry them over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 1.0 g of pure product is obtained (yield 50.8%). C 19 H 23 Calculated MS (ESI) mass of F3N4O2: 396.41; m / z 397.2 [M+H] + .

[0720] Step 3: Synthesis of HBS-065-043: Dissolve compound HBS-065-040 (1.0 g, 2.52 mmol) in dry dioxane (15.0 mL). Add a dioxane solution of 4.0 M HCl (2.52 mL, 10.1 mmol), and stir the reaction mixture at 60 °C for 12 h. LCMS shows the formation of the product (m / z 297.1). Cool the reaction mixture and filter the precipitate. After drying the precipitate, 0.81 g of solid product is obtained (yield 87.0%). C 14 H 15 Calculated mass for F3N4 by MS (ESI): 296.29; m / z 297.1 [M+H] + 。

[0721]

[0722] Step 1: Synthesis of HBS-065-056: Dissolve (2S,5S)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (0.25 g, 1.16 mmol) in dry THF (6.0 mL). Add NaH (0.07 g, 1.74 mmol) at 0 °C. Add 2-chloro-5-(trifluoromethyl)pyridine (0.25 g, 1.39 mmol), and gradually heat the reaction mixture to reflux temperature for 6 h. LCMS shows the formation of the product (m / z 361.2). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. 0.42 g of product is obtained (quantitative yield). C 17 H 23 Calculated mass for F3N2O3 by MS (ESI) 360.37; m / z 361.2 [M+H] + 。

[0723] Step 2: Synthesis of HBS-065-058: Dissolve compound HBS-065-056 (0.42 g, 1.17 mmol) in dioxane (8.0 mL). Add a dioxane solution of 4.0 M HCl (1.16 mL, 4.66 mmol), and stir the reaction mixture at 60 °C for 12 h. LCMS shows the formation of the product (m / z 261.1). Cool the reaction mixture to ambient temperature. Filter the precipitate and dry to obtain 0.31 g of pure product (yield 79.8%). C 12 H 15 Calculated mass for F3N2O by MS (ESI) 260.26; m / z 261.1 [M+H] + 。

[0724]

[0725] Step 1: Synthesis of HBS-065-065: Dissolve compound HBS-055-131 (0.5 g, 2.34 mmol) in dry THF (8.0 mL). Add NaH (0.14 g, 3.51 mmol) at 0 °C. Add 2-chloro-5-trifluoromethylpyridine (0.51 g, 2.81 mmol), and gradually heat the reaction mixture at reflux temperature for 6 hours. LCMS shows the formation of the product (m / z 359.1). Dilute the reaction mixture with water. Extract the product with ethyl acetate. Combine the EtOAc layers, separate, and dry over anhydrous Na2SO4. After evaporation of the solvent, a crude product is obtained. The crude product is purified by column chromatography with mobile phase: EtOAc:hexane, gradient elution. 0.6 g of the product is obtained (yield 71.5%). C 17 H 21 MS (ESI) mass calculated for F3N2O3: 358.36; m / z 359.1 [M+H] + 。

[0726] Step 2: Synthesis of HBS-065-067: Dissolve compound HBS-065-065 (0.6 g, 1.67 mmol) in dioxane (6.0 mL). Add a dioxane solution of 4.0 M HCl (1.67 mL, 6.7 mmol), and stir the reaction mixture at 60 °C for 12 hours. LCMS shows the formation of the product (m / z 259.0). Cool the reaction mixture to ambient temperature and concentrate under reduced pressure to obtain 0.55 g of the pure product (quantitative yield). C 12 H 13 MS (ESI) mass calculated for F3N2O: 258.24; m / z 259.0 [M+H] + 。

[0727]

[0728] Step 1: Synthesis of HBS-065-119: Dissolve (1R,3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.0 g, 8.8 mmol) in dry THF (20.0 mL). Add 2.0 M BH3·Me2S (8.8 mL, 17.6 mmol) at 0 °C. Gradually warm the reaction mixture to ambient temperature over 16 h. LCMS shows formation of the product (m / z 158.1). Quench the reaction mixture with methanol. Dilute the reaction mixture with water. Extract the product with ethyl acetate. Separate the EtOAc layer and dry over anhydrous Na2SO4. Evaporate the solvent to give 1.88 g of crude product (yield quantitative). C 11 H 19 MS (ESI) mass calculated for HNO3: 213.27; m / z 158.1 [M - Boc] + .

