CYP11B2 inhibitor compound, pharmaceutical composition and application thereof

Abstract

The invention provides a CYP11B2 inhibitor compound as shown in a formula (I), a pharmaceutical composition and application of the CYP11B2 inhibitor compound and the pharmaceutical composition, the compound has good CYP11B2 inhibition activity, can be used for treating diseases related to CYP11B2, not only has good biological activity and good safety, but also improves the selectivity of a CYP11B1 inhibitor. # imgabs0 #

Description

[0001] This application claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on July 27, 2023, with patent application number 202310933635.6 and titled “CYP11B2 inhibitor compounds, pharmaceutical compositions and their applications”. The entire text of the prior application is incorporated into this disclosure by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compounds, and in particular relates to CYP11B2 inhibitor compounds, pharmaceutical compositions and applications thereof. Background Art

[0003] Resistant hypertension is also called stubborn hypertension. It is defined as: blood pressure still cannot reach the target after treatment with three antihypertensive drugs with complementary mechanisms of action (one of which is a diuretic), or ≥4 antihypertensive drugs are needed to achieve the target blood pressure (<130 / 80 mmHg). In clinical practice in my country, the cutoff value for diagnosing stubborn hypertension is 140 / 90 mmHg. At present, the existing treatments for resistant hypertension mainly include drug intervention: optimizing diuretic therapy, mineralocorticoids, combined therapy, etc.; and non-drug intervention: changing lifestyle, DASH diet, reducing salt intake, limiting alcohol consumption, etc.

[0004] Aldosterone is a mineralocorticoid secreted by the zona glomerulosa of the adrenal cortex. It maintains water-salt balance by regulating the reabsorption of sodium ions by the kidney. The secretion of aldosterone can be achieved through the renin-angiotensin-aldosterone system (RAAS). That is, the juxtaglomerular cells of the kidney sense the stimulation of decreased blood pressure and decreased sodium, secrete more renin, and renin acts on angiotensinogen to generate angiotensin. Angiotensin can stimulate the zona glomerulosa of the adrenal cortex to synthesize and secrete aldosterone, increase the reabsorption of sodium ions by the kidney, and then increase the reabsorption of water and increase the volume of extracellular fluid; on the contrary, when the volume of extracellular fluid increases, the above-mentioned opposite mechanism reduces the secretion of aldosterone, reduces the reabsorption of sodium ions and water by the kidney, and reduces the volume of extracellular fluid. Reduced blood sodium and increased blood potassium also stimulate the adrenal cortex to increase the secretion of aldosterone.

[0005] Hyperaldosteronism (PA) is a syndrome of hypertension and hypokalemia caused by excessive secretion of aldosterone by the adrenal cortex. PA is a common cause of secondary hypertension, and the prevalence of PA in patients with resistant hypertension ranges from 14% to 21%. Recent evidence shows that increased aldosterone is associated with cardiovascular and cardiometabolic diseases. Among other things, 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, renal damage and increased mortality.

[0006] In addition to promoting the kidney to retain sodium and excrete potassium to maintain water and salt balance, another important function of aldosterone is to bind to the MR of local tissues in an autocrine or paracrine manner to regulate the function of target organs. Aldosterone can regulate the expression of different target genes and protein translation through genomic effects, that is, binding to intracellular receptors; or through non-genomic rapid effects, that is, effects that do not depend on intracellular receptors and the process of transcription and translation, which are not blocked by aldosterone receptor antagonists such as spironolactone. Currently, there are more and more studies on the non-genomic effects of aldosterone, and it has been found that the non-genomic signaling pathways of aldosterone involve cyclic adenosine monophosphate (cAMP), inositol triphosphate (IP3), calcium ions (Ca 2+ ), protein kinase C (PKC), extracellular signal-regulated kinase (ERK1 / 2), phosphatidylinositol 3-kinase (PI3K), non-receptor tyrosine kinase (c-src), angiotensin II (AngⅡ), epidermal growth factor receptor (EGFR), NADPH oxidase / reactive oxygen species (ROS), nitric oxide synthase (NOS), Na+ / H+ exchanger (NHE), etc.

[0007] In addition to hypertension, the role of aldosterone in cardiovascular disease has been gradually recognized in recent years. Studies in humans and transgenic animals have shown that aldosterone causes endothelial dysfunction, and its mechanism is believed to be related to the reduction of vascular NO caused by the increase of superoxide anions. Superoxide anions can degrade NO produced by normal endothelium. In hyperlipidemic rabbits, superoxide anions increase 2 to 3 times, and the amount of superoxide anions decreases 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 wall stress caused by heart failure. In terms of cardiac fibrosis, a study from Japan 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 in patients using spironolactone (4-18%). The reduction in collagen markers also reached statistical significance and was correlated with the end-diastolic volume index after myocardial infarction. This suggests that LV dysfunction and fibrosis are parallel processes and can be reversed by aldosterone antagonists.

[0008] There are two cytochrome P450 isoenzymes (CYP11B1, P450C11, and CYP11B2, P450c11Aldo) with 11β-hydroxylase activity in the human adrenal cortex. Both isoenzymes can 11β-hydroxylate 11-deoxycorticosterone and 11-deoxycortisol, catalyzing the synthesis of cortisol and corticosterone, respectively. The CYP11B1 gene encodes P450C11, which has a molecular weight of about 51kD and is highly expressed in the zona fasciculata. It is mainly involved in the synthesis of cortisol and is regulated by ACTH. The CYP11B2 gene encodes aldosterone synthase (P450C11Aldo), which has a molecular weight of 49kD and is mainly expressed in the zona glomerulosa. It is regulated by the renin-angiotensin system. CYP11B2 has 11β-hydroxylase activity, as well as 18-hydroxylase and 18-oxidase activities, and is involved in the synthesis of aldosterone. Both CYP11B1 and CYP11B2 are located on the long arm of chromosome 8, 8q21-22, and their amino acid sequences have 93% homology. Such a high degree of homology suggests that the development of highly selective CYP11B2 inhibitors is a major challenge. LCI-699 (osilodrostat) is the first aldosterone synthase inhibitor in clinical development. Low doses can inhibit aldosterone secretion and lower blood pressure in hypertensive patients, but it also inhibits CYP11B1 and thus cortisol synthesis. These results hinder its clinical use in the treatment of hypertension.

