2,3-Dihydro-4H-benzo[B][1,4]oxazin-4-yl)(5-(phenyl)-pyridin-3-yl)methanone derivatives and analogues as CYP11A1 inhibitors for the treatment of prostate cancer

Abstract

The present invention provides a compound represented by formula (I) (wherein A is a 3- to 10-membered carbocyclyl or a 4- to 12-membered heterocyclyl containing 1 to 4 heteroatoms selected from O, N, or S; B is any of the following groups (1), (2), or (3); C is any of the following groups (1′), (2′), (3′), or (4′); G1 is CH2, NH, or O; G2 and G3 are independently 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 The compounds of formula (I) are cytochrome P450 monooxygenase 11A1 (CYP11A1) inhibitors. The compounds are useful as pharmaceuticals in the treatment of steroid receptor, e.g., androgen receptor or estrogen receptor, dependent diseases and conditions, such as cancers including prostate cancer and estrogen cancer. TIFF2023551340000101.tif7378

Description

[Technical Field]

[0001] The present invention relates to therapeutically active compounds, and pharmaceutical compositions comprising such compounds, that are useful in the treatment of steroid receptor-dependent conditions and diseases, such as androgen receptor (AR) or estrogen receptor (ER). [Background technology]

[0002] Treatment of steroid receptor-dependent diseases, such as androgen receptor (AR)-dependent and estrogen receptor (ER)-dependent cancers, has been extensively studied. Prostate cancer, for example, is one of the most common cancers in men worldwide. Despite a high 5-year survival rate for patients with localized prostate cancer, patients who develop castration-resistant prostate cancer (CRPC) within a 5-year follow-up period have a poor prognosis.

[0003] The androgen receptor (AR) signaling axis is important in all stages of prostate cancer. In 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 by other steroid hormones and steroid biosynthetic intermediates. Therefore, treatment of advanced prostate cancer involves androgen-deprivation therapy (ADT), such as hormonal manipulation with gonadotropin-releasing hormone (GnRH) agonists / antagonists, surgical castration, and AR antagonists or CYP17A1 inhibitors (e.g., abiraterone acetate in combination with prednisone).

[0004] Although treatment initially leads to disease regression, many patients ultimately develop disease that is ineffective against current therapies. Elevated progesterone levels in patients treated with abiraterone acetate are hypothesized to be one of the resistance mechanisms. Several preclinical and clinical studies have pointed to upregulation of enzymes catalyzing steroid biosynthesis in the later stages of CRPC. More recently, it has been published that 11β-OH androstenedione can be metabolized to 11-ketotestosterone (11-KT) and 11-ketodehydrotestosterone (11-K-DHT), which can bind and activate AR as efficiently as testosterone and dihydrotestosterone. These steroids have been found at elevated levels in the plasma and tissues of prostate cancer patients, suggesting their role as AR agonists in CRPC. Furthermore, it has been noted that prostate cancer resistant to CYP17A1 inhibition remains steroid-dependent and may respond to treatments that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1, such as CYP11A1 inhibitor therapy (Non-patent Document 1).

[0005] Cytochrome P450 monooxygenase 11A1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is a mitochondrial monooxygenase that catalyzes the conversion of cholesterol to pregnenolone (the precursor of all steroid hormones). By inhibiting CYP11A1, a key enzyme in steroid biosynthesis upstream of CYP17A1, global blockade of all steroid biosynthesis can be achieved. CYP11A1 inhibitors may therefore have great potential for treating steroid hormone-dependent cancers, such as prostate cancer, even in advanced stages of the disease, and particularly in those patients considered to be hormone-resistant. It has been shown that compounds with CYP11A1 inhibitory activity significantly inhibited tumor growth in vivo in a mouse CRPC xenograft model (Non-Patent Document 2). CYP11A1 inhibitors have been previously described in Patent Document 1. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2018 / 115591 [Non-patent literature]

[0007] [Non-Patent Document 1] Cai, C. et al, Cancer Res., 71(20), 6503-6513, 2011 [Non-patent document 2] Oksala, R. et al, Annals of Oncology, (2017) 28 (suppl. 5): Abstract / Poster 28P Summary of the Invention

[0008] It has been found that the compound of formula (I) is a strong CYP11A1 inhibitor.Therefore, the compound of the present invention is useful as a medicine for treating steroid hormone-dependent symptoms and diseases, particularly those for which the inhibition of CYP11A1 is desired.Such symptoms and diseases include, but are not limited to, endocrine cancers and diseases such as prostate cancer and breast cancer.In particular, the compound of the present invention is useful for treating AR-dependent symptoms and diseases, such as prostate cancer.