[0729] Step 2: Synthesis of HBS-065-123: Dissolve compound HBS-065-119 (1.86 g, 8.72 mmol) in DCM (25.0 mL). Add DIPEA (2.3 mL, 13.1 mmol), followed by DMAP (1.6 g, 13.1 mmol). Cool the reaction mixture to 0 °C in an ice bath. Add p-TsCl (2.0 g, 10.47 mmol). Stir the reaction mixture and gradually warm to room temperature over 16 h. LCMS shows formation of the product (m / z 268.1, 312.1). Dilute the reaction mixture with water. Extract the product with DCM. Separate the DCM layer and dry over anhydrous Na2SO4. Evaporate the solvent to give the crude product. Purify the crude product by column chromatography, mobile phase: EtOAc:hexane, gradient elution. Obtain 2.76 g of product (yield 86.12%). C 18 H 25 MS (ESI) mass calculated for HNO5S: 367.46; m / z 268.1, 312.1 [M - Boc] + .

[0730] Step 3: Synthesis of HBS-065-126: Dissolve compound HBS-065-123 (0.5 g, 1.36 mmol) and 2-(1H-pyrazol-3-yl)pyridine (0.22 g, 1.5 mmol) in 1,4-dioxane (8.0 mL). Add anhydrous Cs2CO3 (0.89 g, 2.72 mmol), and stir the reaction mixture at reflux temperature for 16 h. LCMS shows the formation of the product (m / z 341.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.12 g of the pure product (yield 24.8%). C 19 H 24 Calculated mass for MS (ESI) of C14H12N4O2: 340.42; m / z 341.2 [M+H] + 。

[0731] Step 4: Synthesis of HBS-065-128: Dissolve compound HBS-065-126 (0.12 g, 0.33 mmol) in dry dioxane (5.0 mL). Add a 4.0 M HCl solution in dioxane (0.33 mL, 1.35 mmol), and stir the reaction mixture at ambient temperature for 24 h. LCMS shows the formation of the product (m / z 241.1). Cool the reaction mixture and filter the precipitate. Dry the precipitate to obtain 0.093 g of the solid product (yield 87.9%). C 14 H 16 Calculated mass for MS (ESI) of C10H10N4: 240.3; m / z 241.1 [M+H] + 。

[0732]

[0733] Step 1: Synthesis of HBS-065-135: Dissolve compound HBS-065-123 (0.5 g, 1.36 mmol) and 2-(1H-pyrazol-4-yl)pyridine (0.22 g, 1.5 mmol) in 1,4-dioxane (10.0 mL). Add anhydrous Cs2CO3 (0.89 g, 2.72 mmol), and stir the reaction mixture at reflux temperature for 16 h. LCMS shows the formation of the product (m / z 341.2). Cool the reaction mixture to ambient temperature and dilute with water. Extract the product with ethyl acetate. Separate the combined EtOAc layers and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by column chromatography with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.46 g of pure product (quantitative yield). C 19 H 24 Calculated mass for MS (ESI) of C14H12N4O2: 340.42; m / z 341.2 [M+H] + 。

[0734] Step 4: Synthesis of HBS-065-140: Dissolve compound HBS-065-135 (0.46 g, 1.36 mmol) in dry dioxane (10.0 mL). Add a dioxane solution of 4.0 M HCl (1.36 mL, 5.44 mmol), and stir the reaction mixture at 55 °C for 8 h. LCMS shows the formation of the product (m / z 241.2). Cool the reaction mixture and filter the precipitate. Dry the precipitate to obtain 0.38 g of solid product (yield 89.1%). C 14 H 16 Calculated mass for MS (ESI) of C10H10N4: 240.3; m / z 241.2 [M+H] + 。

[0735]

[0736] Step 1: Synthesis of HBS-037-167: Dissolve [(2S,3R)-1-[(4-methoxyphenyl)methyl]-3-methylpiperidin-2-yl]methanamine (0.1 g, 0.4 mmol) and 2-chloro-5-fluoropyrimidine (0.12 g, 0.81 mmol) in dry DMF (3.0 mL). Add K2CO3 (0.14 g, 1.01 mmol), and stir the reaction mixture at 120 °C for 5 h. LCMS shows the formation of the product (m / z 345.2). Dilute the reaction mixture with water. 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. Purify the crude product by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. Isolate 0.14 g of the product (quantitative yield). C 19 H 25 Calculated mass for FN4O by MS (ESI): 344.43; m / z 345.2 [M+H] + 。

