2,3-dihydro-4h-benzo[b][1,4]oxazin-4-yl)(5-(phenyl)-pyridin-3-yl)methanone derivatives and analogous compounds as cyp11a1 inhibitors for the treatment of prostate cancer

Abstract

The present invention relates to compounds of formula (I) wherein A is a 3-10 membered carbocyclic ring or a 4-12 membered heterocyclic ring containing 1-4 heteroatoms selected from O, N or S; B is any one of the following groups (1), (2) or (3); C is any one of the following groups (1'), (2'), (3') or (4'); G1 is CH2, NH or O; G2 and G3 are independently of each other CH or N; Z is -C(O)-, -SO2-, -C 1‑3 alkyl- or -CH2-C(O)-; L is a bond, -C 1‑7 alkyl- or -C 1‑7 alkenyl-. The compounds of formula (I) are inhibitors of cytochrome P450 monooxygenase 11A1 (CYP11A1). The compounds are useful as medicaments for the treatment of steroid receptor, e.g. androgen receptor or estrogen receptor dependent diseases and disorders such as cancer including prostate cancer and estrogen cancer.

Description

Technical Field

[0001] This invention relates to therapeutically active compounds that can be used to treat steroid receptor (e.g., androgen receptor (AR) or estrogen receptor (ER)) dependent conditions and diseases, and to pharmaceutical compositions containing such compounds. Background of the Invention

[0003] Treatment of steroid receptor-dependent diseases, such as androgen receptor (AR)-dependent cancers and estrogen receptor (ER)-dependent cancers, has been extensively studied. For example, prostate cancer is one of the most common cancers in men worldwide. Although the 5-year survival rate for patients with localized prostate cancer is high, the prognosis is poor for patients who develop castration-resistant prostate cancer (CRPC) during the 5-year follow-up period.

[0004] The androgen receptor (AR) signaling axis is crucial at all stages of prostate cancer. In the CPRC (castration-resistant prostate cancer) stage, the disease is characterized by high AR expression, AR amplification, and persistent activation of the AR signaling axis by residual tissue / tumor androgens and other steroid hormones and steroid biosynthetic intermediates. Therefore, treatment for advanced prostate cancer involves androgen deprivation therapy (ADT), such as hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists / antagonists or surgical castration, AR antagonists, or CYP17A1 inhibitors (e.g., abiraterone acetate combined with prednisone).

[0005] Although treatment may initially lead to disease remission, most patients eventually develop disease that is refractory to currently available therapies. Increased progesterone levels in patients treated with abiraterone acetate are hypothesized as one mechanism of resistance. Several non-clinical and clinical studies have shown upregulation of enzymes catalyzing steroid biosynthesis in advanced CRPC. Recent reports indicate that 11β-OH androstenedione can be metabolized into 11-ketotestosterone (11-KT) and 11-ketodihydrotestosterone (11-K-DHT), which can bind to and activate AR as efficiently as testosterone and dihydrotestosterone. These steroids have been shown to be present in high levels in the plasma and tissues of prostate cancer patients, suggesting their role as AR agonists in CRPC. Furthermore, it has been demonstrated that resistance to CYP17A1 inhibition in prostate cancer may still depend on steroids and responds to therapies that can further inhibit de novo intratumoral steroid synthesis upstream of CYP17A1 (e.g., via CYP11A1 inhibition therapy) (Cai, C. et al., Cancer Res., 71(20), 6503-6513, 2011).

[0006] Cytochrome P450 monooxygenase 11A1 (CYP11A1), also known as cholesterol side-chain lyase, is a mitochondrial monooxygenase that catalyzes the conversion of cholesterol into pregnenolone, a precursor to all steroid hormones. Complete blockade of steroid biosynthesis can be achieved by inhibiting CYP11A1, a key enzyme upstream of CYP17A1. Therefore, CYP11A1 inhibitors may have great potential for treating steroid hormone-dependent cancers, including prostate cancer, even in advanced stages of the disease, particularly in patients who are refractory to hormone therapy. Compounds with CYP11A1 inhibitory activity have been shown to significantly inhibit tumor growth in vivo in a mouse CRPC xenograft model (Oksala, R. et al., Annals of Oncology, (2017) 28(Supplement 5): Abstract / Poster 28p). CYP11A1 inhibitors are described in WO 2018 / 115591. Invention Overview

[0008] Compounds of formula (I) have been found to be potent CYP11A1 inhibitors. Therefore, the compounds of the present invention are particularly useful as medicines for treating steroid hormone-dependent conditions and diseases requiring inhibition of CYP11A1. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases such as prostate cancer and breast cancer. In particular, the compounds of the present invention can be used to treat AR-dependent conditions and diseases, including prostate cancer.

[0009] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0010]

[0011] in

[0012] B is any one of the following groups.

[0013]

[0014] When B is a group (1) or (2), then

[0015] A is a 3-10 membered carbon ring or a 4-12 membered heterocycle containing 1-4 heteroatoms selected from O, N or S;

[0016] C is any one of the following groups.

[0017]

[0018] G1 is CH2, NH, or O;

[0019] G2 and G3 are independently CH or N;

[0020] Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-;

[0021] L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-;

[0022] R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, nitro, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl or -X-NR6R7;

[0023] R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen;

[0024] R3 is hydrogen, C 1-7 Alkyl or amino;

[0025] R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, hydroxyl C 1-7 Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl;

[0026] R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl;

[0027] X is a key or C 1-7 alkyl;

[0028] R6 and R7 are independently hydrogen or C. 1-7 alkyl;

[0029] When B is a group (3), then

[0030] A is any one of the following groups.

[0031]

[0032] The condition is that if C is a cycle (3'), then A is neither a cycle (2") nor a cycle (7");

[0033] C is any one of the following groups.

[0034]

[0035] G1 is CH2, NH, or O;

[0036] G2 and G3 are independently CH or N;

[0037] Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-;

[0038] L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-;

[0039] R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl group, -X-NR6R7;

[0040] R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen;

[0041] R3 is hydrogen, C 1-7 Alkyl or amino;

[0042] R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl C 1-7 Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl;

[0043] R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl;

[0044] X is a key or C 1-7 alkyl;

[0045] R6 and R7 are independently hydrogen or C. 1-7 alkyl;

[0046] The condition is that the compound of formula (I) is not

[0047] (7-Methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidone-1-yl)pyrazin-2-yl)methyl ketone;

[0048] (8-Fluoro-3,4-dihydro-3-hydroxymethyl-1(2H)-quinolinyl)(6-(1-pyrrolidinyl)-2-pyrazinyl) methyl ketone;

[0049] (3,4-Dihydro-3-methoxy-1(2H)-quinolinyl)(6-phenyl-4-pyridazinyl) methyl ketone;

[0050] (6-Fluoro-3,4-dihydro-4-methyl-1(2H)-quinoxalinyl)(5-phenyl-3-pyridyl) methyl ketone;

[0051] (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridyl) methyl ketone;

[0052] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(3,4-dihydro-1(2H)-quinolinyl) methyl ketone;

[0053] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) methyl ketone;

[0054] (6,8-Difluoro-3,4-dihydro-1(2H)-quinolinyl)(5-(4-(dimethylamino)phenyl)-3-pyridyl) methyl ketone;

[0055] (3,4-Dihydro-1(2H)-quinolinyl)(5-(1-pyrrolidinyl)-3-pyridyl)methyl ketone;

[0056] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(octahydro-4H-1,4-benzoxazin-4-yl) methyl ketone;

[0057] (5-(4-methoxyphenyl)-3-pyridyl)(octahydro-4H-1,4-benzoxazin-4-yl)methyl ketone; or

[0058] (2,3-Dihydro-1H-indol-1-yl)(5-phenyl-3-pyridyl)methyl ketone.

[0059] According to one embodiment, the present invention provides a method for treating steroid receptor-dependent symptoms or diseases, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0060]

[0061] in

[0062] A is a 3-10 membered carbon ring or a 4-12 membered heterocycle containing 1-4 heteroatoms selected from O, N or S;

[0063] B is any one of the following groups.

[0064]

[0065] C is any one of the following groups.

[0066]

[0067] G1 is CH2, NH, or O;

[0068] G2 and G3 are independently CH or N;

[0069] Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-;

[0070] L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-;

[0071] R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, nitro, halogenated C 1-7 alkyl,

[0072] Hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl or -X-NR6R7;

[0073] R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen;

[0074] R3 is hydrogen, C 1-7 Alkyl or amino;

[0075] R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, hydroxyl C 1-7 Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl;

[0076] R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl;

[0077] X is a key or C 1-7 alkyl;

[0078] R6 and R7 are independently hydrogen or C. 1-7 alkyl.

[0079] According to one implementation, steroid receptor-dependent conditions or diseases include, but are not limited to, endocrine cancers and diseases such as prostate cancer, particularly castration-resistant prostate cancer (CRPC) and breast cancer.

[0080] According to one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Invention Details

[0082] This application provides a novel compound of formula (I) that can be used as a CYP11A1 inhibitor or a pharmaceutically acceptable salt thereof.

[0083] One embodiment of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0084]

[0085] in

[0086] B is any one of the following groups.

[0087]

[0088] When B is a group (1) or (2), then

[0089] A is a 3-10 membered carbon ring or a 4-12 membered heterocycle containing 1-4 heteroatoms selected from O, N or S;

[0090] C is any one of the following groups.

[0091]

[0092] G1 is CH2, NH, or O;

[0093] G2 and G3 are independently CH or N;

[0094] Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-;

[0095] L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-;

[0096] R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, nitro, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl or -X-NR6R7;

[0097] R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen;

[0098] R3 is hydrogen, C 1-7 Alkyl or amino;

[0099] R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, hydroxyl C 1-7 Alkyl, Halogenated C 1-7Alkyl or -C(O)-OC 1-7 alkyl;

[0100] R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl;

[0101] X is a key or C 1-7 alkyl;

[0102] R6 and R7 are independently hydrogen or C. 1-7 alkyl;

[0103] When B is a group (3), then

[0104] A is any one of the following groups.

[0105]

[0106] The condition is that if C is a cycle (3'), then A is neither a cycle (2") nor a cycle (7");

[0107] C is any one of the following groups.

[0108]

[0109] G1 is CH2, NH, or O;

[0110] G2 and G3 are independently CH or N;

[0111] Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-;

[0112] L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-;

[0113] R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl group, -X-NR6R7;

[0114] R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen;

[0115] R3 is hydrogen, C 1-7 Alkyl or amino;

[0116] R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl C 1-7Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl;

[0117] R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl;

[0118] X is a key or C 1-7 alkyl;

[0119] R6 and R7 are independently hydrogen or C. 1-7 alkyl;

[0120] The condition is that the compound of formula (I) is not

[0121] (7-Methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidone-1-yl)pyrazin-2-yl)methyl ketone;

[0122] (8-Fluoro-3,4-dihydro-3-hydroxymethyl-1(2H)-quinolinyl)(6-(1-pyrrolidinyl)-2-pyrazinyl) methyl ketone;

[0123] (3,4-Dihydro-3-methoxy-1(2H)-quinolinyl)(6-phenyl-4-pyridazinyl) methyl ketone;

[0124] (6-Fluoro-3,4-dihydro-4-methyl-1(2H)-quinoxalinyl)(5-phenyl-3-pyridyl) methyl ketone;

[0125] (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridyl) methyl ketone;

[0126] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(3,4-dihydro-1(2H)-quinolinyl) methyl ketone;

[0127] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) methyl ketone;

[0128] (6,8-Difluoro-3,4-dihydro-1(2H)-quinolinyl)(5-(4-(dimethylamino)phenyl)-3-pyridyl) methyl ketone;

[0129] (3,4-Dihydro-1(2H)-quinolinyl)(5-(1-pyrrolidinyl)-3-pyridyl)methyl ketone;

[0130] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(octahydro-4H-1,4-benzoxazin-4-yl) methyl ketone;

[0131] (5-(4-methoxyphenyl)-3-pyridyl)(octahydro-4H-1,4-benzoxazin-4-yl) methyl ketone or

[0132] (2,3-Dihydro-1H-indol-1-yl)(5-phenyl-3-pyridyl)methyl ketone.

[0133] It should be understood that the left-hand bond of Z is connected to ring B of formula (I). The wavy line in group A indicates the connection point with L. The wavy line in group C indicates the connection point with Z. The left-hand wavy line in group B indicates the connection point with L, and the right-hand wavy line in group B indicates the connection point with Z.