[0009] At present, mineralocorticoid receptor antagonists (MRA) are the first choice for the treatment of primary aldosteronism. Spironolactone is a nonspecific mineralocorticoid receptor antagonist, which has significant effects on diseases such as heart failure with reduced ejection fraction, refractory hypertension, and aldosteronism. It can also reduce proteinuria in patients with chronic kidney disease and delay the progression of chronic kidney disease. However, due to the low selectivity of spironolactone, there are anti-androgen and progesterone-related side effects. In comparison, the second-generation mineralocorticoid receptor antagonist eplerenone has high selectivity and greatly reduced adverse reactions, but its effect of blocking mineralocorticoid receptors is 40 times lower than that of spironolactone. Representative nonsteroidal MRAs are represented by third-generation mineralocorticoid receptor antagonists, including finerenone, escitalopram, and apalidene. Compared with eplerenone and spironolactone, finerenone has higher selectivity for MR, less effect on other steroid receptors and ion channels, and greater accumulation in the kidneys. Finerenone has lower lipophilicity, higher polarity, and does not pass through the blood-brain barrier. Finerenone has no active metabolites, a short half-life, hyperkalemia can be corrected faster, and has less effect on blood pressure. Ethacicillinone is another new nonsteroidal mineralocorticoid receptor agonist that has been approved in Japan for the treatment of hypertension and diabetic nephropathy. Compared with eplerenone and spironolactone, ethacicillinone has higher potency and selectivity for mineralocorticoid receptors, so the risk of hyperkalemia, female breast development, amenorrhea and impotence is lower. The third-generation mineralocorticoid receptor antagonists have higher selectivity than spironolactone, and the anti-mineralocorticoid receptor effect is higher than that of eplerenone. The first two generations of steroidal MRAs have adverse reactions such as hyperkalemia, male impotence, breast development, and female amenorrhea. Although the third-generation nonsteroidal finerenone has improved selectivity, there is still a safety issue of hyperkalemia; the currently approved indication is patients with type 2 diabetes with chronic kidney disease (CKD). MR has conserved homologous sequences with glucocorticoid receptor, progesterone receptor, androgen receptor, etc. In addition to aldosterone ligand, MR also has other ligands, such as glucocorticoid and progesterone. Therefore, MRA faces the problems of poor selectivity and poor safety.

[0010] Baxtrostat is a small molecule drug that is highly selective for CYP11B2 and inhibits aldosterone synthesis by inhibiting the CYP11B2 enzyme, also known as aldosterone synthase. Studies have shown that in addition to reducing plasma aldosterone levels and blood pressure, Baxdrostat has no substantial effect on plasma cortisol levels. Inhibiting aldosterone synthesis with Baxdrostat may expand the possible options for the treatment of resistant hypertension. The benefits of inhibiting aldosterone synthesis may also extend beyond resistant hypertension itself, as elevated aldosterone levels are associated with the pathophysiology of pulmonary hypertension, obesity, insulin resistance, and metabolic syndrome.

[0011] Therefore, the search for CYP11B2 inhibitors that achieve improved potency and selectivity would be of great interest in achieving therapeutic agents and methods to address currently unmet needs in the treatment and prevention of diseases, disorders, and symptoms thereof. Summary of the invention

[0012] In order to solve the problems existing in the prior art, the present invention provides a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt:

[0013]

[0014] in,

[0015] Ring A is selected from saturated or partially unsaturated C 5-10 Carbocyclic ring, 5-10 membered heterocyclic ring, C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring;

[0016] Each R a are the same or different and are independently selected from H, CN, OH, thiol, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -SC 1-12 Alkyl or -S-(C 3-12 cycloalkyl); each R a1 are the same or different and are independently selected from CN, OH, oxo (=O), halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl;

[0017] Each R b , R c , R d are the same or different and are independently selected from H, CN, OH, mercapto, halogen, the following groups which are unsubstituted or optionally substituted by one, two or more R': amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -SC 1-12 Alkyl or -S-(C 3-12 cycloalkyl); each R' is 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 is connected to an atom in ring A to form the following groups which are unsubstituted or optionally substituted by one, two or more R": saturated or partially unsaturated C 5-8 carbocyclic or 5-8 membered heterocyclic ring; each R" is the same or different and is independently selected from CN, OH, thiol, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or cyano C 1-6 Alkyl, or two R" attached to the same carbon atom and the carbon atom to which they are attached together form a C 3-6 Alkyl ring, halogenated C 3-6 Alkyl ring or cyano C 3-6 Alkyl ring;

[0019] W is selected from -N(R 7 )-or-C(R 8 )(R 9 )-;

[0020] R 7 Selected from -S(=O) 2 R 71 、-S(=O) 2 OR 72 、-S(=O) 2 NR 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 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 7a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0022] R 8 is selected from H, unsubstituted or optionally substituted with one, two or more R 8a Substituted with the following groups: C 1-12 Alkyl, C 3-12Cycloalkyl or 3-12 membered heterocyclic group;

[0023] R 9 is selected from unsubstituted or optionally substituted with one, two or more R 9a Substituted with the following groups: -(CH 2 ) m -NR 10 R 11 or -(CH 2 ) p -OR 12 ;

[0024] R 10 is selected from H, unsubstituted or optionally substituted with one, two or more R 10a Substituted with the following groups: -S(=O) 2 R 101 、-C(=O)R 102 、-C(=O)OR 103 or -C(=O)-N(R 104 )(R 105 );

[0025] R 11 is selected from H, unsubstituted or optionally substituted with one, two or more R 11a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0026] Or, R 10 and R 11 Together with the N atom to which it is attached, it forms an unsubstituted or optionally substituted R 9a Substituted following groups: 3-12 membered N-containing heterocyclic group;

[0027] R 12 is selected from H, unsubstituted or optionally substituted with one, two or more R 12a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl, -S(=O) 2 R 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 , R122 , R 123 , R 124 , R 125 The same or different, independently selected from H, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0029] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are the same or different and are independently selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl;

[0030] Or, R 1 , R 2 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R 1a Substituted with the following groups: C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0031] Or, R 3 , R 4 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R 3a Substituted with the following groups: C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0032] Or, R 5 , R 6 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R 5a Substituted with the following groups: C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[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 are the same or different and are independently selected at each occurrence from H, CN, OH, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R aa Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; each R aa are the same or different and are independently selected from CN, OH, halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl.

[0040] According to some embodiments, Ring A is selected from a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring.

[0041] According to some embodiments, Ring A is selected from a 5-6 membered nitrogen-containing heterocyclic ring or a 5-6 membered nitrogen-containing heteroaromatic ring.

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

[0043] According to some embodiments, Selected from

[0044] According to some embodiments, R a Selected from H, CN, halogen, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-6 Cycloalkyl.

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

[0046] According to some embodiments, R c Selected from H, CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

[0047] According to some embodiments, R c is selected from H, CN, F, Cl, methyl or methoxy.

[0048] According to some embodiments, R d is selected from H, CN, halogen (such as F, Cl), C 1-6 Alkyl or C 1-6 Alkoxy.