[0737] Step 2: Synthesis of HBS-037-170: Dissolve compound HBS-037-167 (0.14 g, 0.4 mmol) in MeOH (4.0 mL). Add 20.0% Pd-OH / C (28.0 mg), and stir the reaction mixture at ambient temperature for 24 h. LCMS shows unreacted starting material and the formation of the product. Further add 20.0% Pd-OH / C (20.0 mg), and stir the reaction mixture at ambient temperature for another 24 h. LCMS shows the formation of the product (m / z 225.1). Filter the reaction mixture through celite and wash with MeOH. Evaporate the filtrate under reduced pressure to obtain 67.0 mg of the crude product (yield 74.0%). The crude product is used directly in the next step without purification. C 11 H 17 Calculated mass for FN4 by MS (ESI): 224.28; m / z 225.1 [M+H] + 。

[0738]

[0739] Step 1: Synthesis of HBS-037-169: Dissolve (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.2 g, 0.1 mmol) and 2-chloro-5-fluoropyrimidine (0.2 g, 1.5 mmol) in anhydrous DMF (4.0 mL). Add K2CO3 (0.35 g, 2.5 mmol), and heat the reaction mixture to 100 °C over 5 h. LCMS shows formation of the product (m / z 297.0) and by-products. Cool the reaction mixture to ambient temperature and dilute with water. 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. Purify the crude product by ISCO Combi-Flash chromatography system, mobile phase: EtOAc:hexane, gradient elution. Obtain 0.25 g of the major product (yield 84.8%). C 14 H 21 MS (ESI) mass calculated for FN4O2: 296.34; m / z 297.0 [M+H] + .

[0740] Step 2: Synthesis of HBS-037-172: Dissolve compound HBS-037-169 (0.25 g, 0.85 mmol) in anhydrous dioxane (3.0 mL). Add a dioxane solution of 4.0 M HCl (2.1 mL, 8.47 mmol), and stir the reaction mixture at 50 °C for 5 h. LCMS shows formation of the product (m / z 197.0). Cool the reaction mixture to ambient temperature and concentrate under reduced pressure to obtain 0.2 g of the product (yield 68.0%). C9H 13 MS (ESI) mass calculated for FN4: 196.22; m / z 197.0 [M+H] + .

[0741]

[0742] Step 1: Synthesis of HBS-037-197: Dissolve tert-butyl-(2S)-2-(aminomethyl)piperidine-1-carboxylate (0.2 g, 0.93 mmol) and 2-chloro-5-trifluoromethylpyridine (0.2 g, 1.11 mmol) in anhydrous DMF (5.0 mL). Add K2CO3 (0.32 g, 2.32 mmol), and heat the reaction mixture to 120 °C over 5 h. LCMS showed formation of the product (m / z 360.0). Cool the reaction mixture to ambient temperature and dilute with water. 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. Purify the crude product by an ISCO Combi-Flash chromatography system with mobile phase: EtOAc:hexane, gradient elution. Obtain 0.17 g of the product (yield 50.6%). C 17 H 24 Calculated MS (ESI) mass for F3N3O2: 359.39; m / z 360.0 [M+H] + 。

[0743] Step 2: Synthesis of HBS-037-200: Dissolve compound HBS-037-197 (0.17 g, 0.47 mmol) in anhydrous dioxane (5.0 mL). Add a dioxane solution of 4.0 M HCl (1.2 mL, 4.7 mmol), and stir the reaction mixture at 50 °C for 5 h. LCMS showed formation of the product (m / z 260.0). Cool the reaction mixture to ambient temperature and concentrate under reduced pressure to obtain 0.17 g of the product (quantitative yield). C 12 H 16 Calculated MS (ESI) mass for F3N3: 259.27; m / z 260.0 [M+H] + 。

[0744] General experimental protocol for the synthesis of the example compounds:

