Cyp11b2 inhibitor compounds, pharmaceutical compositions, and uses thereof

Abstract

The present application provides a CYP11B2 inhibitor compound shown in formula (I), a pharmaceutical composition and application thereof, the compound has good CYP11B2 inhibitory activity, can be used for the treatment of diseases related to CYP11B2, not only has good biological activity, good safety, and improves the selectivity of CYP11B1 inhibitors.

Description

[0001] This application claims priority to an earlier application filed by the applicant with the China National Intellectual Property Administration on July 27, 2023, with patent application number 202310933635.6, entitled "CYP11B2 Inhibitor Compound, Pharmaceutical Composition and Application Thereof". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical compounds, specifically relating to CYP11B2 inhibitor compounds, pharmaceutical compositions and their applications. Background Technology

[0003] Refractory hypertension, also known as intractable hypertension, is defined as follows: blood pressure cannot be controlled despite treatment with three antihypertensive drugs with complementary mechanisms of action (one of which is a diuretic), or blood pressure requires treatment with ≥4 antihypertensive drugs to achieve a target blood pressure (<130 / 80 mmHg). In clinical practice in my country, the cutoff value for diagnosing refractory hypertension is 140 / 90 mmHg. Current treatment methods for refractory hypertension mainly include pharmacological interventions: optimized diuretic therapy, mineralocorticoids, and combination therapy; and non-pharmacological interventions: lifestyle modifications, DASH diet, reduced salt intake, and limited alcohol consumption.

[0004] Aldosterone is a mineralocorticoid secreted by the zona glomerulosa of the adrenal cortex. It maintains water and electrolyte balance by regulating the reabsorption of sodium ions by the kidneys. Aldosterone secretion is mediated through the renin-angiotensin-aldosterone system (RAAS). Specifically, juxtaglomerular cells in the kidneys sense a decrease in blood pressure and sodium levels, leading to increased renin secretion. Renin acts on angiotensinogen to form angiotensin. Angiotensin stimulates the zona glomerulosa of the adrenal cortex to synthesize and secrete aldosterone, increasing sodium ion reabsorption by the kidneys, which in turn increases water reabsorption and extracellular fluid volume. Conversely, when extracellular fluid volume increases, the opposite mechanism reduces aldosterone secretion, decreasing sodium and water reabsorption by the kidneys and decreasing extracellular fluid volume. Decreased serum sodium and increased serum potassium also stimulate the adrenal cortex, increasing aldosterone secretion.

[0005] Primary aldosteronism (PA) is a syndrome of hypertension and hypokalemia caused by excessive aldosterone secretion from the adrenal cortex. PA is a common cause of secondary hypertension, with a prevalence ranging from 14% to 21% in patients with refractory hypertension. Recent evidence shows that elevated aldosterone is associated with cardiovascular and cardiometabolic diseases. In addition, excessive or inappropriate aldosterone activity can lead to cardiac fibrosis, inflammation and remodeling, pathological insulin secretion and / or peripheral resistance, as well as metabolic syndrome, kidney damage, and increased mortality.

[0006] Besides promoting renal sodium retention and potassium excretion to maintain water-electrolyte balance, another important function of aldosterone is to regulate target organ function by binding to receptors (MRs) in local tissues via autocrine or paracrine pathways. Aldosterone can exert its effects through genomic mechanisms, such as binding to intracellular receptors to regulate the expression of different target genes and protein translation; or through non-genomic mechanisms, i.e., by binding to intracellular receptors, it can produce effects independent of intracellular receptors and transcription and translation processes, and this effect is not blocked by aldosterone receptor antagonists such as spironolactone. Currently, research on the non-genomic effects of aldosterone is increasing, and it has been found that non-genomic signaling pathways of aldosterone involve cyclic adenosine monophosphate (cAMP), inositol triphosphate (IP3), and calcium ions (Ca). 2+ Protein kinase C (PKC), extracellular signal-regulated kinases (ERK1 / 2), phosphatidylinositol 3-kinase (PI3K), non-receptor tyrosine kinase (c-src), angiotensin II (Ang II), epidermal growth factor receptor (EGFR), NADPH oxidase / reactive oxygen species (ROS), nitric oxide synthase (NOS), Na+ / H+ exchanger (NHE), etc.

[0007] Besides hypertension, the role of aldosterone in cardiovascular diseases has been increasingly recognized in recent years. Studies in humans and transgenic animals have shown that aldosterone causes endothelial dysfunction, the mechanism of which is believed to be related to the reduction of vascular NO caused by an increase in superoxide anions. Superoxide anions can degrade NO produced by normal endothelium. In hyperlipidemic rabbits, superoxide anions increased 2 to 3 times, and the amount of superoxide anions returned to normal after treatment with aldosterone antagonists. Animal experiments have shown that aldosterone antagonists can prevent aldosterone-induced myocardial damage; aldosterone antagonists can reduce myocardial remodeling and increased ventricular wall stress caused by heart failure. Regarding cardiac fibrosis, a Japanese study observed the effect of spironolactone on left ventricular function in patients after myocardial infarction. Indicators of left ventricular remodeling, such as left ventricular ejection fraction, end-diastolic volume index, and left ventricular end-systolic volume index, were significantly improved (4-18%) in patients using spironolactone. The reduction in collagen markers was also statistically significant and correlated with the end-diastolic volume index after myocardial infarction. This suggests that left ventricular dysfunction and fibrosis are parallel processes and can be reversed by aldosterone antagonists.

[0008] The human adrenal cortex contains two cytochrome P450 isoenzymes (CYP11B1, also known as P450C11, and CYP11B2, also known as P450C11Aldo) with 11β-hydroxylase activity. Both isoenzymes can 11β-hydroxylate 11-deoxycorticosterone and 11-deoxycortisol, catalyzing the synthesis of cortisol and corticosterone, respectively. The CYP11B1 gene encodes P450C11, with a molecular weight of approximately 51 kDa, and is highly expressed in the zona fasciculata. It is primarily involved in cortisol synthesis and is regulated by ACTH. The CYP11B2 gene encodes aldosterone synthase (P450C11Aldo), with a molecular weight of 49 kDa. It is mainly expressed in the zona glomerulosa and is regulated by the renin-angiotensin system. CYP11B2 possesses 11β-hydroxylase activity, as well as 18-hydroxylase and 18-oxidase activities, and participates in aldosterone synthesis. Both CYP11B1 and CYP11B2 are located on the long arm of chromosome 8, 8q21-22, and their amino acid sequences share 93% homology. This high degree of homology suggests that developing highly selective CYP11B2 inhibitors is a significant challenge. LCI-699 (osilodrostat), the first aldosterone synthase inhibitor in clinical development, inhibits aldosterone secretion and lowers blood pressure in hypertensive patients at low doses, but it also inhibits CYP11B1, thereby suppressing cortisol synthesis. These consequences hinder its clinical use in treating hypertension.

[0009] Currently, mineralocorticoid receptor antagonists (MRAs) are the first-line drugs for treating primary aldosteronism. Spironolactone is a nonspecific mineralocorticoid receptor antagonist, showing significant efficacy in treating conditions such as heart failure with reduced ejection fraction, refractory hypertension, and aldosteronism. It can also reduce proteinuria in patients with chronic kidney disease and slow its progression. However, due to its low selectivity, spironolactone has anti-androgen and progesterone-related side effects. In comparison, the second-generation mineralocorticoid receptor antagonist eplerenone has high selectivity and significantly fewer adverse reactions, but its mineralocorticoid receptor blocking effect is 40 times less than that of spironolactone. Third-generation mineralocorticoid receptor antagonists, including phenelzine, ethacilinone, and apalidone, are representative of nonsteroidal MRAs. Compared to eplezine and spironolactone, phenelzine has higher selectivity for MR receptors, less impact on other steroid receptors and ion channels, and accumulates more in the kidneys. Phenelzine is less lipophilic, more polar, and does not cross the blood-brain barrier. Fennellone has no active metabolites, a short half-life, and can correct hyperkalemia more quickly with minimal impact on blood pressure. Exacillinone is another novel nonsteroidal mineralocorticoid receptor agonist, approved in Japan for the treatment of hypertension and diabetic nephropathy. Compared to eplerenone and spironolactone, esacillinone has higher potency and selectivity against mineralocorticoid receptors, resulting in lower risks of hyperkalemia, gynecomastia in women, amenorrhea, and impotence. Third-generation mineralocorticoid receptor antagonists are more selective than spironolactone and have a higher anti-mineralocorticoid receptor effect than eplerenone. The first two generations of steroidal MRAs have adverse effects such as hyperkalemia, impotence in men, gynecomastia, and amenorrhea in women. Although third-generation nonsteroidal fenelone has improved selectivity, the safety concern of hyperkalemia remains; currently, its approved indication is for type 2 diabetes patients with chronic kidney disease (CKD). The MR receptor shares conserved homologous sequences with glucocorticoid receptors, progesterone receptors, and androgen receptors. Besides aldosterone ligands, the MR also has other ligands, such as those for glucocorticoids and progesterone. Therefore, MRAs face issues of poor selectivity and safety.

