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

CYP11B2 inhibitor compounds, pharmaceutical compositions and applications thereof

[0001] This application requires the following:

[0002] Priority to the prior application No. 202310481780.5, filed with the State Intellectual Property Office of China on April 28, 2023, entitled “CYP11B2 Inhibitor Compounds, Pharmaceutical Compositions, and Applications Thereof”;

[0003] Priority to the prior application, application number 202410464787.0, filed with the State Intellectual Property Office of China on April 17, 2024, entitled “CYP11B2 inhibitor compounds, pharmaceutical compositions and their uses”;

[0004] The entire contents of said prior application are incorporated herein by reference. Technical Field

[0005] The present invention belongs to the field of pharmaceutical compounds, and specifically relates to CYP11B2 inhibitor compounds, pharmaceutical compositions and applications thereof. Background Art

[0006] Resistant hypertension, also known as intractable hypertension, is defined as the failure to achieve target blood pressure (<130 / 80 mmHg) despite treatment with three antihypertensive drugs with complementary mechanisms of action (one of which is a diuretic), or the need for ≥4 antihypertensive drugs to achieve target blood pressure (<130 / 80 mmHg). In clinical practice in my country, the cutoff for diagnosing resistant hypertension is 140 / 90 mmHg. Current treatment options for resistant hypertension include pharmacologic interventions (optimizing diuretic therapy, mineralocorticoids, and combination therapy) and non-pharmacologic interventions (lifestyle modification, the DASH diet, salt reduction, and alcohol restriction).

[0007] Aldosterone is a mineralocorticoid hormone secreted by the zona glomerulosa of the adrenal cortex. It maintains salt and water balance by regulating renal sodium reabsorption. Aldosterone secretion is achieved through the renin-angiotensin-aldosterone system (RAAS). Specifically, the juxtaglomerular cells of the kidney respond to decreased blood pressure and sodium levels, increasing the secretion of renin. Renin acts on angiotensinogen to produce angiotensin. Angiotensin stimulates the synthesis and secretion of aldosterone by the zona glomerulosa of the adrenal cortex, increasing sodium ion reabsorption by the kidneys, which in turn increases water reabsorption and increases extracellular fluid volume. Conversely, when extracellular fluid volume increases, the opposite mechanism decreases aldosterone secretion, reducing renal sodium and water reabsorption and decreasing extracellular fluid volume. Decreased serum sodium and elevated serum potassium similarly stimulate the adrenal cortex, increasing aldosterone secretion.

[0008] 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 ranges from 14% to 21% in patients with resistant hypertension. Emerging evidence links elevated aldosterone levels with cardiovascular and cardiometabolic disease. 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 impairment, and increased mortality.

[0009] 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, by 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, and this effect is 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 (Ang II), epidermal growth factor receptor (EGFR), NADPH oxidase / reactive oxygen species (ROS), nitric oxide synthase (NOS), Na+ / H+ exchanger (NHE), etc.

[0010] In addition to hypertension, the role of aldosterone in cardiovascular disease has been increasingly recognized in recent years. Studies in humans and transgenic animals have demonstrated that aldosterone induces endothelial dysfunction, a mechanism believed to involve a decrease in vascular nitric oxide (NO) production due to an increase in superoxide anions. Superoxide anions can degrade NO produced by the normal endothelium. Superoxide anions increase two- to three-fold in hyperlipidemic rabbits, but treatment with aldosterone antagonists reduces superoxide anion levels to normal. Animal studies have shown that aldosterone antagonists can prevent aldosterone-induced myocardial damage and reduce myocardial remodeling and increased ventricular wall stress associated with heart failure. Regarding cardiac fibrosis, a Japanese study investigated the effects of spironolactone on left ventricular function in patients after myocardial infarction. Left ventricular remodeling markers such as left ventricular ejection fraction, end-diastolic volume index, and left ventricular end-systolic volume index were significantly improved (4-18%) in patients treated with spironolactone. Collagen markers also showed statistically significant reductions, which correlated with post-MI end-diastolic volume index. This suggests that left ventricular dysfunction and fibrosis are parallel processes and can be reversed by aldosterone antagonists.

[0011] The human adrenal cortex contains two cytochrome P450 isoenzymes (CYP11B1, also known as P450C11, and CYP11B2, also known as P450c11Aldo) with 11β-hydroxylase activity. Both isoenzymes can 11β-hydroxylate 11-deoxycorticosterone and 11-deoxycortisol, catalyzing the synthesis of cortisol and corticosterone, respectively. The CYP11B1 gene encodes P450C11, which has a molecular weight of approximately 51 kD and is highly expressed in the zona fasciculata. It is primarily involved in the synthesis of cortisol and is regulated by ACTH. The CYP11B2 gene encodes aldosterone synthase (P450C11Aldo), which has a molecular weight of 49 kD and is primarily expressed in the zona glomerulosa. It is regulated by the renin-angiotensin system and possesses 11β-hydroxylase activity, as well as 18-hydroxylase and 18-oxidase activities, participating in the synthesis of aldosterone. CYP11B1 and CYP11B2 are both located on the long arm of chromosome 8, at 8q21-22, and share 93% amino acid sequence identity. This high degree of homology suggests that developing highly selective CYP11B2 inhibitors is a significant 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, thereby inhibiting cortisol synthesis. These findings hinder its clinical use in the treatment of hypertension.

[0012] Currently, mineralocorticoid receptor antagonists (MRAs) are the first-line treatment for primary aldosteronism. Spironolactone, a nonspecific mineralocorticoid receptor antagonist, is highly effective in treating conditions such as heart failure with reduced ejection fraction, refractory hypertension, and aldosteronism. It can also reduce proteinuria in patients with chronic kidney disease and slow the progression of chronic kidney disease. However, due to its low selectivity, spironolactone has anti-androgen and progestin-related side effects. In comparison, the second-generation mineralocorticoid receptor antagonist, eplerenone, offers high selectivity and significantly reduced adverse reactions, but its mineralocorticoid receptor blocking effect is 40-fold lower than that of spironolactone. Representative nonsteroidal MRAs include third-generation mineralocorticoid receptor antagonists, including finerenone, ixazolidinone, and apalidone. Compared with eplerenone and spironolactone, finerenone exhibits higher selectivity for the mineralocorticoid receptor, less effects on other steroid receptors and ion channels, and greater accumulation in the kidney. Finerenone is less lipophilic, more polar, and does not cross the blood-brain barrier. Finerenone has no active metabolites and a short half-life, allowing for more rapid correction of hyperkalemia and minimizing effects on blood pressure. Exacillinone is another novel nonsteroidal mineralocorticoid receptor agonist approved in Japan for the treatment of hypertension and diabetic nephropathy. Compared to eplerenone and spironolactone, ethacillinone exhibits greater potency and selectivity for mineralocorticoid receptors, resulting in a lower risk of hyperkalemia, gynecomastia, amenorrhea, and impotence. Third-generation mineralocorticoid receptor antagonists are more selective than spironolactone and exhibit greater anti-mineralocorticoid receptor activity than eplerenone. The first two generations of steroidal MRAs are associated with adverse reactions such as hyperkalemia, impotence and gynecomastia in men, and amenorrhea in women. Although the third-generation nonsteroidal finerenone has improved selectivity, it still carries the safety concern of hyperkalemia. Its currently approved indication is for patients with type 2 diabetes and chronic kidney disease (CKD). MRs share conserved homologous sequences with glucocorticoid receptors, progesterone receptors, and androgen receptors. Besides aldosterone, MRs also have other ligands, such as glucocorticoids and progesterone. Consequently, MRAs face challenges with selectivity and safety.

[0013] 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 potential therapeutic options for resistant hypertension. The benefits of inhibiting aldosterone synthesis may also extend beyond resistant hypertension itself, as elevated aldosterone levels are implicated in the pathophysiology of pulmonary hypertension, obesity, insulin resistance, and metabolic syndrome.

[0014] Therefore, the search for CYP11B2 inhibitors that achieve improved potency and selectivity would be of great importance in achieving therapeutic agents and methods to address the currently unmet needs in the treatment and prevention of diseases, disorders, and symptoms thereof.

[0015] Summary of the Invention

[0016] 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:

[0017] in,

[0018] Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring;

[0019] X is selected from -O-, -N(R x1 )-、-C(R x2 )(R x3 )-, where R x1 Selected from H, unsubstituted or optionally substituted with one, two or more R x11 Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(=O)-C 1-12 Alkyl, -C(=O)-C 3-12 Cycloalkyl, -C(=O)-(3-12 membered heterocyclyl), -C(=O)-OC 1-12 Alkyl, -C(=O)-OC 3-12 Cycloalkyl, -C(=O)-O-(3-12 membered heterocyclyl); R x2 、R x3 The same or different, independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R x21 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group;

[0020] Y is absent or selected from -C(=O)-, -S(=O)2-, unsubstituted or optionally substituted with one, two or more R y Substituted -C 1- 3-alkylene-;

[0021] Z is selected from -O-, -S-, -S(=O)-, -S(=O)2-, unsubstituted or optionally substituted with one, two or more R z Substituted with the following groups: -N(Rz1 )-C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, -S(=O)-C 1-4 Alkylene-, -S(=O)2-C 1-4 Alkylene-, said alkylene being optionally interrupted by one or more groups selected from: -O-, -S-, -NR z2 -, -S(=O)-, -S(=O)2-; each R z are the same or different and are independently selected from H, halogen, CN, OH, oxo (=O), unsubstituted or optionally substituted by one, two or more R z11 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, amino, 3-12 membered heterocyclic group; or two R groups connected to the same carbon atom z Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group consisting of one, two or more R z11 Substituted with the following groups: C 3-8 Cycloalkyl, 3-12 membered heterocyclic group; R z1 、R z2 The same or different, independently selected from H, unsubstituted or optionally substituted by one, two or more R z11 Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl;

[0022] W is selected from -N(R7)-, -C(R8)(R9)-;

[0023] 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 、-C(=O)NR 77 R 78 ;

[0024] R 71 、R 72 、R 73 、R 74 、R 75 、R 76 、R 77 、R 78 The same or different, independently selected from H, unsubstituted or optionally substituted by one, two or more R 7aSubstituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group;

[0025] R8 is selected from H, unsubstituted or optionally substituted by one, two or more R 8a Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group;

[0026] 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 、-(CH2) p -OR 12 ;

[0027] R 10 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 、-C(=O)-N(R 104 )(R 105 );

[0028] R 11 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, 3-12 membered heterocyclic group;

[0029] 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 3-12 membered N-containing heterocyclic group;

[0030] R 12 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 、-C(=O)-N(R 124 )(R 125 );

[0031] R101 、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, 3-12 membered heterocyclic group;

[0032] 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, C 3-12 Cycloalkyl;

[0033] 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, 3-12 membered heterocyclic group;

[0034] 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, 3-12 membered heterocyclic group;

[0035] 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, 3-12 membered heterocyclic group;

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

[0037] n is selected from 0, 1, 2;

[0038] r is selected from 0, 1, 2;

[0039] s is selected from 0, 1, 2, 3;

[0040] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0041] R a 、R bthe same or different, independently selected from H, CN, OH, 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; 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, C 3-12 Cycloalkyl;

[0042] R y 、R x11 、R x21 、R z11 、R 1a 、R 3a 、R 5a 、R 7a 、R 8a 、R 9a 、R 10a 、R 11a 、R 12a the same or different, each occurrence independently selected from H, CN, OH, oxo (=O), 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; each R "is the same or different, independently selected from CN, OH, halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl.

[0043] According to some embodiments, X is selected from -O-, -N(R x1 )-、-C(R x2 )(R x3 )-, where R x1 Selected from H, unsubstituted or optionally substituted with one, two or more R x11 Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-(3-8 membered heterocyclyl);

[0044] According to some embodiments, X is selected from -N(R x1 )-, where R x1 Selected from H, unsubstituted or optionally substituted with one, two or more Rx11 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(=O)-C 1-3 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocyclyl);

[0045] According to some embodiments, X is selected from O or -N(R x1 )-, where R x1 is selected from methyl, cyclopropanecarbonyl, and acetyl;

[0046] According to some embodiments, each R x11 The same or different, independently selected from CN, OH, halogen, amino, C 1- 6 alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0047] According to some embodiments, R x2 、R x3 The same or different, independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 alkoxy;

[0048] According to some embodiments, X is selected from -CH2-;

[0049] According to some embodiments, Y is absent or selected from -C(=O)-, unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: -C 1-3 Alkylene- (such as methylene);

[0050] According to some embodiments, each R y the same or different, independently selected from CN, OH, halogen (such as F or Cl), amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0051] According to some embodiments, Y is selected from -CH2-, -CF2-, -C(=O)-;

[0052] According to some embodiments, Z is selected from -O-, -S-, unsubstituted or optionally substituted with one, two or more R zSubstituted with the following groups: -NR z1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, said alkylene being optionally interrupted by one or more groups selected from: -O-, -S-, -NR z2 -;

[0053] According to some embodiments, each R z The same or different, independently selected from halogen, CN, OH, oxo (C=O), unsubstituted or optionally substituted by one, two or more R z11 Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl; or two R attached to the same carbon atom z Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group consisting of one, two or more R z11 Substituted with the following groups: C 3-6 Cycloalkyl, 3-8 membered heterocyclic group;

[0054] According to some embodiments, each R z the same or different, independently selected from halogen, CN, OH, oxo (C=O), C 1-3 Alkyl, C 3-6 Cycloalkyl; or two R attached to the same carbon atom z Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group consisting of one, two or more R z11 substituted cyclopropyl;

[0055] According to some embodiments, R z1 、R z2 The same or different, independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0056] According to some embodiments, each R7 11 The same or different, independently selected from CN, OH, halogen, amino, C 1- 6 alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0057] According to some embodiments, Z is selected from -OC 1-4 Alkylene-;

[0058] According to some embodiments, Z is selected from -O-, -O-CH2-, -CH2N(CH3)-.