[0009] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, B is one of the following groups: [ka] When B is group (1) or (2), A is a 3- to 10-membered carbocyclyl ring or a 4- to 12-membered heterocyclyl ring containing 1-4 heteroatoms selected from O, N, or S; C is one of the following groups: [ka] G1 is CH2, NH or O; G2 and G3 are independently 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-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, nitro, halogen C 1-7 Alkyl, Hydroxy C 1-7 Alkyl, -O-HalogenC 1-7 alkyl or -X-NR6R7; R2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R3 is hydrogen, C 1-7 is alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or -C(O)-OC 1-7 is alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R6 and R7 are independently hydrogen or C 1-7 is alkyl; When B is group (3), A is one of the following groups: [ka] However, if C is ring(3'), then A is not ring(2'') or ring(7''); C is one of the following groups: [ka] G1 is CH2, NH or O; G2 and G3 are independently 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-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, halogen C 1-7 Alkyl, Hydroxy C 1-7 Alkyl, -O-HalogenC 1-7 alkyl, -X-NR6R7; R2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R3 is hydrogen, C 1-7 is alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or -C(O)-OC 1-7 is alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R6 and R7 are independently hydrogen or C 1-7 is alkyl; However, the compound of formula (I) (7-Methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidin-1-yl)pyrazin-2-yl)methanone; (8-fluoro-3,4-dihydro-3-hydroxymethyl-1(2H)-quinolinyl)(6-(1-pyrrolidinyl)-2-pyrazinyl)methanone; (3,4-Dihydro-3-methoxy-1(2H)-quinolinyl)(6-phenyl-4-pyridazinyl)methanone; (6-fluoro-3,4-dihydro-4-methyl-1(2H)-quinoxaquinyl)(5-phenyl-3-pyridinyl)methanone; (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(3,4-dihydro-1(2H)-quinolinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methanone; (6,8-difluoro-3,4-dihydro-1(2H)-quinolinyl)(5-(4-(dimethylamino)phenyl)-3-pyridinyl)methanone; (3,4-Dihydro-1(2H)-quinolinyl)(5-(1-pyrrolidinyl)-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(octahydro-4H-1,4-benzoxazin-4-yl)methanone; (5-(4-methoxyphenyl)-3-pyridinyl)(octahydro-4H-1,4-benzoxazin-4-yl)methanone; or (2,3-Dihydro-1H-indol-1-yl)(5-phenyl-3-pyridinyl)methanone (not)

[0010] According to one embodiment, the present invention provides a method for treating steroid receptor dependent conditions and diseases, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] (In the formula, A is a 3- to 10-membered carbocyclyl ring or a 4- to 12-membered heterocyclyl ring containing 1-4 heteroatoms selected from O, N, or S; B is one of the following groups: [ka] C is one of the following groups: [ka] G1 is CH2, NH or O; G2 and G3 are independently 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-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, nitro, halogen C 1-7 Alkyl, Hydroxy C 1-7 Alkyl, -O-HalogenC 1-7 alkyl or -X-NR6R7; R2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R3 is hydrogen, C 1-7 is alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or -C(O)-OC 1-7 is alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R6 and R7 are independently hydrogen or C1-7 alkyl) The present invention provides a method of treatment comprising administering a therapeutically effective amount of

[0011] In one embodiment, 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.

[0012] According to one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) in association with a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides novel compounds of formula (I) or pharmaceutically acceptable salts thereof, which are useful as CYP11A1 inhibitors.

[0014] One embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] (In the formula, B is one of the following groups: [ka] When B is group (1) or (2), A is a 3- to 10-membered carbocyclyl ring or a 4- to 12-membered heterocyclyl ring containing 1-4 heteroatoms selected from O, N, or S; C is one of the following groups: [ka] G1 is CH2, NH or O; G2 and G3 are independently CH or N; Z is -C(O)-, -SO2-, -C 1-3 alkyl- or -CH2-C(O)-; L is a bond, -C1-7 Alkyl- or -C 1-7 alkenyl-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, nitro, halogen C 1-7 Alkyl, Hydroxy C 1-7 Alkyl, -O-HalogenC 1-7 alkyl or -X-NR6R7; R2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R3 is hydrogen, C 1-7 is alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or -C(O)-OC 1-7 is alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R6 and R7 are independently hydrogen or C 1-7 is alkyl; When B is group (3), A is one of the following groups: [ka] However, if C is ring(3'), then A is not ring(2'') or ring(7''); C is one of the following groups: [ka] G1 is CH2, NH or O; G2 and G3 are independently 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-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, halogen C 1-7 Alkyl, Hydroxy C 1-7 Alkyl, -O-HalogenC 1-7 alkyl, -X-NR6R7; R2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R3 is hydrogen, C 1-7 is alkyl or amino; R4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or -C(O)-OC 1-7 is alkyl; R5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R6 and R7 are independently hydrogen or C 1-7 is alkyl; However, the compound of formula (I) (7-Methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidin-1-yl)pyrazin-2-yl)methanone; (8-fluoro-3,4-dihydro-3-hydroxymethyl-1(2H)-quinolinyl)(6-(1-pyrrolidinyl)-2-pyrazinyl)methanone; (3,4-Dihydro-3-methoxy-1(2H)-quinolinyl)(6-phenyl-4-pyridazinyl)methanone; (6-fluoro-3,4-dihydro-4-methyl-1(2H)-quinoxaquinyl)(5-phenyl-3-pyridinyl)methanone; (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(3,4-dihydro-1(2H)-quinolinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methanone; (6,8-difluoro-3,4-dihydro-1(2H)-quinolinyl)(5-(4-(dimethylamino)phenyl)-3-pyridinyl)methanone; (3,4-Dihydro-1(2H)-quinolinyl)(5-(1-pyrrolidinyl)-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(octahydro-4H-1,4-benzoxazin-4-yl)methanone; (5-(4-methoxyphenyl)-3-pyridinyl)(octahydro-4H-1,4-benzoxazin-4-yl)methanone; or (2,3-Dihydro-1H-indol-1-yl)(5-phenyl-3-pyridinyl)methanone isn't it) to provide.