[0010] Baxtrostat is a small molecule drug with high selectivity for CYP11B2, inhibiting aldosterone synthesis by suppressing the CYP11B2 enzyme (also known as aldosterone synthase). Studies have shown that, apart from lowering plasma aldosterone levels and blood pressure, Baxtrostat has no substantial effect on plasma cortisol levels. Using Baxtrostat to inhibit aldosterone synthesis may expand the potential treatment options for refractory hypertension. Its benefits from inhibiting aldosterone synthesis may also extend beyond refractory hypertension itself, as elevated aldosterone levels are associated with the pathophysiology of pulmonary hypertension, obesity, insulin resistance, and metabolic syndrome.

[0011] Therefore, it will be of great significance to find CYP11B2 inhibitors that can achieve better efficacy and selectivity, and to develop therapeutics and methods to address the current unmet needs in the treatment and prevention of diseases, disorders and their symptoms. Summary of the Invention

[0012] To address the problems existing in the prior art, the present invention provides a compound of formula (I) and its racemic mixture, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof:

[0013]

[0014] in,

[0015] Ring A is selected from saturated or partially unsaturated C. 5-10 Carbon rings, 5-10 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0016] Each R a They may be identical or different, and are independently selected from H, CN, OH, mercapto, halogen, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R groups. a1 The following groups are substituted: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, -SC 1-12 Alkyl or -S-(C 3-12 cycloalkyl); each R a1 They are selected independently of CN, OH, oxo (=O), halogen, amino, and C, whether they are the same or different. 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 cycloalkyl;

[0017] Each R b R c R d Identical or different, independently selected from H, CN, OH, mercapto, halogen, unsubstituted or optionally substituted by one, two or more R' groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, -SC 1-12 Alkyl or -S-(C 3-12 Cycloalkyl); each R' may be the same or different, and is independently selected from CN, OH, oxo (=O), halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy or C3-12 cycloalkyl;

[0018] Or, R c The following groups, which connect with atoms in ring A to form unsubstituted or optionally substituted by one, two or more R's: saturated or partially unsaturated C's 5-8 Carbocyclic or 5-8 membered heterocyclic rings; each R may be the same or different, and is independently selected from CN, OH, mercapto, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or cyano C 1-6 Alkyl groups, or two R's attached to the same carbon atom, together with the attached carbon atom, form a C. 3-6 Alkyl rings, halogenated C 3-6 Alkyl ring or cyano C 3-6 Alkyl rings;

[0019] W is selected from -N(R7)- or -C(R8)(R9)-;

[0020] R7 is selected from -S(=O)2R 71 -S(=O)2OR 72 -S(=O)2NR 73 R 74 -C(=O)R 75 -C(=O)OR 76 or -C(=O)NR 77 R 78 ;

[0021] R 71 R 72 R 73 R 74 R 75 R 76 R 77 R 78 They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. 7a The following groups are substituted: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0022] R8 is selected from H, without substitution, or optionally by one, two, or more Rs. 8a The following groups are substituted: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0023] R9 is selected from unsubstituted or optionally replaced by one, two or more R9s. 9a The following groups are substituted: -(CH2) m-NR 10 R 11 Or -(CH2) p -OR 12 ;

[0024] R 10 Selected from H, without substitution, or optionally by one, two, or more Rs 10a The following groups are substituted: -S(=O)2R 101 -C(=O)R 102 -C(=O)OR 103 or -C(=O)-N(R) 104 (R) 105 );

[0025] R 11 Selected from H, without substitution, or optionally by one, two, or more Rs 11a The following groups are substituted: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0026] Or, R 10 and R 11 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. 9a The following groups can be substituted: 3-12 membered N-containing heterocyclic groups;

[0027] R 12 Selected from H, without substitution, or optionally by one, two, or more Rs 12a The following groups are substituted: C 1-12 Alkyl, C 3-12 Cycloalkyl, -S(=O)2R 121 -C(=O)R 122 -C(=O)OR 123 or -C(=O)-N(R) 124 (R) 125 );

[0028] R 101 R 102 R 103 R 104 R 105 R 121 R 122 R 123 R 124 R 125 Whether the two are the same or different, they are selected independently from H and C. 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0029] R1, R2, R3, R4, R5, and R6 may be the same or different, and are independently selected from H, OH, CN, halogens, unsubstituted or optionally substituted by one, two, or more Rs. 1a The following groups are substituted: C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 cycloalkyl;

[0030] Alternatively, R1, R2, together with the atoms they are attached to, form unsubstituted or optionally substituted atoms with one, two, or more R atoms. 1a The following groups are substituted: C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0031] Alternatively, R3, R4, together with the atoms they are attached to, form unsubstituted or optionally substituted groups of one, two, or more R atoms. 3a The following groups are substituted: C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0032] Alternatively, R5, R6, together with the atoms they are attached to, form unsubstituted or optionally substituted groups of one, two, or more R atoms. 5a The following groups are substituted: C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0033] n is selected from 0, 1, or 2;

[0034] r is selected from 0, 1, or 2;

[0035] t is selected from 0, 1, 2, or 3;

[0036] s is selected from 0, 1, 2, 3, 4, 5, or 6;

[0037] m is selected from 0, 1, 2, 3, 4, 5 or 6;

[0038] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0039] Each R 1a R 3a R 5a R 7a R 8a R 9a R 10a R 11a R 12a Whether identical or different, each occurrence is independently selected from H, CN, OH, oxo (=O), halogen, unsubstituted, or optionally surrounded by one, two, or more R atoms. aa The following groups are substituted: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12Cycloalkyl or 3-12 membered heterocyclic groups; each R aa They may be the same or different, and are independently selected from CN, OH, halogen, amino, and C. 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl.

[0040] According to some implementation schemes, ring A is selected from benzene rings, 5-6 membered heterocycles, or 5-6 membered heteroaromatic rings.

[0041] According to some implementation schemes, ring A is selected from 5-6 member nitrogen-containing heterocycles or 5-6 member nitrogen-containing aromatic heterocycles.

[0042] According to some implementation schemes, ring A is selected from isoxazole ring, triazole ring (such as 1,2,3-triazole ring, 1,2,4-triazole ring), tetrazolium ring, pyrazole ring, pyridine ring or 1,2-dihydropyridine ring.

[0043] According to some implementation plans Selected from

[0044] According to some implementation plans, R a Selected from H, CN, halogens, oxo (=O), C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0045] According to some implementation plans, R a Selected from H, CN, F, Cl, oxo (=O), methyl, ethyl, isopropyl, difluoromethyl or cyclopropyl.

[0046] According to some implementation plans, R c Selected from H, CN, halogens, C 1-6 Alkyl or C 1-6 Alkyl group.

[0047] According to some implementation plans, R c Selected from H, CN, F, Cl, methyl or methoxy.

[0048] According to some implementation plans, R d Selected from H, CN, halogens (e.g., F, Cl), C 1-6 Alkyl or C 1-6 Alkyl group.

[0049] According to some implementation plans, R c The following groups, which connect with atoms in ring A to form unsubstituted or optionally substituted by one, two or more R's: saturated or partially unsaturated C's 5-6Carbon rings or 5-6 membered heterocycles; each R may be the same or different, and is independently selected from CN, halogens, C 1-6 Alkyl or C 1-6 An alkoxy group, or two R's attached to the same carbon atom, together with the carbon atom they are attached to, forms a C. 3-6 Cycloalkyl rings.

[0050] According to some implementation schemes, each R” may be the same or different, and may be independently selected from CN, halogen, methyl or methoxy, or two R” attached to the same carbon atom may together with the carbon atom to which they are attached to form a cyclopropyl ring.

[0051] According to some implementation plans, R c When connected to atoms in ring A, Selected from:

[0052] According to some implementation schemes, W is selected from -C(R8)(R9)-; R8 is selected from H; R9 is selected from -NR. 10 R 11 or -OR 12 ;

[0053] According to some implementation plans, R 10 Selected from -C(=O)R 102 or -C(=O)-N(R) 104 (R) 105 ); R 11 Selected from H; or, R 10 and R 11 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. 9a Substituted 3-6 N-containing heterocyclic groups (such as tetrahydropyrrole);

[0054] According to some implementation plans, R 12 Selected from -C(=O)R 122 or -C(=O)-N(R) 124 (R) 125 );

[0055] According to some implementation plans, R 102 R 104 R 105 R 122 R 124 R 125 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0056] According to some implementation plans, R102 R 104 R 105 R 122 R 124 R 125 They may be the same or different, and are independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, or methoxy;

[0057] According to some implementation schemes, R9 is selected from...

[0058] According to some embodiments, the compound represented by formula (I) is selected from the structures shown below:

[0059]

[0060] Among them, rings A, W, and R a R b R c R d R 10 R 11 r, t, and s have the definitions described in this invention.