[0745] Method A: Dissolve 1.0 equivalent (0.1 mmol) of the acid intermediate in anhydrous DCM (2.0 mL). Add 1.5 equivalents (0.15 mmol) of EDC·HCl and 1.5 equivalents (0.15 mmol) of HOBt, followed by 5.0 equivalents (0.5 mmol) of Et3N. Stir the reaction mixture at ambient temperature for 5 minutes. Add the amine intermediate (0.1 mmol) to the reaction mixture. Stir the reaction mixture at ambient temperature for 16 hours. Dilute the reaction mixture with DCM and wash with saturated NaHCO3 solution. Separate the DCM layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO Combi-Flash system with mobile phase: ethyl acetate:hexane or DCM:MeOH, gradient elution.

[0746] Method B: Dissolve 1.0 equivalent (0.1 mmol) of the acid intermediate and 1.1 equivalents (0.11 mmol) of HATU in anhydrous DMF (1.5 mL). Add 4.0 equivalents (0.4 mmol) of DIPEA and stir the reaction mixture at ambient temperature for 5 minutes. Add the amine intermediate (0.1 mmol) to the reaction mixture. Stir the reaction mixture at ambient temperature for 16 hours. Dilute the reaction mixture with DCM and wash with saturated NaHCO3 solution. Separate the DCM layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain the crude product. Purify the crude product by an ISCO Combi-Flash system with mobile phase: ethyl acetate:hexane or DCM:MeOH, gradient elution.

[0747] Table 2 summarizes the acid intermediates, amine intermediates, and methods used to generate each example compound.

[0748] Table 2

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755] [[ID=�0]]II. Bioanalytical experiments

[0756] The antagonistic activity of each example compound against two orexin receptors was measured using the following method:

[0757] In vitro orexin antagonism measurement assay: Intracellular calcium measurement

[0758] Chinese hamster ovary (CHO) cells expressing human orexin receptor and human orexin-2 receptor respectively 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 was used as an agonist and was prepared as a 1 mM stock solution in methanol:water (1:1) 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.

[0759] The antagonist was dissolved in DMSO to prepare a 10 mM stock solution, then diluted in the 384-well plate with DMSO, and then the diluted solution was transferred to HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g / L and 20 mM HEPES. On the day of analysis, 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 stock solution dissolved in DMSO, containing 10% Pluronic)) was added to each well. The 384-well cell plate was incubated at 37 °C in 5% CO2 for 50 minutes and then equilibrated at room temperature for 30 minutes before measurement.

[0760] In a Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), the antagonist was added to the plate at a volume of 10 μL / well, incubated for 120 minutes, and finally 10 μL / well of the agonist was added. Fluorescence of each well was measured at 1-second intervals, and the height of each fluorescence peak was compared with the fluorescence peak height induced by 3 nM orexin-A with the vehicle replacing the antagonist. The IC50 value (the concentration of the compound required to inhibit 50% of the agonist response) was determined and could be normalized using the IC50 value obtained with a reference compound on the plate. Optimized conditions were achieved by adjusting the pipetting speed and cell splitting protocol. The calculated IC 50 values may vary depending on the daily cell assay performance. Such variations are known to those skilled in the art. When measuring the IC 50In the case of values, the geometric mean is given. The antagonistic activities of the example compounds are shown in Table 3.

[0761] Human κ-opioid (KOP) receptor (agonist radioligand) binding assay

[0762] Purpose: To evaluate the affinity of compounds for the human κ-opioid receptor in transfected RBL cells determined in a radioligand binding assay.

[0763] Experimental protocol: In a buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM MgCl2 and 1 mM EDTA, cell membrane homogenates (about 80 μg protein) were incubated with 0.5 nM [3H]U-69593 for 60 minutes at 22 °C in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 10 μM naloxone. After incubation, the samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) pre-impregnated with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and then counted for radioactivity in a scintillation counter (Scintillation Counter, Topcount, Packard) using a scintillation mixture (Microscint 0, Packard). Results were expressed as the percentage of inhibition of specific binding of the control radioligand. The standard reference compound was U-50488, which was tested at multiple concentrations in each experiment to obtain a competition curve from which its IC50 was calculated.