[0059] According to some embodiments, is selected from -C(R8)(R9)-; R8 is selected from H; R9 is selected from -NR 10 R 11 OR 12 ;

[0060] According to some embodiments, R 10 Selected from -C(=O)R 102 、-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);

[0061] According to some embodiments, R 12 Selected from -C(=O)R 122 、-C(=O)-N(R 124) (R 125 );

[0062] 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, C 3-6 Cycloalkyl;

[0063] 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, methoxy;

[0064] According to some embodiments, R9 is selected from

[0065] According to some embodiments, ring A is selected from a benzene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a thiazole ring, an oxazole ring, an isoxazole ring, a pyrimidine ring, a pyridine ring, a pyrazine ring, and a pyridazine ring;

[0066] According to some embodiments, ring A is selected from a benzene ring, a thiophene ring, a pyrazole ring, a pyrimidine ring, and a pyridine ring;

[0067] According to some embodiments, R a Selected from CN, OH, halogen, unsubstituted or optionally substituted by one, two or more R': amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl; R' is selected from CN, OH, halogen;

[0068] According to some embodiments, R a Selected from halogen, C 1-6 alkyl;

[0069] According to some embodiments, R a Selected from F, Cl, Br, methyl;

[0070] According to some embodiments, Ring A has the following structure:

[0071] According to some embodiments, Selected from the following groups:

[0072] According to some embodiments, Selected from the following groups:

[0073] According to some embodiments, the compound represented by formula (I) is selected from the structures shown below:

[0074] Among them, A ring, X, Y, Z, W, R1, R2, R3, R4, R5, R6, R a 、R b 、R x1 、R 10 、R 11 , n, r, s have the definitions as described in this application;

[0075] According to some embodiments, the compound represented by formula (I) is selected from the structures shown below:

[0076] Among them, X, Y, Z, R a 、R b 、R 10 、R 11 , r, s have the definitions as described in this application.

[0077] According to some embodiments, the compound represented by formula (I) is selected from the structures shown below:

[0078] Among them, Z, R a , s has the definition as described in this application;

[0079] Preferably, Z is selected from -O-, -O-CH2-.

[0080] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0081] 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:

[0082] 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.

[0083] In some embodiments, the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of a compound of formula (I) of the present invention and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0084] 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.

[0085] The present invention further provides the use of the compound of formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled product, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of CYP11B2 inhibitors.

[0086] The present invention further provides the use of the compound of formula (I) and its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition in the preparation of drugs for diagnosing, preventing and / or treating refractory hypertension and hyperaldosteronism.

[0087] The present invention also provides a method for diagnosing, preventing and / or treating resistant hypertension, hyperaldosteronism or a condition, 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.

[0088] In some embodiments, the compound is used as a CYP11B2 inhibitor, including but not limited to applications in: refractory hypertension and aldosteronism.

[0089] According to some embodiments, the aldosteronism is selected from pulmonary hypertension, obesity, insulin resistance, and metabolic syndrome.

[0090] The compounds of the present invention may be used in combination with additional therapeutic agents. Beneficial effects

[0091] The compounds provided by the present invention have good CYP11B2 inhibitory 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; furthermore, the compounds provided by the present invention can inhibit aldosterone and have no substantial effect on plasma cortisol levels.

[0092] Definitions and Explanations of Terms

[0093] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application 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 optionally substituted by one, two or more R.

[0094] "More" means three or more.

[0095] The term "C 1-12 "Alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6"Alkyl" means 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" means 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.

[0096] The term "C 1-12 "Alkoxy" should be understood as "C 1-12 Alkyl-O-", C 1-12 Alkyl is as defined above.

[0097] 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 spirocyclic, fused or bridged systems (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 one 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 with 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0098] 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", in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10aryl) 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 one or more (such as one to three) suitable substituents.

[0099] 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, may additionally be benzofused. "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-quinolinyl, 1-, 3-, 4- 1-, 2-, 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-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-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- phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 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-benzoisoquinolinyl, 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]-o-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

[0015] In some embodiments, the present invention further comprises the following: a) carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 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- to 14-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0100] 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 (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" 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 via any one 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 benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3-14 membered heterocyclic group is linked to other groups to form the compound of the present invention, the linking may be to a carbon atom on the 3-14 membered heterocyclic group or to a heteroatom on the 3-14 membered heterocyclic group. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the linking may be to a nitrogen atom on the piperazinyl or to a carbon atom on the piperazinyl.

[0101] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0102] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0103] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0104] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0105] "Halo" means substituted with one or more halogens.

[0106] 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.

[0107] It will be understood by those skilled in the art that when the listed linking groups do not specify their connection direction, their connection direction is arbitrary, for example, In the embodiment, the connecting group Z is selected from -O-CH2-, in which case -O-CH2- can connect the phenyl group and the carbonyl group in the same direction of reading from left to right. It is also possible to connect the phenyl and carbonyl groups in the opposite direction of the reading order from left to right. Such linking groups are permissible only if such attachment results in a stable compound.

[0108] It will be appreciated by those skilled in the art 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 base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0109] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0110] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well 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 resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0111] The corresponding stable isomers can be separated according to known methods, for example, by extraction, filtration or column chromatography.

[0112] 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.

[0113] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit 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) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents 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) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figure 1: Schematic diagram of the efficacy results of the test compounds in the ACTH-induced monkey hypertension model. DETAILED DESCRIPTION

[0115] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 encompassed within the scope of protection that the present invention is intended to protect.

[0116] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0117] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. 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).

[0118] 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.

[0119] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Unless otherwise stated, all reactions of the present invention were carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, with dry solvents, and reaction temperatures are reported in degrees Celsius.

[0120] Example 1

[0121] Preparation of (R)-N-(4-(2,3-dihydrobenzofuran-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (B001) (1) Preparation of intermediates (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a and (S)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionyl Intel 001b

[0122] Step 1: Preparation of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine

[0123] 4-Bromo-6,7-dihydroisoquinolin-8(5H)one 1 (2.5 g, 11.1 mmol), tetraisopropyl titanate (6.31 g, 22.2 mmol), and a 2M ammonia solution in EtOH (50 mL) were stirred at room temperature for 5 hours. The reaction solution was then cooled to 0°C and NaBH4 (0.63 g, 16.6 mmol) was added portionwise over 10 minutes. The reaction solution was stirred at room temperature for an additional 2 hours. After completion, the reaction was quenched by pouring into 25% aqueous ammonia. The precipitate was filtered and washed with methanol. The solution was concentrated to afford the crude product, 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (2.35 g, yellow solid), in a yield of 98%. This crude product was used directly in the next reaction.

[0124] MS m / z(ESI):227.1(M+1).

[0125] Step 2: Preparation of N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0126] 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine 2 (2.35 g, 10.3 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (3.13 g, 30.9 mmol) and propionic anhydride (2.68 g, 20.6 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction was quenched with saturated NaHCO₃ and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting concentrate was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 3 / 97) to obtain N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001 (1.6 g, yellow solid). The product was then subjected to SFC to obtain (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide Intel 001a (700 mg, brown solid, yield 25%) and (S)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide Intel 001b (700 mg, brown solid, yield 25%).

[0127] The chiral separation conditions are as follows:

[0128] Column: Daicel CHIRALCEL IG 250 mm x 30 mm ID, 10 μm;

[0129] Mobile phase: CO2 / MeOH (containing 0.2% NH3);

[0130] Flow rate: 80g / min;

[0131] Detection wavelength: 214nm.

[0132] Intel 001a (RT: 1.207min)

[0133] 1 H NMR (400MHz, DMSO-d6) δ 8.54 (s, 1H), 8.29 (s, 1H), 8.24 (d, J = 8.4Hz, 1H), 5.03 (m, 1H), 2.65 (m, 2H), 2.13 (m, 2H), 1.79 (m, 4H), 1.03 (t, J = 7.6Hz, 3H).

[0134] Intel 001b (RT: 1.657min)

[0135] 1 H NMR (400MHz, DMSO-d6) δ 8.54 (s, 1H), 8.29 (s, 1H), 8.24 (d, J = 8.4Hz, 1H), 5.03 (m, 1H), 2.67 (m, 2H), 2.13 (m, 2H), 1.80 (m, 4H), 1.03 (t, J = 7.6Hz, 3H).

[0136] (2) Preparation of (R)-N-(4-(2,3-dihydrobenzofuran-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (B001)

[0137] Under a nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.07 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Pd(dppf)Cl2 (5 mg, 0.01 mmol), potassium carbonate (14 mg, 0.14 mmol) and (2,3-dihydrobenzofuran-5-yl)boronic acid (23 mg, 0.14 mmol) were added, and the reaction mixture was stirred at 80°C for 2 hours. LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was separated and purified by Prep-HPLC to give (R)-N-(4-(2,3-dihydrobenzofuran-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B001 (2.23 mg), yield: 10%.

[0138] MS m / z (ESI): 323.1 (M+1) + .

[0139] HPLC: 100% (214nm), 100% (254nm).

[0140] 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 8.26 (d, J = 8.4Hz, 1H), 8.16 (s, 1H), 7.20 (s, 1H), 7.04 (dd, J=8.2, 1.6Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 5.08 (dd, J=13.4, 5.8Hz, 1H), 4.57 (t, J=8.8Hz, 2H), 3.23 (t, J=8.8Hz, 2H), 2.62-2.53 (m, 2H), 2 .22-2.09(m, 2H), 1.93-1.81(m, 1H), 1.80-1.61(m, 3H), 1.05(t, J=7.6Hz, 3H).

[0141] Example 2

[0142] Preparation of (R)-N-(4-(Benzo[d][1,3]dioxolan-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B002)

[0143] To a microwave vial equipped with a stirrer, add benzo[d][1,3]dioxolane-5-boronic acid (26.36 mg, 0.1588 mmol), (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (30 mg, 0.1059 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.75 mg, 0.0105 mmol), and potassium carbonate (29.27 mg, 0.2118 mmol). The vial was sealed with an argon purge, and 1,4-dioxane (0.5 mL) and water (0.1 mL) were added via syringe. The microwave vial was stirred at 100°C for 1 hour, then cooled to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by preparative purification (FA, mobile phase: ACN:H2O (0.1% FA) = 15%:85%) to give (R)-N-(4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B002 (10 mg). Yield: 29.08%.

[0144] MS m / z(ESI):325.1(M+1).

[0145] HPLC: 100% (214nm), 99.80% (254nm).

[0146] 1 H NMR (400MHz, CDCl3) δ8.50 (s, 1H), 8.26 (s, 1H), 6.89 (d, J=7.6Hz, 1H), 6.76-6.69 (m, 2H), 6.03 (s, 2H), 5.96 (s, 1H), 5.35-5.34 (m, 1H), 2.66 (m, 3H), 2.30 (q, J=7.4Hz, 2H), 2.12-2.09 (m, 1H), 1.87-1.81 (m, 3H), 1.22 (t, J=7.0Hz, 3H).

[0147] Example 3

[0148] Preparation of (R)-N-(4-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0149] 2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 mg, 0.11 mmol) was dissolved in 1.4-dioxane and water (volume ratio 2:1, 3 mL), followed by the addition of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.071 mmol), potassium carbonate (20 mg, 0.14 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (5.2 mg, 0.0071 mmol), and the reaction was microwaved at 100 °C for 1 hour under nitrogen atmosphere. After the reaction, 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:H2O (0.1% FA) = 28%:72%) to give the product (R)-N-(4-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B003 (8 mg, 32.0%).

[0150] MS m / z(ESI):361.1(M+1).

[0151] HPLC: 214: 99.10% 254: 98.76%

[0152] 1H NMR (400MHz, CDCl3) δ7.19 (s, 1H), 7.07 (d, J = 8.0Hz, 1H), 6.92-6.89 (m, 2H), 5.67 (d, J = 8.0Hz, 1H), 5.29-5.27 (m , 1H), 2.63-2.43(m, 2H), 2.21(dd, J=15.1, 7.5Hz, 2H), 2.18-1.98(m, 2H), 1.76-1.73(m, 3H), 1.18-1.13(m, 3H).

[0153] Example 4

[0154] Preparation of (R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B004)

[0155] 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (24.4 mg, 0.085 mmol) was dissolved in 1.4-dioxane and water (volume ratio 2:1, 3 mL), followed by the addition of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.071 mmol), potassium carbonate (20 mg, 0.142 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (5.2 mg, 0.0071 mmol), and the reaction was microwaved at 100 °C for 1 hour under nitrogen atmosphere. After the reaction, the reaction mixture was cooled to ambient temperature, filtered, and concentrated in vacuo to afford the crude product, which was then purified by preparative purification (FA, mobile phase: ACN:H₂O (0.1% FA) = 15%:85%) to afford (R)-N-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B004 (7 mg, 27.30%). MS m / z (ESI): 364.2 (M+1).

[0156] HPLC: 214: 100% 254: 100%

[0157] 1H NMR (400MHz, CDCl3) δ8.48 (s, 1H), 8.25 (s, 1H), 7.17 (d, J=6.5Hz, 1H), 6.92-6.71 (m, 2H), 5.71-5.60 (m, 1H), 5.30 ( s, 1H), 3.29 (s, 3H), 2.90-2.88 (m, 2H), 2.85-2.57 (m, 4H), 2.23-2.03 (m, 4H), 1.75-1.16 (m, 3H), 0.81-0.78 (m, 1H).

[0158] Example 5

[0159] (R)-N-(4-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine Preparation of 5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (B005)

[0160] Step 1: 7-Bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine Preparation of -2-ketone

[0161] Add 7-bromo-1,3,4,5-tetrahydro-2H-benzo[b]azepine to the reaction flask equipped with a stirrer. To the reaction mixture was added 1,3-dimethyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (100 mg, 0.4165 mmol), acetone (1 mL), and potassium carbonate (51.81 mg, 0.3749 mmol), followed by iodomethane (209.87 mg, 1.4786 mmol). The reaction was stirred at 80°C for 16 hours. Water and dichloromethane were added to the reaction system for quenching and extraction. The organic phases were combined, dried, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50%) to afford 7-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one B005a (40 mg, yellow oil). Yield: 34%.

[0162] MS m / z(ESI):254.1(M+1).