[0061] According to some embodiments, the compound represented by formula (I) is selected from the structures shown below:

[0062]

[0063] Among them, rings A, W, and R a R b R d , R1, R2, R3, R4, R5, R6, R 10 R 11 R, n, r, t, s have the definitions described in this invention; ring B is selected from saturated or partially unsaturated C 5-8 Carbon rings or 5-8 membered heterocycles (preferably saturated or partially unsaturated C rings) 5-6 (Carbon ring or 5-6 membered heterocycle), q is selected from 0, 1 or 2.

[0064] According to some embodiments, the compound represented by formula (I) is selected from the structures shown below:

[0065]

[0066] Among them, rings A and R a R b R c R d r, t, and s have the definitions described in this invention.

[0067] According to embodiments of the present invention, among the compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, exemplary and non-limiting examples of compounds of formula (I) are as follows:

[0068]

[0069]

[0070]

[0071]

[0072] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) as described in the present invention, and its racemic, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula (I) of the present invention and its racemic, stereoisomer, tautomer, isotope label, nitride, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

[0074] The carrier in the pharmaceutical composition is "acceptable," compatible with (and preferably stabilizing) the active ingredient of the composition, and not harmful to the treated subject. One or more pharmaceutical excipients may be used to deliver the active compound.

[0075] The present invention further provides the use of the compound of formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of CYP11B2 inhibitors.

[0076] The present invention further provides the use of the compound of formula (I) and its racemic, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of medicaments for the diagnosis, prevention and / or treatment of refractory hypertension and hyperaldosteronism.

[0077] The present invention also provides a method for diagnosing, preventing and / or treating refractory hypertension, hyperaldosteronism or other conditions, the method comprising administering, alone, a therapeutically effective amount of at least one compound of the present invention to a patient requiring such treatment, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0078] In some embodiments, the compound is used as a CYP11B2 inhibitor, including but not limited to applications in: refractory hypertension, hyperaldosteronism.

[0079] According to some embodiments, the hyperaldosteronism is selected from pulmonary hypertension, obesity, insulin resistance, and metabolic syndrome.

[0080] The compounds of the present invention can be used in combination with other therapeutic agents.

[0081] Beneficial effects

[0082] The compounds provided by this invention have good CYP11B2 inhibitory activity; the compounds of this invention not only have good biological activity and good safety, but also improve the selectivity of CYP11B1 inhibitors; furthermore, the compounds provided by this invention can inhibit aldosterone and have no substantial effect on plasma cortisol levels.

[0083] Terminology Definitions and Explanations

[0084] The term "optional" (or "optionally", "optionally") in the general formula definition of this invention means the case of being substituted by zero or one or more substituents. For example, "optionally substituted by one, two or more R" means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0085] "More than three" means three or more.

[0086] Term "C" 1-12 "alkyl" should be understood to refer to straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6"Alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc., or isomers thereof. The term "alkylene" refers to the corresponding divalent group, including, for example, "C 1-6 Alkylene, C 1-4 "alkylene", etc., specific examples include but are not limited to: methylene, ethylene, propylene, butylene, pentylene, and hexylene, etc.

[0087] Term "C" 1-12 "Alkoxy" should be understood as "C". 1-12 Alkyl-O-”, C 1-12 Alkyl groups are as defined above.

[0088] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclic [1.1.1]pentyl) of 3 to 10 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0089] Term "C" 6-14 "Aryl" should be understood as a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 14 carbon atoms, exhibiting monovalent aromaticity or partial aromaticity. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C". 6-10 "Aryl", particularly a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl, or a ring with 10 carbon atoms ("C9 aryl"). 10Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), such as anthracene. The aryl group may optionally be substituted by one or more (such as one to three) suitable substituents.

[0090] The term "5-14-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-10-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzo[a]fused. "Hyperaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purineyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4- 5, 6, 7 or 8-isoquinolinyl, 1, 4, 5, 6, 7 or 8-phthalazinyl, 2, 3, 4, 5 or 6-naphthidyl, 2, 3, 5, 6, 7 or 8-quinazolinyl, 3, 4, 5, 6, 7 or 8-cenolinyl, 2, 4, 6 or 7-pteridyl, 1, 2, 3, 4, 5, 6, 7 or 8-4aH carbazole, 1, 2, 3, 4, 5, 6, 7 - or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbazolyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenanthrolinel -Phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenthiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazin[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furano[3,2-b]-pyranolyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-azolel, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazolo[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furano[3,4-c]cenolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3] -c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiopheneyl, 2-, 4-, 5-, 6- or 7-benzozolyl, 2-, 4-, 5-, 6- or 7-benzimidazinyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the carbon atom on the 5-14-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-14-membered heteroaryl ring may be linked to other groups. When the 5-14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0091] Unless otherwise defined, the term "3-14 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl; or 8-membered rings, such as... Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be aromatic and fused, including but not limited to benzo-fused (e.g., dihydroisoquinolinyl). When the 3-14 membered heterocyclic group is connected to other groups to form the compound of the present invention, the carbon atom on the 3-14 membered heterocyclic group can be connected to other groups, or the heterocyclic atom on the ring of the 3-14 membered heterocyclic group can be connected to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine, it can be the nitrogen atom on the piperazine group or the carbon atom on the piperazine group connected to other groups.

[0092] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0093] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0094] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0095] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0096] "Halogenation" refers to the replacement of a substance by one or more halogens.

[0097] If a substituent is described as being "independently selected" from a group of groups, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0098] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0099] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0100] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0101] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0102] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0103] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0104] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0105] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0106] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0107] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0108] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is in degrees Celsius.

[0109] Example 1

[0110] (R)-N-(4-(1-methyl-4,5-dihydronaphthoisoxazol-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0111]

[0112] Preparation of 6-bromo-3,4-dihydronaphthyl-2(1H)-one oxime (Step 1)

[0113] 300 mg (1.33 mmol) of 6-bromo-3,4-dihydronaphthyl-2(1H)-one D001a was dissolved in ethanol (5 mL) and water (5 mL). Hydroxylamine hydrochloride (926 mg, 13.3 mmol) and sodium acetate (1093 mg, 13.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, water and sodium carbonate solution were added to adjust the pH of the reaction mixture to 10. The system was extracted with dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 6-bromo-3,4-dihydronaphthyl-2(1H)-one oxime D001b (300 mg, yellow oil), yield: 94%.

[0114] MS m / z(ESI): 240.0(M+H) + .

[0115] Step 2: Preparation of 7-bromo-1-methyl-4,5-dihydronaphthoisoxazole

[0116] Under ice bath conditions, 6-bromo-3,4-dihydronaphthyl-2(1H)-one D001b (300 mg, 1.25 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of diisopropylaminolithium (160 mg, 2.50 mmol) and stirring for 30 minutes. Methyl acetate (56 mg, 0.75 mmol) was then slowly added, and stirring continued for 3 hours. After the reaction was complete, sulfuric acid (0.5 mL) was added, and stirring continued for 1 hour. Water was then added, and the system was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 7-bromo-1-methyl-4,5-dihydronaphthoisoxazole D001c (300 mg, yellow oil), yield: 91%.

[0117] MS m / z (ESI): 264.0 (M+1).

[0118] Step 3: Preparation of 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-4,5-dihydronaphthoxazole

[0119] Under a nitrogen atmosphere, 7-bromo-1-methyl-4,5-dihydronaphthoisoxazole D001c (100 mg, 0.38 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of pinacol diboron ester (128 mg, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (28 mg, 0.04 mmol), and potassium acetate (74 mg, 0.76 mmol). The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain the crude product 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-4,5-dihydronaphthoisoxazole D001d (110 mg, light yellow oil), yield: 93%. The crude product was used directly in the next reaction without further purification.

[0120] MS m / z (ESI): 312.3 (M+1).

[0121] Step 4: Preparation of (R)-N-(4-(1-methyl-4,5-dihydronaphthoisoxazol-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0122] Under a nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (20 mg, 0.07 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (II) (5 mg, 0.01 mmol), potassium carbonate (20 mg, 0.14 mmol), and 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-4,5-dihydronaphthoxazole D001d (26 mg, 0.08 mmol) were added to the mixture. The reaction mixture was stirred at 80 °C for 2 hours. The LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (R)-N-(4-(1-methyl-4,5-dihydronaphthoisoxazol-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001 (2.25 mg), yield: 8%.

[0123] MS m / z(ESI): 388.2(M+1) + .

[0124] HPLC: 100% (214nm), 100% (254nm).

[0125] 1 H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 8.28 (d, J = 8.4Hz, 1H), 8.23 ​​(s, 1H), 7.67 (d,J=7.8Hz,1H),7.34(s,1H),7.30(dd,J=7.8,1.6Hz,1H),5.10(dd,J=13.4, 6.0Hz,1H),3.01(t,J=7.0Hz,2H),2.90(dd,J=8.2,6.0Hz,2H),2.69(s,3H),2 .66–2.58(m,2H),2.22–2.10(m,2H),1.93–1.67(m,4H),1.06(t,J=7.6Hz,3H).