[0764] Table 3

[0765] Example compounds put into practice by the data (% inhibition at 1 μM, % Inh.@1 μM), and IC of selected compounds for orexin type 1 (OX1R), orexin type 2 (OX2R) receptors and κ-opioid receptor (κOR) 50 value

[0766] (“Ex” represents the example compound number)

[0767]

[0768]

[0769]

[0770] [[ID=3^2]]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803] Although certain embodiments have been described in accordance with 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 (II), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, Wherein: R1 includes E which is carbon (C) but not nitrogen (N), and in Formula I, E is connected to J or D by a double bond, or in Formula II, E is connected to A or D by a double bond. R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl, substituted aryl or aromatic group, and substituted heteroaryl; the heteroaryl may optionally be a 5-membered or 6-membered heteroaryl, and the substituted heteroaryl may optionally be a substituted 5-membered or 6-membered heteroaryl; wherein, if R1 is heteroaryl, R1 may optionally be a 5-membered or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aryl, aromatic group or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl and halogen; wherein the halogen is optionally F, Cl, or Br; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4; R5 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R5 is substituted on carbon with Y, Z1, and Z2, where R 5’ is as defined herein; R 5’ selected from the group consisting of an aryl group, an aryl, a heteroaryl, a 5- or 6-membered heteroaryl, a substituted aryl group or aryl, a substituted heteroaryl or a fused two-heteroaryl ring system; wherein the fused two-heteroaryl ring system optionally comprises a 5- or 6-membered ring; wherein the aryl group, 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, (C 3-7 )heterocycloalkyl; R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached to R as alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure; R7 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is substituted by carbon bearing Y, Z1 and Z2, wherein R 5’ is as defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged-ring structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R 10 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 10 is attached to R6 or R as an alkyl group 11 to form a (C 1-3 ) alkyl bridged ring structure; R 11 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 is attached to R6 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure; R 12 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 12 is attached to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure; X is selected from the group consisting of none, CH2, O, CR a R b ; when X is none, a five-membered pyrrolidine ring may optionally be provided; wherein R a and R b are selected from the group consisting of alkyl, cycloalkyl, fluoroalkyl; and wherein: The carbon atom at the 2-position of piperidine or pyrrolidine is optionally of the absolute (S)-configuration; or, wherein when X is oxygen, the carbon atom at the 2-position of the morpholine ring is optionally of the absolute (R)-configuration; Y is selected from the group consisting of none, O, NH, CH2OR 5’ , CH2, NR a and a 5- or 6-membered heteroaryl group; when Y is none, R 5’ is directly connected to the carbon bearing the Z1 and Z2 groups; wherein R a is selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroalkyl group; the 5- or 6-membered heteroaryl group is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl and oxadiazolyl; and Z1 and Z2 are independently selected from the group consisting of H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 2-7 )cycloalkyl; and wherein: The fused or unfused ring system A-B-J-D-E is a five-membered heteroaryl, optionally imidazole, wherein A and J are nitrogen and B, E, D are carbon; optionally pyrazole, wherein A and B are nitrogen and D, E, J are carbon; optionally fused or unfused with one or more additional ring systems; The fused ring system B-J-M-G-K-L is an arrangement of these variables to provide a group consisting of a 6-membered aromatic group, a 6-membered aryl group, a 6-membered substituted aromatic group, a 6-membered substituted aryl group, a 6-membered substituted heteroaryl group, a 6-membered unsubstituted heteroaryl group, a 5- or 6-membered cycloalkyl group and a 5- or 6-membered heterocycloalkyl group; and wherein, optionally: A is nitrogen, optionally imidazole or pyrazole; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon, wherein R1 is as defined above; 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; and L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O and N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