[0015] It should be understood that the left bond of Z is connected to ring B of formula (I). The wavy line in group A indicates the point of attachment to L. The wavy line in group C indicates the point of attachment to Z. The wavy line to the left of group B indicates the point of attachment to L, and the wavy line to the right of group B indicates the point of attachment to Z.

[0016] In one embodiment, specifically, there is provided a compound of formula (I) wherein B is group (1) or group (3), for example, B is group (1), and in another example, B is group (3).

[0017] In one embodiment, specifically, there is provided a compound according to any one of the above embodiments, wherein Z is -C(O)-, SO2-, -CH2-, or -CH2-C(O)-. In another embodiment, specifically, there is provided a compound according to any one of the above embodiments, wherein Z is -C(O)-. In one embodiment, specifically, there is provided a compound according to any one of the above embodiments, wherein L is a bond, -C 1-3 Alkyl- or -C 1-3 Compounds according to any of the above embodiments are provided wherein L is alkenyl-. In subgroups of the above embodiments, L is a bond, -CH2-, or -C(CH2)-. In one embodiment, compounds according to any of the above embodiments are specifically provided wherein L is a bond. In one embodiment, compounds according to any of the above embodiments are specifically provided wherein C is group (1') or (2'). In one embodiment, compounds according to any of the above embodiments are specifically provided wherein C is group (1').

[0018] Furthermore, according to one embodiment, there is provided a compound according to any of the above embodiments, specifically wherein G1 is CH2 or O, for example, G1 is CH2, and as another example, G1 is O. In one aspect, there is provided a compound according to any of the above embodiments, wherein G2 is N and G3 is CH, or G2 is CH and G3 is N.

[0019] In one embodiment, specifically, R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy C 1-7 Alkyl or halogen C 1-7 In another embodiment, compounds are provided in which R is hydrogen, hydroxy, C 1-7 Compounds according to any of the above embodiments are provided in which R is alkyl or halogen. In another embodiment, compounds according to any of the above embodiments are specifically provided in which R is hydrogen. In another embodiment, compounds according to any of the above embodiments are specifically provided in which R is hydrogen, C 1-7 Alkyl, halogen or -C(O)-OC 1-7Compounds according to any of the above embodiments are provided wherein: R is alkyl.

[0020] In one embodiment, specifically, B is group (3) and A is one of the following groups: [ka] Compounds according to any of the above embodiments of formula (I) are provided, wherein R 1 and R 2 are attached to the A ring and the wavy line indicates the point of attachment to L.

[0021] In one embodiment, specifically, B is group (1) or (2) and A is one of the following groups: [ka] Compounds according to any of the above embodiments of formula (I) are provided, wherein R 1 and R 2 are attached to the A ring and the wavy line indicates the point of attachment to L.

[0022] In a subclass of the above embodiment, the compound is one in which A is one of the following groups: [ka] R1 and R2 are bonded to the A ring, and the wavy line indicates the bond position to L.

[0023] In one embodiment, there is specifically provided a compound according to any of the above embodiments of formula (I), wherein A is group (1″), (2″), (3″), (6″), (8″), (9″) or (10″).

[0024] In one embodiment, there is specifically provided a compound according to any of the above embodiments of formula (I), wherein A is group (1″), (2a), (2b), (3a), (6a), (8a), (9b) or (10a).

[0025] According to one embodiment, the compound of the present invention has the formula (IA): [ka] (In the formula, D is N or CH; G is CH2, NH or O; M is CH or N; R1 is hydrogen, C 1-7 Alkyl, C 1-7 is alkoxy or halogen; R2 is hydrogen or halogen; R3 is hydrogen or C 1-7 is alkyl; R4 is hydrogen, C 1-7 Alkyl, halogen or -C(O)-OC 1-7 is alkyl; A is one of the following groups: [ka] However, the compound of formula (I) (3,4-Dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(3,4-dihydro-1(2H)-quinolinyl)methanone; or (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methanone isn't it) It is expressed by:

[0026] In a subclass of the above embodiment, compounds of formula (IA) are those in which 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).

[0027] According to a further embodiment, the present invention provides a method for treating steroid receptor dependent conditions and diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined in any of the above embodiments.

[0028] In 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 present invention, the CRPC to be treated is unresponsive to CYP17A1 inhibitor treatment. In another embodiment, the androgen receptor-dependent disease or condition is an endocrine cancer that depends on CYP11A1 activation.

[0029] The compounds of the present invention can be prepared by various synthetic routes similar to methods known in the literature using appropriate starting materials. Compounds according to formula (I) can be prepared, for example, similarly to or according to the following reaction scheme. Some compounds included in formula (I) can be obtained by converting the functional groups of other compounds of formula (I) obtained according to the following scheme by well-known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, etc. It should be noted that any suitable leaving group, for example, an N-protecting group such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in a well-known manner during synthesis to improve the selectivity of the reaction steps.