[0163] Step 2: 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine Preparation of -2-ketone

[0164] To a reaction tube equipped with a stirrer, 7-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one B005a (40 mg, 0.1574 mmol), pinacol diboron (59.95 mg, 0.2361 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13.01 mg, 0.0157 mmol), and potassium acetate (30.9 mg, 0.3148 mmol) were added. The vial was sealed with an aluminum crimp cap fitted with a septum and purged with argon. N,N-dimethylformamide (1 mL) was then added via syringe. The reaction flask was heated and stirred at 120°C for 3 hours and then cooled to room temperature after completion of the reaction. The mixture was filtered, extracted with water and ethyl acetate, and the organic phases were combined, dried and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 50%) to give 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-Keto B005b (30 mg, yellow oil). Yield: 56.93%.

[0165] MS m / z(ESI):302.1(M+1).

[0166] Step 3: (R)-N-(4-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine Preparation of 5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0167] To a microwave vial equipped with a stirrer, add B005b (30 mg, 0.0996 mmol), (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (33.84 mg, 0.1195 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (7.23 mg, 0.0099 mmol), and potassium carbonate (27.53 mg, 0.1992 mmol). The vial was sealed with an argon purge, and 1,4-dioxane (0.5 mL) and water (0.1 mL) were added via syringe. The microwave vial was stirred at 100°C for 1 hour, then cooled to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined and dried, and the residue was concentrated under reduced pressure and purified by preparative purification (FA, mobile phase: ACN: H2O (0.1% FA) = 10%: 90%) to obtain (R)-N-(4-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine) -7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B005 (30 mg,). Yield: 63.86%.

[0168] MS m / z(ESI):378.2(M+1).

[0169] HPLC: 100% (214nm), 100% (254nm).

[0170] 1 H NMR (400MHz, CDCl3) δ8.53 (s, 1H), 8.32 (s, 1H), 7.24-7.20 (m, 2H), 7.12 (s, 1H), 5.82 (s, 1H), 5.36-5.35 (m, 1H), 3.40 (s, 3H), 2.76 (t, J=7.2Hz, 2H ), 2.71-2.61(m, 2H), 2.37(t, J=7.2Hz, 2H), 2.30(q, J=7.4Hz, 2H), 2.24- 2.20 (m, 2H), 2.14-2.08 (m, 2H), 1.83-1.81 (m, 2H), 1.22 (t, J=7.2Hz, 3H).

[0171] Example 6

[0172] Preparation of (R)-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B006)

[0173] Step 1: Preparation of 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0174] To a reaction flask equipped with a stirrer, 6-bromo-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (200 mg, 0.877 mmol), acetone (2 mL), and potassium carbonate (242.42 mg, 1.754 mmol) were added, followed by iodomethane (0.43 mL, 0.0129 mol). The reaction was stirred at 80°C for 16 hours. The reaction system was quenched with water and dichloromethane and extracted. The organic phases were combined, dried, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50%) to afford 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B006a (100 mg, white solid). Yield: 42.39%.

[0175] MS m / z(ESI):242.0(M+1).

[0176] Step 2: Preparation of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0177] To a reaction tube equipped with a stirrer, 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B006a (100 mg, 0.4131 mmol), pinacol diboron (125.88 mg, 0.4957 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (30.23 mg, 0.0413 mmol), and potassium acetate (121.63 mg, 1.2393 mmol) were added. The vial was sealed with an aluminum crimp cap equipped with a septum and purged with nitrogen. N,N-dimethylformamide (2 mL) was then added vial vial. The reaction flask was heated and stirred at 120° C. for 3 hours and then cooled to room temperature after completion of the reaction. The mixture was filtered, extracted with water and ethyl acetate, and the combined organic phases were dried and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 50%) to afford 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B006b (120 mg, yellow oil). Yield: 80.37%.

[0178] MS m / z(ESI):290.1(M+1).

[0179] Step 3: Preparation of (R)-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0180] To a microwave vial equipped with a stirrer was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B006b (36.74 mg, 0.1271 mmol), (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide Intel 001a (30 mg, 0.1059 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (7.75 mg, 0.0105 mmol), and potassium carbonate (29.27 mg, 0.2118 mmol). The vial was sealed with an argon purge, and 1,4-dioxane (0.5 mL) and water (0.1 mL) were added via syringe. The reaction was stirred in a microwave oven at 100°C for 1 hour, then cooled to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined, dried, and concentrated under reduced pressure to obtain a residue, which was purified by preparative purification (FA, mobile phase: ACN:H2O (0.1% FA) = 15%:85%) to obtain (R)-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B006 (4.98 mg). Yield: 12.84%.

[0181] MS m / z (ESI): 366.2 (M+1).

[0182] HPLC: 100% (214nm), 100% (254nm).

[0183] 1 H NMR (400MHz, CDCl3) δ8.53 (s, 1H), 8.28 (s, 1H), 7.29 (s, 1H), 7.07-7.02 (m, 2H), 5.85 (s, 1H), 5.35 (s, 1H), 5.25 (s, 2H), 3.43 (s, 3H), 2.67-2.58 (m, 2H), 2.33-2.22 (m, 4H), 2.13-2.10 (m, 2H), 1.22 (t, J=7.2Hz, 3H).

[0184] Example 7

[0185] Preparation of (R)-N-(4-(5-chloro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B007)

[0186] Step 1: Preparation of (2-amino-6-chlorophenyl)methanol

[0187] Dissolve 2-amino-6-chlorobenzoic acid (500 mg, 0.003 mol) in methanol (5 mL) and add sodium borohydride (166 mg, 0.004 mol) under ice. Incubate at 0°C for 1 hour. After completion of the reaction, add saturated ammonium chloride solution and extract with ethyl acetate. The organic phase is collected, dried, and filtered to obtain (2-amino-6-chlorophenyl)methanol B007a. The crude product is used directly in the next step. MS m / z (ESI): 158.1 (M+1).

[0188] Step 2: Preparation of 5-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0189] (2-Amino-6-chlorophenyl)methanol B007a (400 mg, 2.5381 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL) and triethylamine (770.49 mg, 7.6143 mmol) was added under ice-cooling. After stirring for 10 minutes, triphosgene (903.81 mg, 3.0457 mmol) was slowly added. The mixture was reacted at 0°C for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 5-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007b (350 mg, yellow solid) in a yield of 75.11%.

[0190] MS m / z(ESI):184.1(M+1).

[0191] Step 3: Preparation of 6-bromo-5-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0192] 5-Chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007b (350 mg, 1.9064 mmol) was dissolved in N,N-dimethylformamide (5 mL). N-bromosuccinimide (373.23 mg, 2.0970 mmol) was added under ice-cooling and allowed to react at 0°C for 1 hour. After the reaction, water was added to precipitate the product, which was filtered to obtain crude 6-bromo-5-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007c. This was used directly in the next step.

[0193] MS m / z(ESI):262.1(M+1).

[0194] Step 4: Preparation of 6-bromo-5-chloro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0195] Dissolve 6-bromo-5-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007c (300 mg, 1.1429 mmol) in N,N-dimethylformamide (3 mL), add iodomethane (178.45 mg, 1.2572 mmol) and potassium carbonate (315.92 mg, 2.2858 mmol). The mixture is reacted at 60°C for 3 hours. After the reaction is complete, water is added to precipitate the product. Filter to obtain the crude product 6-bromo-5-chloro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007d, which is used directly in the next step.

[0196] MS m / z(ESI):276.1(M+1).

[0197] Step 5: Preparation of 5-chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0198] 6-Bromo-5-chloro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007d (250 mg, 0.9041 mmol) was dissolved in 1,4-dioxane (3 mL). 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (344.38 mg, 1.3562 mmol), potassium carbonate (249.91 mg, 1.8082 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (65.61 mg, 0.0904 mmol) were added and reacted at 90°C for 2 hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and the organic phase was collected, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 5-chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007e (100 mg, yellow oil) in a yield of 34.18%.

[0199] MS m / z(ESI):324.7(M+1).

[0200] Step 6: Preparation of (R)-N-(4-(5-chloro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0201] 5-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B007e (100 mg, 0.309 mmol) was dissolved in 1,4-dioxane / water (1 / 1) (5 mL). (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (131.25 mg, 0.4635 mmol), potassium carbonate (85.41 mg, 0.618 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (22.42 mg, 0.0309 mmol) were added and reacted at 80°C for 1 hour. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and the organic phase was collected, dried, filtered, and concentrated. The residue was purified by preparative column chromatography (acetonitrile / water = 17 / 83) to give (R)-N-(4-(5-chloro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B007 (6.04 mg). Yield: 4.89%.

[0202] MS m / z (ESI): 400.1 (M+1).

[0203] HPLC: 99.77% (214nm), 99.68% (254nm).

[0204] 1 H NMR (400MHz, CDCl3) δ8.57 (s, 1H), 8.22 (s, 1H), 7.24-7.15 (m, 1H), 6.94 (dd, J=8.4, 4.7Hz, 1H), 5.69 (dd, J=24.5, 8.3Hz, 1H), 5.51-5.36 (m, 2H), 5.35 (s, 1H), 3.43 (s, 3H), 2.28 (dd, J=15.4, 7.7Hz, 2H), 2.14-1.98 (m, 2H), 1.80 (s, 3H), 1.24-1.18 (m, 3H).

[0205] Example 8

[0206] Preparation of (R)-N-(4-(5-fluoro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B008)

[0207] Step 1: 6-Bromo-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0208] 5-Fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (800 mg, 4.79 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 0°C, and N-bromosuccinimide (895 mg, 5.03 mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction, 30 mL of water was added, and solid precipitated. After filtration, the filter cake was washed with petroleum ether. The resulting filter cake was crude product B008a and used directly in the next reaction without purification.

[0209] Step 2: Preparation of 6-bromo-5-fluoro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0210] 6-Bromo-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B008a (600 mg, 2.45 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 0°C, and iodomethane (1 mL, 7.35 mmol) and potassium carbonate (676.2 mg, 4.9 mmol) were added. The reaction mixture was protected by nitrogen and stirred at room temperature overnight. After completion of the reaction, 30 mL of water was added, and then extracted with ethyl acetate (15 mL x 3). After concentration, the product was separated and purified by flash silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain 6-bromo-5-fluoro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B008b (270 mg, white solid) in a yield of 42%.

[0211] Step 3: Preparation of 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0212] At room temperature, 6-bromo-5-fluoro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B008b (260 mg, 1.01 mmol) was dissolved in 1,4-dioxane (10 mL), and then [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.101 mmol), potassium acetate (198 mg, 2.02 mmol) and pinacol boron ester (386 mg, 1.52 mmol) were added in sequence. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 3 hours. After the reaction, the reaction was filtered and the filtrate was concentrated and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B008c (100 mg, white solid) in a yield of 32%.

[0213] Step 4: Preparation of (R)-N-(4-(5-fluoro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0214] 5-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B008c (90 mg, 0.29 mmol) was dissolved in 1,4-dioxane / water = 4 / 1 (12 mL), followed by the addition of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (82 mg, 0.29 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.029 mmol), and potassium carbonate (120 mg, 0.87 mmol). The reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. After the reaction, the product was filtered and concentrated to afford (R)-N-(4-(5-fluoro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B008 (11 mg) in a 10% yield. MS m / z (ESI): 384.1 (M+1).

[0215] HPLC: 92.68% (214nm), 96.10% (254nm).

[0216] 1 H NMR (400MHz, DMSO-d6) δ8.38 (s, 1H), 8.30 (d, J = 8.1Hz, 1H), 8.22 (s, 1H), 7.35 (t, J = 6.9Hz, 1H), 7.06 (d, J = 8.4Hz, 1H), 5.40 (s, 2H ), 5.10 (dd, J=12.6, 5.7Hz, 1H), 3.39 (s, 3H), 2.46 (d, J=5.8Hz, 2H), 2.22-2.09 (m, 2H), 1.92-1.70 (m, 4H), 1.06 (t, J=7.5Hz, 3H).

[0217] Example 9

[0218] Preparation of (R)-N-(4-(8-fluoro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B009)

[0219] Step 1: Preparation of 2-amino-5-bromo-3-fluorophenylmethanol

[0220] 2-Amino-5-bromo-3-fluorobenzoic acid (540 mg, 2.31 mmol) was dissolved in dry tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (175 mg, 4.62 mmol) was added portionwise under an ice bath. The reaction solution was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate and concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to afford 2-amino-5-bromo-3-fluorophenylmethanol B009a (380 mg, white solid) in a yield of 75%.

[0221] MS m / z(ESI):222.1(M+1).

[0222] Step 2: Preparation of 6-bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0223] 2-Amino-5-bromo-3-fluorophenylmethanol B009a (240 mg, 1.09 mmol) was dissolved in acetonitrile (5 mL), and pyridine (95 mg, 1.20 mmol) and ethyl chloroformate (118 mg, 1.09 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated, and the resulting concentrate was dissolved in methanol (5 mL), and potassium carbonate (226 mg, 1.64 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain the product 6-bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B009b (100 mg, light yellow solid) in a yield of 37%.

[0224] MS m / z(ESI):248.1(M+1).

[0225] Step 3: Preparation of 6-bromo-8-fluoro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0226] 6-Bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B009b (90 mg, 0.37 mmol) was dissolved in DMF (5 mL), and iodomethane (78 mg, 0.55 mmol) and potassium carbonate (152 mg, 1.10 mmol) were added sequentially. The reaction solution was stirred at 50°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and extracted with water (20 mL) and ethyl acetate (10 mL x 3). The organic phase was dried and concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 6-bromo-8-fluoro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B009c (80 mg, white solid) in a yield of 84%.

[0227] MS m / z(ESI):262.0(M+1).

[0228] Step 4: Preparation of 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0229] 6-Bromo-8-fluoro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B009c (60 mg, 0.23 mmol) was dissolved in dioxane (2 mL), and diboronic acid pinacol ester (88 mg, 0.35 mmol), potassium acetate (68 mg, 0.69 mmol), and PdCl2(dppf) (8 mg, 0.012 mmol) were added. The reaction mixture was stirred at 90°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting concentrate was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B009d (50 mg, pale yellow solid) in a yield of 71%.

[0230] MS m / z (ESI): 308.1 (M+1).

[0231] Step 5: Preparation of 4-(5-chloro-6-fluorobenzofuran-2-yl)-5,6,7,8-tetrahydroisoquinolin-8-ylpropionamide

[0232] 8-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B009d (22 mg, 0.072 mmol) was dissolved in dioxane (2 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.072 mmol), potassium carbonate (30 mg, 0.21 mmol), and PdCl2(dppf) (5 mg, 0.0072 mmol) were added. The reaction mixture was stirred at 90°C for 2 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by reverse phase column chromatography (acetonitrile / water (0.5% FA) = 4 / 1) to give the product (R)-N-(4-(8-fluoro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B009 (3 mg) in a yield of 11%.