[0126] Example 2

[0127] N-((8R)-4-(1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0128]

[0129] Preparation of step one: 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one

[0130] 6-Bromo-3,4-dihydroquinoline-2(1H)-one D003a (2 g, 8.8 mmol) was dissolved in N,N-dimethylformamide solution (20 mL), followed by the addition of potassium carbonate (3.04 g, 22 mmol), 4-methoxybenzyl chloride (2.07 g, 13.2 mmol), and 18-crown-6 (0.12 g, 0.44 mmol). The reaction was stirred at 70°C for 16 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D003b (2.5 g, white solid), yield: 74%. MS m / z (ESI): 346.0 (M+1).

[0131] Step 2: Preparation of 6-bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinoline-2(1H)-one

[0132] 1.0 g (2.9 mmol) of 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D003b was dissolved in 10 mL of N,N-dimethylformamide solution. A 1 M solution of lithium bis(trimethylsilyl)aminoacetate (3.2 mL) was added at -10 °C, and the reaction was stirred at -10 °C for 0.5 h under a nitrogen atmosphere. Iodomethane (0.37 g, 2.61 mmol) was then added. The reaction was then continued with stirring at -10 °C for 5 h under a nitrogen atmosphere. After the reaction was complete, the mixture was washed with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 5) to give 6-bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinoline-2(1H)-one D003c (300 mg, yellow oil), yield: 24%.

[0133] MS m / z(ESI): 360.0(M+1).

[0134] Step 3: Preparation of 6-bromo-3-methyl-3,4-dihydroquinoline-2(1H)-one

[0135] 300 mg (0.833 mmol) of 6-bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinoline-2(1H)-one D003c was dissolved in trifluoroacetic acid (475 mg, 4.164 mmol), and the mixture was stirred at 60°C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and a saturated sodium bicarbonate solution (pH = 7) was added dropwise to the reaction solution. The mixture was extracted with ethyl acetate, dried, and concentrated. Crude product 6-bromo-3-methyl-3,4-dihydroquinoline-2(1H)-one D003d (200 mg, yellow oil) was obtained, yield: 90%.

[0136] MS m / z(ESI):240.0(M+1).

[0137] Step 4: Preparation of 6-bromo-3-methyl-3,4-dihydroquinoline-2(1H)-thione

[0138] 6-Bromo-3-methyl-3,4-dihydroquinoline-2(1H)-one D003d (180 mg, 0.75 mmol) and Lawson's reagent (303 mg, 0.75 mmol) were dissolved in toluene (5 mL) and stirred at 110°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. Crude product 6-bromo-3-methyl-3,4-dihydroquinoline-2(1H)-thione D003e (150 mg, yellow solid) was obtained, yield: 66%.

[0139] MS m / z(ESI):256.0(M+1).

[0140] Step 5: Preparation of 7-bromo-1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

[0141] 6-Bromo-3-methyl-3,4-dihydroquinoline-2(1H)-thione D003e (300 mg, 1.17 mmol) and acetylhydrazine (174 mg, 2.35 mmol) were dissolved in tert-butanol (5 mL), and the reaction was stirred at 140 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 7-bromo-1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D003f (80 mg, yellow solid), yield: 22%.

[0142] MS m / z (ESI): 278.0 (M+1).

[0143] Step 6: Preparation of 1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxorbacon-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

[0144] 7-Bromo-1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D003f (50 mg, 0.18 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of pinacol diboronate (46 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium chloride (13 mg, 0.018 mmol). The reaction was stirred at 90°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to ambient temperature, then filtered and concentrated under vacuum to obtain a crude product. The crude product was then purified with silica gel (dichloromethane / methanol = 10 / 1) to obtain the product 1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline. Preparation: D003g (30mg, 46%), yellow solid. MS m / z (ESI): 326.2 (M+1).

[0145] Step 7: Preparation of N-((8R)-4-(1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0146] Preparation of 1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline: D003 g (23 mg, 0.071 mmol) was dissolved in 1,4-dioxane and water (2:1 = 3 mL), followed by the addition of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (20 mg, 0.071 mmol), potassium carbonate (20 mg, 0.142 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (6 mg, 0.0071 mmol). The reaction was carried out at 100°C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to ambient temperature, then filtered and vacuum concentrated to obtain the crude product. The crude product was purified by preparation (FA, mobile phase: ACN:H2O (0.1% FA) = 13%:87%) to obtain the product N-((8R)-4-(1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D003 (2 mg, 6.6%).

[0147] MS m / z(ESI): 402.2(M+1).

[0148] HPLC: 214: 92.03% 254: 92.92%

[0149] 1 H NMR (400MHz, CD3OD) δ8.42(d,J=8.2Hz,1H),8.25(s,1H),7.79(d,J=8.2Hz,1H),7 .44(d,J=5.6Hz,2H),5.23(t,J=5.8Hz,1H),3.27(dd,J=12.0,6.0Hz,1H),3.26-3. 25(m,1H),2.89-2.86(m,1H),2.82(s,3H),2.83-2.60(m,2H),2.35–2.22(m,2H),2 .11–1.99(m,1H),1.90-1.85(m,3H),1.51(d,J=6.8Hz,3H),1.20(t,J=7.6Hz,3H).

[0150] Example 3

[0151] (R)-N-(4-(1'-methyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]-7'-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0152]

[0153] Preparation of step one: 6-bromo-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one

[0154] At -78°C, lithium bis(trimethylsilylamino)acetate (1.16 g, 8.70 mmol) was slowly added dropwise to a tetrahydrofuran (20 mL) solution of 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D004a (2 g, 5.80 mmol) and stirred for 30 minutes. Then, 1-bromo-2-chloroethane D004b (2.50 g, 17.40 mmol) was added at 10°C. The reaction mixture was then heated to room temperature and stirred for 16 hours. After the reaction was completed, water was slowly added under ice cooling, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 6-bromo-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D004c (900 mg, yellow solid), yield: 38%.

[0155] MS m / z (ESI): 432.0 (M+Na) + .

[0156] Step 2: Preparation of 6-bromo-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one

[0157] Sodium iodide (661 mg, 4.40 mmol) was added to a 15 mL solution of 6-bromo-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D004c (900 mg, 2.20 mmol), and the reaction was stirred at 80 °C for 10 hours. After the reaction was complete, water and ethyl acetate were added to the system for extraction. The organic phases were combined, dried, and concentrated to give the crude product 6-bromo-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D004d (900 mg, yellow solid), yield: 80%. The crude product was used directly in the next reaction without further purification.

[0158] MS m / z (ESI): 521.9 (M+Na) + .

[0159] Step 3: Preparation of 6'-bromo-1'-(4-methoxybenzyl)-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one

[0160] At -78°C, lithium bis(trimethylsilylamino)lithium (301 mg, 1.80 mmol) was slowly added dropwise to a tetrahydrofuran (10 mL) solution of 6-bromo-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoline-2(1H)-one D004d (900 mg, 1.80 mmol) and stirred for 1 hour. The reaction mixture was then heated to room temperature and stirred for 15 hours. After the reaction was complete, water was slowly added under ice-cooling, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 6'-bromo-1'-(4-methoxybenzyl)-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one D004e (600 mg, yellow solid), yield: 90%.

[0161] MS m / z(ESI): 372.0(M+1) + .

[0162] Step 4: Preparation of 6'-bromo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one

[0163] 6'-Bromo-1'-(4-methoxybenzyl)-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one D004e (600 mg, 1.61 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at 60 °C with stirring for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude product 6'-Bromo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one D004f (500 mg, yellow oil), yield: 98%. The crude product was used directly in the next reaction without further purification.

[0164] MS m / z(ESI): 252.0(M+1) + .

[0165] Step 5: Preparation of 6'-bromo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-thione

[0166] 6'-Bromo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-one D004f (500 mg, 1.98 mmol) was dissolved in toluene (10 mL), Lawson's reagent (1604 mg, 3.97 mmol) was added, and the mixture was stirred and refluxed at 120 °C for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate aqueous solution and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 6'-Bromo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-thione D004g (200 mg, yellow solid), yield: 38%.

[0167] MS m / z(ESI): 267.9(M+1) + .

[0168] Step 6: Preparation of 7'-bromo-1'-methyl-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]

[0169] 6'-Bromo-1'-,4'-dihydro-2'-H-spiro[cyclopropane-1,3'-quinoline]-2'-thione D004 g (190 mg, 0.71 mmol) was dissolved in n-butanol (5 mL), and acetylhydrazine D004 h (131 mg, 1.77 mmol) was added. The mixture was stirred at 140 °C for 1 hour. After the reaction was complete, water and dichloromethane were added to the system for extraction. The organic phases were combined, dried, and concentrated. The residue was purified by column chromatography to give 7'-bromo-1'-methyl-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]D004i (55 mg, yellow oil), yield: 27%. MS m / z (ESI): 290.0 (M+1) + .

[0170] Step 7: Preparation of 1'-methyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]

[0171] Under a nitrogen atmosphere, 7'-bromo-1'-methyl-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]D004i (55 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL), and pinacol diboronate (58 mg, 0.23 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (14 mg, 0.02 mmol) and potassium acetate (37 mg, 0.38 mmol) were added, and the reaction solution was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude product 1'-methyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline D004j (20 mg, yellow oil), yield: 31%. The crude product was used directly in the next reaction without further purification.