[0030] Compounds of formula (I) where L is a bond can be prepared according to Scheme 1 (wherein X is a halogen, preferably chloro or bromo, and A, B, C, Z, R1, R2, R3, R4, and R5 are as defined above). In the method of Scheme 1, a compound of formula [1] is coupled with a boronic 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 elevated temperature to produce a compound of formula [Ia]. Instead of the boronic acid derivative [2], a corresponding boronic acid ester, such as a pinacol boronic acid ester, can also be used. [ka]

[0031] Compounds of formula (I) where Z is -C(O)- can also be prepared according to Scheme 2, where A, B, C, L, R1, R2, R3, R4, and R5 are as defined above (for clarity, the ring nitrogen atom of compound [4] is depicted in Scheme 2), and R6 is methyl or ethyl. In the method of Scheme 2, a compound of formula [3] is coupled with a compound of formula [4] in the presence of trimethylaluminum and a base such as triethylamine (TEA) in a suitable solvent such as toluene to produce a compound of formula [Ib]. [ka]

[0032] Alternatively, compounds of formula (I) in which Z is -C(O)- can be prepared according to Scheme 3, in which A, B, C, L, R1, R2, R3, R4, and R5 are as defined above (for clarity, the ring nitrogen atom of compound [4] is depicted in Scheme 3). In the method of Scheme 3, a compound of formula [5] is coupled with a compound of formula [4] in a suitable solvent such as DMF in the presence of a base such as triethylamine (TEA) and, optionally, a coupling reagent such as propylphosphonic anhydride (T3P) to produce a compound of formula [Ib]. [ka]

[0033] Alternatively, compounds of formula (I) in which Z is -C(O)- can be prepared according to Scheme 4, in which A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the ring nitrogen atom of compound [4] is depicted in Scheme 4). In the method of Scheme 4, a compound of formula [6] is coupled with a compound of formula [4] in a suitable solvent such as DCM in the presence of a base such as triethylamine (TEA) to produce a compound of formula [Ib]. [ka]

[0034] Compounds of formula (I) in which L is a bond and A contains an -NH group (e.g., A is pyrrolidine, imidazole, or pyrazole) can also be prepared according to Scheme 5, where X is a halogen, preferably chloro or bromo, and A, B, C, Z, R, R, R, R, and R are as defined above (for clarity, the ring nitrogen atom of compound [7] is depicted in Scheme 5). In the method of Scheme 5, a compound of formula [1] is coupled with a compound of formula [7] in a suitable solvent, such as dry toluene or dry DMSO, in the presence of a base, such as tert-butoxide (STB), DIPEA, or potassium phosphate, and optionally a catalyst, such as tris(dibenzylideneacetone)dipalladium Pd(dba) at elevated temperature to produce a compound of formula [Ia]. [ka]

[0035] Compounds of formula (I) where Z is -CH2-C(O)- can also be prepared according to Scheme 6, where A, B, C, L, R1, R2, R3, R4 and R5 are as defined above (for clarity, the ring nitrogen atom of compound [4] is depicted in Scheme 6). In the method of Scheme 6, a compound of formula [8] is coupled with a compound of formula [4] in a suitable solvent such as DMF in the presence of a base such as trimethylamine (TMA) and, optionally, a coupling reagent such as propylphosphonic anhydride (T3P) to produce a compound of formula [Ic]. [ka]

[0036] Z is -C 1-3The alkyl-containing compounds of formula (I) can also be prepared according to Scheme 7, where A, B, C, L, R1, R2, R3, R4, and R5 are as defined above (for clarity, the ring nitrogen atom of compound [4] is depicted in Scheme 7). In the method of Scheme 7, an aldehyde compound of formula [9] is reacted with a compound of formula [4] in the presence of acetic acid and a reducing agent such as sodium triacetoxyborohydride (STAB) in a suitable solvent such as 1,2-dichloroethane to produce a compound of formula [Id]. [ka]

[0037] Intermediate compounds can be prepared according to methods disclosed in the literature or as illustrated in this disclosure.

[0038] For example, the intermediate compound of formula [1a] can be prepared according to Scheme 8, where B, C, R3, R4 and R5 are as defined above, and X and Y are halogen, preferably chloro or bromo (for clarity, the ring nitrogen atom of compound [4] is depicted in Scheme 8). In the method of Scheme 8, a compound of formula

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

[0039] Intermediate compounds of formula [3a] in which A contains an -NH group (e.g., A is pyrrolidine, imidazole, or pyrazole) can be prepared, for example, according to Scheme 9, in which A, B, R1, R3, R2, and R3 are as defined above, and X is a halogen, preferably chloro or bromo (for clarity, the ring nitrogen atom of compound [7] is depicted in Scheme 9). In the method of Scheme 9, a compound of formula

[11] is coupled with a compound of formula [7] in a suitable solvent, such as toluene-dioxane, in the presence of a base, such as potassium phosphate, and a catalyst, such as a mixture of tris(dibenzylideneacetone)dipalladium and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, to produce a compound of formula [3a]. [ka]

[0040] 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 halogen, preferably chloro or bromo, and R6 is methyl or ethyl. In the method of Scheme 10, a compound of formula

[11] is coupled with a 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 elevated temperature to produce a compound of formula [3a]. [ka]

[0041] The intermediate compound of formula [8a] can be prepared, for example, according to Scheme 11, in which A, B, R1, R2, and R3 are as defined above, and X is a halogen, preferably chloro or bromo. In the method of Scheme 11, a compound of formula

[12] is coupled with a 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 tetrakis(triphenylphosphine)palladium, to produce a compound of formula [8a]. [ka]

[0042] Alternatively, compounds of formula (I) can be prepared as disclosed in the specific examples of the present disclosure.