[0233] MS m / z(ESI):384.1(M+1).

[0234] HPLC: 99.30% (214nm), 97.34% (254nm).

[0235] 1 H NMR (400MHz, MeOD) δ 8.40 (s, 1H), 8.23 ​​(s, 1H), 7.21 (d, J = 13.6Hz, 1H), 7.08 (s, 1H), 5.26 (s, 2H), 5.20 (t, J = 5.6Hz, 1H), 3. 54 (d, J=6.4Hz, 3H), 2.74-2.64 (m, 2H), 2.27 (q, J=7.6Hz, 2H), 2.04-2.01 (m, 1H), 1.90-1.82 (m, 3H), 1.18 (t, J=7.6Hz, 3H).

[0236] Example 10

[0237] Preparation of (R)-N-(4-(8-chloro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B010)

[0238] Step 1: Preparation of methyl 2-amino-5-bromo-3-chlorobenzoate

[0239] Methyl 2-amino-3-chlorobenzoate (1.5 g, 8.1 mmol) and N-bromosuccinimide (1.6 g, 8.9 mmol) were dissolved in acetonitrile (30 mL). The reaction mixture was reacted at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and the resulting concentrate was purified by silica gel column chromatography (ethyl acetate = 25%) to obtain the product, methyl 2-amino-5-bromo-3-chlorobenzoate B010a (1.9 g, white solid), in a yield of 89%.

[0240] MS m / z (ESI): 265.9 (M+1).

[0241] Step 2: Preparation of 2-amino-5-bromo-3-chlorophenylmethanol

[0242] Methyl 2-amino-5-bromo-3-chlorobenzoate B010a (1.9 g, 7.2 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and lithium aluminum tetrahydride (0.55 g, 14.4 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, the reaction mixture was quenched by adding water: 15% sodium hydroxide: water in a ratio of 1:1:3. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated and the resulting concentrate was purified by silica gel column chromatography (ethyl acetate = 96%) to obtain the product, 2-amino-5-bromo-3-chlorophenylmethanol B010b (1 g, white solid), in a yield of 58%.

[0243] MS m / z(ESI):238.0(M+1).

[0244] Step 3: Preparation of 6-bromo-8-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0245] 2-Amino-5-bromo-3-chlorophenylmethanol (B010b) (400 mg, 1.7 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Triphosgene (602.3 mg, 2.03 mmol) and triethylamine (599.03 mg, 5.92 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the concentrate was concentrated and purified by silica gel column chromatography (ethyl acetate = 30%) to afford the product, 6-bromo-8-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (Preparation B010c) (300 mg, white solid) in a yield of 67%. MS m / z (ESI): 264.0 (M+1).

[0246] Step 4: Preparation of 6-bromo-8-chloro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0247] Preparation of 6-bromo-8-chloro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (B010c, 200 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (105.3 mg, 0.76 mmol) and iodomethane (108.14 mg, 0.76 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting concentrate was purified by silica gel column chromatography (ethyl acetate = 20%) to obtain the product, 6-bromo-8-chloro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (B010d, 200 mg, white solid), in a yield of 95%.

[0248] MS m / z (ESI): 276.0 (M+1).

[0249] Step 5: Preparation of 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0250] Under a nitrogen atmosphere, 6-bromo-8-chloro-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B010d (200 mg, 0.72 mmol) was dissolved in 1,4-dioxane (10 mL). Diboronic acid pinacol bis(pyrazol)diol (275.51 mg, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (104.97 mg, 0.14 mmol) and potassium acetate (212.96 mg, 2.17 mmol) were added, and the reaction solution was stirred at 90° C. for 2 hours. After the reaction, the mixture was filtered through Celite to obtain the crude product, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B010e (150 mg, brown oil), in a yield of 64%. The crude product was used directly in the next reaction without further purification.

[0251] MS m / z(ESI):324.1(M+1).

[0252] Step 6: Preparation of (R)-N-(4-(8-chloro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0253] Under a nitrogen atmosphere, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B010e (20 mg, 0.06 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (9 mg, 0.01 mmol), potassium carbonate (17 mg, 0.12 mmol), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (17.5 mg, 0.06 mmol) were added. The reaction mixture was stirred at 80° C. for 2 hours. LCMS detected the disappearance of the starting material. After the reaction, the reaction solution was filtered, the filtrate was collected, and the product was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by Prep-HPLC to give (R)-N-(4-(8-chloro-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B010 (2.08 mg), yield: 8%.

[0254] MS m / z (ESI): 400.1 (M+1) + .

[0255] HPLC: 98.45% (214nm), 99.79% (254nm).

[0256] 1 H NMR (400MHz, MeOD) δ8.39 (s, 1H), 8.21 (s, 1H), 7.42 (d, J=1.6Hz, 1H), 7.23 (d, J=1.6Hz, 1H), 5.21 (s, 3H), 3.6 1(s, 3H), 2.81-2.59(m, 2H), 2.34-2.21(m, 2H), 2.07-1.97(m, 2H), 1.89-1.81(m, 2H), 1.18(t, J=7.6Hz, 3H).

[0257] Example 11

[0258] Preparation of (R)-N-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B011)

[0259] Step 1: Preparation of 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0260] 7-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.88 mmol) was dissolved in acetone (5 mL), followed by the addition of potassium carbonate (110 mg, 1.32 mmol) and iodomethane (187 mg, 1.33 mmol). The reaction was stirred in a sealed container at 80°C for 12 hours. After completion of the reaction, the reaction solution was cooled to ambient temperature, filtered, and concentrated in vacuo to obtain a crude product, which was then purified on silica gel (PE / EA = 10 / 1) to obtain 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B011a (200 mg, 84.80%) as a white solid.

[0261] MS m / z(ESI):242.0(M+1).

[0262] Step 2: Preparation of 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0263] 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B011a (200 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of pinacol diboron (210 mg, 0.83 mmol), potassium carbonate (229 mg, 1.66 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (61 mg, 0.083 mmol), and the reaction was stirred at 100 °C for 12 h under a nitrogen atmosphere. After the reaction, the reaction solution was cooled to ambient temperature, then filtered and concentrated in vacuo to obtain a crude product, which was then purified by silica gel (PE / EA=20 / 1) to give the product 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one B011b (60 mg, 22.61%) as a white solid.

[0264] MS m / z(ESI):290.1(M+1).

[0265] Step 3: Preparation of (R)-N-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0266] 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one B011b (41 mg, 0.142 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)propionamide Intel 001a (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 microwaved at 100 °C for 1 hour under nitrogen atmosphere. After the reaction, 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:H2O (0.1% FA) = 28%:72%) to obtain the product (R)-N-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B011 (5 mg, 20%).

[0267] MS m / z(ESI):366.1(M+1).

[0268] HPLC: 214: 98.69% 254: 98.85%

[0269] 1 H NMR (400MHz, CDCl3) δ8.47 (s, 1H), 8.21 (s, 1H), 6.99 (d, J=8.0Hz, 1H), 6.93-6.73 (m, 2H), 5.96 (s, 1H), 5.27 (s, 1H), 4. 61(s, 2H), 3.34(s, 3H), 2.64-2.55(m, 2H), 2.18-1.81(m, 2H), 1.79-1.75(m, 2H), 1.17-1.13(m, 3H), 0.81-0.78m, 1H).

[0270] Example 12

[0271] Preparation of (R)-N-(4-(5-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B012)

[0272] Step 1: Preparation of 7-bromo-5-chloro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0273] 2-Amino-3-chlorophenol 1 (1000 mg, 6.99 mmol) and Br2 (2212 mg, 14.00 mmol) were dissolved in MeCN (50 mL), and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was washed with saturated brine, extracted with ethyl acetate, dried, and concentrated. Subsequently, the crude product was dissolved in MeCN (50 mL), cesium carbonate (2275 mg, 7.00 mmol) and chloroacetyl chloride (391.8 mg, 3.50 mmol) were added, and the reaction solution was stirred at 60 ° C for 12 hours. It was then dissolved in MeCN (5 mL), and iodomethane (184 mg, 1.30 mmol) and cesium carbonate (420 mg, 1.30 mmol) were added. The reaction solution was stirred at 60 ° C for 10 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 11) to give 7-bromo-5-chloro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B012a (150 mg, white solid) in a yield of 8%.

[0274] MS m / z (ESI): 275.9 (M+1).

[0275] Step 2: Preparation of 5-chloro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0276] 7-Bromo-5-chloro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B012a (150 mg, 0.55 mmol) was dissolved in 1,4-dioxane (10 mL), and diboronic acid pinacol ester (255 mg, 1.00 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (12.9 mg, 0.018 mmol), and potassium acetate (98 mg, 1.00 mmol) were added. The reaction mixture was stirred at 100° C. under nitrogen for 3 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 11) to give 5-chloro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one B012b (100 mg, white solid) in a yield of 57%.

[0277] MS m / z (ESI): 324.1 (M+1).

[0278] Step 3: Preparation of (R)-N-(4-(5-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0279] 5-Chloro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one B012b (20 mg, 0.06 mmol) was dissolved in 1,4-dioxane (2 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (18 mg, 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (5 mg, 0.006 mmol), and potassium carbonate (20 mg, 0.19 mmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 4 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by high performance liquid chromatography (FA 0.1%) to give (R)-N-(4-(5-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B012 (3 mg) in a yield of 12%.

[0280] LCMS: 400.1 (M+1).

[0281] HPLC: 96.93% (214nm), 98.52% (254nm).

[0282] 1 H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 8.27 (s, 1H), 7.04-7.02 (m, 1H), 6.91-6.89 (m, 1H), 5.73 (d, J=8.4Hz, 1H), 5.37-5.30 (m, 1H), 4.57 (s, 2H), 3.58 (s, 3H), 2.80-2.50 (m, 2H), 2.28 (q, J=7.6Hz, 2H), 2.17-2.02 (m, 1H), 1.90-1.75 (m, 3H), 1.22 (t, J=7.6Hz, 3H).

[0283] Example 13

[0284] Preparation of (R)-N-(4-(5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B013)

[0285] Step 1: Preparation of 7-bromo-5-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

[0286] To a reaction flask equipped with a stirrer were added 2-amino-5-bromo-3-fluorophenol (350 mg, 1.70 mmol), 2-chloroacetyl chloride (192 mg, 1.70 mmol), and potassium carbonate (470 mg, 3.40 mmol). N,N-dimethylformamide (5 mL) was then added as solvent and the reaction was stirred at 80° C. for 2 hours. After completion of the reaction, water and ethyl acetate were added to the reaction system for extraction. The organic phases were combined, dried, and concentrated. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate) to afford 7-bromo-5-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one B013a (300 mg, white solid). Yield: 65%.

[0287] MS m / z(ESI):246.0(M+1).

[0288] Step 2: Preparation of 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0289] To a reaction flask equipped with a stirrer, 7-bromo-5-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one B013a (300 mg, 1.22 mmol) and sodium hydride (29 mg, 1.22 mmol) were added, followed by the addition of N,N-dimethylformamide (5 mL) and iodomethane (173 mg, 1.22 mmol) at 0°C. The reaction was stirred at 0°C for 2 hours. After completion of the reaction, ice water was added to quench the reaction system and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to afford 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B013b (300 mg, white solid). Yield: 85%.

[0290] MS m / z(ESI):260.0(M+1).

[0291] Step 3: Preparation of 5-fluoro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0292] To a reaction flask equipped with a stirrer, 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B013b (300 mg, 1.15 mmol), pinacol diboronate (293 mg, 1.15 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (169 mg, 0.23 mmol), potassium acetate (226 mg, 2.31 mmol), and 1,4-dioxane (5 mL) were added. The reaction flask was heated and stirred at 90°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered, dried, and concentrated. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate) to afford 5-fluoro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one B013c (270 mg, white solid). Yield: 76%.

[0293] MS m / z (ESI): 308.1 (M+1).

[0294] Step 4: Preparation of (R)-N-(4-(5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0295] To a reaction flask equipped with a stirrer, 5-fluoro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one B013c (30 mg, 0.10 mmol), (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (28 mg, 0.10 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (7 mg, 0.01 mmol), sodium carbonate (21 mg, 0.20 mmol), 1,4-dioxane (5 mL) and water (0.5 mL) were added. The reaction mixture was stirred at 80°C for 2 hours and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to obtain a residue, which was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150 x 19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20% to 100%, flow rate: 20 mL / min) to obtain (R)-N-(4-(5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B013 (2.54 mg). Yield: 33.27%.

[0296] MS m / z(ESI):384.1(M+1).

[0297] HPLC: 99.30% (214nm), 99.68% (254nm).

[0298] 1 H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 8.27 (s, 1H), 6.77 (d, J = 10.4Hz, 2H), 5.73 (d, J = 8.4Hz, 1H), 5.35-5.32 (m, 1H), 4.61 (s, 2H) , 3.53 (d, J=6.0Hz, 3H), 2.70-2.56 (m, 2H), 2.28 (q, J=7.6Hz, 2H), 2.10-1.84 (m, 1H), 1.80-1.60 (m, 2H), 1.22 (t, J=7.6Hz, 3H).

[0299] Example 14

[0300] Preparation of (R)-N-(4-(1-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B014)

[0301] Step 1: Preparation of (6-bromo-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

[0302] 6-Bromo-1,2,3,4-tetrahydroquinoline (200 mg, 0.94 mmol) and N,N-diisopropylethylamine (243 mg, 1.88 mmol) were dissolved in dichloromethane (5 mL). Cyclopropanecarbonyl chloride (148 mg, 1.41 mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was washed with saturated brine, extracted with dichloromethane, dried, and concentrated to obtain the product (6-bromo-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone B014a (200 mg, yellow solid), which was used directly in the next step.

[0303] MS m / z(ESI):280.1(M+1).