[0134] According to one embodiment, a compound of formula (I) is specifically provided, wherein B is a group (1) or a group (3), for example, B is a group (1), or as another example, B is a group (3).

[0135] According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein Z is -C(O)-, -SO2-, -CH2-, or -CH2-C(O)-. According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein Z is -C(O)-. According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein L is a bond, -C 1-3 Alkyl- or -C 1-3 Alkenyl-. In a subgroup of the preceding embodiments, L is a bond, -CH2-, or –C(CH2)-. According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein L is a bond. According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein C is a group (1') or (2'). According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein C is a group (1').

[0136] According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein G1 is CH2 or O, for example, G1 is CH2, or as another example, G1 is O. On one hand, a compound according to any of the above embodiments is provided, wherein G2 is N and G3 is CH, or wherein G2 is CH and G3 is N.

[0137] According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl C 1-7 Alkyl or halogenated C 1-7Alkyl group. According to another embodiment, a compound according to any of the above embodiments is specifically provided, wherein R2 is hydrogen, hydroxyl, or C. 1-7 Alkyl or halogen. According to another embodiment, a compound according to any of the above embodiments is specifically provided, wherein R3 is hydrogen. According to another embodiment, a compound according to any of the above embodiments is specifically provided, wherein R4 is hydrogen, C 1-7 Alkyl, halogen or -C(O)-OC 1-7 alkyl.

[0138] According to one embodiment, a compound of formula (I) according to any of the above embodiments is specifically provided, wherein when B is group (3), A is any one of the following groups:

[0139]

[0140] R1 and R2 are connected to the aforementioned ring A, and the wavy line indicates the position where they are connected to L.

[0141] According to one embodiment, a compound of formula (I) according to any of the above embodiments is specifically provided, wherein when B is group (1) or (2), then A is any one of the following groups:

[0142]

[0143] R1 and R2 are connected to the aforementioned ring A, and the wavy line indicates the position where they are connected to L.

[0144] In one subclass of the above embodiments, compounds are provided, wherein A is any one of the following groups:

[0145]

[0146] R1 and R2 are connected to the aforementioned ring A, and the wavy line indicates the position where they are connected to L.

[0147] According to one embodiment, a compound of formula (I) according to any of the above embodiments is specifically provided, wherein A is a group (1"), (2"), (3"), (6"), (8"), (9") or (10").

[0148] According to one embodiment, a compound of formula (I) according to any of the above embodiments is specifically provided, wherein A is a group (1"), (2a), (2b), (3a), (6a), (8a), (9b), or (10a).

[0149] According to one embodiment, the compound of the present invention is as shown in formula (IA), or a pharmaceutically acceptable salt thereof.

[0150]

[0151] in

[0152] D is either N or CH;

[0153] G is CH2, NH, or O;

[0154] M is CH or N;

[0155] R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy or halogen;

[0156] R2 is hydrogen or halogen;

[0157] R3 is hydrogen or C. 1-7 alkyl;

[0158] R4 is hydrogen, C 1-7 Alkyl, halogen or -C(O)-OC 1-7 alkyl;

[0159] A is any one of the following groups:

[0160]

[0161] The condition is that the compound of formula (I) is not

[0162] (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridyl) methyl ketone;

[0163] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(3,4-dihydro-1(2H)-quinolinyl) methyl ketone or

[0164] (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) methyl ketone.

[0165] In one subclass of the above embodiments, a compound of formula (IA) is provided, wherein R1 is hydrogen, methyl, methoxy or halogen; R3 is hydrogen or methyl; R4 is hydrogen, methyl or halogen; and A is a group (1"), (2a), (3a), (9b) or (10a).

[0166] According to yet another embodiment, the present invention provides a method for treating steroid receptor-dependent symptoms and diseases, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) as defined in any of the above embodiments.

[0167] According to one embodiment, the steroid receptor-dependent disease or condition is an androgen receptor- or estrogen receptor-dependent disease or condition, including endocrine cancers and diseases such as prostate cancer or breast cancer, particularly castration-resistant prostate cancer (CRPC). According to one embodiment of the invention, the CRPC to be treated is CYP17A1 inhibitor-refractory. According to another embodiment, the androgen receptor-dependent disease or condition is an endocrine cancer dependent on CYP11A1 activation.

[0168] The compounds of the present invention can be prepared using suitable starting materials via a variety of synthetic routes similar to those known in the literature. Compounds of formula (I) can be prepared, for example, in a manner similar to or according to the following reaction scheme. Some compounds included in formula (I) can be obtained by transforming the functional groups of other compounds of formula (I) obtained according to the following scheme through well-known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, etc. It should be noted that any suitable leaving group, such as an N-protecting group, such as a tert-butoxycarbonyl (t-BOC) group or a benzenesulfonyl group, can be used in a well-known manner during the synthesis to improve the selectivity of the reaction steps.

[0169] Compound of formula (I), where L is a bond, can be prepared according to Scheme 1, where X is a halogen, preferably chlorine or bromine, and A, B, C, Z, R1, R2, R3, R4 and R5 are as defined above. In the method of Scheme 1, the compound of formula [1] is coupled with the boric acid derivative of formula [2] in a suitable solvent such as a mixture of ethanol, toluene and water, in the presence of a base such as sodium carbonate and a catalyst such as bis(triphenylphosphine)palladium(II) dichloride at an elevated temperature to generate the compound of formula [Ia]. The corresponding boric acid ester such as pinacol borate can also be used instead of the boric acid derivative [2].

[0170] Option 1

[0171]

[0172] The compound of formula (I), where Z is -C(O)-, can also be prepared according to scheme 2, wherein A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the cyclic nitrogen atom of compound [4] is drawn in scheme 2), and R6 is methyl or ethyl. In the method of scheme 2, the compound of formula [3] and the compound of formula [4] are coupled in a suitable solvent such as toluene in the presence of trimethylaluminum and a base such as triethylamine (TEA) to generate the compound of formula [Ib].

[0173] Option 2

[0174]

[0175] Alternatively, the compound of formula (I), where Z is -C(O)-, can be prepared according to scheme 3, wherein A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the cyclic nitrogen atom of compound [4] is drawn in scheme 3). In the method of scheme 3, the compound of formula [5] is coupled with the compound of formula [4] in a suitable solvent such as DMF in the presence of a base such as triethylamine (TEA) and an optional coupling agent such as propylphosphohydrin (T3P) to generate the compound of formula [Ib].

[0176] Option 3

[0177]

[0178] Alternatively, the compound of formula (I), where Z is -C(O)-, can be prepared according to scheme 4, wherein A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the cyclic nitrogen atom of compound [4] is drawn in scheme 4). In the method of scheme 4, the compound of formula [6] is coupled with the compound of formula [4] in a suitable solvent such as DCM in the presence of a base such as triethylamine (TEA) to generate the compound of formula [Ib].

[0179] Option 4

[0180]

[0181] Compound of formula (I), where L is a bond and A contains a -NH group (e.g., A is pyrrolidine, imidazole, or pyrazole), can also be prepared according to scheme 5, where X is a halogen, preferably chlorine or bromine, and A, B, C, Z, R1, R2, R3, R4, and R5 are as defined above (for clarity, the cyclic nitrogen atom of compound [7] is drawn in scheme 5). In the method of scheme 5, compound [1] and compound [7] are coupled in a suitable solvent such as dry toluene or dry DMSO in the presence of a base such as sodium tert-butoxide (STB), DIPEA, or potassium phosphate and an optional catalyst such as tris(dibenzylacetone)dipalladium Pd2(dba)3 at elevated temperatures to generate compound [Ia].

[0182] Option 5

[0183]

[0184] The compound of formula (I), where Z is -CH2-C(O)-, can also be prepared according to scheme 6, wherein A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the cyclic nitrogen atom of compound [4] is drawn in scheme 6). In the method of scheme 6, compound [8] and compound [4] are coupled in a suitable solvent such as DMF in the presence of a base such as trimethylamine (TMA) and an optional coupling agent such as propylphosphonic anhydride (T3P) to generate compound [Ic].

[0185] Option 6

[0186]

[0187] Where Z is -C 1-3 Alkyl-type compounds of formula (I) can also be prepared according to Scheme 7, wherein A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the cyclic nitrogen atom of compound [4] is drawn in Scheme 7). In the method of Scheme 7, the aldehyde compound of formula [9] is reacted with the compound of formula [4] in a suitable solvent such as 1,2-dichloroethane in the presence of acetic acid and a reducing agent such as sodium triacetoxyborohydride (STAB) to produce the compound of formula [Id].

[0188] Option 7

[0189]

[0190] The intermediate compound can be prepared according to the methods disclosed in the literature or according to the methods disclosed in this disclosure.

[0191] For example, the intermediate compound of formula [1a] can be prepared according to scheme 8, wherein B, C, R3, R4 and R5 are as defined above and X and Y are halogens, preferably chlorine or bromine (for clarity, the cyclic nitrogen atom of compound [4] is drawn in scheme 8). In the method of scheme 8, the compound of formula

[10] is coupled with the compound of formula [4] in a suitable solvent such as DCM in the presence of a base such as TEA to generate the compound of formula [1a].

[0192] Option 8

[0193]

[0194] Intermediate compounds of formula [3a], wherein A contains a -NH group (e.g., A is pyrrolidine, imidazole, or pyrazole), can be prepared, for example, according to scheme 9, wherein A, B, R1, R3, R2, and R3 are as defined above, and X is a halogen, preferably chlorine or bromine (for clarity, the cyclic nitrogen atom of compound [7] is drawn in scheme 9). In the method of scheme 9, compound

[11] and compound [7] are coupled in a suitable solvent such as toluene-dioxane in the presence of a base such as potassium phosphate and a catalyst such as tris(dibenzylacetone)dipalladium and 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl to generate compound [3a].

[0195] Option 9

[0196]

[0197] The intermediate compound of formula [5a] can be prepared, for example, according to scheme 10, wherein A, B, R1, R2 and R3 are as defined above, X is a halogen, preferably chlorine or bromine, and R6 is methyl or ethyl. In the method of scheme 10, the compound of formula

[11] is coupled with the compound of formula [2] in a suitable solvent such as acetonitrile / ethanol / water in the presence of a base such as sodium carbonate and a catalyst such as PdCl2(PPh3)2 at an elevated temperature to generate the compound of formula [3a].

[0198] Option 10

[0199]

[0200] The intermediate compound of formula [8a] can be prepared, for example, according to scheme 11, wherein A, B, R1, R2, and R3 are as defined above, and X is a halogen, preferably chlorine or bromine. In the method of scheme 11, the compound of formula

[12] is coupled with the compound of formula [2] in a suitable solvent such as DME-water in the presence of a base such as cesium carbonate and a catalyst such as added tetra(triphenylphosphine)palladium to generate the compound of formula [8a].

[0201] Option 11

[0202]

[0203] Alternatively, the compound of formula (I) can be prepared as disclosed in the specific embodiments of this disclosure.

[0204] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject pertains. As used herein, the following definitions are provided to facilitate understanding of the invention.

[0205] As used in this article, the term "individual" refers to both humans and animals.

[0206] The term "steroid receptor" refers to a receptor that binds to and is activated by steroid hormones. Examples of steroid receptors include, but are not limited to, androgen, estrogen, glucocorticoid, and progesterone receptors.

[0207] The term "endocrine cancer" refers to the partial or complete unregulated growth of one or more cellular components of the endocrine system, including but not limited to cancers of one or more adrenal glands.

[0208] The term "elevated temperature" refers to a temperature above room temperature, typically between about 30 and 120°C, for example, between about 40 and 100°C or between about 50 and 80°C.

[0209] As used herein or as part of another group, the term “halogenated” or “halogen” refers to chlorine, bromine, fluorine, or iodine.

[0210] As used herein or as part of another group, the term "C" 1-7 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. 1-7 Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl. 1-7 A preferred embodiment of "alkyl" is C 1-3 Alkyl group. The term "C" 1-3 "Alkyl" refers to a compound with 1, 2, or 3 carbon atoms. 1-7 Preferred embodiments of "alkyl".

[0211] As used herein or as part of another group, the term "C" 2-7 "Alkenyl" refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or more double bonds. Representative examples include, but are not limited to, vinyl, propenyl, and cyclohexenyl.

[0212] As used herein or as part of another group, the term "C" 3-7 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0213] As used herein or as part of another group, the term "hydroxyl group" refers to the -OH group.