[0043] 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 the subject matter herein belongs. As used herein, the following definitions are provided to facilitate the understanding of the present invention.

[0044] As used herein, the term "subject" means humans and animals.

[0045] The term "steroid receptor" refers to a receptor that binds to and is activated by a steroid hormone. Examples of steroid receptors include, but are not limited to, androgen receptors, estrogen receptors, glucocorticoid receptors, and progesterone receptors.

[0046] The term "endocrine cancer" refers to the partially or completely uncontrolled growth of one or more cellular components of the endocrine system, including but not limited to cancer of one or more adrenal glands.

[0047] The term "elevated temperature" means a temperature above room temperature, typically from about 30 to about 120°C, for example, from about 40 to about 100°C, or from about 50 to about 80°C.

[0048] The terms "halo" or "halogen" as used herein by themselves or as part of another group mean chlorine, bromine, fluorine, or iodine.

[0049] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atoms. 1-7 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl. 1-7 One preferred embodiment of "alkyl" is C 1-3 The term "C" is an alkyl group. 1-3 "Alkyl" refers to a group having 1, 2 or 3 carbon atoms. 1-7 "Alkyl" refers to a preferred embodiment of "alkyl."

[0050] As used herein, the term "C" as used by itself or as part of another group 2-7 "Alkenyl" means an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl, and cyclohexenyl.

[0051] As used herein, the term "C" as used by itself or as part of another group 3-7 "Cycloalkyl" means a saturated cyclic hydrocarbon group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] The term "hydroxy" as used herein by itself or as part of another group refers to an --OH group.

[0053] The term "cyano" as used herein by itself or as part of another group refers to the group --CN.

[0054] The term "carboxy" as used herein by itself or as part of another group refers to a -COOH group.

[0055] The term "carbonyl" as used herein by itself or as part of another group means a carbon atom double bonded to an oxygen atom (C=O).

[0056] The term "oxo" as used herein by itself or as part of another group refers to an oxygen atom (=O) that is attached to another atom by a double bond.

[0057] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkoxy" refers to a C alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. 1-7 It means alkyl. 1-7 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0058] As used herein, the term "hydroxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 means at least one hydroxy group, as defined herein, attached through an alkyl group. 1-7Representative examples of alkyl 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.

[0059] As used herein, the term "halogen C" 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 HaloC means at least one halogen, as defined herein, attached through an alkyl group. 1-7 Representative examples of alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.

[0060] As used herein, the term "cyano C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 It means a cyano group attached through an alkyl group. Cyano C 1-7 Representative examples of alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, and 2-cyanopropyl.

[0061] As used herein, the term "halogen C" 1-7 "Alkoxy" refers to the parent molecular moiety C as defined herein. 1-7 It means at least one halogen, as defined herein, attached through an alkoxy group.

[0062] As used herein, the term "phenyl C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 It means at least one phenyl group attached through an alkyl group.

[0063] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkylcarbonyl" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. 1-7 It means an alkyl group.

[0064] As used herein, the term "C" as used by itself or as part of another group 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 at least one C as defined herein attached through an alkyl group 1-7 It means an alkoxy group.

[0065] The term "4- to 12-membered heterocyclyl" as used herein means a saturated, partially saturated, or aromatic ring having 4 to 12 ring atoms, 1 to 4 of which are heteroatoms selected from the group consisting of N, O, and S. One embodiment of "4- to 12-membered heterocyclyl" is "4- to 10-membered heterocyclyl," which means a saturated, partially saturated, or aromatic ring having 4 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from the group consisting of N, O, and S. Representative examples of 4 to 12 membered heterocyclyl include, but are not limited to, oxetanyl, azetidinyl, pyrazolyl, 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, pyrimidinyl, pyridinyl, piperidinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyltetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl, and 4,5-dihydroimidazolyl rings.

[0066] The term "3- to 10-membered carbocyclyl" as used herein refers to a saturated, partially saturated, or aromatic ring having 3 to 10 ring atoms consisting solely of carbon atoms. One embodiment of "3- to 10-membered carbocyclyl" is "3- to 6-membered carbocyclyl," which refers to a saturated, partially saturated, or aromatic ring having 3 to 6 ring atoms consisting solely of carbon atoms. Representative examples of 3- to 10-membered carbocyclyl include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0067] The term "substituted" as used herein in connection with various residues means, unless otherwise specified, halogen substituents such as fluorine, chlorine, bromine, iodine, or C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxy, amino, nitro, cyano, thiol C 1-7 Alkyl, methylsulfonyl, C 1-7 Alkoxy, HaloC 1-7 Alkyl, Hydroxy C 1-7 Alkyl or amino C 1-7 alkyl substituents. Preferred substituents are halogen, C 1-7 Alkyl, hydroxy, amino, haloC 1-7 Alkyl, C 1-7 Alkoxy and methylsulfonyl substituents. One group of preferred substituents is C 1-7 one or two substituents selected from alkyl or halogen substituents, in particular C 1-3 Alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro, bromo substituents.