[0172] MS m / z (ESI): 338.2 (M+1) + .

[0173] Step 8: Preparation of (R)-N-(4-(1'-methyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]-7'-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0174] Under a nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (10 mg, 0.04 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (3 mg, 0.003 mmol), potassium carbonate (15 mg, 0.11 mmol), and 1'-methyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]D004j (18 mg, 0.05 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. The LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (R)-N-(4-(1'-methyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]-7'-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D004 (1.21 mg), yield: 8%.

[0175] MS m / z(ESI): 414.2(M+1) + .

[0176] HPLC: 99.39% (214nm), 97.67% (254nm).

[0177] 1 H NMR (400MHz, MeOD) δ8.40(s,1H),8.24(s,1H),7.84(d,J=8.3Hz,1H),7.43(m,2H),5.22(t,J=5.8Hz,1H),3.05(s,2H ),2.83(s,3H),2.72(m,2H),2.29(m,2H),2.04(m,1H),1.86(m,3H),1.35(m,2H),1.19(t,J=7.6Hz,3H),1.06(m,2H).

[0178] Example 4

[0179] (R)-N-(4-(1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0180]

[0181] Preparation of step one: 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-one

[0182] 6-Bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinoline-2(1H)-one D005a (800 mg, 2.22 mmol) was dissolved in NN-dimethylformamide solution (10 mL), and bis(trimethylsilyl)aminolithium solution (1 M, 2.7 mL) was added at -10 °C. The reaction was stirred at -10 °C for 0.5 h under a nitrogen atmosphere. Iodomethane (788 mg, 5.55 mmol) was then added. The reaction was then continued to be stirred at -10 °C for 5 h under a nitrogen atmosphere. After the reaction was complete, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-one D005b (300 mg, yellow oil), yield: 34%. MS m / z (ESI): 374.1 (M+1).

[0183] Step 2: Preparation of 6-bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-one

[0184] 300 mg (0.833 mmol) of 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-one D005b was dissolved in 5 mL of trifluoroacetic acid and stirred at 60 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and a saturated sodium bicarbonate solution (pH = 7) was added dropwise to the reaction solution. The mixture was extracted with ethyl acetate, dried, and concentrated. Crude product 6-bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-one D005c (150 mg, yellow oil) was obtained, with a yield of 67%.

[0185] MS m / z(ESI):254.0(M+1).

[0186] Step 3: Preparation of 6-bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-thione

[0187] 6-Bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-one D005c (150 mg, 0.59 mmol) and Lawson's reagent (239 mg, 0.59 mmol) were dissolved in toluene (5 mL) and stirred at 110°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. Crude product 6-bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-thione D005d (100 mg, yellow solid) was obtained, yield: 56%.

[0188] MS m / z(ESI):270.0(M+1).

[0189] Step 4: Preparation of 7-bromo-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

[0190] 6-Bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)-thione D005d (100 mg, 0.37 mmol) and acetylhydrazine (55 mg, 0.74 mmol) were dissolved in tert-butanol (5 mL), and the reaction was stirred at 140 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 7-bromo-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D005e (50 mg, yellow solid), yield: 41%.

[0191] MS m / z (ESI): 292.0 (M+1).

[0192] Step 5: Preparation of 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

[0193] 7-Bromo-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D005e (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of pinacol diboronate (44 mg, 0.17 mmol), potassium acetate (34 mg, 0.34 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium chloride (13 mg, 0.017 mmol). The reaction was stirred at 90°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to ambient temperature, then filtered and concentrated under vacuum to obtain a crude product. The crude product was then purified with silica gel (dichloromethane / methanol = 10 / 1) to obtain the product 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D005f (40 mg, yellow solid), 62%. MS m / z (ESI): 340.2 (M+1).

[0194] Step 6: Preparation of (R)-N-(4-(1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0195] 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D005f (24 mg, 0.071 mmol) was dissolved in 1,4-dioxane and water (2:1 = 3 mL), followed by the addition of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (20 mg, 0.071 mmol), potassium carbonate (20 mg, 0.142 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (6 mg, 0.0071 mmol). The reaction was carried out at 100°C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to ambient temperature, then filtered and concentrated under vacuum to obtain the crude product. The crude product was purified by preparation (FA, mobile phase: ACN:H2O (0.1% FA) = 16%:84%) to obtain product (R)-N-(4-(1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D005 (1.4 mg, 4.5%).

[0196] MS m / z(ESI): 416.3(M+1).

[0197] HPLC: 214: 93.94% 254: 95.38%

[0198] 1 H NMR (400MHz, CD3OD) δ8.44(s,2H),7.81(d,J=8.2Hz,1H),7.45(s,2H),5.22(t,J=5.8Hz,1H),3.00(s,2H),2.81(s,3H),2 .78–2.64(m,2H),2.33–2.23(m,2H),2.03(dd,J=13.0,6.8Hz,1H),1.93–1.77(m,3H),1.40(s,6H),1.20(d,J=7.6Hz,3H).

[0199] Example 5

[0200] (R)-N-(4-(4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0201]

[0202] Preparation of N-(4-bromophenyl)acetylthioamide (Step 1)

[0203] N-(4-bromophenyl)acetamide D006a (2 g, 9.3 mmol) was dissolved in toluene (30 mL), and Lawson's reagent (2.26 g, 5.5 mmol) was added. The reaction mixture was stirred at 110 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated, and the concentrate was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give N-(4-bromophenyl)acetylthioamide D006b (1.3 g, yellow solid), yield: 60%.

[0204] MS m / z (ESI): 230.1 (M+1).

[0205] Step 2: Preparation of (Z)-N-(4-bromophenyl)ethylaminothioate methyl ester

[0206] N-(4-bromophenyl)ethylthioamide D006b (1.3 g, 5.6 mmol) was dissolved in acetonitrile (30 mL), and potassium carbonate (1.55 g, 11.2 mmol) and methyl iodoform (0.95 g, 6.7 mmol) were added. The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated, and the concentrate was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give product (Z)-N-(4-bromophenyl)ethylaminothioate methyl ester D006c (900 mg, white solid), yield: 66%.

[0207] MS m / z (ESI): 244.2 (M+1).

[0208] Step 3: Preparation of 4-(4-bromophenyl)-3-methyl-4H-1,2,4-triazole

[0209] (Z)-N-(4-bromophenyl)ethylaminothiocyanate methyl ester D006c (800 mg, 3.27 mmol) was dissolved in N,N-dimethylformamide (30 mL), and formyl hydrazide (295 mg, 4.9 mmol) and p-toluenesulfonic acid hydrate (62 mg, 0.32 mmol) were added. The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate, washed with saturated brine (30 mL x 3), concentrated, and the concentrate was subjected to silica gel column chromatography (methanol / dichloromethane = 1 / 15) to give product 4-(4-bromophenyl)-3-methyl-4H-1,2,4-triazole D006d (500 mg), yield: 64%.

[0210] LCMS: 238.2 [M+H] + ).

[0211] 1 H NMR (400MHz, MeOD) δ8.62(s,1H),7.87–7.70(d,J=7.6Hz,2H),7.43(d,J=7.6Hz,2H),2.42(s,3H).

[0212] Step 4: Preparation of 3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4H-1,2,4-triazole

[0213] 4-(4-bromophenyl)-3-methyl-4H-1,2,4-triazole D006d (60 mg, 0.25 mmol) was dissolved in dioxane (10 mL), and pinacol diboronate (128 mg, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (20.83 mg, 0.025 mmol), and potassium acetate (49 mg, 0.50 mmol) were added. The reaction mixture was stirred at 100 °C for 6 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated, and the concentrate was subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give the product 3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4H-1,2,4-triazole D006e (40 mg). The product obtained did not require further purification and was directly added to the next step.

[0214] LCMS: 286.1 (M+1).

[0215] Step 5: Preparation of (R)-N-(4-(4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0216] 3-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4H-1,2,4-triazole D006e (40 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide (20 mg, 0.07 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8 mg, 0.01 mmol), and potassium carbonate (20 mg, 0.14 mmol) were added. The reaction mixture was stirred at 110 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the concentrate was prepared by high performance liquid chromatography (FA 0.1%) to obtain product (R)-N-(4-(4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D006 (5 mg), yield: 19.5%.

[0217] LCMS:362.1(M+1).

[0218] HPLC: 100% (214nm), 100% (254nm).

[0219] 1 H NMR(400MHz,MeOD)δ8.68(s,1H),8.42(s,1H),8.25(s,1H),7.60 -7.58(m,4H),5.23(t,J=5.6Hz,1H),2.85–2.59(m,2H),2.49(s,3H),2.28-2.25(m,2H),2.05 -2.02(m,1H),1.97–1.71(m,3H),1.19(t,J=7.6Hz,3H).