[0049] According to some embodiments, R c is connected to an atom in ring A to form the following groups which are unsubstituted or optionally substituted by one, two or more R": saturated or partially unsaturated C 5-6 carbocyclic or 5-6 membered heterocyclic ring; each R" is the same or different and is independently selected from CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R" attached to the same carbon atom and the carbon atom to which they are attached together form a C 3-6 Cycloalkyl ring.

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

[0051] According to some embodiments, R c When connected to an atom in ring A, Selected from:

[0052] According to some embodiments, W is selected from -C(R 8 )(R 9 )-;R 8 Selected from H; R 9 Selected from -NR 10 R 11 OR 12 ;

[0053] According to some embodiments, 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 to which it is attached, it forms an unsubstituted or optionally substituted R 9a Substituted 3-6 membered N-containing heterocyclic group (such as tetrahydropyrrolyl);

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

[0055] According to some embodiments, R 102 , R 104 , R 105 , R 122 , R 124 , R 125 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0056] According to some embodiments, R 102 , R 104 , R 105 , R 122 , R 124 , R 125 are the same or different and are independently selected from H, methyl, ethyl, isopropyl, cyclopropyl or methoxy;

[0057] According to some embodiments, R 9 Selected from

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

[0059]

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

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

[0062]

[0063] Among them, ring A, W, R a , R b , R d , R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 10 , R 11 , R", n, r, t, s have the same definitions as described in the present invention; Ring B is selected from saturated or partially unsaturated C 5-8 Carbocyclic or 5-8 membered heterocyclic ring (preferably saturated or partially unsaturated C 5-6 carbocyclic or 5-6 membered heterocyclic ring), 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, ring A, R a , R b , R c , R d , r, t, and s have the definitions as described in the present invention.

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

[0068]

[0069]

[0070]

[0071]

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

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

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

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

[0076] The present invention further provides the use of the compound of formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of drugs for diagnosing, preventing and / or treating refractory hypertension and hyperaldosteronism.

[0077] The present invention also provides a method for diagnosing, preventing and / or treating resistant hypertension, hyperaldosteronism or a disorder, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention alone, 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: refractory hypertension, aldosteronism.

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

[0080] The compounds of the invention may be used in combination with additional therapeutic agents.

[0081] Beneficial Effects

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

[0083] Definition and explanation of terms

[0084] The term "optional" (or "optionally", "optionally") in the general formula definition of the present invention means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be selectively substituted by one, two or more R.

[0085] "More" means three or more.

[0086] The term "C 1-12 The term "alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms. 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups 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, or the like or isomers thereof. The term "alkylene" refers to the corresponding divalent radicals, including, for example, "C 1-6 Alkylene", "C 1-4 Specific examples include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene and hexylene.

[0087] The term "C 1-12 "Alkoxy" is understood to mean "C 1-12 Alkyl-O-", C 1-12 Alkyl is 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., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) 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 of 3 to 10 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0089] The term "C 6-14 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-10 Aryl", especially a ring having 6 carbon atoms ("C 6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 The aryl group is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.

[0090] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) 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" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 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-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbozolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9- 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 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-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3 1-, 2-, 3-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 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-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0091] Unless otherwise defined, the term "3-14 membered heterocyclyl" 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 (e.g., fused, bridged, spiro) 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 also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)-. 2 -state. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic group". The term "3-10 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be connected to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). The heterocyclic group may include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl; or an 8-membered ring, such as Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 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 with other groups to form the compound of the present invention, the carbon atom on the 3-14 membered heterocyclic group may be connected with other groups, or the heterocyclic atom on the 3-14 membered heterocyclic group may be connected with other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl or the carbon atom on the piperazinyl may be connected with other groups.

[0092] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

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

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

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

[0096] "Halo" means substituted with one or more halogens.

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

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

[0099] The compounds of the present invention may exist in the form of solvates (e.g. hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.

[0100] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into 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 prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0101] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

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

[0103] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0104] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations 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 included in the scope that the present invention is intended to protect.

[0105] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

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

[0107] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0108] Unless otherwise specified, 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, with 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-tetrahydroisoquinolin-8-yl)propanamide

[0111]

[0112] The first step is the preparation of 6-bromo-3,4-dihydronaphthalene-2(1H)-one oxime

[0113] 6-bromo-3,4-dihydronaphthalene-2(1H)-one D001a (300 mg, 1.33 mmol) 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 thereto in sequence, and the reaction solution 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 solution to 10, and the system was extracted with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product 6-bromo-3,4-dihydronaphthalene-2(1H)-one oxime D001b (300 mg, yellow oil), with a yield of 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, 6-bromo-3,4-dihydronaphthalene-2(1H)-one D001b (300 mg, 1.25 mmol) was dissolved in tetrahydrofuran (10 mL), lithium diisopropylamide (160 mg, 2.50 mmol) was added and stirred for 30 minutes, then methyl acetate (56 mg, 0.75 mmol) was slowly added and stirred for 3 hours. After the reaction was completed, sulfuric acid (0.5 mL) was added and stirred for another hour, then water was added, 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 a crude product, and the crude product was separated and purified by column chromatography to obtain 7-bromo-1-methyl-4,5-dihydronaphthaleneisoxazole 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-dioxaborolan-2-yl)-4,5-dihydronaphthoxazole

[0119] Under nitrogen atmosphere, 7-bromo-1-methyl-4,5-dihydronaphthoisoxazole D001c (100 mg, 0.38 mmol) was dissolved in 1,4-dioxane (5 mL), and diboronic acid pinacol ester (128 mg, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride (28 mg, 0.04 mmol) and potassium acetate (74 mg, 0.76 mmol) were added in sequence. 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-dioxaborolane-2-yl)-4,5-dihydronaphthoisoxazole D001d (110 mg, light yellow oil), with a yield of 93%. The crude product was directly used in the next step 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-tetrahydroisoquinolin-8-yl)propanamide

[0122] Under nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D001e (20 mg, 0.07 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (5 mg, 0.01 mmol), potassium carbonate (20 mg, 0.14 mmol) and 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydronaphthoxazole D001d (26 mg, 0.08 mmol) were added thereto, and the reaction mixture was stirred at 80°C for 2 hours. LCMS detected that the starting material disappeared. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain (R)-N-(4-(1-methyl-4,5-dihydronaphthoisoxazol-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 (400 MHz, DMSO-d 6 )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]quinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0128]

[0129] The first step is the preparation of 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0130] 6-Bromo-3,4-dihydroquinolin-2(1H)-one D003a (2g, 8.8mmol) was dissolved in NN-dimethylformamide solution (20mL), followed by addition of potassium carbonate (3.04g, 22mmol), 4-methoxybenzyl chloride (2.07g, 13.2mmol) and 18-crown-6 (0.12g, 0.44mmol), and the reaction was stirred at 70 degrees for 16 hours. After the reaction was completed, the reaction solution was concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one D003b (2.5g, 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-dihydroquinolin-2(1H)-one

[0132] 6-Bromo-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one D003b (1.0 g, 2.9 mmol) was dissolved in NN-dimethylformamide solution (10 mL), and bis(trimethylsilyl)amide lithium solution (1 M, 3.2 mL) was added at -10 degrees Celsius, and the reaction was stirred at -10 degrees Celsius for 0.5 hours under a nitrogen atmosphere. Then iodomethane (0.37 g, 2.61 mmol) was added. The reaction was then continued to stir at -10 degrees Celsius for 5 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate=100 / 5) to give 6-bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinolin-2(1H)-one D003c (300 mg, yellow oil) with a yield of 24%.