[0214] As used herein or as part of another group, the term "cyano" refers to the -CN group.

[0215] As used herein or as part of another group, the term "carboxyl" refers to the -COOH group.

[0216] As used herein or as part of another group, the term "carbonyl" refers to a carbon atom (C=O) bonded to an oxygen atom by a double bond.

[0217] As used herein or as part of another group, the term "oxo" refers to an oxygen atom (=O) connected to another atom via a double bond.

[0218] As used herein or as part of another group, the term "C" 1-7 "Alkoxy" refers to a C-type molecule that is attached to the parent molecule via an oxygen atom, as defined in this article. 1-7 Alkyl group. C 1-7 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0219] As used in this article, the term "hydroxyl C" 1-7 "alkyl" refers to a group formed by the formation of C14 atoms as defined herein. 1-7 An alkyl group is attached to at least one hydroxyl group, as defined herein, of the parent molecule moiety. Hydroxyl group C 1-7 Representative examples of alkyl groups include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl, and 1-methyl-1-hydroxypropyl.

[0220] As used in this article, the term "halogenated C" 1-7 "alkyl" refers to a group formed by the formation of C14 atoms as defined herein. 1-7 An alkyl group is attached to at least one halogen as defined herein to the parent molecule moiety. Halogenated C 1-7 Representative examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.

[0221] As used in this article, the term "cyanoC" 1-7 "alkyl" refers to a group formed by the formation of C14 atoms as defined herein. 1-7 An alkyl group is attached to a cyano group, as defined herein, at the parent molecule site. The cyano group (C) 1-7 Representative examples of alkyl groups include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, and 2-cyanopropyl.

[0222] As used in this article, the term "halogenated C" 1-7 "Alkoxy" refers to a group formed by the formation of an alkoxy group as defined in this article. 1-7 An alkoxy group is attached to at least one halogen as defined herein, which is a moiety of the parent molecule.

[0223] As used herein, the term "phenyl C" 1-7 "alkyl" refers to a group formed by the formation of C14 atoms as defined herein. 1-7 An alkyl group is attached to at least one phenyl group of the parent molecule.

[0224] As used herein or as part of another group, the term "C" 1-7 "alkyl carbonyl" refers to a carbonyl group attached to the parent molecule via a carbonyl group as defined herein, and a C1 group as defined herein. 1-7 alkyl.

[0225] As used herein or as part of another group, the term "C" 1-7 Alkoxy C 1-7 "alkyl" refers to a group formed by the formation of C14 atoms as defined herein. 1-7 An alkyl group is attached to at least one C1 as defined herein to the parent molecule moiety. 1-7 Alkyl group.

[0226] As used herein, the term "4-12 membered heterocyclic group" refers to a saturated, partially saturated, or aromatic ring having 4-12 ring atoms, wherein 1-4 atoms are heteroatoms selected from N, O, and S. One embodiment of "4-12 membered heterocyclic group" is "4-10 membered heterocyclic group," which refers to a saturated, partially saturated, or aromatic ring having 4-10 ring atoms, wherein 1-4 atoms are heteroatoms selected from N, O, and S. Representative examples of 4-12 membered heterocycles include, but are not limited to, oxo-heterocyclic butyl, aza-cyclic butyl, pyrazolyl, 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, pyrimidinyl, pyridinyl, piperidinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazole, indoleyl, and 4,5-dihydroimidazolyl rings.

[0227] As used herein, the term "3-10 membered carbocyclic group" refers to a saturated, partially saturated, or aromatic ring having 3 to 10 ring atoms consisting only of carbon atoms. One embodiment of "3-10 membered carbocyclic group" is "3-6 membered carbocyclic group," which refers to a saturated, partially saturated, or aromatic ring having 3 to 6 ring atoms consisting only of carbon atoms. Representative examples of 3-10 membered carbocyclic groups include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0228] As used herein, unless otherwise defined, the term "substitution" in relation to various residues refers to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C. 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxyl, amino, nitro, cyano, thiol C 1-7 Alkyl, Methylsulfonyl, C 1-7 Alkoxy, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl or amino C 1-7 Alkyl substituents. Halogens and C are preferred.1-7 Alkyl, hydroxyl, amino, halogenated C 1-7 Alkyl, C 1-7 Alkoxy and methanesulfonyl substituents. In a preferred group of substituents, the substituent is 1-2 selected from C... 1-7 Alkyl or halogen substituents, especially C 1-3 Alkyl or halogen substituents, especially methyl, ethyl, chlorine, fluorine or bromine substituents.

[0229] Unless otherwise defined, the "substituted" group may contain 1 to 3, preferably 1 or 2 of the above-mentioned substituents.

[0230] Optically active enantiomers or diastereomers of compounds of formula (I) can be prepared, for example, by resolving the racemic final product using known methods or by using suitable optically active raw materials. Similarly, racemic compounds of formula (I) can be prepared using racemic raw materials. The resolution of racemic compounds of formula (I) or their racemic raw materials can be accomplished, for example, by reacting the racemic compound with an optically active acid to convert it into a salt of its diastereomer and subsequently separating the diastereomer by crystallization. Representative examples of such optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography can also be used to resolve racemic mixtures.

[0231] Pharmaceutically acceptable salts are well known in the pharmaceutical field. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts such as sodium and potassium salts; and alkaline earth metal salts such as calcium and magnesium salts. Non-limiting examples of salts formed with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbic acid salts, acetates, oxalates, fumarates, hemifumarates, and succinates. When applicable, pharmaceutically acceptable esters can be prepared using known methods with pharmaceutically acceptable acids; these esters are routine in the pharmaceutical field and retain the pharmacological properties of their free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester. Phosphate esters and carbonates are also within the scope of this invention.

[0232] The definition of formula (I) above includes all possible isotopes and isomers of the compound, such as stereoisomers, including geometric isomers, such as Z and E isomers (cis and trans isomers), and optical isomers, such as diastereomers and enantiomers, as well as prodrug esters, such as phosphate esters and carbonates.

[0233] Those skilled in the art will understand that the compounds of the present invention can contain at least one chiral center. Therefore, these compounds can exist in optically active or racemic forms. It should be understood that formula (I) includes any racemic or optically active form, or a mixture thereof. In one embodiment, the compound is a pure (R)-isomer. In another embodiment, the compound is a pure (S)-isomer. In another embodiment, the compound is a mixture of (R) and (S) isomers. In another embodiment, the compound is a racemic mixture containing equal amounts of (R) and (S) isomers. The compound may contain two chiral centers. In this case, according to one embodiment, the compound is a mixture of diastereomers. According to another embodiment, the compounds of the present invention are a mixture of enantiomers. According to yet another embodiment, the compound is a pure enantiomer. Individual isomers can be obtained using the corresponding isomer forms of the starting materials, or they can be separated according to conventional separation methods after the preparation of the final compound. For the separation of optical isomers, such as separating enantiomers or diastereomers from their mixtures, conventional resolution methods, such as fractional crystallization, can be employed.

[0234] The compounds of the present invention may also exist as tautomers or equilibrium mixtures thereof, wherein a proton of the compound is transferred from one atom to another. Examples of tautomers include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-acid-nitro, imine-enamine, intracyclic tautomers of heterocycles such as pyrazole rings, etc. Tautomer forms are intended to be included in compounds of formula (I), even if only one tautomer form may be described.

[0235] Examples of preferred compounds of formula (I) include

[0236] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl ketone (compound 1);

[0237] (7-Fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 2);

[0238] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl) methyl ketone (compound 3);

[0239] (3,4-Dihydroquinoline-1(2H)-yl)(4-methyl-5-phenylpyridin-3-yl)methyl ketone (compound 4);

[0240] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl) methyl ketone (compound 5);

[0241] (4-amino-5-phenylpyridin-3-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 6);

[0242] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methyl ketone (compound 7);

[0243] (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 8);

[0244] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)methyl ketone (compound 9);

[0245] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 10);

[0246] (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 11);

[0247] (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 12);

[0248] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(2,3-Dihydrobenzofuran-6-yl)pyrazin-2-yl)methyl ketone (compound 13);

[0249] (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-methoxyphenyl)pyrazin-2-yl)methyl ketone (compound 14);

[0250] (3,4-Dihydroquinoline-1(2H)-yl)(6-phenylpyrazin-2-yl)methyl ketone (compound 15);

[0251] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 16);

[0252] (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 17);

[0253] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 18);

[0254] (5-(3,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 19);

[0255] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyrazin-2-yl)methyl ketone (compound 20);

[0256] (6-(4-fluorophenyl)pyrazin-2-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methyl ketone (compound 21);

[0257] (6-(4-fluorophenyl)pyrazin-2-yl)(2-methyl-3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 22);

[0258] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 23);

[0259] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 24);

[0260] (3,4-Dihydroquinoline-1(2H)-yl)(6-(3-methoxyphenyl)pyrazin-2-yl)methyl ketone (compound 25);

[0261] (6-(4-fluorophenyl)pyrazin-2-yl)(3-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 26);

[0262] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-hydroxyphenyl)pyridin-3-yl)methyl ketone (compound 27);

[0263] (5-(2,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 28);

[0264] (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 29);

[0265] (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methyl ketone (compound 30);

[0266] (5-(4-fluorophenyl)pyridin-3-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methyl ketone (compound 31);

[0267] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-nitrophenyl)pyridin-3-yl)methyl ketone (compound 32);

[0268] (5-(cyclohex-1-en-1-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 33);

[0269] (3,4-Dihydro-1,5-Naphtho-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 34);

[0270] 4-(6-(4-fluorophenyl)pyrazine-2-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid ethyl ester (compound 35);

[0271] 1-(5-Phenylanoyl)-2,3-Dihydroquinoline-4(1H)-one (Compound 36);

[0272] (3,4-Dihydro-1,5-Naphthoid-1(2H)-yl)(6-Phenylen-2-yl)methyl ketone (compound 37);

[0273] (3,4-Dihydroquinoline-1(2H)-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 38);

[0274] (5-(1H-pyrrolo-1-yl)pyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methyl ketone (compound 39);

[0275] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methyl ketone (compound 40);

[0276] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(2-fluorophenyl)pyridin-3-yl)methyl ketone (compound 41);

[0277] (3,4-Dihydro-1,5-Naphtho-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 42);

[0278] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)methyl ketone (compound 43);

[0279] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl ketone (compound 44);

[0280] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 45);

[0281] 4-((5-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 46);

[0282] 1-((5-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline (compound 47);

[0283] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl ketone (compound 48);

[0284] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6'-fluoro-[3,3'-bipyridine]-5-yl)methyl ketone (compound 49);

[0285] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 50);

[0286] (3,4-Dihydroquinoline-1(2H)-yl)(5-(1-phenylvinyl)pyridin-3-yl)methyl ketone (compound 51);

[0287] (3,4-Dihydroquinoline-1(2H)-yl)(6-phenylpyridazin-4-yl)methyl ketone (compound 52);

[0288] (6-Methoxy-3,4-dihydroquinoline-1(2H)-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 53);

[0289] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methyl ketone (compound 54);

[0290] (5-(4-fluorophenyl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 55);

[0291] (5-(4-fluorophenyl)pyridin-3-yl)((4aS,8aS)-octahydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 56);

[0292] (5-(4-fluorophenyl)pyridin-3-yl)((4aR,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 57);

[0293] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-nitrophenyl)pyridin-3-yl)methyl ketone (compound 58);

[0294] (5-Methoxy-3,4-dihydroquinoline-1(2H)-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 59);

[0295] (5-(4-fluorophenyl)pyridin-3-yl)(dihydroindol-1-yl)methyl ketone (compound 60);

[0296] (3,4-Dihydro-1,5-Naphtho-1(2H)-yl)(5-Phenyridin-3-yl)methyl ketone (compound 61);

[0297] [3,4'-Bipyridine]-5-yl(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 62);

[0298] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)methyl ketone (compound 63);

[0299] (6-(4-fluorophenyl)pyridazin-4-yl)(2-methyl-3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 64);

[0300] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methyl ketone (compound 65);

[0301] (5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 66);

[0302] 1-(5-phenylnicotinyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid methyl ester (compound 67);

[0303] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-((dimethylamino)methyl)phenyl)pyridin-3-yl)methyl ketone (compound 68);

[0304] (7-Methoxy-3,4-dihydroquinoline-1(2H)-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 69);

[0305] [3,3'-Bipyridine]-5-yl(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 70);

[0306] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(p-tolyl)pyridin-3-yl)methyl ketone (compound 71);

[0307] (5-(2,3-dihydrobenzofuran-6-yl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 72);

[0308] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl ketone (compound 73);

[0309] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(pyrrolidine-1-yl)pyridin-3-yl)methyl ketone (compound 74);

[0310] 2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl) methyl ketone (compound 75);

[0311] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidine-1-yl)pyrazin-2-yl)methyl ketone (compound 76);

[0312] (6-(3,3-difluoroazacyclobutane-1-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 77);

[0313] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methyl ketone (compound 78);

[0314] 1-(3,4-dihydroquinolin-1(2H)-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethyl-1-one (compound 79);

[0315] 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-methoxyphenyl)pyridin-3-yl)ethyl-1-one (compound 80);

[0316] 4-((5-phenylpyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 81);

[0317] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl ketone (compound 82);

[0318] (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-methyl-1H-imidazol-1-yl)pyrazin-2-yl)methyl ketone (compound 83);

[0319] (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl ketone (compound 84);

[0320] (6-Benzylpyrazin-2-yl)(3,4-Dihydroquinoline-1(2H)-yl)methyl ketone (compound 85);

[0321] 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethyl-1-one (compound 86);

[0322] (3,4-Dihydroquinoline-1(2H)-yl)(6-(3,5-Dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl ketone (compound 87);

[0323] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl ketone (compound 88);

[0324] 1-((5-(4-fluorophenyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroquinoline (compound 89); or

[0325] 1-((5-(4-fluorophenyl)pyridin-3-yl)methyl)dihydroindole (compound 90);

[0326] And its tautomers and pharmaceutically acceptable salts.