[0304] Step 2: Preparation of cyclopropyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone

[0305] (6-Bromo-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone B014a (200 mg, 0.785 mmol) was dissolved in 1,4-dioxane (30 mL), and diboronic acid pinacol ester (200 mg, 0.78 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (86 mg, 0.12 mmol), and potassium acetate (154 mg, 1.57 mmol) were added. The reaction mixture was stirred at 110° C. under nitrogen for 3 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give the product cyclopropyl (6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydroquinolin-1 (2H) -yl)methanone B014b (180 mg, white solid) in a yield of 70%.

[0306] MS m / z(ESI):382.2(M+1).

[0307] Step 3: Preparation of (R)-N-(4-(1-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0308] Cyclopropyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone B014b (46 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (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 mixture was stirred at 110°C under nitrogen for 4 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by high performance liquid chromatography (FA 0.1%) to give the product (R)-N-(4-(1-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B014 (7 mg) in a yield of 24%.

[0309] LCMS: 404.1 (M+1).

[0310] HPLC: 95.1% (214nm), 96.7% (254nm).

[0311] 1 H NMR (400MHz, CDCl3) δ8.57 (brs, 1H), 8.35 (brs, 1H), 7.53 (d, J=4.7Hz, 1H), 7.10 (brs, 2H), 5.92 (brs, 1H), 5.40 (brs, 1H), 3.88 (t, J =6.3Hz, 2H), 2.95-2.64(m, 4H), 2.33-2.30(m, 3H), 2.14-2.10(m, 2H), 2.02-2.20(m, 4H), 1.27-1.16(m, 5H), 0.86(d, J=4.4Hz, 2H).

[0312] Example 15

[0313] Preparation of (R)-N-(4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B015)

[0314] Step 1: Preparation of 1-(6-bromo-3,4-diisoquinolin-1(2H)-yl)ethan-1-one

[0315] To a reaction flask equipped with a stirrer were added 6-bromo-1,2,3,4-tetrahydroquinoline (100 mg, 0.4715 mmol), dichloromethane (2 mL), and N,N-diisopropylethylamine (152.34 mg, 1.1788 mmol). The mixture was cooled to 0°C and acetyl chloride (55.52 mg, 0.7071 mmol) was added. The reaction was stirred at room temperature for 4 hours, and then quenched with water and extracted. The organic phases were combined, dried, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50%) to afford 1-(6-bromo-3,4-diisoquinolin-1(2H)-yl)ethan-1-one B015a (100 mg, yellow solid). Yield: 79%.

[0316] MS m / z(ESI):254.1(M+1).

[0317] Step 2: Preparation of 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

[0318] To a reaction tube equipped with a stirrer, 1-(6-bromo-3,4-diisoquinolin-1(2H)-yl)ethan-1-one B015a (100 mg, 0.3935 mmol), pinacol diboron (119.91 mg, 0.4722 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (45.47 mg, 0.0394 mmol), and potassium acetate (115.86 mg, 1.1805 mmol) were added. The vial was sealed with an aluminum crimp cap fitted with a septum and purged with argon. N,N-dimethylformamide (2 mL) was then added via syringe. The reaction flask was heated and stirred at 120°C for 3 hours, and then cooled to room temperature after completion of the reaction. The mixture was filtered, extracted with water and ethyl acetate, and the combined organic phases were dried and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 50%) to give 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one B015b (90 mg, yellow oil). Yield: 83%.

[0319] MS m / z(ESI):302.2(M+1).

[0320] Step 3: Preparation of (R)-N-(4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0321] To a microwave vial equipped with a stirrer was added 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one B015b (25.52 mg, 0.0847 mmol), (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide Intel 001a (20 mg, 0.0706 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (8.16 mg, 0.007 mmol), and potassium carbonate (19.52 mg, 0.1412 mmol). The vial was sealed with an argon purge, and 1,4-dioxane (0.5 mL) and water (0.1 mL) were added via syringe. The microwave vial was stirred and reacted at 100°C for 1 hour, then cooled to room temperature. The reaction mixture was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by preparative purification (FA, mobile phase: ACN:H2O (0.1% FA) = 15%:85%) to obtain (R)-N-(4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B015 (10 mg). Yield: 30%.

[0322] MS m / z(ESI):378.2(M+1).

[0323] HPLC: 100% (214nm), 100% (254nm).

[0324] 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 8.29 (s, 1H), 7.27 (s, 1H), 7.10-7.06 (m, 2H), 5.78 (d, J=8.4Hz, 1H), 5.36-5.32 (m, 1H), 3.83 (t, J=6.4Hz, 2 H), 2.78 (t, J=6.4Hz, 2H), 2.72-2.59 (m, 2H), 2.30 (s, 3H), 2.28 (q, J=7.6Hz, 2H), 2.12-1.99 (m, 4H), 1.81-1.78 (m, 2H), 1.22 (t, J=7.6Hz, 3H).

[0325] Example 16

[0326] Preparation of (R)-N-(4-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B016)

[0327] Step 1: Preparation of 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one

[0328] 5-Bromobenzo[d]oxazol-2(3H)-one (200 mg, 0.935 mmol), iodomethane (200 mg, 0.935 mmol), and potassium carbonate (200 mg, 0.935 mmol) were dissolved in acetone, and the reaction mixture was incubated at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered, concentrated, dried, and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to afford 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one B016a (150 mg, pale yellow solid) in a 70% yield.

[0329] MS m / z(ESI):228.0(M+1).

[0330] Step 2: Preparation of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one

[0331] 5-Bromo-3-methylbenzo[d]oxazol-2(3H)-one B016a (150 mg, 0.658 mmol), pinacol diboron (200 mg, 0.789 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23.3 mg, 0.066 mmol) and potassium acetate (23.3 mg, 1.645 mmol) were dissolved in 1,4-dioxane and reacted at 100°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was filtered and concentrated, dried and concentrated, and then separated and purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one B016b (120 mg, light yellow solid) in a yield of 66%.

[0332] MS m / z(ESI):276.1(M+1).

[0333] 1 H NMR (400MHz, DMSO-d6) δ7.48 (dd, J=7.9, 1.0Hz, 1H), 7.44 (s, 1H), 7.34 (d, J=7.9Hz, 1H), 3.37 (s, 3H), 1.31 (s, 12H).

[0334] Step 3: Preparation of (R)-N-(4-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0335] 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one B016b (23.3 mg, 0.085 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.17 mg, 0.007 mmol) and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.070 mmol) were dissolved in 1,4-dioxane:water (volume ratio 5:1, 1.2 mL). Potassium carbonate (20 mg, 0.140 mmol) was added to the reaction solution, which was then heated to 100°C and microwaved under nitrogen protection for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated, and the concentrate was purified and freeze-dried to obtain (R)-N-(4-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B016 (8.95 mg) with a yield of 36.1%.

[0336] MS m / z(ESI):352(M+1).

[0337] HPLC: 100% (214nm), 100% (254nm).

[0338] 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.28 (d, J = 8.2Hz, 1H), 7.01 (d, J = 7.9Hz, 1H), 6.88 (s, 1H), 5.88 (s, 1H), 5. 36 (s, 1H), 3.43 (s, 3H), 2.62 (s, 2H), 2.31 (d, J = 7.4Hz, 2H), 2.11 (s, 1H), 1.83 (s, 2H), 1.23 (t, J = 7.2Hz, 3H).

[0339] Example 17

[0340] Preparation of (R)-N-(4-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B017)

[0341] 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (24 mg, 0.085 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.17 mg, 0.007 mmol) and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.070 mmol) were dissolved in 1,4-dioxane:water (volume ratio 5:1, 1.2 mL). Potassium carbonate (20 mg, 0.140 mmol) was added to the reaction solution, which was then heated to 100°C and microwaved under nitrogen protection for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated, and the concentrate was purified and freeze-dried to obtain (R)-N-(4-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B017 (8.56 mg) with a yield of 34.56%.

[0342] MS m / z (ESI): 352 (M+1).

[0343] HPLC: 100% (214nm), 98.95% (254nm).

[0344] 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 8.35 (s, 1H), 7.14 (s, 1H), 7.11 (d, J = 4.9Hz, 2H), 5.33 (d, J = 5.5Hz, 1H), 3.47 (s, 3H ), 2.79 (td, J=18.9, 12.8Hz, 2H), 2.34 (q, J=7.4Hz, 2H), 2.25-2.09 (m, 1H), 1.96-1.85 (m, 2H), 1.20 (t, J=7.4Hz, 3H).

[0345] Example 18

[0346] Preparation of (R)-N-(4-(1-methyl-2-oxoindolin-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B018)

[0347] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (23.2 mg, 0.085 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.17 mg, 0.007 mmol) and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.070 mmol) were dissolved in 1,4-dioxane:water (volume ratio 5:1, 1.2 mL). Potassium carbonate (20 mg, 0.140 mmol) was added to the reaction solution, which was then heated to 100°C and microwaved under nitrogen protection for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated, and the concentrate was purified and freeze-dried to obtain (R)-N-(4-(1-methyl-2-oxoindolin-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B018 (5.85 mg) with a yield of 23.65%.

[0348] MS m / z(ESI):350(M+1).

[0349] HPLC: 95.08% (214nm), 95.73% (254nm).

[0350] 1 H NMR (400MHz, CDCl3) δ8.51 (s, 1H), 8.29 (s, 1H), 7.16 (s, 1H), 6.90 (d, J = 7.9Hz, 1H), 5.81 (d, J = 8.2Hz, 1H), 5.38-5.30 (m, 1H), 3.58 (s, 2H), 3.26 (s , 3H), 2.64 (dd, J=14.4, 6.4Hz, 2H), 2.33-2.27 (m, 2H), 2.14-2.04 (m, 2H) , 1.85 (dd, J=10.8, 4.3Hz, 1H), 1.83-1.77 (m, 2H), 1.23 (d, J=7.5Hz, 3H).

[0351] Example 19

[0352] Preparation of (R)-N-(4-(1-methyl-2-oxoindolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B019)

[0353] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (23.14 mg, 0.085 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.17 mg, 0.007 mmol) and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.070 mmol) were dissolved in 1,4-dioxane:water (volume ratio 5:1, 1.2 mL). Potassium carbonate (20 mg, 0.140 mmol) was added to the reaction solution, which was then heated to 100°C and microwaved under nitrogen protection for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated, and the concentrate was purified and freeze-dried to obtain (R)-N-(4-(1-methyl-2-oxoindolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B019 (2.36 mg) with a yield of 9.6%.

[0354] MS m / z(ESI):350(M+1).

[0355] HPLC: 94.57% (214nm), 96.25% (254nm).

[0356] 1 H NMR (400MHz, cdcl3) δ7.33 (d, J=7.4Hz, 1H), 6.94 (d, J=7.4Hz, 1H), 6.72 (s, 1H), 6.08 (s, 1H), 5.35 (s, 1H), 3.59 (s, 2H ), 3.23 (s, 3H), 2.78-2.57 (m, 2H), 2.31-2.30 (m, 2H), 2.11 (d, J = 5.2Hz, 1H), 1.93-1.80 (m, 3H), 1.22 (t, J = 7.6Hz, 3H).

[0357] Example 20

[0358] Preparation of (R)-N-(4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B020)

[0359] Step 1: Preparation of 6-bromo-1,3-dimethyl-3,4-dihydroquinazolin-2(1H)-one

[0360] Under ice bath, 6-bromo-3-methyl-3,4-dihydroquinazolin-2(1H)-one (100 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (15 mg, 0.62 mmol) was added and stirred for 30 minutes, followed by addition of iodomethane (65 mg, 0.46 mmol), and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, water was added for quenching, the system was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography to give 6-bromo-1,3-dimethyl-3,4-dihydroquinazolin-2(1H)-one B020a (60 mg, yellow oil) in a yield of 57%.

[0361] MS m / z (ESI): 255.0 (M+H) + .

[0362] Step 2: Preparation of 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-2(1H)-one

[0363] Under a nitrogen atmosphere, 6-bromo-1,3-dimethyl-3,4-dihydroquinazolin-2(1H)-one B020a (60 mg, 0.24 mmol) was dissolved in 1,4-dioxane (5 mL). Diboronic acid pinacol bis(pyrazolyl)boronate (72 mg, 0.28 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (17 mg, 0.02 mmol), and potassium acetate (46 mg, 0.47 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-2(1H)-one B020b (50 mg, light yellow oil) in a yield of 70%. The crude product was used directly in the next reaction without further purification.

[0364] MS m / z(ESI):303.1(M+1).

[0365] Step 3: Preparation of (R)-N-(4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0366] Under a nitrogen atmosphere, (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (20 mg, 0.07 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (5 mg, 0.01 mmol), potassium carbonate (20 mg, 0.14 mmol) and 1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-2(1H)-one B020b (26 mg, 0.08 mmol) were added. The reaction mixture was stirred at 80° C. for 2 hours. LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the product 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-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B020 (2.13 mg), yield: 8%.

[0367] MS m / z (ESI): 379.2 (M+1) + .

[0368] HPLC: 100% (214nm), 100% (254nm).

[0369] 1 H NMR (400MHz, DMSO-d6) δ8.32 (s, 1H), 8.27 (d, J = 8.4Hz, 1H), 8.19 (s, 1H), 7.28-7.22 (m, 1H), 7.17 (s, 1H), 7.01 (d, J = 8.4Hz, 1H), 5.09 (dd, J = 12.8, 5. 4Hz, 1H), 4.42(s, 2H), 3.23(s, 3H), 2.92(s, 3H), 2.66-2.56(m, 2H), 2.21- 2.09 (m, 2H), 1.93-1.83 (m,, 1H), 1.83-1.64 (m, 3H), 1.05 (t, J=7.6Hz, 3H).

[0370] Example 21

[0371] Preparation of (R)-N-(4-(1′-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B021)

[0372] Step 1: Preparation of 1′-methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3′-indolin]-2′-one

[0373] 5′-Bromospiro[3′-cyclopropane-1,3′-indolin]-2′-one (100 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (0.7 mmol) and iodomethane (0.56 mmol) were then added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with saturated brine, extracted with dichloromethane, dried, and concentrated. The crude product was then dissolved in 1,4-dioxane (2 mL). Diboron (pinacol diboron) (143 mg, 0.56 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (8.6 mg, 0.012 mmol), and potassium acetate (154 mg, 1.57 mmol) were added. The reaction mixture was stirred at 110°C under nitrogen for 3 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain 1′-methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3′-indoline]-2′-one B021a (51 mg), yield: 34%.