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

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

[0135] Dissolve 6-bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinolin-2(1H)-one D003c (300 mg, 0.833 mmol) in trifluoroacetic acid (475 mg, 4.164 mmol) and stir at 60 degrees for 16 hours. After the reaction is completed, cool to room temperature, and add saturated sodium bicarbonate solution (pH=7) dropwise to the reaction solution, extract with ethyl acetate, dry, and concentrate. Obtain crude product 6-bromo-3-methyl-3,4-dihydroquinolin-2(1H)-one D003d (200 mg, yellow oil), 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] Dissolve 6-bromo-3-methyl-3,4-dihydroquinolin-2(1H)-one D003d (180 mg, 0.75 mmol) and Lawesson's reagent (303 mg, 0.75 mmol) in toluene (5 mL) and stir at 110 degrees for 2 hours. After the reaction is completed, cool to room temperature and concentrate. Obtain crude product 6-bromo-3-methyl-3,4-dihydroquinolin-2(1H)-thione D003e (150 mg, yellow solid) with a yield of 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 acetic hydrazide (174 mg, 2.35 mmol) were dissolved in tert-butyl alcohol (5 mL) and stirred at 140 degrees 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 (dichloromethane / methanol = 10 / 1) to obtain 7-bromo-1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D003f (80 mg, yellow solid) with a yield of 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-dioxaborolan-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 diboron (46 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (13 mg, 0.018 mmol), and the reaction was stirred at 90 °C for 2 hours under nitrogen atmosphere. After the reaction, the reaction solution was cooled to ambient temperature, filtered and concentrated in vacuo to obtain a crude product, which was then purified by silica gel (dichloromethane / methanol=10 / 1) to obtain the product 1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline Preparation D003g (30 mg, 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]quinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0146] Preparation of 1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D003g (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-tetrahydroisoquinolin-8-yl)propanamide D001e (20 mg, 0.071 mmol), potassium carbonate (20 mg, 0.142 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (6 mg, 0.0071 mmol), and the reaction was reacted at 100 degrees Celsius for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to ambient temperature, then filtered and concentrated in vacuo to obtain a crude product, which was purified by preparative purification (FA, mobile phase: ACN:H 2 O (0.1% FA) = 13%: 87%) to give the product N-((8R)-4-(1,4-dimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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, CD 3 OD)δ8.42(d,J=8.2Hz,1H),8.25(s,1H),7.79(d,J=8.2Hz,1H),7.44(d,J=5.6 Hz,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-tetrahydroisoquinolin-8-yl)propanamide

[0152]

[0153] The first step is the preparation of 6-bromo-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

[0154] To a solution of 6-bromo-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one D004a (2 g, 5.80 mmol) in tetrahydrofuran (20 mL) was slowly added bis(trimethylsilylamide) lithium (1.16 g, 8.70 mmol) at -78°C and stirred for 30 minutes. Then, 1-bromo-2-chloroethane D004b (2.50 g, 17.40 mmol) was added thereto at 10°C, and the reaction mixture was then warmed to room temperature and stirred for 16 hours. After the reaction, water was slowly added under ice cooling, extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 6-bromo-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-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-dihydroquinolin-2(1H)-one

[0157] Sodium iodide (661 mg, 4.40 mmol) was added to a solution of 6-bromo-3-(2-chloroethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one D004c (900 mg, 2.20 mmol) in acetone (15 mL), and the mixture was stirred at 80°C for 10 hours. After the reaction, water and ethyl acetate were added to the system for extraction, and the organic phases were combined, dried and concentrated to give a crude product 6-bromo-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one D004d (900 mg, yellow solid) with a yield of 80%. The crude product was used directly in the next step 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, bis(trimethylsilylamide)lithium (301 mg, 1.80 mmol) was slowly added dropwise to a solution of 6-bromo-3-(2-iodoethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one D004d (900 mg, 1.80 mmol) in tetrahydrofuran (10 mL) and stirred for 1 hour. The reaction mixture was then warmed to room temperature and stirred for 15 hours. After the reaction was completed, water was slowly added under ice cooling, the mixture was extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated and 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), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at 60°C 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 directly used in the next step 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), Lawesson's reagent (1604 mg, 3.97 mmol) was added and stirred 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 a crude product, which was separated and 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 D004g (190 mg, 0.71 mmol) was dissolved in n-butanol (5 mL), acetylhydrazine D004h (131 mg, 1.77 mmol) was added and stirred at 140°C for 1 hour. After the reaction was completed, water and dichloromethane were added to the system for extraction, the organic phases were combined, dried and concentrated, and the residue was purified by column chromatography to obtain 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-dioxaborolan-2-yl)-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline]

[0171] Under 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 diboronic acid pinacol ester (58 mg, 0.23 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (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 a crude product 1'-methyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline D004j (20 mg, yellow oil) with a yield of 31%. The crude product was directly used 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-tetrahydroisoquinolin-8-yl)propanamide

[0174] Under nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D001e (10 mg, 0.04 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (3 mg, 0.003 mmol), potassium carbonate (15 mg, 0.11 mmol) and 1'-methyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'-H-spiro[cyclopropane-1,4'-[1,2,4]triazoloquinoline] D004j (18 mg, 0.05 mmol) were added thereto, and the reaction mixture was stirred at 80°C for 2 hours. LCMS detected that the starting material disappeared. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain a crude product. The crude product was separated and 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-tetrahydroisoquinolin-8-yl)propanamide 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)propanamide

[0180]

[0181] The first step is the preparation of 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one

[0182] 6-Bromo-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinolin-2(1H)-one D005a (800 mg, 2.22 mmol) was dissolved in NN-dimethylformamide solution (10 mL), and bis(trimethylsilyl)amide lithium solution (1M, 2.7 mL) was added at -10 degrees Celsius, and the reaction was stirred at -10 degrees Celsius for 0.5 hours under a nitrogen atmosphere. Then iodomethane (788 mg, 5.55 mmol) was added. Then the reaction was continued to stir at -10 degrees Celsius for 5 hours under a nitrogen atmosphere. After the reaction was completed, a saturated ammonium chloride solution was added, and the organic phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate=20 / 1) to give 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinolin-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-dihydroquinolin-2(1H)-one