2. The compound according to claim 1, which has formula I-a or II-a: wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl, substituted aryl or aromatic group, and substituted heteroaryl; the heteroaryl is optionally a 5- or 6-membered heteroaryl, and the substituted heteroaryl is optionally a substituted 5- or 6-membered heteroaryl; wherein, if R1 is a heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the aryl, aromatic group or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7 ) cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl, and halogen; the halogen may optionally be F, Cl, or Br; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4; R5 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R5 is substituted by carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein; R 5’ selected from the group consisting of an aryl group, an aryl, a heteroaryl, a 5- or 6-membered heteroaryl, a substituted aryl group or aryl, a substituted heteroaryl or a fused two-heteroaryl ring system; the fused two-heteroaryl ring system optionally includes a 5- or 6-membered ring; wherein the aryl group, 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, (C 3-7 ) heterocycloalkyl; R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached to R as alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure; R7 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is substituted by carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R as alkyl 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R 10 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 10 is linked to R6 or R as an alkyl group to 11 form a (C 1-3 ) alkyl bridged ring structure; R 11 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 is attached to R6 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure; R 12 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 12 is linked to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure; X is selected from the group consisting of none, CH2, O, CR a R b ; when X is none, a five-membered pyrrolidine ring is optionally provided; wherein R a and R b are selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and wherein: The carbon atom at the 2-position of piperidine or pyrrolidine is optionally of the absolute (S)-configuration; or, wherein when X is oxygen, the carbon atom at the 2-position of the morpholine ring is optionally of the absolute (R)-configuration; Y is selected from the group consisting of nothing, O, NH, CH2OR 5’ , CH2, NR a and 5- or 6-membered heteroaryl; when Y is nothing, R 5’ is directly connected to the carbon bearing the Z1 and Z2 groups; wherein R a is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; Z1 and Z2 are independently selected from the group consisting of H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 2-7 )cycloalkyl; wherein: The fused ring system B-J-M-G-K-L is an arrangement of these variables to provide a group consisting of a 6-membered aromatic group, a 6-membered aryl group, a 6-membered substituted aromatic group, a 6-membered substituted aryl group, a 6-membered substituted heteroaryl group, a 6-membered unsubstituted heteroaryl group, a 5- or 6-membered cycloalkyl group and a 5- or 6-membered heterocycloalkyl group; and preferably: 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; or none, to provide a 5-membered cycloalkyl and heterocycloalkyl; and L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O and N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

3. The compound according to claim 1, which has the formula I-b or II-b: Wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl, substituted aryl or aromatic group, and substituted heteroaryl; the heteroaryl is optionally a 5- or 6-membered heteroaryl, and the substituted heteroaryl is optionally a substituted 5- or 6-membered heteroaryl; wherein, if R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the aryl, aromatic group or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy and (C 3-7 ) cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; the halogen is, for example, F, Cl, or Br; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4; R5 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R5 is substituted on carbon with Y, Z1, and Z2, where R 5’ is as defined herein; R 5’ selected from the group consisting of an aryl group, an aryl, a heteroaryl, a 5- or 6-membered heteroaryl, a substituted aryl group or aryl, a substituted heteroaryl or a fused two-heteroaryl ring system; the fused two-heteroaryl ring system optionally comprises a 5- or 6-membered ring; wherein the aryl group, 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, (C 3-7 )heterocycloalkyl; R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is linked to R as alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure; R7 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R7 is substituted with carbon bearing Y, Z1, and Z2, where R 5’ is as defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R 10 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 10 is attached to R6 or R as an alkyl group 11 to form a (C 1-3 ) alkyl bridged-ring structure; R 11 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 11 is attached to R6 as alkyl to form a (C 1-3 ) alkyl bridged ring structure; R 12 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 12 is linked to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure; X is selected from the group consisting of nothing, CH2, O, CR a R b ; when X is nothing, a five-membered pyrrolidine ring may optionally be provided; wherein R a and R b are selected from the group consisting of alkyl, cycloalkyl and fluoroalkyl; and wherein: The carbon atom at the 2-position of piperidine or pyrrolidine is optionally in the absolute (S)-configuration; or, Wherein, when X is oxygen, the carbon atom at the 2-position of the morpholine ring is optionally in the absolute (R)-configuration; Y is selected from the group consisting of nothing, O, NH, CH2OR 5’ , CH2, NR a and 5- or 6-membered heteroaryl; when Y is nothing, R 5’ is directly connected to the carbon bearing the Z1 and Z2 groups; wherein R a is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; Z1 and Z2 are independently selected from the group consisting of H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 2-7 )cycloalkyl; Wherein: The fused ring system B-J-M-G-K-L is selected from the permutations of these variables to provide a group consisting of a 6-membered aromatic group, a 6-membered aryl group, a 6-membered substituted aromatic group, a 6-membered substituted aryl group, a 6-membered substituted heteroaryl group, a 6-membered unsubstituted heteroaryl group, a 5- or 6-membered cycloalkyl group, and a 5- or 6-membered heterocycloalkyl group; And preferably: 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; or none, to provide a 5-membered cycloalkyl group and a heterocycloalkyl group; and L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; Or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