[0068] A "substituted" group can contain from 1 to 3, preferably 1 or 2, of the above substituents, unless otherwise specified.

[0069] Optically active enantiomers or diastereomers of compounds of formula (I) can be prepared, for example, by resolution of racemic final products by known methods or by using appropriate optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared using racemic starting materials. Resolution of racemic compounds of formula (I) or their racemic starting materials can be achieved, for example, by converting the racemic compound to a mixture of diastereomeric salts by reaction with an optically active acid, followed by separation of the diastereomers by crystallization. Representative examples of optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography can be used to resolve racemic mixtures.

[0070] Pharmaceutically acceptable salts are well known in the field of formulation. 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 salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbic acids, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, if applicable, can be prepared by known methods using pharmaceutically acceptable acids commonly used in the pharmaceutical field, and retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate and carbonate esters are also within the scope of the present invention.

[0071] The above definition of formula (I) includes all possible isotopes and isomers, such as stereoisomers, of the compounds, geometric isomers, e.g., Z and E isomers (cis and trans isomers), and optical isomers, e.g., diastereomers and enantiomers, and all prodrug esters, such as phosphate esters and carbonate esters.

[0072] It will be understood by those skilled in the art that the compounds of the present invention can have at least one chiral center. Therefore, the compounds can exist in optically active or racemic forms. Formula (I) should be understood to encompass any racemic or optically active form, or mixtures thereof. In one embodiment, the compound is the pure (R)-isomer. In yet another embodiment, the compound is the pure (S)-isomer. In another embodiment, the compound is a mixture of the (R)- and (S)-isomers. In another embodiment, the compound is a racemic mixture containing an equal mixture of the (R)- and (S)-isomers. The compound may also have two chiral centers. In such cases, according to one embodiment, the compound is a mixture of diastereomers. In another embodiment, the compounds of the present invention are mixtures of enantiomers. In yet another embodiment, the compounds are pure enantiomers. The individual isomers may be obtained using the corresponding isomers of the starting materials, or may be separated after preparation of the final compound using conventional separation methods. Separation of optical isomers, eg enantiomers or diastereomers, from a mixture thereof may be achieved using conventional resolution methods, eg fractional crystallisation.

[0073] The compounds of the present invention may exist as tautomers or as equal mixtures thereof in which the protons of the compounds shift from one atom to another. Examples of tautomers include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-aza, imine-enamine, and cyclic tautomers of heterocycles such as pyrazole rings. Tautomeric forms are intended to be encompassed by the compounds of formula (I), even if only one tautomeric form is shown.