[0327] Depending on age, sex, weight, race, patient condition, the disease to be treated, route of administration, and active ingredient used, the compounds of the present invention can be administered to patients in therapeutically effective amounts typically ranging from about 0.5 to about 2000 mg / day, more typically from about 1 to about 500 mg / day, for example from about 2 to about 100 mg / day. The compounds of the present invention can be formulated into dosage forms using principles known in the art. The compounds can be given to patients as is or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. Selecting suitable ingredients for the composition is routine for those skilled in the art. Suitable carriers, solvents, gel-forming components, dispersion-forming components, antioxidants, colorants, sweeteners, wetting compounds, and other ingredients commonly used in this field can also be used. Compositions containing the active compound can be administered enterally or parenterally, with oral administration being preferred. The content of the active compound in the composition is about 0.5% to 100% of the total weight of the composition, typically from about 0.5% to about 20%.

[0328] The compounds of the present invention can be administered to an individual as the sole active ingredient or in combination with one or more other active ingredients for treating a specific disease.

[0329] In the treatment of steroid receptor-dependent diseases or conditions, such as endocrine cancers and conditions including prostate and breast cancer, a combination of the primary therapeutic agent and / or other treatments (e.g., radiation therapy) is often advantageous. The second (or third) agent to be administered may have the same or different mechanisms of action as the primary therapeutic agent.

[0330] Therefore, the compounds of the present invention can be administered in combination with other anticancer treatments that can be used to treat cancers such as prostate cancer or breast cancer. For example, the compounds of the present invention can be packaged with instructions indicating that the compound will be used in combination with other anticancer agents and cancer treatments. The present invention further includes combinations of the compounds of the present invention and one or more other reagents in kit form, for example, they are packaged together or placed in separate packages for sale as kits, or they are packaged in a form for co-preparation.

[0331] According to one embodiment of the invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered with glucocorticoids and / or mineralocorticoids, and optionally with one or more anticancer agents.

[0332] Examples of suitable glucocorticoids include, but are not limited to, hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. Examples of suitable mineralocorticoids include, but are not limited to, fludrocortisone, deoxycorticosterone, 11-deoxycortisone, and deoxycorticosterone acetate.

[0333] In addition to compounds of formula (I) or their pharmaceutically acceptable salts, other optional anticancer agents that may be administered include, but are not limited to,

[0334] - Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and dalolutamide);

[0335] - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and seviteronel);

[0336] - Chemotherapy agents (such as docetaxel and paclitaxel);

[0337] - Anti-estrogens (such as tamoxifen and fulvestrant);

[0338] - Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors);

[0339] -mTOR inhibitors (e.g., everolimus);

[0340] -AKT inhibitors (e.g., AZ5363);

[0341] - Radiopharmaceuticals (e.g., Alpharadin);

[0342] -GnRH / LHRH analogues (such as leuprolide);

[0343] -PI3K inhibitors (such as ederaris); and

[0344] -CDK4 / 6 inhibitors (e.g., ribociclib).

[0345] According to one embodiment of the invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual in need, along with a therapeutically effective amount of one or more anticancer agents selected from the following list:

[0346] - Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and dalolutamide);

[0347] - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and seviteronel);

[0348] - Chemotherapy agents (such as docetaxel and paclitaxel);

[0349] - Anti-estrogens (such as tamoxifen and fulvestrant);

[0350] - Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors);

[0351] -mTOR inhibitors (e.g., everolimus);

[0352] -AKT inhibitors (e.g., AZ5363);

[0353] - Radiopharmaceuticals (e.g., Alpharadin);

[0354] -GnRH / LHRH analogues (such as leuprolide);

[0355] -PI3K inhibitors (such as ederaris); and

[0356] -CDK4 / 6 inhibitors (e.g., ribociclib).

[0357] According to one embodiment of the invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual in need, along with a therapeutically effective amount of a steroidogenic inhibitor (e.g., a CYP17A1 inhibitor). Examples of suitable CYP17A1 inhibitors include, but are not limited to, abiraterone acetate and seveterinol.

[0358] According to one embodiment of the invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual in need, along with a therapeutically effective amount of a nonsteroidal androgen receptor (AR) antagonist. Examples of suitable AR antagonists include, but are not limited to, enzalutamide, apalutamide, and dalolutamide.

[0359] According to yet another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active ingredient selected from the following list:

[0360] - Glucocorticoids,

[0361] -Mineralocorticoids,

[0362] - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors),

[0363] -Nonsteroidal androgen receptor antagonists,

[0364] - Chemotherapy agents (such as docetaxel and paclitaxel);

[0365] - Anti-estrogens (such as tamoxifen and fulvestrant);

[0366] - Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors);

[0367] -mTOR inhibitors (e.g., everolimus);

[0368] -AKT inhibitors (e.g., AZ5363);

[0369] - Radiopharmaceuticals (e.g., Alpharadin);

[0370] -GnRH / LHRH analogues (such as leuprolide);

[0371] -PI3K inhibitors (such as ederaris); and

[0372] -CDK4 / 6 inhibitors (e.g., ribociclib),

[0373] For simultaneous, single, or sequential administration.

[0374] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amount indicated in the Physicians' Desk Reference (PDR) or in the amount determined by those skilled in the art.

[0375] The compounds of this invention can be prepared using suitable starting materials via various synthetic routes similar to those known in the literature. The invention is explained in more detail through the following experiments and examples. These experiments and examples are for illustrative purposes only and do not limit the scope of the invention as defined in the claims. Example:

[0376] Intermediate 1: 6-(2,3-dihydrobenzofuran-5-yl)pyrazine-2-carboxylic acid

[0377]

[0378] A mixture of methyl 6-chloro-2-pyrazincarboxylate (0.5 g, 2.90 mmol), 2,3-dihydrobenzofuran-5-boric acid (0.47 g, 2.90 mmol), PdCl₂(PPh₃)₂ (102.0 mg, 0.145 mmol), and sodium carbonate (0.30 g, 2.90 mmol) in acetonitrile / ethanol / water (2 ml / 2 ml / 2 ml) was degassed and heated in a microwave oven at 100 °C for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 ml) and filtered. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude residue was purified by column chromatography to give the title compound. LC-MS: m / z 243.1 [M+H] + .

[0379] The following intermediates are prepared from the raw materials shown in the table below according to the method described for intermediate 1.

[0380]

[0381] Intermediate 11: (5-bromopyridin-3-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone

[0382]

[0383] TEA (1.80 mL, 13.61 mmol) was added to a mixture of 5-bromopyridine-3-carbonyl chloride (1.0 g, 4.54 mmol) and 1,2,3,4-tetrahydroquinoline (0.60 g, 4.54 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. Water (10 mL) was added, and the product was extracted with DCM, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude residue was purified by column chromatography to give the title compound. LC-MS: m / z 317.4 [M+H] +

[0384] The following intermediates are prepared from the raw materials shown in the table below according to the method described for intermediate 12.

[0385]

[0386] Intermediate 18: (6-chloropyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone

[0387]

[0388] A few drops of DMF and oxaloyl chloride (0.858 ml, 10.0 mmol) were added to a mixture of 6-chloropyrazine-2-carboxylic acid (0.793 g, 5.0 mmol) and dried DCM (10 ml). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and fresh DCM (10 ml) was added. The mixture was cooled to 0–5 °C (ice-cold) and DIPEA (1.742 ml, 10.0 mmol) and 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.676 g, 5.0 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by rapid chromatography to give 0.92 g of the title compound. 1 H NMR (400MHz, d6-DMSO): δ8.95(s,2H),7.5-8.5(br,1H),7.00-7.17(m,1H),6.94(dd,1H),6.65-6.95(br,1H),4.14-4.52(m,2H),3.74-4.08(m,2H).

[0389] Intermediate 19: 2-(5-bromopyridin-3-yl)-1-(3,4-dihydroquinolin-1(2H)-yl)ethyl-1-one

[0390]

[0391] To a mixture of ice-cold 5-bromo-3-pyridinecarboxylic acid (0.216 g, 1.00 mmol), 1,2,3,4-tetrahydroquinoline (0.147 g, 1.10 mmol), and trimethylamine (0.558 mL, 4.00 mmol) in dried DMF (5.5 mL), 1-propanephosphocyclic anhydride (50% EtOAc solution, 0.795 mL, 1.35 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc and water and separated into phases. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by rapid chromatography to give 0.27 g of the title compound. 1 H NMR (400MHz, CDCl3): δ8.53(d,1H),8.23(br s,1H),7.74(br s,1H),6.98-7.26(m,4H),3.83(s,2H),3.81(t,2H),2.52-2.70(m,2H),1.94(quint,2H).

[0392] Intermediate 20: 2-(5-bromopyridin-3-yl)-1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetoone

[0393]

[0394] This compound was prepared from 5-bromo-3-pyridinecarboxylic acid and 3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials, according to the method described with respect to intermediate 19. Yield: 0.24 g. 1 H NMR (400MHz, CDCl3): δ8.58(d,1H),8.35(br s,1H),7.78-7.85(m,1H),6.99-7.22(m,2H),6.89-6.98(m,2H),4.24-4.32(m,2H),3.83-4.05(m,4H).

[0395] Intermediate 21: 4-((5-bromopyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0396]

[0397] A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.170 g, 1.259 mmol), 3-bromo-5-(chloromethyl)pyridine (0.260 g, 1.259 mmol), cesium carbonate (0.821 g, 2.52 mmol), and potassium iodide (0.021 g, 0.126 mmol) in dry acetonitrile (5.0 mL) was stirred at 90 °C until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The filtrate was evaporated and the crude product was purified by rapid chromatography to give 0.12 g of the title compound. 1 H NMR (400MHz, d6-DMSO): δ8.61(d,1H),8.54(d,1H),7.95-8.00(m,1H),6.63-6.7 5(m,3H),6.52-6.59(m,1H),4.53(s,2H),4.20-4.27(m,2H),3.38-3.45(m,2H).

[0398] Intermediate 22: Ethyl 5-(4-methyl-1H-imidazol-1-yl)nicotinic acid ester

[0399]

[0400] A mixture of tris(dibenzylacetone)dipalladium (7.33 mg, 0.008 mmol) and 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (8.65 mg, 0.018 mmol) in degassed toluene-dioxane (5:1, 1.0 mL) was stirred at 120 °C for 10 min under nitrogen atmosphere. Ethyl 5-bromonicotinic acid (0.23 g, 1.00 mmol), 4-methylimidazole (0.099 g, 1.20 mmol), and potassium phosphate (0.425 g, 2.00 mmol) were added, and the mixture was stirred at 120 °C until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The filtrate was dried and evaporated. The crude product was purified by rapid chromatography to obtain the pure compound. 1 H NMR (400MHz, CDCl3): δ9.18(dd,1H),8.88(dd,1H),8.28(dd,1H),7.85(d,1H),7.07-7.10(m,1H),4.47(q,2H),2.33(d,3H),1.45(t,3H).