4. The compound according to claim 1, which has the formula I-a4, I-a5, I-a6, II-a4, II-a5, or II-a6: Wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aromatic group, heteroaryl, substituted aryl or aromatic group, and substituted heteroaryl; the heteroaryl is optionally a 5- or 6-membered heteroaryl, and the substituted heteroaryl is optionally a substituted 5- or 6-membered heteroaryl; wherein, if R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the aryl, aromatic group or heteroaryl is unsubstituted, monosubstituted or disubstituted, and the substituents are independently selected from the group consisting of (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen, (C 1-3 ) fluoroalkyl, (C 1-3 ) fluoroalkoxy, and (C 3-7 ) cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; the halogen is, for example, F, Cl, Br; where each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4; R5 is H, or is replaced by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein; R 5’ selected from the group consisting of an aryl group, an aryl, a heteroaryl, a 5- or 6-membered heteroaryl, a substituted aryl group or aryl, a substituted heteroaryl or a fused two-heteroaryl ring system; the fused two-heteroaryl ring system optionally contains a 5- or 6-membered ring; wherein the aryl group, 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, (C 3-7 )heterocycloalkyl; R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached to R as alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure; R7 is H, or is replaced by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R 10 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 10 is linked to R6 or R as an alkyl group 11 to form a (C 1-3 ) alkyl bridged-ring structure; R 12 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 12 is linked to R9 as alkyl to form a (C 1-3 ) alkyl bridged-ring structure; X is selected from the group consisting of nothing, CH2, O, CR a R b ; when X is nothing, a five-membered pyrrolidine ring is optionally provided; wherein R a and R b are selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and wherein: The carbon atom at the 2-position of piperidine or pyrrolidine is optionally in the absolute (S)-configuration; or, Wherein, when X is oxygen, the carbon atom at the 2-position of the morpholine ring is optionally in the absolute (R)-configuration; Y is selected from the group consisting of nothing, O, NH, CH2OR 5’ , CH2, NR a and 5- or 6-membered heteroaryl; when Y is nothing, R 5’ is directly connected to the carbon bearing the Z1 and Z2 groups; wherein R a is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; Z1 and Z2 are independently selected from the group consisting of H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 2-7 )cycloalkyl; And preferably: L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N; Or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

5. The compound according to claim 1, which has the formula I-b4, I-b5, I-b6, II-b4, II-b5, or II-b6: Wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aryl or aryl group, heteroaryl, substituted aryl or aryl group, and substituted heteroaryl group; the heteroaryl group is optionally a 5-membered or 6-membered heteroaryl group, and the substituted heteroaryl group is optionally a substituted 5-membered or 6-membered heteroaryl group; wherein, if R1 is a heteroaryl group, R1 is optionally a 5-membered or 6-membered heteroaryl group, selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; wherein the aryl group, aryl group or heteroaryl group 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 group; R2, R3, and R4 are independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-7 )cycloalkyl; the halogen is, for example, F, Cl, Br; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents, the substituents being independently selected from one, two, or all of R2, R3, and R4; R5 is H, or is replaced by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein; R 5’ selected from the group consisting of an aryl group, an aryl, a heteroaryl, a 5- or 6-membered heteroaryl, a substituted aryl group or aryl, a substituted heteroaryl or a fused two-heteroaryl ring system; the fused two-heteroaryl ring system optionally contains a 5- or 6-membered ring; wherein the aryl group, 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, (C 3-7 )heterocycloalkyl; R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R6 is attached to R as alkyl 10 or R 11 to form a (C 1-3 ) alkyl bridged ring structure; R7 is H, or is replaced by a carbon bearing Y, Z1 and Z2, where R 5’ is as defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R8 is attached to R 10 , R 11 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R9 is attached to R6 or R 12 to form a (C 1-3 ) alkyl bridged ring structure; R 10 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 10 is linked to R6 or R as an alkyl group 11 to form a (C 1-3 ) alkyl bridged ring structure; R 12 selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C 1-3 ) fluoroalkyl, cycloalkyl, and R 12 is attached to R9 as an alkyl group to form a (C 1-3 ) alkyl bridged-ring structure; X is selected from the group consisting of nothing, CH2, O, CR a R b ; when X is nothing, a five-membered pyrrolidine ring is optionally provided; wherein R a and R b are selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and wherein: The carbon atom at the 2-position of piperidine or pyrrolidine is optionally in the absolute (S)-configuration; or, Wherein, when X is oxygen, the carbon atom at the 2-position of the morpholine ring is optionally in the absolute (R)-configuration; Y is selected from the group consisting of nothing, O, NH, CH2OR 5’ , CH2, NR a and 5- or 6-membered heteroaryl; when Y is nothing, R 5’ is directly attached to the carbon bearing the Z1 and Z2 groups; wherein R a is selected from the group consisting of alkyl, cycloalkyl and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl and oxadiazolyl; Z1 and Z2 are independently selected from the group consisting of H, F, (C 1-4 )alkyl, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and (C 2-7 )cycloalkyl; And preferably: M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, N; Or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