[0074] Examples of preferred compounds of one group of formula (I) are: (2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methanone (compound 1); (7-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 2); (2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (compound 3); (3,4-Dihydroquinolin-1(2H)-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (compound 4); (2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methanone (compound 5); (4-amino-5-phenylpyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 6); (2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methanone (compound 7); (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 8); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)methanone (compound 9); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-phenylpyridin-3-yl)methanone (compound 10); (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 11); (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 12); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)methanone (compound 13); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-methoxyphenyl)pyrazin-2-yl)methanone (compound 14); (3,4-Dihydroquinolin-1(2H)-yl)(6-phenylpyrazin-2-yl)methanone (compound 15); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 16); (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 17); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methanone (compound 18); (5-(3,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 19); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyrazin-2-yl)methanone (compound 20); (6-(4-fluorophenyl)pyrazin-2-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone (compound 21); (6-(4-fluorophenyl)pyrazin-2-yl)(2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (compound 22); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methanone (compound 23); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 24); (3,4-Dihydroquinolin-1(2H)-yl)(6-(3-methoxyphenyl)pyrazin-2-yl)methanone (compound 25); (6-(4-fluorophenyl)pyrazin-2-yl)(3-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 26); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-hydroxyphenyl)pyridin-3-yl)methanone (compound 27); (5-(2,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 28); (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 29); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methanone (compound 30); (5-(4-fluorophenyl)pyridin-3-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone (compound 31); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-nitrophenyl)pyridin-3-yl)methanone (compound 32); (5-(cyclohex-1-en-1-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 33); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methanone (compound 34); Ethyl 4-(6-(4-fluorophenyl)pyrazine-2-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (compound 35); 1-(5-phenylnicotinoyl)-2,3-dihydroquinolin-4(1H)-one (compound 36); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(6-phenylpyrazin-2-yl)methanone (compound 37); (3,4-Dihydroquinolin-1(2H)-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methanone (compound 38); (5-(1H-pyrrol-1-yl)pyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 39); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methanone (compound 40); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(2-fluorophenyl)pyridin-3-yl)methanone (compound 41); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 42); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)methanone (compound 43); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methanone (compound 44); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanone (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)methanone (compound 48); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6′-fluoro-[3,3′-bipyridin]-5-yl)methanone (compound 49); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methanone (compound 50); (3,4-Dihydroquinolin-1(2H)-yl)(5-(1-phenylvinyl)pyridin-3-yl)methanone (compound 51); (3,4-Dihydroquinolin-1(2H)-yl)(6-phenylpyridazin-4-yl)methanone (compound 52); (6-Methoxy-3,4-dihydroquinolin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 53); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methanone (compound 54); (5-(4-fluorophenyl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 55); (5-(4-fluorophenyl)pyridin-3-yl)((4aS,8aS)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 56); (5-(4-fluorophenyl)pyridin-3-yl)((4aR,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 57); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-nitrophenyl)pyridin-3-yl)methanone (compound 58); (5-Methoxy-3,4-dihydroquinolin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 59); (5-(4-fluorophenyl)pyridin-3-yl)(indolin-1-yl)methanone (compound 60); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 61); [3,4′-bipyridin]-5-yl(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 62); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanone (compound 63); (6-(4-fluorophenyl)pyridazin-4-yl)(2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (compound 64); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methanone (compound 65); (5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 66); Methyl 1-(5-phenylnicotinoyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (compound 67); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-((dimethylamino)methyl)phenyl)pyridin-3-yl)methanone (compound 68); (7-Methoxy-3,4-dihydroquinolin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 69); [3,3′-bipyridin]-5-yl(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 70); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(p-tolyl)pyridin-3-yl)methanone (compound 71); (5-(2,3-dihydrobenzofuran-6-yl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 72); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methanone (compound 73); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone (compound 74); 2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methanone (compound 75); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidin-1-yl)pyrazin-2-yl)methanone (compound 76); (6-(3,3-difluoroazetidin-1-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 77); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (compound 78); 1-(3,4-dihydroquinolin-1(2H)-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (compound 79); 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-methoxyphenyl)pyridin-3-yl)ethan-1-one (compound 80); 4-((5-phenylpyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 81); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanone (compound 82); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-methyl-1H-imidazol-1-yl)pyrazin-2-yl)methanone (compound 83); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl)methanone (compound 84); (6-benzylpyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 85); 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (compound 86); (3,4-Dihydroquinolin-1(2H)-yl)(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methanone (compound 87); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanone (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)indoline (compound 90); and tautomers and pharmaceutically acceptable salts thereof.

[0075] The compounds of the present invention can be administered to patients in therapeutically effective amounts, typically in the range of about 0.5 to about 2000 mg per day, more typically about 1 to about 500 mg, e.g., about 2 to 100 mg, depending on the patient's age, sex, weight, ethnicity, condition, symptoms to be treated, route of administration, and active ingredient used. The compounds of the present invention can be formulated into dosage forms using principles known in the art. The compounds can be administered to patients either alone or in combination with appropriate pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. Selecting appropriate components for a composition is a routine task for those skilled in the art. Suitable carriers, solvents, gel-forming ingredients, dispersion-forming ingredients, antioxidants, colorants, sweeteners, wetting compounds, and other ingredients commonly used in the art can also be used. Compositions containing the active compound can be administered enterally or parenterally, with the oral route being the most preferred route. The active compound content of the composition is about 0.5 to 100% by weight of the total composition, typically about 0.5 to about 20%.

[0076] The compounds of the invention can be administered to a patient as the sole active ingredient or in combination with one or more other active ingredients for the treatment of a particular disease.

[0077] In the treatment of steroid receptor-dependent diseases or conditions, such as endocrine cancers and disorders, including prostate and breast cancer, the combination of therapeutic agents and / or other treatments (e.g., radiation therapy) is often beneficial. The second (or third) agent administered may have the same mechanism of action as the first therapeutic agent, or it may have a different mechanism of action.

[0078] Therefore, the compound of the present invention can be administered in combination with other anti-cancer treatments that are useful in treating cancer, such as prostate cancer or breast cancer.For example, the compound of the present invention can be packaged with instructions that the compound is to be used in combination with other anti-cancer drugs and treatments for treating cancer.The present invention also includes the combination of the compound of the present invention and one or more additional drugs in the form of a kit, for example, they are packaged together, or they are packaged separately but sold together as a kit, or they are formulated and packaged together.

[0079] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a glucocorticoid and / or a mineralocorticoid, and optionally one or more anti-cancer agents.

[0080] 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-desoxycortisone, and deoxycorticosterone acetate.

[0081] Any other anticancer agent that can be administered in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof includes, but is not limited to, -Nonsteroidal androgen receptor antagonists (e.g., ezalutamide, apalutamide, and darolutamide); -steroidogenesis inhibitors (e.g., CYP17A1 inhibitors such as abiraterone acetate and seviteronel); - Chemotherapeutic agents (e.g., docetaxel and paclitaxel); -Antiestrogens (e.g., tamoxifen and fulvestrant); -epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); -AKT inhibitors (e.g., AZ5363); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); and -CDK4 / 6 inhibitors (e.g., ribociclib) Examples include:

[0082] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof: -Nonsteroidal androgen receptor antagonists (e.g., ezalutamide, apalutamide, and darolutamide); -steroidogenesis inhibitors (e.g., CYP17A1 inhibitors such as abiraterone acetate and seviteronel); - Chemotherapeutic agents (e.g., docetaxel and paclitaxel); -Antiestrogens (e.g., tamoxifen and fulvestrant); -epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); -AKT inhibitors (e.g., AZ5363); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); and -CDK4 / 6 inhibitors (e.g., ribociclib) is administered in addition to a therapeutically effective amount of one or more anti-cancer drugs selected from the list consisting of:

[0083] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in addition to a therapeutically effective amount of a steroidogenesis inhibitor (e.g., a CYP17A1 inhibitor). Suitable CYP17A1 inhibitors include, but are not limited to, abiraterone acetate and ceviteronel.