[0374] MS m / z (ESI): 300.1 (M+1).

[0375] Step 2: Preparation of (R)-N-(4-(1′-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0376] 1′-Methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3′-indolin]-2′-one B021a (20 mg, 0.06 mmol) was dissolved in 1,4-dioxane (2 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (18 mg, 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (5 mg, 0.006 mmol), and sodium carbonate (20 mg, 0.19 mmol) were added. The reaction mixture was stirred at 110° C. under nitrogen for 4 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by high performance liquid chromatography (FA 0.1%) to give (R)-N-(4-(1′-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B021 (2 mg) in a yield of 19%.

[0377] LCMS: 376.1 (M+1).

[0378] HPLC: 96.04% (214nm), 99.32% (254nm).

[0379] 1 H NMR (400MHz, CDCl3) δ8.58 (s, 1H), 8.22 (s, 1H), 7.15 (d, J=7.6Hz, 1H), 6.98 (d, J=7.7Hz, 2H), 6.74 (s, 1H), 5.30 (s, 1H), 3.34 (s, 3H) , 3.01-2.65 (m, 2H), 2.37 (d, J=7.3Hz, 2H), 2.19 (s, 1H), 2.02 (s, 3H), 1.94 (s, 2H), 1.83 (s, 3H), 1.56 (s, 2H), 1.22 (t, J=6.9Hz, 3H).

[0380] Example 22

[0381] Preparation of (R)-N-(4-(8-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B022)

[0382] Step 1: Preparation of 6-amino-3-bromo-2-fluorophenol B022a

[0383] 3-Fluoro-2-methoxyaniline (500 mg, 3.54 mmol) and N-bromosuccinimide (712 mg, 4.00 mmol) were dissolved in MeCN (20 mL), and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was washed with saturated brine, extracted with ethyl acetate, dried, and concentrated. Subsequently, the crude product was dissolved in 45% HBr (20 mL), and the reaction solution was stirred at 80° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain 6-amino-3-bromo-2-fluorophenol B022a (250 mg, white solid) in a yield of 34%.

[0384] MS m / z (ESI): 206.0 (M+1).

[0385] Step 2: Preparation of 7-bromo-8-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0386] 6-Amino-3-bromo-2-fluorophenol B022a (250 mg, 1.22 mmol) was dissolved in MeCN (5 mL), and cesium carbonate (975 mg, 3.00 mmol) and chloroacetyl chloride (145.6 mg, 1.30 mmol) were added. The reaction solution was stirred at 60°C for 12 hours. Subsequently, MeCN (5 mL) was added, and iodomethane (184 mg, 1.30 mmol) and cesium carbonate (420 mg, 1.30 mmol) were added. The reaction solution was stirred at 60°C for 10 hours. After the reaction was completed, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 11) to obtain 7-bromo-8-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B022b (250 mg, white solid) in a yield of 74%.

[0387] MS m / z (ESI): 260.0 (M+1).

[0388] Step 3: Preparation of (R)-N-(4-(8-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0389] 7-Bromo-8-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B022b (150 mg, 0.58 mmol) was dissolved in methanol (10 mL), and tetrahydroxydiboron (267 mg, 3.00 mmol), XPhos Pd G2 (22.8 mg, 0.029 mmol), XPhos (27.7 mg, 0.058 mmol), and potassium acetate (98 mg, 1.00 mmol) were added. The reaction mixture was stirred at 80°C under nitrogen for 3 hours. After the reaction, the reaction mixture was concentrated and dissolved in 1,4-dioxane (6 mL) and water (2 mL). (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (100 mg, 0.35 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (29 mg, 0.035 mmol), and potassium carbonate (207 mg, 1.50 mmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 4 hours. After the reaction, the reaction solution was concentrated, and the obtained concentrate was purified by high performance liquid chromatography (FA 0.1%) to prepare (R)-N-(4-(5-chloro-4-methyl-3-oxo-(R)-N-(4-(8-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B022 (16 mg), yield: 12%.

[0390] LCMS: 384.1 (M+1).

[0391] HPLC: 95.40% (214nm), 98.62% (254nm).

[0392] 1 H NMR (400MHz, CDCl3) δ8.56 (s, 1H), 8.29 (s, 1H), 6.91-6.83 (m, 2H), 5.75-5.67 (m, 1H), 5.40-5.32 (m, 1H), 4.75 (s, 2H), 3.42 (s, 3H), 2.80-2.40 (m, 2H), 2.36-2.17 (m, 3H), 2.16-1.95 (m, 3H), 1.22 (t, J=7.6Hz, 3H).

[0393] Example 23

[0394] Preparation of (R)-N-(4-(6-chloro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B024)

[0395] Step 1: Preparation of 5-bromo-6-chlorobenzo[d]oxazol-2(3H)-one

[0396] 2-Amino-4-bromo-5-chlorophenol (500 mg, 2.25 mmol) was dissolved in dry tetrahydrofuran (10 mL), and then CDI (547 mg, 3.37 mmol) was added. The solution was stirred at room temperature for 16 hours. After the reaction, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was separated and purified by silica gel column to give 5-bromo-6-chlorobenzo[d]oxazol-2(3H)-one B024a (450 mg, yellow solid) in a yield of 80.58%.

[0397] MS m / z(ESI):248.1(M+1).

[0398] Step 2: Preparation of 5-bromo-6-chloro-3-methylbenzo[d]oxazol-2(3H)-one

[0399] 5-Bromo-6-chlorobenzo[d]oxazol-2(3H)-one B024a (400 mg, 1.61 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (787 mg, 2.41 mmol) and iodomethane (274 mg, 1.93 mmol) were then added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered through celite and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified on a silica gel column to afford 5-bromo-6-chloro-3-methylbenzo[d]oxazol-2(3H)-one B024b (300 mg, white solid) in a yield of 71%.

[0400] MS m / z (ESI): 262.2 (M+1) + .

[0401] Step 3: Preparation of 6-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one

[0402] 5-Bromo-6-chloro-3-methylbenzo[d]oxazol-2(3H)-one B024b (150 mg, 0.57 mmol) was dissolved in 1,4-dioxane (12 mL). 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (174 mg, 0.69 mmol), potassium acetate (84 mg, 0.86 mmol), and DPPF palladium dichloride (42 mg, 0.06 mmol) were added and reacted at 80°C for 16 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 6-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one B024c (150 mg, white solid) in a yield of 84.79%.

[0403] MS m / z (ESI): 310.1 (M+1).

[0404] Step 4: Preparation of (R)-N-(4-(6-chloro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0405] Under nitrogen atmosphere, 6-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one B024c (120 mg, 0.39 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). To the solution were added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.039 mmol), potassium carbonate (107 mg, 0.78 mmol), and (R)N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (121 mg, 0.43 mmol). The reaction mixture was stirred at 100° C. for 16 hours. After the reaction, the reaction solution was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was separated and purified by Prep-HPLC to give (R)-N-(4-(6-chloro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B024 (20 mg), yield: 13.36%.

[0406] MS m / z (ESI): 386.1 (M+1) + .

[0407] HPLC: 100% (214nm), 98.63% (254nm).

[0408] 1 H NMR (400MHz, CDCl3) δ8.60 (s, 1H), 8.26 (s, 1H), 7.37 (s, 1H), 6.82 (s, 1H), 5.74 (s, 1H), 5.37 (s, 1H), 3.41 (s, 3H), 2.55 (s, 1H), 2.31 (s, 3H), 2.10 (s, 1H), 1.81-1.72 (m, 3H), 1.25 (s, 3H).

[0409] Example 24

[0410] Preparation of (R)-N-(4-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B025)

[0411] Step 1: Preparation of 3-bromo-2-fluoro-6-methoxyaniline

[0412] 1-Bromo-2-fluoro-4-methoxy-3-nitrobenzene (560 mg, 2.24 mmol) was dissolved in ethanol (10 mL) and water (10 mL), and ammonium chloride (599 mg, 11.20 mmol) and iron powder (626 mg, 11.20 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain crude 3-bromo-2-fluoro-6-methoxyaniline B025a (400 mg, yellow solid) in an 89% yield.

[0413] MS m / z (ESI): 222.1 (M+1).

[0414] Step 2: Preparation of 6-bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0415] 3-Bromo-2-fluoro-6-methoxyaniline B025a (480 mg, 2.18 mmol) was dissolved in dichloromethane (10 mL), and a 1M solution of BBr in dichloromethane (6.5 mL, 6.5 mmol) was added under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to afford 6-bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B025b (400 mg, light yellow solid) in a yield of 89%.

[0416] MS m / z (ESI): 208.1 (M+1).

[0417] Step 3: Preparation of 6-bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0418] 6-Bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B025b (400 mg, 1.94 mmol) was dissolved in tetrahydrofuran (5 mL) and CDI (630 mg, 3.88 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain the product 6-bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B025c (370 mg, white solid) in a yield of 82%.

[0419] MS m / z (ESI): 232.1 (M+1).

[0420] Step 4: Preparation of 5-bromo-4-fluoro-3-methylbenzo[d]oxazol-2(3H)-one

[0421] 6-Bromo-8-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one B025c (350 mg, 1.51 mmol) was dissolved in acetonitrile (10 mL), and iodomethane (321 mg, 2.26 mmol) and cesium carbonate (983 mg, 3.02 mmol) were added sequentially. The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to afford 5-bromo-4-fluoro-3-methylbenzo[d]oxazol-2(3H)-one B025d (300 mg, white solid) in an 81% yield.

[0422] MS m / z (ESI): 248.0 (M+1).

[0423] Step 5: Preparation of (4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)boronic acid

[0424] 5-Bromo-4-fluoro-3-methylbenzo[d]oxazol-2(3H)-one B025d (170 mg, 0.69 mmol) was dissolved in methanol (3 mL). Tetrahydroxydiboron (93 mg, 1.04 mmol), XPhos Pd G2 (54 mg, 0.069 mmol), XPhos (66 mg, 0.14 mmol), and potassium acetate (203 mg, 2.07 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to afford crude (4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)boronic acid B025e (146 mg, brown solid) in a 100% yield.

[0425] MS m / z (ESI): 212.2 (M+1).

[0426] Step 6: Preparation of (R)-N-(4-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0427] (4-Fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)boronic acid B025e (146 mg, 0.69 mmol) was dissolved in dioxane / water = 4 / 1 (5 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (157 mg, 0.55 mmol), potassium carbonate (287 mg, 2.08 mmol), and PdCl2(dppf) (51 mg, 0.069 mmol) were added. The reaction mixture was stirred at 100°C for 4 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by reverse phase column chromatography (acetonitrile / water (0.5% FA) = 4 / 1) to give the product (R)-N-(4-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B025 (1.7 mg) in a yield of 0.66%.

[0428] MS m / z (ESI): 370.3 (M+1).

[0429] HPLC: 90.68% (214nm), 93.02% (254nm).

[0430] 1H NMR (400MHz, MeOD) δ8.33 (s, 1H), 8.12 (s, 1H), 7.12 (d, J = 8.4Hz, 1H), 6.93 (s, 1H), 5.13 (s, 1H), 3. 47 (s, 3H), 2.49 (s, 2H), 2.25-2.13 (m, 2H), 1.92 (s, 1H), 1.77-1.72 (m, 3H), 1.09 (t, J=7.6Hz, 3H).

[0431] Example 25

[0432] Preparation of (R)-N-(4-(4-chloro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B026)

[0433] Step 1: Preparation of 1-bromo-2-chloro-4-methoxy-3-nitrobenzene

[0434] 1-Chloro-3-methoxy-2-nitrobenzene (500 mg, 2.67 mmol) was dissolved in acetic acid (10 mL), and liquid bromine (1.7 g, 10.66 mmol) was added. The reaction mixture was stirred at 55°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain the product, 3-bromo-2-chloro-6-methoxyaniline B026a (360 mg, white solid), in a yield of 51%.

[0435] MS m / z (ESI): 268.0 (M+1).

[0436] Step 2: Preparation of 3-bromo-2-chloro-6-methoxyaniline

[0437] 1-Bromo-2-chloro-4-methoxy-3-nitrobenzene B026a (360 mg, 1.35 mmol) was dissolved in ethanol (15 mL) and water (15 mL), and ammonium chloride (362 mg, 6.76 mmol) and iron powder (377 mg, 6.76 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain crude 3-bromo-2-chloro-6-methoxyaniline B026b (260 mg, yellow solid) in an 81% yield.

[0438] MS m / z (ESI): 238.1 (M+1).

[0439] Step 3: Preparation of 2-amino-4-bromo-3-chlorophenol

[0440] 3-Bromo-2-chloro-6-methoxyaniline B026b (260 mg, 1.10 mmol) was dissolved in dichloromethane (20 mL), and a 1M solution of BBr in dichloromethane (3.3 mL, 3.3 mmol) was added under ice-cooling. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain the product, 2-amino-4-bromo-3-chlorophenol B026c (240 mg, light yellow solid), in a yield of 98%.

[0441] MS m / z (ESI): 223.9 (M+1).

[0442] Step 4: Preparation of 5-bromo-4-chlorobenzo[d]oxazol-2(3H)-one

[0443] 2-Amino-4-bromo-3-chlorophenol B026c (244 mg, 1.10 mmol) was dissolved in tetrahydrofuran (10 mL), and CDI (356 mg, 2.19 mmol) was added. The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the product 5-bromo-4-chlorobenzo[d]oxazol-2(3H)-one B026d (230 mg, white solid) in a yield of 84%.

[0444] MS m / z (ESI): 249.9 (M+1).

[0445] Step 5: Preparation of 5-bromo-4-chloro-3-methylbenzo[d]oxazol-2(3H)-one

[0446] 5-Bromo-4-chlorobenzo[d]oxazol-2(3H)-one B026d (230 mg, 0.93 mmol) was dissolved in acetonitrile (10 mL), and iodomethane (197 mg, 1.39 mmol) and cesium carbonate (302 mg, 0.93 mmol) were added sequentially. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to afford 5-bromo-4-chloro-3-methylbenzo[d]oxazol-2(3H)-one B026e (243 mg, light yellow solid) in a yield of 100%.

[0447] MS m / z (ESI): 264.0 (M+1).