[0401] The following intermediates are prepared from the raw materials shown in the table below according to the method described for intermediate 22.

[0402]

[0403] Intermediate 25: Methyl 6-benzylpyrazine-2-carboxylate

[0404]

[0405] To a degassed THF mixture (10 mL) of methyl 6-chloropyrazine-2-carboxylate (0.173 g, 1.00 mmol), potassium phosphate (0.637 g, 3.00 mmol), dicyclohexylphosphine-2,6-dimethoxybiphenyl (0.041 g, 0.10 mmol), and palladium acetate (0.011 g, 0.05 mmol), β-benzyl-9-boronabicyclo[3.3.1]nonane (0.5 M THF solution, 2.5 mL, 5.0 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 65 °C until the reaction was complete. The cooled mixture was diluted with DCM and filtered through a diatomaceous earth short column. The filtrate was washed with 5% Na₂CO₃ aqueous solution, water, and brine, dried, and evaporated. The crude product was purified by rapid chromatography to give 0.16 g of the title compound. 1 H NMR (400MHz, CDCl3): δ 9.14 (d, 1H), 8.57 (d, 1H), 7.23-7.37 (m, 5H), 4.31 (s, 2H), 4.05 (s, 3H).

[0406] Example 1

[0407] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl ketone (Compound 1)

[0408]

[0409] a)(5-bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone(3)

[0410] Methyl 5-bromonicotinic acid (8.0 g, 37.0 mmol) was treated with 4-dihydro-2H-benzo[b][1,4]oxazine (7.5 g, 56.0 mmol) in 40 mL of toluene at 25 °C for 16 h in the presence of triethylamine (11.0 g, 15 mL, 0.11 mol) and trimethylaluminum (28.0 mL, 2 M toluene solution, 56.0 mmol). The title compound was purified by Combi-flash chromatography. 1H-NMR(400MHz,DMSO-d6)δ:8.80(d,1H),8.68(d,1H),8.20-8.26(m,1H),7.20-7.45(m, 1H),7.04(t,1H),6.92(d,1H),6.70-6.80(m,1H),4.31-4.40(m,2H),3.82-3.90(m,2H). MS(ESI)m / z[M+1]+: 318.99.

[0411] b)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl ketone (compound 1)

[0412] Under an inert atmosphere, 3-(trifluoromethoxy)phenyl)boronic acid (142 mg, 0.689 mmol) and sodium carbonate (133 mg, 1.25 mmol) were added to a solution of methyl(5-bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) ketone (200 mg, 0.627 mmol) in a mixture of 2.5 mL ethanol, 10 mL toluene, and 2.5 mL water. The reaction mixture was degassed for 10 min, and then bis(triphenylphosphine)palladium(II) dichloride was added. Degassed for another 10 min. The resulting reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete as indicated by TLC, the mixture was filtered through a diatomaceous earth bed. The resulting filtrate was diluted with water (10 mL) and EtOAc (21 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Combi-flash chromatography, and eluted with a 5-40% heptane solution of EtOAc to give 0.08 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 9.05(d,1H),8.73(s,1H),8.28(s,1H),7.81(d,1H),7.76(s,1H),7.65(t,1H),7.45(d d,1H),7.10-7.30(m,1H),7.03(dt,1H),6.94(dd,1H),6.70-6.80(m,1H),4.32-4.40(m,2H),3.86-3.95(m,2H). MS(ESI)m / z[M+1] + :401.13.

[0413] Example 2

[0414] (7-Fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 2)

[0415]

[0416] a) Methyl 5-(4-fluorophenyl)nicotinic acid (3)

[0417] Methyl 5-bromonicotinic acid (2.0 g, 9.3 mmol) was treated with (4-fluorophenyl)boronic acid (1.4 g, 10.0 mmol) in 40 mL of DME and 20 mL of water in the presence of sodium carbonate (2.0 g, 19.0 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.65 g, 0.93 mmol) at 90 °C for 4 h. Purification was performed by Combi-flash chromatography, eluting with a 5–30% EtOAc solution in heptane as the eluent to give 1.7 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ: 9.13 (s, 1H), 9.07 (s, 1H), 8.47 (d, 1H), 7.87 (t, 2H), 7.37 (t, 2H), 3.93 (s, 3H). MS(ESI)m / z[M+1]+: 232.06.

[0418] b)(7-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 2)

[0419] Methyl 5-(4-fluorophenyl)nicotinic acid (200 mg, 0.865 mmol) was treated with 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (199 mg, 1.30 mmol) in 8 mL toluene at 25 °C for 16 h in the presence of TEA (0.36 mL, 2.59 mmol) and trimethylaluminum (0.65 mL, 2.0 M toluene solution, 1.30 mmol). Purification was performed by Combi-flash chromatography, eluting with a 5–25% EtOAc solution in heptane as the eluent to give 0.235 g of the title compound. 1 H NMR(400MHz, DMSO-d6)δ: 8.99(d,1H),8.69(s,1H),8.22(s,1H),7.00-7.9 0(m,5H),6.84(dd,1H),6.67(m,1H),4.30-4.40(m,2H),3.84-3.93(m,2H). MS(ESI)m / z[M+1] + :352.11.

[0420] Example 3

[0421] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methyl ketone (compound 3)

[0422]

[0423] a) 3-Bromo-4-methyl-5-phenylpyridine (3)

[0424] 3,5-Dibromo-4-methylpyridine (5.0 g, 20.0 mmol) was treated with phenylboronic acid (2.7 g, 22.0 mmol) in the presence of sodium carbonate (4.2 g, 40.0 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.4 g, 2.0 mmol) in 60 mL DME and 30 mL water at 90 °C for 6 h. Purification was performed by Combi-flash chromatography, eluting with a 5–30% EtOAc solution in heptane as the eluent to give 3.1 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ: 8.69 (s, 1H), 8.35 (s, 1H), 7.43-7.54 (m, 3H), 7.38-7.44 (m, 2H), 2.30 (s, 3H). MS(ESI)m / z[M+1]+: 248.01.

[0425] b) 4-Methyl-5-phenylnicotinate (4)

[0426] Triethylamine (7.8 mL, 56.0 mmol) was added to a MeOH:DMSO (1:1) solution of 3-bromo-4-methyl-5-phenylpyridine (2.8 g, 11.0 mmol). The reaction mixture was degassed with argon for 10 min, followed by the addition of palladium(II) acetate (0.51 g, 2.3 mmol), 1,3-bis(diphenylphosphine)propane (0.93 g, 2.3 mmol), and CO gas. The resulting reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete as indicated by TLC, all volatiles were evaporated under reduced pressure. The resulting residue was diluted with water (20 mL) and EtOAc (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Combi-flash chromatography, eluting with a 5–40% EtOAc solution in heptane to give 2.3 g of the title compound. 1H-NMR (400MHz, DMSO-d6): δ: 8.87 (s, 1H), 8.52 (s, 1H), 7.41-7.53 (m, 3H), 7.36-7.41 (m, 2H), 3.89 (s, 3H), 2.39 (s, 3H). MS(ESI)m / z[M+1]+: 228.03.

[0427] c)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methyl ketone (compound 3)

[0428] 4-Methyl-5-phenylnicotinate (500 mg, 2.20 mmol) was treated with 3,4-dihydro-2H-benzo[b][1,4]oxazine (446 mg, 3.30 mmol) in 12 mL of toluene at 100 °C for 16 h in the presence of triethylamine (0.93 mL, 6.60 mmol) and trimethylaluminum (1.65 mL, 2.0 M toluene solution, 3.30 mmol). Purification was performed by Combi-flash chromatography, eluting with a 5–40% EtOAc solution in heptane as the eluent to give 0.05 g of the title compound. Rf (50% EtOAc / heptane) = 0.2. 1 HNMR (400MHz, DMSO-d6) δ: 8.48 (s, 1H), 8.40 (s, 1H), 7.26-7.54 (m, 6H), 7.06 (s, 1H) ,6.92(d,1H),6.75-6.84(m,1H),4.31-4.40(m,2H),3.31-3.40(m,2H),2.16(s,1H). MS(ESI)m / z[M+1] + 330.97.

[0429] Example 4

[0430] (3,4-Dihydroquinoline-1(2H)-yl)(4-methyl-5-phenylpyridin-3-yl)methyl ketone (compound 4)

[0431]

[0432] 4-Methyl-5-phenylnicotinate (500 mg, 2.20 mmol) was treated with 1,2,3,4-tetrahydroquinoline (440 mg, 3.30 mmol) in 15 mL toluene at 100 °C for 16 h in the presence of triethylamine (0.93 mL, 6.60 mmol) and trimethylaluminum (1.65 mL, 2.0 M toluene solution, 3.30 mmol). Purification was performed by Combi-flash chromatography, eluting with a 5–30% EtOAc solution in heptane as the eluent to give 0.15 g of the title compound. Rf (50% EtOAc / heptane) = 0.2. 1 H NMR (400MHz, DMSO-d6) δ: 8.35 (s, 2H), 7.40-7.55 (m, 3H), 7.25-7.35 (m, 2H), 7.18-7.22 (m ,1H),6.98-7.07(m,2H),3.74-3.80(m,2H),2.84(t,2H),2.09(s,3H),1.94-2.03(m,2H). MS(ESI)m / z[M+1] + 329.15.

[0433] Example 5

[0434] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methyl ketone (compound 5)

[0435]

[0436] a) 3-Bromo-5-(4-fluorophenyl)-4-methylpyridine (3)

[0437] 3,5-Dibromo-4-methylpyridine (5.0 g, 0.02 mol) was treated with (4-fluorophenyl)boronic acid (3.0 g, 0.02 mol), Na₂CO₃ (6.0 g, 0.06 mol), and Pd(PPh₃)₂Cl₂ (1.0 g, 2.0 mmol) in 60 mL of DME and 30 mL of water at 100 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 5-40% ethyl acetate as the eluent to give 4.2 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ: 8.65 (s, 1H), 8.31 (s, 1H), 7.23-7.30 (m, 2H), 7.10-7.20 (m, 2H), 2.33 (s, 3H). MS(ESI)m / z[M+1]+: 265.90.

[0438] b) 5-(4-fluorophenyl)-4-methylnicotinic acid methyl ester (4)

[0439] 3-Bromo-5-(4-fluorophenyl)-4-methylpyridine (5.0 g, 0.02 mol) was treated with triethylamine (8.0 g, 11 mL, 79.0 mmol), palladium(II) acetate (0.71 g, 3.2 mmol), 1,3-bis(diphenylphosphine)propane (1.3 g, 3.2 mmol), and CO gas in 60 mL DMSO and 60 mL MeOH at 100 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 10–40% ethyl acetate as the eluent to give 3.2 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ: 8.87 (s, 1H), 8.52 (s, 1H), 7.41-7.50 (m, 2H), 7.30-7.37 (m, 2H), 3.89 (s, 3H), 2.38 (s, 3H). MS(ESI)m / z[M+1]+: 343.10.

[0440] c)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methyl ketone (compound 5)

[0441] Methyl 5-(4-fluorophenyl)-4-methylnicotinate (400 mg, 1.63 mmol) was treated with 3,4-dihydro-2H-benzo[b][1,4]oxazine (331 mg, 2.45 mmol) in 10 mL toluene at 95 °C for 18 h in the presence of triethylamine (0.68 mL, 4.89 mmol) and trimethylaluminum (1.22 mL, 2 M toluene solution, 2.45 mmol). Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 5-40% ethyl acetate as the eluent to give 0.118 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 8.18-8.57(m,2H),7.41-7.55(m,2H),7.34(t,2H),7.00-7.10(m ,1H),6.93(d,2H),6.30-6.60(m,1H),4.20-4.50(m,2H),3.54-3.80(m,2H),2.16(s,3H). MS(ESI)m / z[M+1] + 349.12.