[0184] Dissolve 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one D005b (300 mg, 0.833 mmol) in trifluoroacetic acid (5 mL) and stir at 60 degrees for 16 hours. After the reaction is completed, cool to room temperature, and add saturated sodium bicarbonate solution (pH = 7) dropwise to the reaction solution, extract with ethyl acetate, dry, and concentrate. Obtain crude product 6-bromo-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one D005c (150 mg, yellow oil), yield: 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] Dissolve 6-bromo-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one D005c (150 mg, 0.59 mmol) and Lawesson's reagent (239 mg, 0.59 mmol) in toluene (5 mL) and stir at 110 degrees for 2 hours. After the reaction is completed, cool to room temperature and concentrate. Obtain crude product 6-bromo-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-thione D005d (100 mg, yellow solid) with a yield of 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 acetic hydrazide (55 mg, 0.74 mmol) were dissolved in tert-butyl alcohol (5 mL) and stirred at 140 degrees 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 (dichloromethane / methanol = 10 / 1) to obtain 7-bromo-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline D005e (50 mg, yellow solid) with a yield of 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-dioxaborolan-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 diboron (44 mg, 0.17 mmol), potassium acetate (34 mg, 0.34 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (13 mg, 0.017 mmol), and the reaction was stirred at 90 °C for 2 hours under nitrogen atmosphere. After the reaction, the reaction solution was cooled to ambient temperature, filtered and concentrated in vacuo to obtain a crude product, which was then purified by silica gel (dichloromethane / methanol=10 / 1) to obtain the product 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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]quinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0195] 1,4,4-Trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-tetrahydroisoquinolin-8-yl)propanamide D001e (20 mg, 0.071 mmol), potassium carbonate (20 mg, 0.142 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (6 mg, 0.0071 mmol), and the reaction was reacted at 100 degrees Celsius for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to ambient temperature, then filtered and concentrated in vacuo to obtain a crude product, which was purified by preparative purification (FA, mobile phase: ACN:H 2 O (0.1% FA) = 16%: 84%) to give the product (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) propanamide 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, CD 3 OD)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),2.78–2.6 4(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-tetrahydroisoquinolin-8-yl)propanamide

[0201]

[0202] The first step is the preparation of N-(4-bromophenyl) ethanethioamide

[0203] N-(4-bromophenyl)acetamide D006a (2g, 9.3mmol) was dissolved in toluene (30mL), Lawesson's reagent (2.26g, 5.5mmol) was added, and the reaction solution was stirred at 110°C for 3 hours under nitrogen protection. After the reaction, the reaction solution was concentrated, and the concentrate was chromatographed on a silica gel column (ethyl acetate / petroleum ether=1 / 3) to obtain the product N-(4-bromophenyl)ethanesulfamide D006b (1.3g, yellow solid), with a yield of 60%.

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

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

[0206] N-(4-bromophenyl) ethylthioamide D006b (1.3 g, 5.6 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (1.55 g, 11.2 mmol) and iodomethane (0.95 g, 6.7 mmol) were added, and the reaction solution was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained concentrate was subjected to silica gel column chromatography (ethyl acetate / petroleum ether=1 / 5) to obtain the product (Z)-N-(4-bromophenyl) ethylaminothioic acid methyl ester D006c (900 mg, white solid), with a yield of 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)ethylaminothioic acid methyl ester D006c (800 mg, 3.27 mmol) was dissolved in N,N-dimethylformamide (30 mL), and formic hydrazide (295 mg, 4.9 mmol) and p-toluenesulfonic acid hydrate (62 mg, 0.32 mmol) were added, and the reaction solution was stirred at 120°C for 1 hour. After the reaction was completed, water (30 mL) was added, ethyl acetate was extracted, and saturated brine was washed (30 mL x 3), and concentrated. The concentrate was subjected to silica gel column chromatography (methanol / dichloromethane = 1 / 15) to obtain the product 4-(4-bromophenyl)-3-methyl-4H-1,2,4-triazole D006d (500 mg), with a yield of 64%.

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

[0211] 1H 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-dioxaborolan-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 diboronic acid pinacol ester (128 mg, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (20.83 mg, 0.025 mmol) and potassium acetate (49 mg, 0.50 mmol) were added. The reaction solution was stirred at 100°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the concentrate was chromatographed on a silica gel column (ethyl acetate / petroleum ether = 1 / 3) to obtain the product 3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole D006e (40 mg), and the obtained product was directly used for the next step without further purification.

[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-tetrahydroisoquinolin-8-yl)propanamide

[0216] 3-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-tetrahydroisoquinolin-8-yl)propanamide (20 mg, 0.07 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (8 mg, 0.01 mmol) and potassium carbonate (20 mg, 0.14 mmol) were added. The reaction solution was stirred at 110°C for 4 hours under nitrogen protection. After the reaction, the reaction solution was concentrated, and the concentrate was prepared by high performance liquid chromatography (FA 0.1%) to obtain the product (R)-N-(4-(4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D006 (5 mg) with a yield of 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-(isoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0222]

[0223] The first step is the preparation of 4-(4-bromophenyl)isoxazole

[0224] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole D007a (300 mg, 1.5383 mmol), 1-bromo-4-iodobenzene D007b (435.19 mg, 1.5383 mmol), 1,1-bis(diphenylphosphine)dichloropalladium iron (112.56 mg, 0.1538 mmol), cesium carbonate (1002.42 mg, 3.0766 mmol) were added to a microwave tube equipped with a stirrer. The vial was sealed after purging with argon, and 1,4-dioxane (3 mL) and water (0.6 mL) were added via a syringe. The microwave vial was stirred at 50 degrees for 16 hours and then cooled to room temperature. The reaction mixture was filtered, water and ethyl acetate were added to the filtrate for extraction, the organic phases were combined and dried, and the residue obtained by concentration under reduced pressure was purified by column chromatography (petroleum ether:ethyl acetate=23%) to obtain 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-(isoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0227] 4-(4-bromophenyl)isoxazole D007c (29.8 mg, 0.133 mmol), (R)-(8-propionamide-5,6,7,8-tetrahydroisoquinolin-4-yl)boronic acid D007d (30 mg, 0.1209 mmol), 1,1-bis(diphenylphosphine)diferronichloridopalladium (8.85 mg, 0.0121 mmol), sodium carbonate (25.63 mg, 0.2418 mmol) were added to a microwave vial equipped with a stirrer. The vial was sealed after purging with argon, and 1,4-dioxane (0.5 mL) and water (0.1 mL) were added via a syringe. The microwave vial was stirred at 50 degrees for 1 hour and then cooled to room temperature. The reaction mixture was filtered, water and ethyl acetate were added to the filtrate for extraction, the organic phases were combined and dried, and the residue obtained by concentration under reduced pressure was purified by preparative purification (FA, mobile phase: ACN:H2O (0.1% FA) = 12%:88%) to obtain (R)-N-(4-(4-(isoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 (400 MHz, DMSO-d 6 )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-tetrahydroisoquinolin-8-ylpropanamide