[0448] Step 6: Preparation of 4-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one

[0449] 5-Bromo-4-chloro-3-methylbenzo[d]oxazol-2(3H)-one B026e (243 mg, 0.93 mmol) was dissolved in dioxane (10 mL), and pinacol borate (353 mg, 1.39 mmol), potassium acetate (273 mg, 2.78 mmol), and PdCl2(dppf) (68 mg, 0.093 mmol) were added. The reaction mixture was stirred at 90°C for 3 hours. After completion of the reaction, the reaction mixture was concentrated to afford crude 4-chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one B026f (287 mg, brown solid) in a yield of 100%.

[0450] MS m / z (ESI): 310.1 (M+1).

[0451] Step 7: Preparation of (R)-N-(4-(4-chloro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0452] 4-Chloro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one B026f (120 mg, 0.39 mmol) was dissolved in dioxane / water = 4 / 1 (5 mL), and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide Intel 001a (55 mg, 0.19 mmol), potassium carbonate (160 mg, 1.16 mmol), and PdCl2(dppf) (29 mg, 0.039 mmol) were added. The reaction mixture was stirred at 100°C for 4 hours. After the reaction, the reaction solution was concentrated, and the concentrate was purified by reverse phase column chromatography (acetonitrile / water (0.5% FA) = 4 / 1) to give the product (R)-N-(4-(4-chloro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B026 (7 mg) in a yield of 4.67%.

[0453] MS m / z (ESI): 386.1 (M+1).

[0454] HPLC: 97.11% (214nm), 96.95% (254nm).

[0455] 1H NMR (400MHz, CDCl3) δ8.57 (s, 1H), 8.22 (s, 1H), 7.21 (dd, J=8.0, 4.4Hz, 1H), 6.95 (dd, J=10.4, 8.0Hz, 1H), 5.72 (dd, J=16.8, 8.8Hz, 1H), 5.42-5.31 (m, 1H), 3.75 (s, 3H), 2.58-2.36 (m, 2H), 2.35-2.26 (m, 2H), 2.12-2.04 (m, 1H), 1.84-1.78 (m, 3H), 1.23 (td, J=7.6, 6.0Hz, 3H).

[0456] Example 26

[0457] Preparation of (R)-N-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydrobenzoxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (B027)

[0458] Step 1: Preparation of 2-amino-4-bromo-6-fluorophenol

[0459] 4-Bromo-2-fluoro-6-nitrophenol (950 mg, 4.03 mmol), iron powder (1.12 g, 20.13 mmol), and ammonium chloride (1.08 g, 20.13 mmol) were dissolved in ethanol (10 mL), and water (2 mL) was added dropwise. The reaction solution was then stirred at 70° C. for 2 hours. After completion of the reaction, the residue was directly spin-dried and filtered through celite, washed with ethyl acetate, and the filtrate was collected and concentrated to give the product, 2-amino-4-bromo-6-fluorophenol B027a (600 mg, brown solid), in a yield of 72%.

[0460] MS m / z (ESI): 205.9 (M+1) + .

[0461] Step 2: Preparation of 5-bromo-7-fluorobenzoxazol-2(3H)-one

[0462] 2-Amino-4-bromo-6-fluorophenol B027a (600 mg, 2.91 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N′-carbonyldiimidazole (614 mg, 3.79 mmol) was added. The reaction solution was then stirred at 80°C for 2 hours. After completion of the reaction, the reaction solution was washed sequentially with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution, extracted with ethyl acetate, and the organic layer was dried and concentrated. The resulting residue was separated and purified by column chromatography to obtain the product, 5-bromo-7-fluorobenzoxazol-2(3H)-one B027b (500 mg, light brown solid), in a yield of 74%.

[0463] MS m / z (ESI): 232.0 (M+1) + .

[0464] Step 3: Preparation of 5-bromo-7-fluoro-3-methylbenzoxazol-2(3H)-one

[0465] 5-Bromo-7-fluorobenzoxazol-2(3H)-one B027b (450 mg, 1.94 mmol) and cesium carbonate (948 mg, 2.91 mmol) were dissolved in acetonitrile (10 mL). Methyl iodide (413 mg, 2.91 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was collected, and concentrated under reduced pressure to give the crude product 5-bromo-7-fluoro-3-methylbenzoxazol-2(3H)-one B027c (400 mg, yellow solid) in a yield of 84%.

[0466] MS m / z (ESI): 246.0 (M+1) + .

[0467] Step 4: Preparation of 7-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)-one

[0468] Under a nitrogen atmosphere, 5-bromo-7-fluoro-3-methylbenzoxazol-2(3H)-one B027c (400 mg, 1.63 mmol) was dissolved in 1,4-dioxane (5 mL). Diboronic acid pinacol bis(pyrazolyl)dichloride (495 mg, 1.95 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (118 mg, 0.16 mmol), and potassium acetate (449 mg, 3.25 mmol) were added sequentially. The reaction mixture was stirred at 90°C for 2 hours and cooled to room temperature after completion. The mixture was directly dried and concentrated, and the resulting residue was purified by column chromatography to obtain 7-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)-one B027d (350 mg, yellow solid). Yield: 73%.

[0469] MS m / z (ESI): 294.1 (M+1) + .

[0470] Step 5: Preparation of (R)-N-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydrobenzoxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0471] Under nitrogen atmosphere, 7-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)-one B027d (124 mg, 0.42 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (26 mg, 0.04 mmol), potassium carbonate (98 mg, 0.71 mmol), and (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-propionamide Intel 001a (100 mg, 0.35 mmol) were added. The reaction mixture was stirred at 100° C. for 2 hours. LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the product was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by Prep-HPLC to give (R)-N-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydrobenzoxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B027 (40 mg) in a yield of 31%.

[0472] MS m / z (ESI): 370.1 (M+1) + .

[0473] HPLC: 98.13% (214nm), 99.05% (254nm).

[0474] 1 H NMR (400MHz, DMSO-d6) δ8.37 (s, 1H), 8.28 (d, J = 8.4Hz, 1H), 8.25 (s, 1H), 7.18 (d, J = 1.2Hz, 1H), 7.15-7.08 (m, 1H), 5.19-5.00 (m, 1H), 3.38 (s, 3H), 2.63 (t, J=5.6Hz, 2H), 2.22-2.11 (m, 2H), 1.93-1.67 (m, 4H), 1.06 (t, J=7.6Hz, 3H).

[0475] Example 27

[0476] Preparation of (R)-N-(4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzoxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ylpropionamide (B028)

[0477] Step 1: Preparation of 2-amino-4-bromo-5-fluorophenol

[0478] 4-Bromo-5-fluoro-2-nitrophenol (1 g, 4.2 mmol), iron powder (1.17 mg, 2.1 mmol), and ammonium chloride (1.12 g, 12.1 mmol) were dissolved in ethanol / H₂O (1 / 1 = 20 mL). The reaction mixture was stirred at 70°C for 2 h. After completion of the reaction, the reaction mixture was filtered through celite, and the organic phase was concentrated to obtain 2-amino-4-bromo-5-fluorophenol B028a (550 mg, brown solid) in a yield of 63%.

[0479] MS m / z (ESI): 206.0 (M+1).

[0480] Step 2: Preparation of 5-bromo-6-fluorobenzoxazol-2(3H)one

[0481] 2-Amino-4-bromo-5-fluorophenol B028a (550 mg, 2.67 mmol) was dissolved in tetrahydrofuran (20 mL), and N,N′-carbonyldiimidazole (649.3 mg, 4.0 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. After the reaction, the organic phase was concentrated, and the resulting residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the product, 5-bromo-6-fluorobenzoxazol-2(3H)-one B028b (240 mg, yellow solid), in a yield of 39%.

[0482] MS m / z (ESI): 232.0 (M+1).

[0483] Step 3: Preparation of 5-bromo-6-fluoro-3-methylbenzoxazol-2(3H)one

[0484] 5-Bromo-6-fluorobenzoxazol-2(3H)one B028b (230 mg, 0.99 mmol) and cesium carbonate (645.97 mg, 1.98 mmol) were dissolved in acetonitrile (20 mL). Methyl iodide (281.41 mg, 0.1.98 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction, the organic phase was concentrated, and the resulting residue was purified by column chromatography (petroleum ether / ethyl acetate) to afford 5-bromo-6-fluoro-3-methylbenzoxazol-2(3H)one B028c (230 mg, yellow solid) in a 94% yield.

[0485] MS m / z (ESI): 246.0 (M+1).

[0486] Step 4: Preparation of 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)one

[0487] Under a nitrogen atmosphere, 5-bromo-6-fluoro-3-methylbenzoxazol-2(3H)one B028c (100 mg, 0.41 mmol), pinacol diboron (154.8 mg, 0.61 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (58.98 mg, 0.08 mmol), and potassium acetate (119.65 mg, 1.22 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction flask was heated and stirred at 90°C for 2 hours. After completion of the reaction, the reaction was cooled to room temperature. The mixture was filtered, dried, and concentrated. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate) to afford 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)one B028d (67 mg, white solid). Yield: 56%.

[0488] MS m / z (ESI): 294.2 (M+1).

[0489] Step 5: Preparation of (R)-N-(4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzoxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0490] Under a nitrogen atmosphere, 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)-one B028d (67 mg, 0.23 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL). 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (33.18 mg, 0.05 mmol), potassium carbonate (63.19 mg, 0.46 mmol) and 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-propionamide (64.73 mg, 0.23 mmol) were added, and the reaction mixture was stirred at 80° C. for 2 hours. LCMS detected the disappearance of the starting material. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the product was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by Prep-HPLC to give (R)-N-(4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzoxazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide B028 (17 mg) in a yield of 20%.

[0491] MS m / z (ESI): 370.1 (M+1).

[0492] HPLC: 100% (214nm), 100% (254nm).

[0493] 1H NMR (400MHz, CDCl3) δ8.57 (s, 1H), 8.32 (s, 1H), 7.11 (d, J = 8.4Hz, 1H), 6.78 (s, 1H), 5.75 (s, 1H), 5.37 ( s, 1H), 3.42 (s, 3H), 2.70-2.37 (m, 2H), 2.30 (d, J=7.3Hz, 2H), 2.02-1.79 (m, 4H), 1.23 (t, J=8.0Hz, 3H).

[0494] Biological evaluation

[0495] Test Example 1: Construction of G402-hCYP11B1 / G402-hCYP11B2 Monoclonal Cell Lines

[0496] This 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.

[0497] 1. Test materials and instruments

[0498] 1.1 Culture medium

[0499] MCCOYS 5A MED MOD medium (Invitrogen, Cat#10131)

[0500] Penicillin-Streptomycin (Corning, Cat#15140-122)

[0501] FBS (GIBCO, Cat#10091-148)

[0502] GLUTAMAX I-100X (Invitrogen, Cat#35050061)

[0503] Puromycin (Invitrogen, Cat#ant-pr-5)

[0504] Penicillin / Streptomycin (Invitrogen, Cat#15140)

[0505] 1.2 Reagents and consumables

[0506] Neon Transfection Kit (Invitrogen, Cat#MPK10096)

[0507] DMEM (Gibco, Cat#11965-092)

[0508] Polybrene (Sigma, Cat#TR-1003-G)

[0509] FuGENE HD Transfection Reagent (Promega, Cat#E2311)

[0510] Opti-MEM (Gibco, Cat#11058-021)

[0511] 2. Experimental steps

[0512] 2.1 Retroviral packaging: pMSCV-CYP11B1 and pMSCV-CYP11B2 were co-transfected with helper plasmids into GP2-293 cells, and after 72 h, the cell supernatant was collected and centrifuged to obtain the packaged retrovirus.

[0513] 2.2 Cell transfection: G402 wild-type cells were infected with retrovirus. After 48 h, the cell culture medium was changed and positive cells were selected using culture medium containing 3 μg / mL Puromycin.

[0514] 2.3 Monoclonal Screening: One week after puromycin screening, if the cells are growing well, monoclonal screening is performed using the limiting dilution method and the growth of monoclonal cells is recorded using an Incucyte.

[0515] 2.4 Monoclonal Identification. After 14 days, cells that have maintained good growth were digested from the 96-well plate and subcultured into 6-well plates. After cell expansion, cells were sampled and protein expression was analyzed by Western blotting.

[0516] 2.5 Monoclonal expansion: Positive monoclonal cells are transferred to T-75 flasks for further culture and expansion.

[0517] Test Example 2: Inhibitory activity test of the compounds of the present invention on CYP11B2-mediated aldosterone / CYP11B1-mediated cortisol production

[0518] 1. Test materials and instruments

[0519] 1.1 Reagents

[0520] TrypLE TM Express Enzyme (Gibco, Cat#12604021)

[0521] Penicillin-Streptomycin(Coming, Cat#15140-122)

[0522] MCCOYS 5A MED MOD medium (Invitrogen, Cat#10131)

[0523] Puromycin (Invitrogen, Cat#ant-pr-5)

[0524] FBS (Gibco, Cat#10099-141C)

[0525] DPBS (Gibco, Cat#14190250)

[0526] DMSO (Sigma, Cat# D8418-1L)

[0527] Cortisol HTRF kit (Cisbio, Cat#62CRTPEG)

[0528] Charcoal stripped FBS (BIOSUN, Cat# BS-0004-500)

[0529] Osilodrostat(LCI699)(MCE,Cat#HY-16276)

[0530] Cortodoxone (LCI699) (MCE, Cat#HY-77839)

[0531] 1.2 Consumables

[0532] 384-well plate(Corning, Cat#3764)

[0533] Plate shaker(QILINBEIER,Cat#QB-9002)

[0534] Centrifuge (Eppendorf, Cat#5810R)

[0535] CO2 incubator (Thermo Scientific, Cat#371)

[0536] Microscope(OLYMPUS,Cat#CKX41)

[0537] Countess (Gibco, Cat# C10281)

[0538] 384-well microplate (Greiner, Cat#784075)

[0539] Envision (PerkinElmer, Cat#2105)

[0540] 2. Experimental steps

[0541] 2.1 Compound Preparation

[0542] 2.1.1 Dissolve the test compound in DMSO to a stock solution of 8.7 mM. For the G402 CYP11B1 assay, dilute the compound from the 8.7 mM stock solution three-fold in DMSO into eight doses. Prepare the diluted compounds in a 384PP-0200 plate and echo-dip 47.5 nL into 40 μL of cells. The final working concentrations of the compounds are: 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.041 μM, 0.014 μM, and 0.0046 μM. In the G402 CYP11B2 assay, the compound stock solution was diluted three-fold from 0.253 mM with DMSO into eight doses and prepared in a 384PP-0200 plate. 47.5 nL was echo-labeled into 40 μl of cells. The final working concentrations of the compound were: 300 nM, 100 nM, 33.33 nM, 11.11 nM, 3.70 nM, 1.23 nM, 0.41 nM, and 0.14 nM.