[0442] Example 6

[0443] (4-Amino-5-phenylpyridin-3-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 6)

[0444]

[0445] a) 3-Bromo-5-phenylpyridine-4-amine (3)

[0446] 3,5-Dibromopyridin-4-amine (6.0 g, 24.0 mmol) was treated with phenylboronic acid (3.2 g, 26.0 mmol), Na₂CO₃ (5.0 g, 48.0 mmol), and Pd(PPh₃)₂Cl₂ (1.7 g, 2.4 mmol) in 12 mL of DME and 6 mL of water at 90 °C for 4 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 5–40% ethyl acetate as the eluent to give 3.6 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ: 8.29 (s, 1H), 7.91 (s, 1H), 7.47-7.55 (m, 2H), 7.38-7.47 (m, 3H), 5.73 (bs, 2H). MS(ESI)m / z[M+1]+: 248.97.

[0447] b) Methyl 4-amino-5-phenylnicotinic acid (4)

[0448] 3-Bromo-5-phenylpyridin-4-amine (2.8 g, 11.0 mmol) was treated with triethylamine (5.7 g, 7.8 mL, 56.0 mmol), palladium(II) acetate (1.0 g, 4.5 mmol), 1,3-bis(diphenylphosphine)propane (1.9 g, 4.5 mmol), and CO gas in 50 mL MeOH and 50 mL DMSO at 80 °C for 12 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 10–40% ethyl acetate as the eluent to give 1.6 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ8.74(s,1H),8.03(s,1H),7.48-7.55(m,2H),7.38-7.48(m,3H),6.87(bs,2H),3.85(s,3H). MS(ESI)m / z[M+1]+: 229.19.

[0449] c)(4-amino-5-phenylpyridin-3-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 6)

[0450] Methyl 4-amino-5-phenylnicotinic acid (500 mg, 2.19 mmol) was treated with a 20 mL toluene solution of 1,2,3,4-tetrahydroquinoline (438 mg, 3.29 mmol), triethylamine (0.92 mL, 6.57 mmol), and trimethylaluminum (1.64 mL, 2.0 M toluene solution, 3.29 mmol) at 100 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a 5-30% ethyl acetate solution in heptane to give 0.025 g of the title compound. (NMR / MS data are in Table 2). 1 H NMR (400MHz, DMSO-d6) δ: 7.90 (s, 1H), 7.79 (s, 1H), 7.51 (t, 2H), 7.37-7.47 (m, 3H), 7 .20(d,1H),6.92-7.06(m,3H),5.83(bs,2H),3.78(t,2H),2.82(t,2H),1.96(q,2H). MS(ESI)m / z[M+1] + :302.20.

[0451] Example 7

[0452] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methyl ketone (compound 7)

[0453]

[0454] a) 3-Chloro-5-(4-fluorophenyl)pyridazine (3)

[0455] 3,5-Dichloropyridazine (3.0 g, 20.1 mmol) was treated with (4-fluorophenyl)boric acid (3.10 g, 22.2 mmol), KF (2.93 g, 50.3 mmol), diacetoxypalladium (226 mg, 1.01 mmol), and Q-PHOS (716 mg, 1.01 mmol) in 40 mL toluene and 10 mL of aqueous solution at 80 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a 5-40% ethyl acetate solution in heptane to give 1.0 g of the title compound. Rf (70% EtOAc / heptane) = 0.4. 1 H-NMR (400MHz, DMSO-d6) δ: 9.68 (d, 1H), 8.29 (d, 1H), 8.09 (dt, 2H), 7.43 (dd, 2H). MS(ESI)m / z[M+1]+: 209.02.

[0456] b) Methyl 5-(4-fluorophenyl)pyridazine-3-carboxylate (4)

[0457] 3-Chloro-5-(4-fluorophenyl)pyridazine (850 mg, 4.07 mmol) was treated with 50 mL of MeOH solution containing triethylamine (1.14 mL, 8.15 mmol), PdCl2 (dppf) (298 mg, 0.407 mmol), and CO gas at 100 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 10-40% ethyl acetate as the eluent to give 0.87 g of the title compound. 1 H-NMR (400MHz, DMSO-d6): δ9.86(d,1H),8.45(d,1H),8.11(dd,2H),7.44(dd,2H),3.99(s,3H). MS(ESI)m / z[M+1]+: 233.02.

[0458] c)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methyl ketone (compound 7)

[0459] Methyl 5-(4-fluorophenyl)pyridazine-3-carboxylate (500 mg, 2.15 mmol) was treated with a 15 mL toluene solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (437 mg, 3.23 mmol), triethylamine (0.91 mL, 6.46 mmol), and trimethylaluminum (1.61 mL, 2.0 M toluene solution, 3.23 mmol) at 100 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a 5-40% ethyl acetate solution in heptane to give 0.142 g of the title compound. Rf (50% EtOAc / heptane) = 0.2.

[0460] Example 8

[0461] (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 8)

[0462]

[0463] a)(6-bromopyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone(3)

[0464] Methyl 5-(4-fluorophenyl)pyridazine-3-carboxylate (20 mg, 0.086 mmol) was treated with a 5 mL toluene solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (18.2 mg, 0.129 mmol), triethylamine (36 μl, 0.258 mmol), and trimethylaluminum (65 μl, 2.0 M toluene solution, 0.129 mmol) at 100 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 20-60% ethyl acetate as the eluent to give 0.025 g of the title compound. Rf (50% EtOAc / heptane) = 0.2. Yield: 70%. 1 H-NMR (400MHz, DMSO-d6): δ: 9.01 (s, 1H), 8.96 (s, 1H), 7.50-8.50 (m, 1H), 7.08 (t,1H),6.93(d,1H),6.70-6.90(m,1H),4.20-4.48(m,2H),3.80-3.92(m,2H). MS(ESI)m / z[M+1]+:320.05.

[0465] b)(6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 8)

[0466] (6-bromopyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (500 mg, 1.56 mmol) was treated with 2.5 mL of ethanol, 10 mL of toluene, and 2.5 mL of aqueous solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)benzo[d]oxazole (383 mg, 1.56 mmol), sodium carbonate (331 mg, 3.12 mmol), and Pd(PPh3)2Cl2 (110 mg, 0.156 mmol) at 90 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 0-50% ethyl acetate as the eluent to give 0.3 g of the title compound. 1 HNMR (400MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.10 (d, 1H), 7. 90(d,1H),7.41-7.51(m,1H),7.06(t,1H),6.96(d,1H),6.78(t,1H),4.39(t,2H),4.05(t,2H). MS(ESI)m / z[M+1] + : m / z359.15.

[0467] Example 9

[0468] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)methyl ketone (compound 9)

[0469]

[0470] (6-bromopyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (500 mg, 1.56 mmol) was treated with (3-(trifluoromethoxy)phenyl)boronic acid (354 mg, 1.72 mmol), sodium carbonate (331 mg, 3.12 mmol), and Pd(PPh3)2Cl2 (110 mg, 0.156 mmol) in 0.63 mL of ethanol, 2.5 mL of toluene, and 0.63 mL of aqueous solution at 90 °C for 16 h. Purification was performed by Combi-flash chromatography, eluting with a heptane solution of 0-35% ethyl acetate as the eluent to give 0.4 g of the title compound. 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.96(s,1H),8.07(d,1H),7.89(s,1H),7.65(t,1H),7.4 8(d,1H),7.35-7.46(m,1H),7.05(t,1H),6.94(d,1H),6.77(t,1H),4.38(t,2H),4.03(t,2H). MS(ESI)m / z[M+1] + : m / z 402.12.

[0471] Example 10

[0472] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 10)

[0473]

[0474] A solution of 50% propylphosphonic anhydride (T3P) in EtOAc (0.6 mL, 1.0 mmol) was added to a mixture of 5-phenylnicotinic acid (0.10 g, 1.50 mmol), 2,3-dihydro-1,4-benzoxazine (0.07 g, 0.50 mmol), and Et3N (0.41 mL, 4.02 mmol) in DMF (2 mL). The mixture was stirred overnight at room temperature under N2. The mixture was diluted with EtOAc (10 mL) and 5% Na2CO3 (5 mL) and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography to give the title compound.1 ¹H NMR (chloroform-d, 400MHz) δ: 8.88 (d, 1H), 8.69 (d, 1H), 7.99 (t, 1H), 7.4–7.5 (m, 5H), 6.8–7.1 (m, 3H), 6.6–6.8 (m, 1H), 4.3–4.5 (m, 2H), 4.0–4.1 (m, 2H).

[0475] Example 11

[0476] (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 11)

[0477]

[0478] A mixture of 5-phenylnicotinic acid chloride (0.1 g, 0.46 mmol) and 1,2,3,4-tetrahydro-1,6-naphthylidine (61.6 mg, 0.46 mmol) in DCM (5 mL) was cooled to 0 °C, and then Et3N (0.2 mL, 1.38 mmol) was added. The mixture was stirred at room temperature for 12 h. Water (10 mL) was added and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude residue was purified by column chromatography to give the title compound. 1 H NMR(DMSO-d6,600MHz)δ: 8.99(d,1H),8.63(d,1H),8.39(s,1H),8.17(t,1H),8.13(d,1H),7.72(d,2H),7.51(t,2H),7.4-7.5(m,1H),7.20(br d,1H),3.8-3.8(m,2H),2.86(t,2H),1.99(quin,2H). LC-MS: m / z 316.4(M+H) + .

[0479] The following compounds were prepared according to the methods described above. The compound numbers, characterization data, starting materials and reaction conditions (mentioned in the example numbers), and purification methods are shown in the table below.

[0480] Purification method used:

[0481] a) Crystallization

[0482] b) Column chromatography

[0483] c) Precipitation in an aqueous medium

[0484] d) Semi-preparative HPLC

[0485] e) Research and development

[0486] f) Formation into salt.

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501] Example 12

[0502] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl ketone (compound 73)

[0503]

[0504] To a degassed mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (0.091 g, 0.438 mmol), (5-bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (0.112 g, 0.35 mmol), and cesium carbonate (0.319 g, 0.98 mmol) in DME-water (2.5:1, 3.5 mL), tetrakis(triphenylphosphine)palladium (0.040 g, 0.035 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 90 °C until the reaction was complete. The cooled reaction mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The filtrate was washed with water and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give 0.083 g of the title compound. 1 H NMR (400MHz, CDCl3): δ8.78(d,1H),8.51(d,1H),7.88(t,1H),7.74(d,1H),7.65(s,1H),7.00-7.06(m,1H ),6.94(dd,1H),6.64-6.74(m,1H),6.60-6.70(m,1H),4.37-4.48(m,2H),4.03-4.11(m,2H),3.97(s,3H). LC-MS: m / z 321.8 (M+H).

[0505] Example 13

[0506] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(pyrrolidine-1-yl)pyridin-3-yl)methyl ketone (compound 74)

[0507]

[0508] A mixture of pyrrolidine (0.067 mL, 0.80 mmol), (5-bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (0.128 g, 0.40 mmol), sodium tert-butoxide (0.050 g, 0.52 mmol), tris(dibenzylacetone)dipalladium (0.018 g, 0.020 mmol), and racemic-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (0.025 g, 0.10 mmol) in dry toluene (1.5 mL) was stirred at 100 °C under a nitrogen atmosphere until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The filtrate was evaporated. The crude product was purified by reversed-phase rapid chromatography to give 0.046 g of the title compound. 1H NMR (400MHz, CDCl3): δ8.01(d,1H),7.93(d,1H),7.00-7.17(br,1H),6.97-7.04(m,1H),6.94(dd,1H),6.9 1(dd,1H),6.66-6.77(m,1H),4.33-4.42(m,2H),3.98-4.07(m,2H),3.24-3.35(m,4H),1.99-2.09(m,4H). LC-MS: m / z 310.7 (M+H).

[0509] Example 14

[0510] 2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl) methyl ketone (compound 75)

[0511]

[0512] This compound was prepared according to the method described in Example 13 from 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (0.047 g, 0.42 mmol) and (5-bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (0.112 g, 0.35 mmol) as starting materials. Yield: 0.028 g. 1 H NMR (400MHz, CDCl3): δ7.95(d,1H),7.92(d,1H),6.58-7.20(m,5H),4.30-4.44(m,2H),3.95 -4.08(m,2H),3.37-3.47(m,2H),3.21(d,2H),1.49-1.56(m,2H),1.08(s,3H),0.84(s,3H). LC-MS: m / z 350.9 (M+H).