[0233]

[0234] The first step is the preparation of 4-(4-bromophenyl)-5-methylisoxazole

[0235] 5-methylisoxazole-4-boronic acid pinacol ester D008a (350 mg, 1.6742 mmol), 1-bromo-4-iodobenzene (521 mg, 1.8416 mmol), 1,1-bis(diphenylphosphine)dibrominated iron palladium dichloride (121.49 mg, 0.1674 mmol), cesium carbonate (1090.98 mg, 3.3484 mmol) and solvent 1,4-dioxane (10 mL) and water (1 mL) were added to a reaction bottle equipped with a stirrer. The reaction solution was stirred at 50 degrees for 2 hours and then cooled to room temperature. The reaction mixture was filtered, the organic phase was concentrated, and the resulting residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain 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-tetrahydroisoquinolin-8-ylpropionamide

[0238] 4-(4-bromophenyl)-5-methylisoxazole D008b (35 mg, 0.14508 mmol), (R)-(8-propionamido-5,6,7,8-tetrahydroisoquinolin-4-yl)boric acid (30 mg, 0.1209 mmol), 1,1-bis(diphenylphosphine)diferronichloridopalladium (8.77 mg, 0.0121 mmol), sodium carbonate (25.63 mg, 0.2418 mmol) and solvent 1,4-dioxane (5 mL) and water (0.5 mL) were added to a reaction bottle equipped with a stirrer. The reaction solution was stirred at 50 degrees for 2 hours and then cooled to room temperature. The reaction mixture was filtered, and the obtained filtrate was directly concentrated under reduced pressure to obtain a residue, which was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic 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: 25mL / min) to obtain (R)-N-(4-(5-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-ylpropanamide 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 (400 MHz, CDCl 3 )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-tetrahydroisoquinolin-8-yl)propanamide

[0244]

[0245] The first step is the preparation of 4-(4-bromophenyl)-3,5-dimethylisoxazole

[0246] (3,5-Dimethylisoxazol-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 PdCl were added. 2 (dppf) (26 mg, 0.035 mmol). The reaction solution 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 chromatographed on a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain the product 4-(4-bromophenyl)-3,5-dimethylisoxazole D009b (130 mg, brown solid), with a yield of 73%.

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

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

[0249] (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 solution was stirred at 80 ° C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to obtain crude (R)-(8-propanamide-5,6,7,8-tetrahydroisoquinolin-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-tetrahydroisoquinolin-8-yl)propanamide

[0252] 4-(4-Bromophenyl)-3,5-dimethylisoxazole D009b (30 mg, 0.12 mmol) was dissolved in dioxane / water = 4 / 1 (2.5 mL), and (R)-(8-propionamide-5,6,7,8-tetrahydroisoquinolin-4-yl)boronic acid D007d (49 mg, 0.2 mmol), potassium carbonate (49 mg, 0.36 mmol) and PdCl were added. 2 (dppf) (5 mg, 0.006 mmol). The reaction solution 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 reverse phase column chromatography (acetonitrile / water (0.5% FA) = 4 / 1) to obtain the product (R)-N-(4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 (400 MHz, CDCl 3)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),2.4 7(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-tetrahydroisoquinolin-8-yl)propanamide

[0258]

[0259] The first step is the preparation of 5-(4-bromophenyl)-1-methyl-1H-pyrazole

[0260] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole D010a (100 mg, 0.48 mmol) was dissolved in dioxane / water = 4 / 1 (2.5 mL), and 1-bromo-4-iodobenzene (150 mg, 0.53 mmol), cesium carbonate (313 mg, 0.96 mmol) and PdCl were added. 2 (dppf) (18 mg, 0.024 mmol). The reaction solution was stirred at 50°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the concentrate was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain the product 5-(4-bromophenyl)-1-methyl-1H-pyrazole D010b (90 mg, white solid), with a yield of 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-dioxaborolan-2-yl)phenyl)-1H-pyrazole

[0263] The obtained product 5-(4-bromophenyl)-1-methyl-1H-pyrazole D010b (90 mg, 0.38 mmol) was dissolved in dioxane (5 mL), and pinacol borate (145 mg, 0.57 mmol), potassium acetate (112 mg, 1.14 mmol) and PdCl were added. 2(dppf) (14 mg, 0.019 mmol). The reaction solution was stirred at 90°C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-tetrahydroisoquinolin-8-yl)propanamide

[0266] 1-Methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-tetrahydroisoquinolin-8-yl)propanamide (30 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol) and PdCl were added. 2 (dppf) (4 mg, 0.0052 mmol). The reaction solution 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 chromatographed by reverse phase column (acetonitrile / water (0.5% FA) = 4 / 1) to obtain the product (R)-N-(4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D010 (10 mg), yield: 26%.

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

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

[0269] 1H 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-tetrahydroisoquinolin-8-yl)propanamide

[0272]

[0273] The first step is the preparation of (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid

[0274] Under 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), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (67 mg, 0.09 mmol), potassium carbonate (320 mg, 2.32 mmol) and 1,4-phenylenediboronic acid D011b (384 mg, 2.32 mmol) were added thereto, and the reaction mixture was stirred at 80°C for 2 hours. After LCMS detection, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography to obtain (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid D011c (90 mg, yellow oil), with a yield of 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-tetrahydroisoquinolin-8-yl)propanamide

[0277] Under nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D001e (50 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (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 thereto, and the reaction mixture was stirred at 80°C for 3 hours. LCMS detected that the starting material disappeared. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain (R)-N-(4-(4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D011 (7 mg), yield: 11%.