[0543] 2.2 Determination of CYP11B1-mediated cortisol production

[0544] 2.2.1 4000 G402 cells / well / 35 μl were seeded into 384-well plates and incubated at 37°C and CO2 for 6 hours.

[0545] 2.2.2 Add 5ul of 0.4μM Cortodoxone to the cells (final concentration is 0.05μM)

[0546] 2.2.3 Add 40 nL of the test compound to the cells and incubate at 37°C and CO2 for 16 h

[0547] 2.2.4 Collect the supernatant and test for cortisol by HTRF

[0548] 2.2.5 Dispense 10 μL of cortisol standard (standard 0-standard 6) into each standard well; dispense 10 μL of each sample into each sample well

[0549] 2.2.6 Add 5 μL of cortisol receptor reagent (d2) working solution to the standards and samples.

[0550] 2.2.7 Add 5 μL of Cryptate working solution to all wells

[0551] 2.2.8 Seal the plate and incubate at room temperature for 2 hours

[0552] 2.2.9 Remove the plate sealer and Read on compatible card readers

[0553] 2.3 Determination of CYP11B2-mediated aldosterone production

[0554] 2.3.1 4000 G402 cells / well / 35 μl were seeded into 384-well plates and incubated at 37°C and CO2 for 6 hours.

[0555] 2.3.2 Add 5ul 8μM 11-deoxycorticosterone into cells (final concentration is 1μM)

[0556] 2.3.3 Add 40 nL of the test compound to the cells and incubate at 37°C and CO2 for 16 h

[0557] 2.3.4 Collect the supernatant and test for aldosterone by HTRF

[0558] 2.3.5 Dispense 10 μL of aldosterone standard (Standard 0-Standard 6) into each standard well; dispense 10 μL of each sample into each sample well.

[0559] 2.3.6 Add 5 μL of aldosterone receptor reagent (XL665) working solution to the standards and samples.

[0560] 2.3.7 Add 5 μL of aldosterone donor antibody (Cryptate) working solution to all wells

[0561] 2.3.8 Seal the plate and incubate at room temperature for 2 hours

[0562] 2.3.9 Remove the plate sealer and Read on compatible card readers

[0563] 3. Data Analysis

[0564] Xlfit was used to calculate the release of cortisol and aldosterone from cells, and GraphPad Prism 8 Software was used to plot the graphs.

[0565] 4 Experimental results

[0566] Following the above steps, the Envision reader calculated the factor release amount. Using the calculated factor concentration, the experimental results were analyzed as follows.

[0567] Table 1 IC50 values ​​of the compounds of the present invention in the inhibitory activity test of CYP11B2-mediated aldosterone / CYP11B1-mediated cortisol production.

[0568] Test Example 3: Pharmacokinetics of the Compounds of the Invention in Rats

[0569] 1. Experimental Purpose

[0570] The pharmacokinetic behavior of the compound of the present invention in rats was studied to evaluate its pharmacokinetic characteristics.

[0571] 2. Experimental plan

[0572] 2.1 Experimental drugs

[0573] CIN-107, an example compound of the present invention.

[0574] 2.2 Experimental animals

[0575] Healthy adult SD rats.

[0576] 2.3 Drug preparation

[0577] An appropriate amount of sample was weighed and ultrasonically prepared into a 0.3 mg / mL suspension using a formula of 5% DMSO + 10% Solutol + 85% Saline for the oral administration group and a 0.2 mg / mL suspension for the intravenous administration group.

[0578] 2.4 Administration

[0579] SD rats were fasted overnight and administered with oral gavage and intravenous injection, respectively. The oral dose was 2 mg / kg, and the intravenous dose was 1 mg / kg. Three animals were used in each administration group for parallel experiments.

[0580] 3. Operation

[0581] Before administration and at 5, 15, 30, 1, 2, 4, 8, and 24 hours after administration, 0.1 mL of blood was collected from heparinized tubes and centrifuged at 3500 rpm for 10 minutes to separate the plasma, which was then stored at -20°C. Four hours after administration, the animals were allowed to resume free access to food and water.

[0582] The content of the test compound in rat plasma after oral administration was determined by LC / MS / MS.

[0583] The test results are shown in Table 2.

[0584] Table 2 Pharmacokinetic results of the test compounds in rats

[0585] Experimental conclusion: The above data show that the compound of the present invention has better pharmacokinetic absorption in rats after oral gavage, higher drug exposure, better bioavailability, and has obvious pharmacokinetic absorption effect.

[0586] Test Example 4: Efficacy Experiment on the Monkey Hypertension Model Induced by Twenty-tetraopeptide Corticotropin

[0587] 1. Experimental Purpose

[0588] The purpose of this study was to evaluate the efficacy of the test compound in an ACTH-induced hypertension model in monkeys.

[0589] 2. Experimental plan

[0590] 2.1 Experimental drugs

[0591] CIN-107, an example compound of the present invention.

[0592] 2.2 Experimental animals

[0593] Healthy male cynomolgus monkeys.

[0594] 2.3 Drug preparation

[0595] An appropriate amount of sample was weighed and ultrasonically prepared into a 0.02 mg / mL suspension using a formula of 5% DMSO + 10% Solutol + 85% Saline for the oral administration group.

[0596] 2.4 Administration

[0597] The monkeys were divided into 6 groups. The first group was the normal group (Normal); the second group was the model group (ATCH); the third group was given CIN-107 0.1 mg / kg, and the fourth group was given B013 compound 0.035 mg / kg (low-dose group); the fifth group was given B013 compound 0.1 mg / kg (medium-dose group); and the sixth group was given B013 compound 0.3 mg / kg (high-dose group). There were 2 animals in each group.

[0598] 2.5 Detection

[0599] 2.5.1 After administration, the second to sixth groups were given ACTH stimulation and then tested with the drug (the normal group was given the corresponding volume of dissolved coal), and plasma samples were collected 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours later.

[0600] 2.5.2 Analyze the steroid level in plasma using LC-MS / MS and calculate the inhibition rate compared to that after ATCH stimulation as follows: % inhibition = (1-(Ald cmpd / Aldo ACTH ))x100

[0601] (Compared the compound groups with the ACTH group at the same time point to calculate the inhibition rate)

[0602] Aldo cmpd : Average aldosterone production of animals in the test compound group

[0603] Aldo ACTH :Average aldosterone production in ACTH model group animals

[0604] 2.6 Experimental Results: The serum aldosterone levels and relative inhibition rates are shown in Figure 1. Aldosterone production reached its maximum 1 hour after ACTH stimulation and began to decline 4 hours later. B013 significantly inhibited aldosterone production at all time points, showing a good dose-dependent effect at 15 minutes, 30 minutes, 1 hour, and 2 hours. Both the medium- and high-dose groups were superior to the Yangshen compound CIN-107.

[0605] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection 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 a benzene ring or a 5-6 membered heteroaromatic ring; X is selected from -O-, -N(R x1 )-、-C(R x2 )(R x3 )-, where R x1 is selected from H, unsubstituted or optionally substituted with one, two or more R x11 Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, -C(=O)-C 1-12 Alkyl, -C(=O)-C 3-12 Cycloalkyl, -C(=O)-(3-12 membered heterocyclic group), -C(=O)-OC 1-12 Alkyl, -C(=O)-OC 3-12 Cycloalkyl, -C(=O)-O-(3-12 membered heterocyclic group); R x2 , R x3 are the same or different and are independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R x21 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group; Y is absent or selected from -C(=O)-, -S(=O) 2 -, unsubstituted or optionally substituted with one, two or more R y Replaced-C 1- 3 Alkylene-; Z is selected from -O-, -S-, -S(=O)-, -S(=O) 2 -, unsubstituted or optionally substituted with one, two or more R z Substituted with the following groups: -N(R z1 )-C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, -S(=O)-C 1-4 Alkylene-, -S(=O) 2 -C 1-4 Alkylene-, the alkylene is optionally interrupted by one or more groups selected from the group consisting of: -O-, -S-, -NR z2 -、-S(=O)-、-S(=O) 2 -; Each R z are the same or different and are independently selected from H, halogen, CN, OH, oxo (=O), unsubstituted or optionally substituted by one, two or more R z11 Substituted with the following groups: C 1-1z Alkyl, C 1-1z Alkoxy, C 3-12 Cycloalkyl, amino, 3-12 membered heterocyclic group; or two R groups connected to the same carbon atom z Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted with one, two or more R z11 Substituted with the following groups: C 3-8 Cycloalkyl, 3-12 membered heterocyclic group; R z1 , R z2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R z11 Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl; W is selected from -N(R 7 )-、-C(R 8 )(R 9 )-; 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 、-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, 3-12 membered heterocyclic group; 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 3-12 Cycloalkyl, 3-12 membered heterocyclic group; 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 、- (CH 2 ) p -O-R 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) 2 R 101 、-C(=O)R 102 、-C(=O)OR 103 、-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, 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) 2 R 121 、-C(=O)R 122 、-C(=O)OR 123 、-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, 3-12 membered heterocyclic group; 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, C 3-12 Cycloalkyl; 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, 3-12 membered heterocyclic group; 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, 3-12 membered heterocyclic group; 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, 3-12 membered heterocyclic group; m is selected from 0, 1, 2, 3, 4, 5 or 6; n is selected from 0, 1, 2; r is selected from 0, 1, 2; s is selected from 0, 1, 2, 3; p is selected from 0, 1, 2, 3, 4, 5 or 6; R a , R b are the same or different and are independently selected from H, CN, OH, 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; 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, C 3-12 Cycloalkyl; R y , R x11 , R x21 , R z11 , 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, 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; each R "is the same or different, independently selected from CN, OH, halogen, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl.

2. The compound according to claim 1, It is characterized in that X is selected from -O-, -N(R x1 )-、-C(R x2 )(R x3 )-, where R x1 is selected from H, unsubstituted or optionally substituted with one, two or more R x11 Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-8 Cycloalkane -C(=O)-(3-8 membered heterocyclic group); Preferably, X is selected from -N(R x1 )-, where R x1 is selected from H, unsubstituted or optionally substituted with one, two or more R x11 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(=O)-C 1-3 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocyclyl); Preferably, X is selected from O or -N(R x1 )-, where R x1 is selected from methyl, cyclopropanecarbonyl, acetyl; Preferably, each R x11 are the same or different and are independently selected from CN, OH, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Preferably, R x2 , R x3 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy; Preferably, X is selected from -CH 2 -; Preferably, Y is absent or selected from -C(=O)-, unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: -C 1-3 Alkylene- (such as methylene); Preferably, Y is selected from -CH 2 -、-CF 2 -, -C(=O)-; Preferably, each R y are the same or different and are independently selected from CN, OH, halogen (such as F or Cl), amino, C 1- 6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Preferably, Z is selected from -O-, -S-, unsubstituted or optionally substituted with one, two or more R z Substituted with the following groups: -NR z1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, the alkylene is optionally interrupted by one or more groups selected from the group consisting of: -O-, -S-, -NR z2 -; Preferably, each R z are the same or different and are independently selected from halogen, CN, OH, oxo (C=O), unsubstituted or optionally substituted by one, two or more R z11 Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl; or two R attached to the same carbon atom z Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted with one, two or more R z11 Substituted with the following groups: C 3-6 Cycloalkyl, 3-8 membered heterocyclic group; Preferably, each R z are the same or different and are independently selected from halogen, CN, OH, oxo (C=O), C 1-3 Alkyl, C 3-6 Cycloalkyl; or two R attached to the same carbon atom z Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted with one, two or more R z11 Substituted cyclopropyl; Preferably, R z1 , R z2 The same or different, independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl; Preferably, each R z11 are the same or different and are independently selected from CN, OH, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Preferably, Z is selected from -OC 1-4 Alkylene-; Preferably, Z is selected from -O-, -O-CH 2 -、-CH 2 N(CH 3 )-.

3. The compound according to claim 1 or 2, It is characterized in that W is selected from -C(R 8 )(R 9 )-; R 8 Selected from H; R 9 Selected from -NR 10 R 11 OR 12 ; Preferably, R 10 Selected from -C(=O)R 102 、-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 groups: 3-6 membered N-containing heterocyclic groups (such as tetrahydropyrrolyl); Preferably, R 12 Selected from -C(=O)R 122 、-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, 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, methoxy; More preferably, R 9 Selected from 4. A compound according to any one of claims 1 to 3, It is characterized in that Ring A is selected from a benzene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a thiazole ring, an oxazole ring, an isoxazole ring, a pyrimidine ring, a pyridine ring, a pyrazine ring, and a pyridazine ring; Preferably, ring A is selected from a benzene ring, a thiophene ring, a pyrazole ring, a pyrimidine ring, a pyridine ring, and a thiazole ring; Preferably, R a Selected from CN, OH, halogen, unsubstituted or optionally substituted by one, two or more R': amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl; R' is selected from CN, OH, halogen; Preferably, R a Selected from halogen, C 1-6 alkyl; Preferably, R a is selected from F, Cl, Br, methyl; Preferably, the A ring has the following structure: Preferably, Selected from the following groups: Preferably, Selected from the following groups:

5. The compound according to any one of claims 1 to 4, It is characterized in that The compound represented by the formula (I) is selected from the following structures: Among them, A ring, X, Y, Z, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , R x1 , R 10 , R 11 , n, r, 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, X, Y, Z, R a , R b , R 10 , R 11 , r, 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, Z, R a s has the meaning as defined in any one of claims 1 to 4; Preferably, Z is selected from -O-, -O-CH 2 -.

6. The compound according to any one of claims 1 to 5, It is characterized in that The compound is selected from the following structures: Preferably, 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, It is 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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