6. A compound selected from the group consisting of the compounds shown in Examples 1-263, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination of the shown compounds, 7. The compound according to claim 6, wherein the compound is selected from the group consisting of the compounds of Example 4, Example 6, Example 7, Example 8, Example 10, Example 12, Example 13, Example 20, Example 22, Example 24, Examples 25 - 29, Example 34, Example 40, Examples 42 - 50, Examples 53 - 64, Examples 66 - 69, Example 73, Example 75, Example 78, Example 80, Example 89, Example 90, Example 92, Example 94, Example 95, Example 97, Example 107, Example 111, Example 112, Examples 117 - 119, Examples 122 - 142, Examples 147 - 151, Example 156, Example 158, Examples 171 - 183, Examples 185 - 198, Examples 201 - 203, Example 205, Example 207, Example 208, Examples 210 - 214, Example 223 and Example 224; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination of the compound.

8. The compound according to claim 6 or 7, wherein the compound is selected from the group consisting of the compounds of Example 53, Example 55, Example 66, Example 95, Example 112, Example 118, Example 119, Example 122, Example 123, Example 124, Example 129, Example 130, Example 131, Example 134, Example 135, Example 138, Example 139, Example 140, Example 141, Example 142, Example 147, Example 148, Example 156, Example 171, Example 172, Example 173, Example 174, Example 175, Example 176, Example 177, Example 178, Example 179, Example 180, Example 181, Example 182, Example 191, Example 195, Example 203, Example 205, Example 211, Example 223 and Example 224; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination of the compound.

9. The compound according to any one of the preceding claims, wherein the compound is unlabeled or isotopically labeled.

10. 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 at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle.

11. The pharmaceutical composition according to claim 8, which comprises a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer and / or combination.

12. The pharmaceutical composition according to claim 10 or 11, wherein the composition further comprises at least one second therapeutic agent.

13. A method of antagonizing and / or modulating at least one orexin receptor and / or at least one κ-opioid receptor in a cell, the method comprising the steps of: Expose the cells to a compound and / or composition according to any one of the preceding claims; Optionally, wherein the method is carried out in vitro.

14. A method for modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a subject in need thereof, the method comprising the steps of: Administer a compound and / or composition according to any one of the preceding claims.

15. 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), neurodegenerative diseases, autism, schizophrenia, pain, Alzheimer's disease (AD), and central nervous system (CNS) disorders, said method comprising the steps of: Administer a compound and / or composition according to any one of the preceding claims.

16. The method according to claim 15, wherein the substance corresponding to substance addiction or substance dependence is selected from the group consisting of one or more opioids; one or more stimulants; one or more sedatives and / or tranquillizers, benzodiazepines and barbiturates; the one or more opioids are optionally heroin, morphine, oxycodone, fentanyl and hydrocodone; the one or more stimulants are optionally selected from the group consisting of amphetamine, cocaine, crack cocaine and methamphetamine.

17. The method according to any one of claims 13-16, wherein the compound antagonizes at least one orexin receptor and / or antagonizes or modulates at least one κ-opioid receptor.

18. A method for preparing a compound or composition according to any one of the preceding claims, the method using at least one suitable combination of the acid intermediate, amine intermediate and method shown in Table 2.

Images