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

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

[0280] 1 H NMR (400 MHz, DMSO-d 6 )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] Embodiment 11

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

[0283]

[0284] The first step is the preparation of (4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)boronic acid

[0285] Under 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), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (67 mg, 0.09 mmol), potassium carbonate (320 mg, 2.32 mmol) and 1,4-phenylenediboronic acid D012b (384 mg, 2.32 mmol) were added thereto, and the reaction mixture was stirred at 80°C for 2 hours. After the reaction was completed by LCMS detection, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography to obtain (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)boronic acid D012c (100 mg, yellow oil), with a yield of 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-tetrahydroisoquinolin-8-yl)propanamide

[0288] Under nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide D001e (50 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (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 thereto, and the reaction mixture was stirred at 80°C for 3 hours. LCMS detected that the starting material disappeared. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain (R)-N-(4-(4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 (400 MHz, 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-tetrahydroisoquinolin-8-yl)propanamide

[0294]

[0295] The first step is the preparation of 5-(4-bromophenyl)-1-methyl-1H-tetrazole

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

[0297] 1 H NMR (400 MHz, CDCl 3 )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-dioxaborolan-2-yl)phenyl)-1H-tetrazole

[0299] 5-(4-bromophenyl)-1-methyl-1H-tetrazolyl 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-dioxaborane) (82 mg, 0.32 mmol), potassium acetate (61 mg, 0.63 mmol), DPPF palladium dichloride (23 mg, 0.03 mmol) were added, and the mixture was reacted at 80 degrees 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 purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-tetrahydroisoquinolin-8-yl)propanamide

[0301] Under nitrogen atmosphere, 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-tetrazolyl D013c (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (13 mg, 0.017 mmol), potassium carbonate (48 mg, 0.35 mmol) and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (54 mg, 0.19 mmol) were added thereto, and the reaction mixture was stirred at 90°C for 2 hours. LCMS detected that the starting material disappeared. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain (R)-N-(4-(4-(1-methyl-1H-tetrazol-5-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 (400 MHz, CDCl 3)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] Embodiment 13

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

[0307]

[0308] The first step is the preparation of 4-(4-bromophenyl)-3-methylisoxazole

[0309] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole D014a (150 mg, 0.7175 mmol), 1-bromo-4-iodobenzene (202.98 mg, 0.7175 mmol), 1,1-bis(diphenylphosphino)diferronichloridopalladium (105 mg, 0.1435 mmol), cesium carbonate (467.55 mg, 1.435 mmol) were added to a microwave tube equipped with a stirrer. The vial was sealed after purging with argon, and 1,4-dioxane (2 mL) and water (0.4 mL) were added via a syringe. The microwave vial was stirred at 50 degrees for 16 hours and then cooled to room temperature. The reaction mixture was filtered, water and ethyl acetate were added to the filtrate for extraction, the organic phases were combined and dried, and the residue obtained by concentration under reduced pressure was purified by column chromatography (petroleum ether:ethyl acetate = 10%) to obtain 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-tetrahydroisoquinolin-8-yl)propanamide

[0312] 4-(4-bromophenyl)-3-methylisoxazole D014b (34.54 mg, 0.1451 mmol), (R)-(8-propionamide-5,6,7,8-tetrahydroisoquinolin-4-yl)boronic acid D007d (30 mg, 0.1209 mmol), 1,1-bis(diphenylphosphine)dichloroferropalladium (17.69 mg, 0.0242 mmol), sodium carbonate (25.63 mg, 0.2418 mmol) were added to a microwave tube equipped with a stirrer. The vial was sealed after purging with argon, and 1,4-dioxane (1 mL) and water (0.2 mL) were added via a syringe. The microwave vial was stirred at 50 degrees for 2 hours and then cooled to room temperature. The reaction mixture was filtered, and water and ethyl acetate were added to the filtrate for extraction. The organic phases were combined and dried, and the residue obtained by concentration under reduced pressure was purified by preparative purification (FA, mobile phase: ACN:H 2 O (0.1% FA) = 20%: 80%) to give (R)-N-(4-(4-(3-methylisoxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 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 (400 MHz, DMSO-d 6 )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] Referring to the similar conditions in Example 7 above, the compounds shown in Table 1 below were prepared, 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 line

[0323] The method is used to test the inhibitory effect of the compounds of the present invention on the enzyme activity of human CYP11B1 / CYP11B2 expressed in the G402-hCYP11B1 / G402-hCYP11B2 stable cell line.

[0324] 1. Test 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 steps

[0339] 2.1 Retrovirus packaging. pMSCV-CYP11B1 and pMSCV-CYP11B2 were co-transfected with the helper plasmid into GP2-293 cells, and after 72 hours, the cell supernatant was collected and centrifuged to obtain the packaged retrovirus.

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

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

[0342] 2.4 Monoclonal identification. After 14 days, cells with good growth status were digested from 96-well plates and subcultured to 6-well plates for culture. After cell expansion, cells were sampled and protein expression was detected by WB.

[0343] 2.5 Monoclonal expansion: The monoclonal cells that tested positive were transferred to T-75 flasks for further culture and expansion.

[0344] Test Example 2: Test on the inhibitory activity of the compounds of the present invention on CYP11B2-mediated aldosterone / CYP11B1-mediated cortisol production

[0345] 1. Test 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] Charcoal stripped FBS (BIOSUN, Cat# BS-0004-500)

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

[0357] Cortodoxone (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] CO 2 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 steps

[0368] 2.1 Determination of CYP11B1-mediated cortisol production

[0369] 2.1.1 4000 G402 cells / well / 35 μl were seeded into a 384-well plate and incubated at 37°C and CO2 for 6 hours

[0370] 2.1.2 Add 5ul 0.4μM Cortodoxone to the cells (final concentration is 0.05μM)

[0371] 2.1.3 Add 40 nL of the test compound to the cells and incubate at 37°C and CO 2 Incubate for 16 h

[0372] 2.1.4 Collect supernatant and test cortisol by HTRF

[0373] 2.1.5 Dispense 10 μL of cortisol standard (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 standards and samples.

[0375] 2.1.7 Add 5 μL of 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 plate sealer and Read on compatible card readers

[0378] 2.2 Determination of CYP11B2-mediated aldosterone production

[0379] 2.2.1 4000 G402 cells / well / 35 μl were seeded into a 384-well plate and incubated at 37°C and CO 2 Incubate for 6 hours

[0380] 2.2.2 Add 5ul 8μM 11-deoxycorticosterone into cells (final concentration is 1μM)

[0381] 2.2.3 Add 40 nL of the test compound to the cells and incubate at 37°C and CO 2 Incubate for 16 h

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

[0383] 2.2.5 Dispense 10 μL of aldosterone standard (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 standards and samples.