[0220] Example 6

[0221] (R)-N-(4-(4-(isoxazo-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0222]

[0223] Step 1: Preparation of 4-(4-bromophenyl)isoxazole

[0224] Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoxazole D007a (300 mg, 1.5383 mmol), 1-bromo-4-iodobenzene D007b (435.19 mg, 1.5383 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (112.56 mg, 0.1538 mmol), and cesium carbonate (1002.42 mg, 3.0766 mmol) to a microwave-safe tube equipped with a stir bar. After purging the vial with argon gas and sealing it, add 1,4-dioxane (3 mL) and water (0.6 mL) using a syringe. Stir the vial at 50°C for 16 hours, then cool to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined and dried. The residue was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 23%) to give 4-(4-bromophenyl)isoxazole D007c (250 mg, white solid). Yield: 65%.

[0225] MS m / z (ESI): 224.0 (M+1).

[0226] Step 2: Preparation of (R)-N-(4-(4-(isoxazo-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0227] Add 4-(4-bromophenyl)isoxazole D007c (29.8 mg, 0.133 mmol), (R)-(8-propamido-5,6,7,8-tetrahydroisoquinoline-4-yl)boronic acid D007d (30 mg, 0.1209 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (8.85 mg, 0.0121 mmol), and sodium carbonate (25.63 mg, 0.2418 mmol) to a microwave-safe tube equipped with a stir bar. After purging the vial with argon gas and sealing it, add 0.5 mL of 1,4-dioxane and 0.1 mL of water using a syringe. Stir the vial at 50°C for 1 hour, then cool to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined and dried. The residue obtained by concentration under reduced pressure was purified preparatively (FA, mobile phase: ACN:H2O (0.1% FA) = 12%:88%) to give (R)-N-(4-(4-(isoxazo-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D007 (10 mg). Yield: 23.6%.

[0228] MS m / z (ESI): 348.1 (M+1).

[0229] HPLC: 99.28% (214nm), 99.13% (254nm).

[0230] 1 H NMR (400MHz, DMSO-d6) δ9.53(s,1H),9.23(s,1H),8.35(s,1H),8.29–8.24(m,2H),7.81(d,J=8.2Hz,2H),7.44(d,J =8.2Hz,2H),5.13-5.08(m,1H),2.62(t,J=5.6Hz,2H),2.19-2.12(m,2H),1.88-1.66(m,4H),1.06(t,J=7.6Hz,3H).

[0231] Example 7

[0232] (R)-N-(4-(5-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-ylpropionamide

[0233]

[0234] Preparation of 4-(4-bromophenyl)-5-methylisoxazole (Step 1)

[0235] To a reaction flask equipped with a stir bar, add 5-methylisoxazole-4-borate pinacol ester D008a (350 mg, 1.6742 mmol), 1-bromo-4-iodobenzene (521 mg, 1.8416 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (121.49 mg, 0.1674 mmol), cesium carbonate (1090.98 mg, 3.3484 mmol), and solvents 1,4-dioxane (10 mL) and water (1 mL). Stir the reaction mixture at 50°C for 2 hours, then cool to room temperature. Filter the reaction mixture, concentrate the organic phase, and purify the residue by column chromatography (petroleum ether / ethyl acetate) to give 4-(4-bromophenyl)-5-methylisoxazole D008b (300 mg). Yield: 75%.

[0236] MS m / z (ESI): 238.0 (M+1).

[0237] Step 2: Preparation of (R)-N-(4-(5-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-ylpropionamide

[0238] Add 4-(4-bromophenyl)-5-methylisoxazole D008b (35 mg, 0.14508 mmol), (R)-(8-propamido-5,6,7,8-tetrahydroisoquinoline-4-yl)boronic acid (30 mg, 0.1209 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (8.77 mg, 0.0121 mmol), sodium carbonate (25.63 mg, 0.2418 mmol), and solvents 1,4-dioxane (5 mL) and water (0.5 mL) to a reaction flask equipped with a stir bar. Stir the reaction mixture at 50°C for 2 hours, then cool to room temperature. The reaction mixture was filtered, and the residue obtained by direct concentration under reduced pressure was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 20%-30%, flow rate: 25 mL / min) to obtain (R)-N-(4-(5-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-ylpropionamide D008 (7 mg). Yield: 16%.

[0239] MS m / z (ESI): 362.2 (M+1).

[0240] HPLC: 99.12% (214nm), 100% (254nm).

[0241] 1 H NMR(400MHz, CDCl3)δ8.56(s,1H),8.41–8.34(m,3H),7.47(s,2H),7.38(s,2H),5.75( s,1H),5.40(s,2H),2.63(s,3H),2.31(s,2H),2.11(s,2H),1.83(s,2H),1.23(s,3H).

[0242] Example 8

[0243] (R)-N-(4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0244]

[0245] Step 1: Preparation of 4-(4-bromophenyl)-3,5-dimethylisoxazole

[0246] (3,5-Dimethylisoxazole-4-yl)boronic acid D009a (100 mg, 0.71 mmol) was dissolved in dioxane / water = 4 / 1 (2.5 mL), and 1-bromo-4-iodobenzene (221 mg, 0.78 mmol), cesium carbonate (694 mg, 2.13 mmol), and PdCl2 (dppf) (26 mg, 0.035 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated, and the concentrate was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give product 4-(4-bromophenyl)-3,5-dimethylisoxazole D009b (130 mg, brown solid), yield: 73%.

[0247] MS m / z (ESI): 254.0 (M+1).

[0248] Step 2: Preparation of (R)-(8-propionamide-5,6,7,8-tetrahydroisoquinoline-4-yl)boronic acid

[0249] (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (56 mg, 0.2 mmol) was dissolved in methanol (5 mL), and tetrahydroxydiboron (89 mg, 1.0 mmol), potassium acetate (58 mg, 0.6 mmol), Xphos (9 mg, 0.02 mmol), and Xphos Pd G2 (16 mg, 0.02 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated to give crude (R)-(8-propionamide-5,6,7,8-tetrahydroisoquinoline-4-yl)boronic acid D007d (49 mg, brown solid), yield: 100%.

[0250] MS m / z (ESI): 249.1 (M+1).

[0251] Step 3: Preparation of (R)-N-(4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0252] 4-(4-bromophenyl)-3,5-dimethylisoxazole D009b (30 mg, 0.12 mmol) was dissolved in a dioxane / water mixture of 4 / 1 (2.5 mL), and (R)-(8-propamido-5,6,7,8-tetrahydroisoquinoline-4-yl)boronic acid D007d (49 mg, 0.2 mmol), potassium carbonate (49 mg, 0.36 mmol), and PdCl2 (dppf) (5 mg, 0.006 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the concentrate was subjected to reversed-phase column chromatography (acetonitrile / water (0.5% FA) = 4 / 1) to obtain product (R)-N-(4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D009 (10 mg), yield: 22%.

[0253] MS m / z (ESI): 376.1 (M+1).

[0254] HPLC: 98.63% (214nm), 99.75% (254nm).

[0255] 1 H NMR (400MHz, CDCl3) δ8.58(s,1H),8.41(s,1H),7.42-7.29(m,4H),5.74(d,J=8.4Hz,1H),5.45-5.28(m,1H),2.80-2.56(m ,2H),2.47(s,3H),2.34(s,3H),2.29(dd,J=15.2,7.6Hz,2H),2.13-2.07(m,1H),1.83-1.80(m,3H),1.23(t,J=7.6Hz,3H).

[0256] Example 9

[0257] (R)-N-(4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0258]

[0259] Preparation of 5-(4-bromophenyl)-1-methyl-1H-pyrazole (Step 1)

[0260] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole D010a (100 mg, 0.48 mmol) was dissolved in a 4 / 1 (2.5 mL) solution of dioxane / water. 1-Bromo-4-iodobenzene (150 mg, 0.53 mmol), cesium carbonate (313 mg, 0.96 mmol), and PdCl2 (dppf) (18 mg, 0.024 mmol) were added. The reaction mixture was stirred at 50 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated, and the concentrate was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5-(4-bromophenyl)-1-methyl-1H-pyrazole D010b (90 mg, white solid), yield: 79%.

[0261] MS m / z (ESI): 237.1 (M+1).

[0262] Step 2: Preparation of 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1H-pyrazole

[0263] The product 5-(4-bromophenyl)-1-methyl-1H-pyrazole D010b (90 mg, 0.38 mmol) was dissolved in dioxane (5 mL), and pinacol ester of borate (145 mg, 0.57 mmol), potassium acetate (112 mg, 1.14 mmol), and PdCl2 (dppf) (14 mg, 0.019 mmol) were added. The reaction solution was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated to give crude product 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1H-pyrazole D010c (108 mg, brown solid), yield: 100%.

[0264] MS m / z (ESI): 285.1 (M+1).

[0265] Step 3: Preparation of (R)-N-(4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0266] 1-Methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1H-pyrazole D010c (30 mg, 0.11 mmol) was dissolved in dioxane / water = 4 / 1 (2.5 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide (30 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol), and PdCl2 (dppf) (4 mg, 0.0052 mmol) were added. The reaction mixture was stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the concentrate was subjected to reversed-phase column chromatography (acetonitrile / water (0.5% FA) = 4 / 1) to obtain product (R)-N-(4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D010 (10 mg), yield: 26%.