[0513] Example 15

[0514] (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidine-1-yl)pyrazin-2-yl)methyl ketone (compound 76)

[0515]

[0516] A mixture of (6-chloropyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (0.096 g, 0.35 mmol) and pyrrolidine (0.146 mL, 1.75 mmol) in dry DMSO (1.0 mL) was stirred at 90 °C until the reaction was complete. The cooled mixture was diluted with EtOAc, washed with water and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to obtain the pure compound. 1 H NMR (400MHz, CDCl3): δ8.09(br s,1H),7.89(s,1H),6.96-7.07(m,1H),6.97-6.96(m,1H),6.3-6.87(m,2H), 4.24-4.49(m,2H),3.90-4.14(m,2H),3.15-3.63(m,4H),1.85-2.12(m,4H). LC-MS: m / z 311.8 (M+H).

[0517] The following compounds were prepared according to the method of Example 15. The compound numbers, characterization data, adjusted reaction conditions, and starting materials are shown in the table below.

[0518]

[0519] Example 16

[0520] 1-(3,4-Dihydroquinolin-1(2H)-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethyl-1-one (Compound 79)

[0521]

[0522] To a degassed DME-water mixture (6:1, 1.75 mL) of 2-(5-bromopyridin-3-yl)-1-(3,4-dihydroquinolin-1(2H)-yl)ethyl-1-one (0.116 g, 0.35 mmol), 4-fluorophenylboronic acid (0.059 g, 0.42 mmol), and sodium carbonate (0.104 g, 0.98 mmol) in 1.75 mL of water (6:1), tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 90 °C until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The filtrate was washed with water and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to obtain the pure compound. 1H NMR (400MHz, CDCl3): δ 8.66(d,1H),8.28(br s,1H),7.75(br s,1H),7.47-7.56(m,2H),7.01-7.27(m,6H),3.92(s,2H),3.82(t,2H),2.52-2.71(m,2H),1.93(quint,2H). LC-MS: m / z 347.9 (M+H).

[0523] The following compounds were prepared according to the method of Example 16. The compound numbers, characterization data, and starting materials are shown in the table below.

[0524]

[0525] Example 17

[0526] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl ketone (compound 82)

[0527]

[0528] A mixture of ethyl 5-(4-methyl-1H-imidazol-1-yl)nicotinate (0.080 g, 0.346 mmol), 1,2,3,4-tetrahydroquinoline (0.043 mL, 0.346 mmol), and di(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (0.071 g, 0.277 mmol) in dried toluene (0.5 mL) was stirred at 120 °C until the reaction was complete. The cooled mixture was terminated with 2 M HCl solution and then extracted with DCM. The organic phase was dried and evaporated. The crude product was purified by reversed-phase rapid chromatography to obtain the pure compound. 1 H NMR (600MHz, d6-DMSO): δ8.91(d,1H),8.35(s,1H),8.19(s,1H),8.06(s,1H),7.50(s,1H),7.24( d,1H),7.04(t,1H),6.65-7.00(m,2H),3.80(t,2H),2.85(t,2H),2.16(s,3H),1.99(quint,2H). LC-MS: m / z 319.7 (M+H).

[0529] The following compounds were prepared according to the method of Example 17. The compound numbers, characterization data, and starting materials are shown in the table below.

[0530]

[0531]

[0532] Example 18

[0533] 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethyl-1-one (Compound 86)

[0534]

[0535] a) 2-(5-(4-fluorophenyl)pyridin-3-yl)acetic acid

[0536]

[0537] To a degassed DME-water mixture (3:1, 8 mL) of 5-bromo-3-pyridineacetic acid (0.216 g, 1 mmol), 4-fluorophenylboronic acid (0.175 g, 1.25 mmol), and cesium carbonate (0.912 g, 2.80 mmol) under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (0.116 g, 0.10 mmol). The mixture was stirred at 90 °C until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The phases were separated, and the pH of the aqueous phase was adjusted to 6 with 2 M NaOH aqueous solution. The aqueous phase was extracted with EtOAc. The organic phase was dried and evaporated to give 0.10 g of the title compound. 1 H NMR (400MHz, d6-DMSO): δ12.56(s,1H),8.77(d,1H),8.46(d,1H),7.97(t,1H),7.74-7.81(m,2H),7.31-7.40(m,2H),3.73(s,2H).

[0538] b) 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)acet-1-one (Compound 85)

[0539]

[0540] This compound was prepared from 2-(5-(4-fluorophenyl)pyridin-3-yl)acetic acid (0.090 g, 0.35 mmol) and 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.052 g, 0.385 mmol) as starting materials, according to the method described in Intermediate 19. The crude product was purified by reversed-phase rapid chromatography. Yield: 0.039 g. 1H NMR (400MHz, CDCl3): δ8.70d(1H),8.40(brs,1H),7.78(br s,1H),7.48-7.58(m,2H),7.00-7.24(m,4H),6.87-6.99(m,2H),4.21-4.34(m,2H),3.89-4.11(m,4H). LC-MS: m / z 349.9 (M+H).

[0541] Example 19

[0542] (3,4-Dihydroquinoline-1(2H)-yl)(6-(3,5-Dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl ketone (compound 87)

[0543]

[0544] a)(6-bromopyrazin-2-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone

[0545]

[0546] This compound was prepared from methyl 6-bromopyrazine-2-carboxylate (0.217 g, 1.00 mmol) and 1,2,3,4-tetrahydroquinoline (0.126 ml, 1.00 mmol) as starting materials, according to the method in Example 17. The crude product was purified by rapid chromatography to give 0.080 g of the title compound. 1 H NMR (400MHz, CDCl3): δ8.30-8.88(m,2H),7.15-7.22(m,1H),7.07(t,1H),6.77-7. 07(br,1H),6.0-6.75(br,1H),3.76-4.12(m,2H),2.87(t,2H),2.09(quint.,2H).

[0547] b)(3,4-dihydroquinoline-1(2H)-yl)(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl ketone (compound 86)

[0548]

[0549] This compound was prepared according to the method described in Intermediate 22 from (6-bromopyrazin-2-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (0.080 g, 0.251 mmol) and 3,5-dimethylpyrazole (0.024 g, 0.251 mmol) as starting materials. The crude product was purified by reversed-phase rapid chromatography to give 0.012 g of the title compound. 1H NMR (400MHz, CDCl3): δ9.26(s,1H),8.72(d,1H),7.12-7.18(m,1H),6.99(t,1H),6.76-6.93(m,1H) ),6.19-6.6(m,1H),5.90(s,1H),3.97(t,2H),2.84(t,2H),2.26(s,3H),2.10(quint,2H),1.98(br s,3H). LC-MS: m / z334.7(M+H).

[0550] Example 20

[0551] (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl ketone (compound 88)

[0552]

[0553] A mixture of (5-bromopyridin-3-yl)(3,4-dihydroquinoline-1(2H)-yl) methyl ketone (0.111 g, 0.35 mmol), 4-methylpyrazole (0.035 mL, 0.438 mmol), potassium phosphate (0.097 g, 0.455 mmol), copper iodide (0.013 g, 0.070 mmol), and N,N'-dimethylenediamine (0.015 mL, 0.140 mmol) in dry toluene (1.0 mL) was stirred at 110 °C until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a diatomaceous earth short column. The filtrate was washed with an aqueous solution of NH4Cl-NH3 (4:1), water, and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give 0.016 g of the title compound. 1 H NMR (400MHz, CDCl3): δ8.94(d,1H),8.27(s,1H),8.06(dd,1H),7.63-7.67(m,1H),7.56(s,1H),7.17-7.23(m,1H) ),7.05(td,1H),6.87-6.94(m,1H),6.60-6.80(m,1H),3.95(t,2H),3.86(t,2H),2.16(s,3H),2.09(quint,2H). LC-MS: m / z 319.7 (M+H).

[0554] Example 21

[0555] 1-((5-(4-fluorophenyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroquinoline (compound 89)

[0556]

[0557] To a mixture of 1,2,3,4-tetrahydroquinoline (0.050 mL, 0.40 mmol), 1,2-dichloroethane (1.0 mL), and acetic acid (0.25 mL), 5-(4-fluorophenyl)pyridinecarboxaldehyde (0.089 g, 0.44 mmol) dissolved in 1,2-dichloroethane (1.0 mL) was added. The mixture was stirred at room temperature for 6 h. Sodium triacetoxyborohydride (0.1287 g, 0.88 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM and alkalized with a saturated aqueous solution of NaHCO3. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried and evaporated. The crude product was purified by reversed-phase rapid chromatography to obtain a pure compound. 1 H NMR (400MHz, CDCl3): δ8.69(d,1H),8.51-8.54(m,1H),7.70-7.73(m,1H),7.46-7.53(m,2H),7.10-7.18(m,2H),6. 97-7.03(m,2H),6.62(td,1H),6.51-6.55(m,1H),4.54(s,2H),3.36-3.42(m,2H),2.83(t,2H),2.00-2.08(m,2H). LC-MS: m / z 319.8 (M+H).

[0558] The following compounds were prepared according to the method of Example 21. The compound numbers, characterization data, and starting materials are shown in the table below.

[0559]

[0560] abbreviations

[0561] DCM – dichloromethane

[0562] DIPEA-N,N-Diisopropylethylamine

[0563] DME – dimethoxyethane

[0564] DMF-N,N-dimethylformamide

[0565] DMSO-dimethyl sulfoxide

[0566] dppp-1,3-bis(diphenylphosphine)propane

[0567] HPLC – High Performance Liquid Chromatography

[0568] LC-MS – Liquid Chromatography – Mass Spectrometry

[0569] PdCl2(dppf)-[1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride

[0570] Pd(OAc)2–palladium(II) acetate

[0571] Pd2(dba)3–tris(dibenzylacetone)dipalladium

[0572] PdCl2(PPh3)2-bis(triphenylphosphine)palladium(II) dichloride

[0573] Q-PHOS-1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene

[0574] RT – room temperature

[0575] Sodium STB-tert-Butyl alcohol

[0576] STAB – Sodium Triacetoxyborohydride

[0577] TEA-Triethylamine

[0578] T3P–propylphosphoanhydride

[0579] THF-Tetrahydrofuran

[0580] TLC (Thin Layer Chromatography)

[0581] TMA-Trimethylamine

[0582] experiment

[0583] Experiment 1. CYP11A1 inhibition

[0584] The ability of the test compound to inhibit pregnenolone biosynthesis was measured by enzyme-linked immunosorbent assay (ELISA) (Abnova Pregnenolone ELISA kit, KA1912). The human adrenocortical cancer cell line NCI-H295R, which expresses all key steroid-producing enzymes, was used as the enzyme source. To determine the half-maximal inhibitory concentration (IC50) of the test compound against CYP11A1... 50 Cells were treated with increased concentrations of the test compounds for 24 hours. The final DMSO concentration was 0.4%. Culture medium samples were diluted 1:6, and the amount of pregnenolone was determined by ELISA. Pregnenolone (Sigma-Aldrich, P9129) standards were prepared in cell culture medium using the manufacturer's recommended protocol. Absorbance (A450) was measured using an Envision plate reader (PerkinElmer). All test compounds were studied in duplicate at 10 concentrations.

[0585] The compounds of the present invention were screened in the above-described assays, and the IC50 of the compounds was... 50 The values ​​are listed in Table 1 below, where "A" refers to IC.50 Values ​​less than 50 nM, "B" refers to IC 50 Values ​​in the range of 51 to 200 nM, where "C" refers to IC. 50 The value is in the range of 201 nM to 2500 nM.

[0586] Table 1.