[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 plate sealer and Read on compatible card readers

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

[0389] Compound No. 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 above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt: in, Ring A is selected from saturated or partially unsaturated C 5-10 Carbocyclic ring, 5-10 membered heterocyclic ring, C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring; Each R a are the same or different and are independently selected from H, CN, OH, thiol, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -SC 1-12 Alkyl or -S-(C 3-12 cycloalkyl); each R a1 are the same or different and are independently selected from CN, OH, oxo (=O), halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; Each R b , R c , R d are the same or different and are independently selected from H, CN, OH, mercapto, halogen, the following groups which are unsubstituted or optionally substituted by one, two or more R': amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -SC 1-12 Alkyl or -S-(C 3-12 cycloalkyl); each R' is the same or different and is independently selected from CN, OH, oxo (=O), halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; Or, R c is connected to an atom in ring A to form the following groups which are unsubstituted or optionally substituted by one, two or more R": saturated or partially unsaturated C 5-8 carbocyclic or 5-8 membered heterocyclic ring; each R" is the same or different and is independently selected from CN, OH, thiol, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or cyano C 1-6 Alkyl, or two R" attached to the same carbon atom and the carbon atom to which they are attached together form a C 3-6 Alkyl ring, halogenated C 3-6 Alkyl ring or cyano C 3-6 Alkyl ring; W is selected from -N(R7)- or -C(R8)(R9)-; 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 ; R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 7a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; R8 is selected from H, unsubstituted or optionally substituted with one, two or more R 8a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; R9 is selected from unsubstituted or optionally substituted with one, two or more R 9a Substituted with the following groups: -(CH2) m -NR 10 R 11 or -(CH2) p -OR 12 ; R 10 is selected from H, unsubstituted or optionally substituted with one, two or more R 10a Substituted with the following groups: -S(=O)2R 101 、-C(=O)R 102 、-C(=O)OR 103 or -C(=O)-N(R 104 )(R 105 ); R 11 is selected from H, unsubstituted or optionally substituted with one, two or more R 11a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; Or, R 10 and R 11 Together with the N atom to which it is attached, it forms an unsubstituted or optionally substituted R 9a Substituted following groups: 3-12 membered N-containing heterocyclic group; R 12 is selected from H, unsubstituted or optionally substituted with one, two or more R 12a Substituted with the following groups: 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 ); R 101 , R 102 , R 103 , R 104 , R 105 , R 121 , R 122 , R 123 , R 124 , R 125 The same or different, independently selected from H, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; R1, R2, R3, R4, R5, R6 are the same or different and are independently selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; Alternatively, R1, R2 together with the atoms to which they are attached form an unsubstituted or optionally substituted group consisting of one, two or more R 1a Substituted with the following groups: C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; Alternatively, R3, R4 together with the atoms to which they are attached form an unsubstituted or optionally substituted group consisting of one, two or more R 3a Substituted with the following groups: C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; Alternatively, R5, R6 together with the atoms to which they are attached form an unsubstituted or optionally substituted group consisting of one, two or more R 5a Substituted with the following groups: C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; n is selected from 0, 1 or 2; 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, 5 or 6; m is selected from 0, 1, 2, 3, 4, 5 or 6; p is selected from 0, 1, 2, 3, 4, 5 or 6; Each R 1a , R 3a , R 5a , R 7a , R 8a , R 9a , R 10a , R 11a , R 12a are the same or different and are independently selected at each occurrence from H, CN, OH, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R aa Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; each R aa are the same or different and are independently selected from CN, OH, halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl.

2. The compound according to claim 1, characterized in that Ring A is selected from a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; Preferably, ring A is selected from a 5-6 membered nitrogen-containing heterocyclic ring or a 5-6 membered nitrogen-containing heteroaromatic ring; Preferably, ring A is selected from an isoxazole ring, a triazole ring (such as a 1,2,3-triazole ring, a 1,2,4-triazole ring), a tetrazole ring, a pyrazole ring, a pyridine ring or a 1,2-dihydropyridine ring; Preferably, Selected from Preferably, R a Selected from H, CN, halogen, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-6 Cycloalkyl; Preferably, R a is selected from H, CN, F, Cl, oxo (=O), methyl, ethyl, isopropyl, difluoromethyl or cyclopropyl; Preferably, R c Selected from H, CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; Preferably, R c is selected from H, CN, F, Cl, methyl or methoxy; Preferably, R d is selected from H, CN, halogen (such as F, Cl), C 1-6 Alkyl or C 1-6 Alkoxy.

3. The compound according to claim 1, characterized in that R c is connected to an atom in ring A to form the following groups which are unsubstituted or optionally substituted by one, two or more R": saturated or partially unsaturated C 5-6 carbocyclic or 5-6 membered heterocyclic ring; each R" is the same or different and is independently selected from CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R" attached to the same carbon atom and the carbon atom to which they are attached together form a C 3-6 Cycloalkyl ring; Preferably, each R" is the same or different and is independently selected from CN, halogen, methyl or methoxy, or two R" attached to the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl ring; Preferably, R c When connected to an atom in ring A, Selected from:

4. The compound according to any one of claims 1 to 3, characterized in that W is selected from -C(R8)(R9)-; R8 is selected from H; R9 is selected from -NR 10 R 11 OR 12 ; Preferably, 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 to which it is attached, it forms an unsubstituted or optionally substituted R 9a Substituted 3-6 membered N-containing heterocyclic group (such as tetrahydropyrrolyl); Preferably, R 12 Selected from -C(=O)R 122 or -C(=O)-N(R 124 )(R 125 ); Preferably, R 102 , R 104 , R 105 , R 122 , R 124 , R 125 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; Preferably, R 102 , R 104 , R 105 , R 122 , R 124 , R 125 are the same or different and are independently selected from H, methyl, ethyl, isopropyl, cyclopropyl or methoxy; Preferably, R9 is selected from 5. The compound according to any one of claims 1 to 4, characterized in that The compound represented by the formula (I) is selected from the following structures: Among them, ring A, W, R a , R b , R c , R d , R 10 , R 11 , r, t, s have the definitions as described in any one of claims 1-4; Preferably, the compound represented by formula (I) is selected from the following structures: Among them, ring A, W, R a , R b , R d , R1, R2, R3, R4, R5, R6, R 10 , R 11 , R", n, r, t, s have the definitions as described in any one of claims 1 to 4; Ring B is selected from saturated or partially unsaturated C 5-8 Carbocyclic or 5-8 membered heterocyclic ring (preferably saturated or partially unsaturated C 5-6 carbocyclic or 5-6 membered heterocyclic ring), q is selected from 0, 1 or 2; Preferably, the compound represented by formula (I) is selected from the following structures: Among them, ring A, 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 compound according to any one of claims 1 to 5, characterized in that The compound is selected from the following structures:

7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

8. Use of at least one of the compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug, Preferably, the drug is a CYP11B2 inhibitor; Preferably, the medicament is used for the diagnosis, prevention and / or treatment of refractory hypertension, hyperaldosteronism (eg, pulmonary hypertension, obesity, insulin resistance and metabolic syndrome).

9. A method for diagnosing, preventing and / or treating refractory hypertension, aldosteronism, comprising administering to a patient in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 alone, or optionally, in combination with at least one other type of therapeutic agent.

10. The use according to claim 8 or the method according to claim 9, characterized in that The disease or condition is associated with increased secretion of aldosterone; preferably, the compound inhibits aldosterone and has no substantial effect on plasma Cortisol levels.

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