[0267] MS m / z (ESI): 361.1 (M+1).

[0268] HPLC: 100% (214nm), 100% (254nm).

[0269] 1 H NMR (400MHz, MeOD) δ8.41(s,1H),8.26(s,1H),7.65(d,J=8.4Hz,2H),7.55(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,2H),6.47(d,J=2.0Hz,1H),5.2 5(t,J=6.0Hz,1H),3.96(s,3H),2.86-2.64(m,2H),2.31(qd,J=7.6,2.0Hz,2H),2.12-2.00(m,1H),1.98-1.76(m,3H),1.22(t,J=7.6Hz,3H).

[0270] Example 10

[0271] (R)-N-(4-(4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0272]

[0273] Step 1: Preparation of (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid

[0274] Under a nitrogen atmosphere, 5-bromo-1-methyl-1H-1,2,3-triazole D011a (150 mg, 0.93 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL). Then, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (67 mg, 0.09 mmol), potassium carbonate (320 mg, 2.32 mmol), and 1,4-phenyldiboronic acid D011b (384 mg, 2.32 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed as determined by LCMS, the reaction mixture was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid D011c (90 mg, yellow oil), yield: 48%.

[0275] MS m / z(ESI): 204.1(M+H) + .

[0276] Step 2: Preparation of (R)-N-(4-(4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0277] Under a nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (50 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (II) (50 mg, 0.25 mmol), potassium carbonate (73 mg, 0.53 mmol), and (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid D011c (50 mg, 0.25 mmol) were added to the mixture. The reaction mixture was stirred at 80 °C for 3 hours. The LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (R)-N-(4-(4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D011 (7 mg), yield: 11%.

[0278] MS m / z(ESI): 362.1(M+1) + .

[0279] HPLC: 99.7% (214nm), 99.74% (254nm).

[0280] 1H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.30(d,J=8.4Hz,1H),8.27(s,1H),7.99(s,1H),7.73(d,J=8.2Hz,2H),7.54(d,J=8. 2Hz,2H),5.18–5.03(m,1H),4.14(s,3H),2.67–2.59(m,2H),2.19–2.10(m,2H),1.92–1.69(m,4H),1.06(t,J=7.6Hz,3H).

[0281] Example 11

[0282] (R)-N-(4-(4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0283]

[0284] Step 1: Preparation of (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid

[0285] Under a nitrogen atmosphere, 5-bromo-1-methyl-1H-1,2,4-triazole D012a (150 mg, 0.93 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL). Then, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (67 mg, 0.09 mmol), potassium carbonate (320 mg, 2.32 mmol), and 1,4-phenyldiboronic acid D012b (384 mg, 2.32 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed as determined by LCMS, the reaction mixture was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography to obtain (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)boronic acid D012c (100 mg, yellow oil), yield: 53%.

[0286] MS m / z(ESI): 204.1(M+H) + .

[0287] Step 2: Preparation of (R)-N-(4-(4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0288] Under a nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D001e (50 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (II) (50 mg, 0.25 mmol), potassium carbonate (73 mg, 0.53 mmol), and (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)boronic acid D012c (50 mg, 0.25 mmol) were added to the mixture. The reaction mixture was stirred at 80 °C for 3 hours. The LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (R)-N-(4-(4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D012 (12 mg), yield: 19%.

[0289] MS m / z(ESI): 362.1(M+1) + .

[0290] HPLC: 99.79% (214nm), 100% (254nm).

[0291] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.30(d,J=8.4Hz,1H),8.28(s,1H),8.04(s,1H),7.89(d,J=8.4Hz,2H),7.56(d,J=8. 4Hz,2H),5.18–5.05(m,1H),4.03(s,3H),2.66–2.58(m,2H),2.19–2.12(m,2H),1.92–1.69(m,4H),1.06(t,J=7.6Hz,3H).

[0292] Example 12

[0293] (R)-N-(4-(4-(1-methyl-1H-tetrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0294]

[0295] Preparation of 5-(4-bromophenyl)-1-methyl-1H-tetrazole (Step 1)

[0296] 5-(4-bromophenyl)-1H-tetrazole D013a (1 g, 4.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (260 mg, 6.6 mmol) and methyl iodide (940 mg, 6.6 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 5-(4-bromophenyl)-1-methyl-1H-tetrazole D013b (70 mg, white solid), yield: 6.82%. MS m / z (ESI): 239.0 (M+1) + .

[0297] 1 H NMR (400MHz, CDCl3) δ7.71(m,2H),7.62(m,2H),4.16(s,3H).

[0298] Step 2: Preparation of 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-1H-tetrazole

[0299] 5-(4-bromophenyl)-1-methyl-1H-tetrazole 133b (70 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoborane) (82 mg, 0.32 mmol), potassium acetate (61 mg, 0.63 mmol), and DPPF palladium dichloride (23 mg, 0.03 mmol) were added. The reaction was carried out at 80°C for 16 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, filtered, dried, and enriched. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-1H-tetrazole D013c (80 mg, white solid), yield: 89.13%. MS m / z (ESI): 287.1 (M+1).

[0300] Step 3: Preparation of (R)-N-(4-(4-(1-methyl-1H-tetrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0301] Under a nitrogen atmosphere, 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl)-1H-tetrazole D013c (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (13 mg, 0.017 mmol), potassium carbonate (48 mg, 0.35 mmol), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide (54 mg, 0.19 mmol) were added to the mixture. The reaction mixture was stirred at 90 °C for 2 hours. The LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (R)-N-(4-(4-(1-methyl-1H-tetrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D013 (17 mg), yield: 26.85%.

[0302] MS m / z(ESI): 363.1(M+1) + .

[0303] HPLC: 100% (214nm), 100% (254nm).

[0304] 1 H NMR (400MHz, CDCl3) δ8.57(s,1H),8.34(s,1H),7.85(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),5.77(d,J=8.5Hz,1H),5.43–5 .30(m,1H),4.25(s,3H),2.74–2.56(m,2H),2.35–2.25(m,2H),2.16–2.05(m,1H),1.90–1.79(m,3H),1.23(t,J=7.6Hz,3H).

[0305] Example 13

[0306] (R)-N-(4-(4-(3-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0307]

[0308] Preparation of 4-(4-bromophenyl)-3-methylisoxazole (Step 1)

[0309] Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoxazole D014a (150 mg, 0.7175 mmol), 1-bromo-4-iodobenzene (202.98 mg, 0.7175 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (105 mg, 0.1435 mmol), and cesium carbonate (467.55 mg, 1.435 mmol) to a microwave-safe tube equipped with a stir bar. After purging the vial with argon gas and sealing it, add 1,4-dioxane (2 mL) and water (0.4 mL) using a syringe. Stir the vial at 50°C for 16 hours, then cool to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined and dried. The residue was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 10%) to give 4-(4-bromophenyl)-3-methylisoxazole D014b (167 mg, colorless oil). Yield: 88%.

[0310] MS m / z (ESI): 238.0 (M+1).

[0311] Step 2: Preparation of (R)-N-(4-(4-(3-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0312] Add 4-(4-bromophenyl)-3-methylisoxazole D014b (34.54 mg, 0.1451 mmol), (R)-(8-propamido-5,6,7,8-tetrahydroisoquinoline-4-yl)boronic acid D007d (30 mg, 0.1209 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (17.69 mg, 0.0242 mmol), and sodium carbonate (25.63 mg, 0.2418 mmol) to a microwave-safe tube equipped with a stir bar. After purging the vial with argon gas and sealing it, add 1,4-dioxane (1 mL) and water (0.2 mL) using a syringe. Stir the vial at 50°C for 2 hours, then cool to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined and dried. The residue was concentrated under reduced pressure and purified preparatively (FA, mobile phase: ACN:H2O (0.1% FA) = 20%:80%) to give (R)-N-(4-(4-(3-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide D014 (10.28 mg). Yield: 23%.

[0313] MS m / z (ESI): 362.2 (M+1).

[0314] HPLC: 99.22% (214nm), 100% (254nm).

[0315] 1 H NMR(400MHz, DMSO-d6)δ9.22(s,1H),8.36(s,1H),8.31–8.25(m,2H),7.64(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H), 5.18-5.13(m,1H),2.62(t,J=5.6Hz,2H),2.45(s,3H),2.18-2.13(m,2H),1.92–1.71(m,4H),1.06(t,J=7.6Hz,3H).

[0316] Compounds were prepared under similar conditions as in Example 7 above, as shown in Table 1 below, and their structural characterization data are shown in Table 1.

[0317] Table 1

[0318]

[0319]

[0320]

[0321] Biological evaluation:

[0322] Test Example 1: Construction of G402-hCYP11B1 / G402-hCYP11B2 monoclonal cell lines

[0323] This method was used to test the inhibitory effect of the compounds in this invention on the activity of human CYP11B1 / CYP11B2 enzymes expressed in stable G402-hCYP11B1 / G402-hCYP11B2 cell lines.