[0587]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof ； in B is any one of the following groups , or ; When B is a group (1) or (2), then A is a 3-10 membered carbon ring or a 4-12 membered heterocycle containing 1-4 heteroatoms selected from O, N or S; C is any one of the following groups , or ; G1 is CH2, NH, or O; G2 and G3 are independently CH or N; Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-; L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, nitro, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl or -X-NR6R7; R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen; R3 is hydrogen, C 1-7 Alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, hydroxyl C 1-7 Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl; X is a key or C 1-7 alkyl; R6 and R7 are independently hydrogen or C. 1-7 alkyl; When B is a group (3), then A is any one of the following groups. , , , , , , , , , or ; The condition is that if C is a cycle (3'), then A is neither a cycle (2") nor a cycle (7"); C is any one of the following groups , , or ; G1 is CH2, NH, or O; G2 and G3 are independently CH or N; Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-; L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl group, -X-NR6R7; R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen; R3 is hydrogen, C 1-7 Alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl C 1-7 Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl; X is a key or C 1-7 alkyl; R6 and R7 are independently hydrogen or C. 1-7 alkyl; The condition is that the compound of formula (I) is not (7-Methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidone-1-yl)pyrazin-2-yl)methyl ketone; (8-Fluoro-3,4-dihydro-3-hydroxymethyl-1(2H)-quinolinyl)(6-(1-pyrrolidinyl)-2-pyrazinyl) methyl ketone; (3,4-Dihydro-3-methoxy-1(2H)-quinolinyl)(6-phenyl-4-pyridazinyl) methyl ketone; (6-Fluoro-3,4-dihydro-4-methyl-1(2H)-quinoxalinyl)(5-phenyl-3-pyridyl) methyl ketone; (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridyl) methyl ketone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(3,4-dihydro-1(2H)-quinolinyl) methyl ketone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) methyl ketone; (6,8-Difluoro-3,4-dihydro-1(2H)-quinolinyl)(5-(4-(dimethylamino)phenyl)-3-pyridyl) methyl ketone; (3,4-Dihydro-1(2H)-quinolinyl)(5-(1-pyrrolidinyl)-3-pyridyl)methyl ketone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(octahydro-4H-1,4-benzoxazin-4-yl) methyl ketone; (5-(4-methoxyphenyl)-3-pyridyl)(octahydro-4H-1,4-benzoxazin-4-yl)methyl ketone; (2,3-Dihydro-1H-indol-1-yl)(5-phenyl-3-pyridyl)methyl ketone; [3,4-Dihydro-3-(hydroxymethyl)-1(2H)-quinolinyl][6-(1-pyrrolidinyl)-2-pyrazinyl] methyl ketone; (3,4-Dihydro-1(2H)-quinoxalinyl)[6-(1-pyrrolidinyl)-2-pyrazinyl] methyl ketone or (3,4-Dihydro-3-isopropyl-1(2H)-quinoxalinyl)[6-(1-pyrrolidinyl)-2-pyrazinyl] methyl ketone.

2. The compound according to claim 1, wherein B is a group (1) or a group (3).

3. The compound according to claim 1 or 2, wherein Z is -C(O)-.

4. The compound according to claim 1, wherein L is a bond.

5. The compound according to claim 1, wherein group C is (1').

6. The compound according to claim 5, wherein G1 is CH2 or O.

7. The compound according to claim 5 or 6, wherein G2 is N and G3 is CH.

8. The compound according to claim 5 or 6, wherein G2 is CH and G3 is N.

9. The compound according to claim 1, wherein R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl C 1-7 Alkyl or halogenated C 1-7 alkyl.

10. The compound according to claim 1, wherein R2 is hydrogen, hydroxyl, C 1-7 Alkyl or halogen.

11. The compound according to claim 1, wherein R3 is hydrogen.

12. The compound according to claim 1, wherein R4 is hydrogen, C 1-7 Alkyl, halogen or -C(O)-OC 1-7 alkyl.

13. The compound according to claim 1, wherein R5 is hydrogen.

14. The compound according to claim 1, wherein when B is group (3), then A is any one of the following groups: , , , , , , , , , , , , or .

15. The compound according to claim 1, wherein when B is group (1) or (2), then A is any one of the following groups: , , , , , , , , , , , or .

16. The compound according to claim 15, wherein A is any one of the following groups: , , , , , , , , , , , , , , or .

17. The compound according to claim 1, represented by formula (IA) or a pharmaceutically acceptable salt thereof. ； in D is either N or CH; G is CH2, NH, or O; M is CH or N; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy or halogen; R2 is hydrogen or halogen; R3 is hydrogen or C. 1-7 alkyl; R4 is hydrogen, C 1-7 Alkyl, halogen or -C(O)-OC 1-7 alkyl; A is any one of the following groups: , , , , , , or ; The condition is that the compound of formula (I) is not (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridyl) methyl ketone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(3,4-dihydro-1(2H)-quinolinyl) methyl ketone or (5-(2,3-dihydro-5-benzofuranyl)-3-pyridyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) methyl ketone.

18. The compound according to claim 17, wherein A is a group (1”), (2a), (3a), (9b) or (10a).

19. The compound of claim 1, wherein the compound is (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl ketone (compound 1); (7-Fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 2); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methyl ketone (compound 3); (3,4-Dihydroquinoline-1(2H)-yl)(4-methyl-5-phenylpyridin-3-yl)methyl ketone (compound 4); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methyl ketone (compound 5); (4-amino-5-phenylpyridin-3-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 6); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methyl ketone (compound 7); (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 8); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)methyl ketone (compound 9); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 10); (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 11); (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 12); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(2,3-Dihydrobenzofuran-6-yl)pyrazin-2-yl)methyl ketone (compound 13); (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-methoxyphenyl)pyrazin-2-yl)methyl ketone (compound 14); (3,4-Dihydroquinoline-1(2H)-yl)(6-phenylpyrazin-2-yl)methyl ketone (compound 15); (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 16); (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 17); (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 18); (5-(3,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 19); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyrazin-2-yl)methyl ketone (compound 20); (6-(4-fluorophenyl)pyrazin-2-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methyl ketone (compound 21); (6-(4-fluorophenyl)pyrazin-2-yl)(2-methyl-3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 22); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 23); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 24); (3,4-Dihydroquinoline-1(2H)-yl)(6-(3-methoxyphenyl)pyrazin-2-yl)methyl ketone (compound 25); (6-(4-fluorophenyl)pyrazin-2-yl)(3-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 26); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-hydroxyphenyl)pyridin-3-yl)methyl ketone (compound 27); (5-(2,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 28); (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 29); (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methyl ketone (compound 30); (5-(4-fluorophenyl)pyridin-3-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methyl ketone (compound 31); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-nitrophenyl)pyridin-3-yl)methyl ketone (compound 32); (5-(cyclohex-1-en-1-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 33); (3,4-Dihydro-1,5-Naphtho-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 34); 4-(6-(4-fluorophenyl)pyrazine-2-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid ethyl ester (compound 35); 1-(5-Phenylanoyl)-2,3-Dihydroquinoline-4(1H)-one (Compound 36); (3,4-Dihydro-1,5-Naphthoid-1(2H)-yl)(6-Phenylen-2-yl)methyl ketone (compound 37); (3,4-Dihydroquinoline-1(2H)-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 38); (5-(1H-pyrrolo-1-yl)pyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methyl ketone (compound 39); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methyl ketone (compound 40); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(2-fluorophenyl)pyridin-3-yl)methyl ketone (compound 41); (3,4-Dihydro-1,5-Naphtho-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methyl ketone (compound 42); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)methyl ketone (compound 43); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl ketone (compound 44); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 45); 4-((5-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 46); 1-((5-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline (compound 47); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl ketone (compound 48); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6'-fluoro-[3,3'-bipyridine]-5-yl)methyl ketone (compound 49); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methyl ketone (compound 50); (3,4-Dihydroquinoline-1(2H)-yl)(5-(1-phenylvinyl)pyridin-3-yl)methyl ketone (compound 51); (3,4-Dihydroquinoline-1(2H)-yl)(6-phenylpyridazin-4-yl)methyl ketone (compound 52); (6-Methoxy-3,4-dihydroquinoline-1(2H)-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 53); (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methyl ketone (compound 54); (5-(4-fluorophenyl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 55); (5-(4-fluorophenyl)pyridin-3-yl)((4aS,8aS)-octahydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 56); (5-(4-fluorophenyl)pyridin-3-yl)((4aR,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 57); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-nitrophenyl)pyridin-3-yl)methyl ketone (compound 58); (5-Methoxy-3,4-dihydroquinoline-1(2H)-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 59); (5-(4-fluorophenyl)pyridin-3-yl)(dihydroindol-1-yl)methyl ketone (compound 60); (3,4-Dihydro-1,5-Naphtho-1(2H)-yl)(5-Phenyridin-3-yl)methyl ketone (compound 61); [3,4'-Bipyridine]-5-yl(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 62); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)methyl ketone (compound 63); (6-(4-fluorophenyl)pyridazin-4-yl)(2-methyl-3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 64); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methyl ketone (compound 65); (5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 66); 1-(5-phenylnicotinyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid methyl ester (compound 67); (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-((dimethylamino)methyl)phenyl)pyridin-3-yl)methyl ketone (compound 68); (7-Methoxy-3,4-dihydroquinoline-1(2H)-yl)(5-phenylpyridin-3-yl)methyl ketone (compound 69); [3,3'-Bipyridine]-5-yl(3,4-dihydroquinoline-1(2H)-yl)methyl ketone (compound 70); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(p-tolyl)pyridin-3-yl)methyl ketone (compound 71); (5-(2,3-dihydrobenzofuran-6-yl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methyl ketone (compound 72); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl ketone (compound 73); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(pyrrolidine-1-yl)pyridin-3-yl)methyl ketone (compound 74); 2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl) methyl ketone (compound 75); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidine-1-yl)pyrazin-2-yl)methyl ketone (compound 76); (6-(3,3-difluoroazacyclobutane-1-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) methyl ketone (compound 77); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methyl ketone (compound 78); 1-(3,4-dihydroquinolin-1(2H)-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethyl-1-one (compound 79); 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-methoxyphenyl)pyridin-3-yl)ethyl-1-one (compound 80); 4-((5-phenylpyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 81); (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl ketone (compound 82); (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-methyl-1H-imidazol-1-yl)pyrazin-2-yl)methyl ketone (compound 83); (3,4-Dihydroquinoline-1(2H)-yl)(6-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl ketone (compound 84); (6-Benzylpyrazin-2-yl)(3,4-Dihydroquinoline-1(2H)-yl)methyl ketone (compound 85); 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethyl-1-one (compound 86); (3,4-Dihydroquinoline-1(2H)-yl)(6-(3,5-Dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methyl ketone (compound 87); (3,4-Dihydroquinoline-1(2H)-yl)(5-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl ketone (compound 88); 1-((5-(4-fluorophenyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroquinoline (compound 89); or 1-((5-(4-fluorophenyl)pyridin-3-yl)methyl)dihydroindole (compound 90); Or its tautomers and pharmaceutically acceptable salts.

20. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of steroid receptor-dependent conditions or diseases. ； in A is a 3-10 membered carbon ring or a 4-12 membered heterocycle containing 1-4 heteroatoms selected from O, N or S; B is any one of the following groups , or C is any one of the following groups. , , or ; G1 is CH2, NH, or O; G2 and G3 are independently CH or N; Z represents -C(O)-, -SO2-, -C 1-3 Alkyl group or -CH2-C(O)-; L is a key, -C 1-7 Alkyl- or -C 1-7 alkenyl-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, nitro, halogenated C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, -O-halogenated C 1-7 Alkyl or -X-NR6R7; R2 is hydrogen, hydroxyl group, C 1-7 Alkyl or halogen; R3 is hydrogen, C 1-7 Alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxyl, hydroxyl C 1-7 Alkyl, Halogenated C 1-7 Alkyl or -C(O)-OC 1-7 alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 alkyl; X is a key or C 1-7 alkyl; R6 and R7 are independently hydrogen or C. 1-7 alkyl.

21. The use of claim 20, wherein the steroid receptor-dependent condition or disease is cancer.

22. The use of claim 21, wherein the steroid receptor-dependent condition or disease is prostate cancer or breast cancer.

23. The use according to any one of claims 20-22, wherein the compound of formula (I) is administered, along with glucocorticoids and / or mineralocorticoids and optionally one or more anticancer agents.

24. The use according to any one of claims 20-23, wherein the compound of formula (I) is administered along with one or more anticancer agents selected from the group consisting of: - Nonsteroidal androgen receptor antagonists; - Steroid synthesis inhibitors; - Chemotherapy agents; - Anti-estrogens; - Epigenetic regulators; - mTOR inhibitor; - AKT inhibitor; - Radiopharmaceuticals; - GnRH / LHRH analogs; - PI3K inhibitors; and - CDK4 / 6 inhibitors, For simultaneous, single, or sequential administration.

25. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising the compound of claim 1 and at least one additional active ingredient selected from the group consisting of: - Glucocorticoids; - Mineralocorticoids; - Nonsteroidal androgen receptor antagonists; - Steroid synthesis inhibitors; - Chemotherapy agents; - Anti-estrogens; - Epigenetic regulators; - mTOR inhibitor; - AKT inhibitor; - Radiopharmaceuticals; - GnRH / LHRH analogs; - PI3K inhibitors; and - CDK4 / 6 inhibitors; For simultaneous, single, or sequential administration.

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