[0324] 1. Experimental materials and instruments

[0325] 1.1 Culture medium

[0326] MCCOYS 5A MED MOD medium (Invitrogen, Cat#10131)

[0327] Penicillin-Streptomycin(Corning,Cat#15140-122)

[0328] FBS (GIBCO, Cat#10091-148)

[0329] GLUTAMAX I-100X(Invitrogen,Cat#35050061)

[0330] Puromycin(Invitrogen,Cat#ant-pr-5)

[0331] Penicillin / Streptomycin(Invitrogen,Cat#15140)

[0332] 1.2 Reagents and Consumables

[0333] Neon Transfection Kit(Invitrogen,Cat#MPK10096)

[0334] DMEM (Gibco, Cat#11965-092)

[0335] Polybrene(Sigma,Cat#TR-1003-G)

[0336] FuGENE HD Transfection Reagent(Promega,Cat#E2311)

[0337] Opti-MEM (Gibco, Cat#11058-021)

[0338] 2. Experimental Procedure

[0339] 2.1 Retrovirus Packaging. pMSCV-CYP11B1 and pMSCV-CYP11B2 were co-transfected with helper plasmids into GP2-293 cells. After 72 h, the cell supernatant was collected, centrifuged, and filtered to obtain the packaged retroviruses.

[0340] 2.2 Cell transfection. G402 wild-type cells were infected with retroviruses. After 48 hours, the cell medium was changed, and positive cells were selected using medium containing 3 g / ml Puromycin.

[0341] 2.3 Monoclonal screening. One week after puromycin screening, when the cells were in good growth condition, the cells were screened for monoclonal cells using the limiting dilution method, and the growth of monoclonal cells was recorded using Incucyte.

[0342] 2.4 Single-clone identification. After 14 days, cells in good growth condition were digested from 96-well plates and passaged into 6-well plates. After cell expansion, cells were sampled, and protein expression was detected using Western blotting.

[0343] 2.5 Monoclonal expansion. Positive monoclonal cells were transferred to T-75 flasks for further culture and expansion.

[0344] Test Example 2: Inhibitory activity test of the compounds of the present invention against CYP11B2-mediated aldosterone / CYP11B1-mediated cortisol production.

[0345] 1. Experimental materials and instruments

[0346] 1.1 Reagents

[0347] TrypLE TM Express Enzyme (Gibco, Cat#12604021)

[0348] Penicillin-Streptomycin(Corning,Cat#15140-122)

[0349] MCCOYS 5A MED MOD medium (Invitrogen, Cat#10131)

[0350] Puromycin(Invitrogen,Cat#ant-pr-5)

[0351] FBS (Gibco, Cat#10099-141C)

[0352] DPBS (Gibco, Cat#14190250)

[0353] DMSO (Sigma, Cat#D8418-1L)

[0354] Cortisol HTRF kit (Cisbio, Cat#62CRTPEG)

[0355] Activated carbon treatment of fetal bovine serum charcoal stripped FBS (BIOSUN, Cat#BS-0004-500)

[0356] Osilodrostat(LCI699)(MCE,Cat#HY-16276)

[0357] Deoxycortisone (LCI699) (MCE, Cat#HY-77839)

[0358] 1.2 Consumables

[0359] 384-well plate(Corning,Cat#3764)

[0360] Plate shaker(QILINBEIER,Cat#QB-9002)

[0361] Centrifuge(Eppendorf,Cat#5810R)

[0362] CO2 incubator(Thermo Scientific,Cat#371)

[0363] Microscope (OLYMPUS, Cat#CKX41)

[0364] Countess(Gibco,Cat#C10281)

[0365] 384-well microplate (Greiner, Cat#784075)

[0366] Envision(PerkinElmer,Cat#2105)

[0367] 2. Experimental Procedure

[0368] 2.1 Assay for CYP11B1-mediated cortisol production

[0369] 2.1.1 Seed 4000 G402 cells / well / 35μl into 384-well plates and incubate at 37°C and CO2 for 6 hours.

[0370] 2.1.2 Add 5 μL of 0.4 μM Cortodoxone (final concentration 0.05 μM) to the cells.

[0371] 2.1.3 Add 40 nL of the test compound to the cells and incubate at 37 °C and CO2 for 16 h.

[0372] 2.1.4 Collect the supernatant and test for cortisol using HTRF.

[0373] 2.1.5 Dispense 10 μL of cortisol standards (Standard 0-Standard 6) into each standard well; dispense 10 μL of each sample into each sample well.

[0374] 2.1.6 Add 5 μL of cortisol receptor reagent (d2) working solution to the standard and sample.

[0375] 2.1.7 Add 5 μL of cortisol donor antibody (Cryptate) working solution to all wells.

[0376] 2.1.8 Seal the plate and incubate at room temperature for 2 hours.

[0377] 2.1.9 Remove the sealing plate and, Read on compatible card reader

[0378] 2.2 Assay for CYP11B2-mediated aldosterone production

[0379] 2.2.1 4000 G402 cells / well / 35 μl were seeded into 384-well plates and incubated at 37°C and CO2 for 6 hours.

[0380] 2.2.2 Add 5 μL of 8 μM 11-deoxycorticosterone into the cells (final concentration 1 μM).

[0381] 2.2.3 Add 40 nL of the test compound to the cells and incubate at 37 °C and CO2 for 16 h.

[0382] 2.2.4 Collect the supernatant and test for aldosterone using HTRF.

[0383] 2.2.5 Dispense 10 μL of aldosterone standards (Standard 0-Standard 6) into each standard well; dispense 10 μL of each sample into each sample well.

[0384] 2.2.6 Add 5 μL of aldosterone receptor reagent (XL665) working solution to the standard and sample.

[0385] 2.2.7 Add 5 μL of aldosterone donor antibody (Cryptate) working solution to all wells.

[0386] 2.2.8 Seal the plate and incubate at room temperature for 2 hours.

[0387] 2.2.9 Remove the sealing plate and, Read on compatible card reader

[0388] Table 2 shows the IC50 values ​​of the compounds in this invention in the assay of inhibitory activity against CYP11B2-mediated aldosterone / CYP11B1-mediated cortisol production.

[0389] Compound numbering hCYP11B2(nM) hCYP11B1(nM) D001 14.7 2742 D007 8.55 1456 D008 6.46 1124 D009 234.1 >10000 D010 6.7 1310 D011 58.1 9319 D013 161 11832 D014 4.8 614 D025 7.5 3514 D026 4.1 2180 D030 25.5 5818 D039 16.06 1490

[0390] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of formula (IV-1), its racemate, or a pharmaceutically acceptable salt thereof: Formula IV-1 in, Ring A is selected from a 5-membered nitrogen-containing heteroaromatic ring; Each R a They are either the same or different, and are independently selected from H, CN, halogens, oxometalates (=O), and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 cycloalkyl; R b Selected from H; R c Selected from H, CN, halogens, C 1-6 Alkyl or C 1-6 Alkoxy; Or, R c The following groups are formed by bonding with atoms in ring A to form unsubstituted or optionally substituted groups with one, two or more R'': saturated or partially unsaturated C 5-6 A carbon ring or a 5-6 membered heterocycle; each R'' may be the same or different, and may be independently selected from CN, halogen, methyl or methoxy, or two R'' attached to the same carbon atom and the carbon atom attached to them may together form a cyclopropyl ring; R d Selected from H, CN, halogens, C 1-6 Alkyl or C 1-6 Alkoxy; r is selected from 0, 1, or 2; t is selected from 0, 1, 2, or 3; s is selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, characterized in that, Selected from , , , , , , , , , , , , , , , , , , , , , , .

3. The compound according to claim 1, characterized in that, R c Selected from H, CN, F, Cl, methyl, or methoxy; Or, R c When connected to atoms in ring A, Selected from: , , , , or .

4. The compound according to claim 1, characterized in that, R d Selected from H, CN, F, and Cl.

5. The compound according to any one of claims 1-4, characterized in that, The compound represented by formula (IV-1) is selected from the structures shown below: ； Formula IV-2 Among them, rings A and R a R b R c R d r, t, and s have the definitions as described in any one of claims 1-4.

6. The following compounds, their racemates, or pharmaceutically acceptable salts thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 7. A pharmaceutical composition comprising at least one of the compounds of any one of claims 1-6, their racemates, or pharmaceutically acceptable salts thereof; optionally, the pharmaceutical composition further comprising one or more pharmaceutically acceptable excipients.

8. The use of at least one of the compounds of any one of claims 1-6, their racemates, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament, characterized in that, The application is in the preparation of a drug for treating refractory hypertension and hyperaldosteronism; the refractory hypertension and hyperaldosteronism are related to increased aldosterone secretion.

9. The application according to claim 8, characterized in that, The aldosteronism mentioned is selected from pulmonary hypertension, obesity, insulin resistance, and metabolic syndrome.

10. The application according to claim 8, characterized in that, At least one of the compound, its racemate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can inhibit aldosterone and has no substantial effect on plasma cortisol levels.

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