[0084] According to another embodiment of the present invention, a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt is administered to a subject in need thereof in addition to a therapeutically effective amount of a non-steroidal androgen receptor antagonist.Suitable non-steroidal androgen receptor (AR) antagonists include, but are not limited to, ezalutamide, apalutamide and darolutamide.

[0085] According to yet another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof - glucocorticoids, - mineralocorticoids, -steroidogenesis inhibitors (e.g., CYP17A1 inhibitors), -nonsteroidal androgen receptor antagonists, -chemotherapeutic agents (e.g., docetaxel and paclitaxel), antiestrogens (e.g., tamoxifen and fulvestrant), epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors), -mTOR inhibitors (e.g., everolimus); -AKT inhibitors (e.g., AZ5363); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); and -CDK4 / 6 inhibitors (e.g., ribociclib) and at least one additional active ingredient selected from the list consisting of:

[0086] Such other therapeutic agents, when used in combination with the compounds of the present invention, can be used, for example, in those amounts as described in the Physicians' Desk Reference (PDR), or as otherwise determined by one of skill in the art.

[0087] The compounds of the present invention can be prepared by various synthetic routes analogous to methods known in the literature using appropriate starting materials. The present invention is explained in more detail by the following experiments and examples. The experiments and examples are intended for illustrative purposes only and do not limit the scope of the invention as defined in the claims. [Example]

[0088] Intermediate 1: 6-(2,3-dihydrobenzofuran-5-yl)pyrazine-2-carboxylic acid [ka] A mixture of methyl-6-chloro-2-pyrazinecarboxylate (0.5 g, 2.90 mmol), 2,3-dihydrobenzofuran-5-boronic acid (0.47 g, 2.90 mmol), PdCl(PPh) (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 RT, the reaction mixture was diluted with EtOAc (10 ml) and filtered. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound. LC-MC: m / z 243.1 [M+H] +

[0089] The following intermediates were prepared from the starting materials indicated in the table following the procedure described for Intermediate 1. TIFF0007824953000031.tif217164

[0090] Intermediate 11: (5-Bromopyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone [ka] 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., TEA (1.80 ml, 13.61 mmol) was added. The reaction mixture was stirred at RT for 5 h. Water (10 ml) was added and the product was extracted with DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound. LC-MS: m / z 317.4 [M+H] +

[0091] The following intermediates were prepared from the starting materials indicated in the table following the procedure described for Intermediate 12. TIFF0007824953000033.tif155164

[0092] Intermediate 18: (6-chloropyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone [ka] To a mixture of 6-chloropyrazine-2-carboxylic acid (0.793 g, 5.0 mmol) in dry DCM (10 mL) was added a few drops of DMF and oxalyl chloride (0.858 mL, 10.0 mmol). The mixture was stirred at RT for 2 h. The solvent was evaporated, and fresh DCM (10 mL) was added. The mixture was cooled to 0-5 °C (ice-cooled), 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 RT overnight. The mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to give 0.92 g of the title compound. 1 H NMR (400 MHz, 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).

[0093] Intermediate 19: 2-(5-bromopyridin-3-yl)-1-(3,4-dihydroquinolin-1(2H)-yl)ethan-1-one [ka] To an ice-cooled mixture of 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 dry DMF (5.5 mL) was added 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 0.795 mL, 1.35 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc and water, and the phases were separated. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to give 0.27 g of the title compound. 1H NMR (400 MHz, 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).

[0094] Intermediate 20: 2-(5-bromopyridin-3-yl)-1-(2,3-dihydro-4H-benzo[b][1,4]-oxazin-4-yl)ethan-1-one [ka] The compound was prepared starting from 5-bromo-3-pyridinecarboxylic acid and 3,4-dihydro-2H-benzo[b][1,4]oxazine following the procedure described for intermediate 19. Yield: 0.24 g. 1 H NMR (400 MHz, 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).

[0095] Intermediate 21: 4-((5-bromopyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]-oxazine [ka] 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 short plug of Celite. The filtrate was evaporated, and the crude product was purified by flash chromatography to give 0.12 g of the title compound. 1 H NMR (400 MHz, d6-DMSO):δ8.61 (d, 1H), 8.54 (d, 1H), 7.95-8.00 (m, 1H), 6.63-6.75 (m, 3H), 6.52-6.59 (m, 1H), 4.53 (s, 2H), 4.20-4.27 (m, 2H), 3.38-3.45 (m, 2H).

[0096] Intermediate 22: Ethyl 5-(4-methyl-1H-imidazol-1-yl)nicotinate [ka] A mixture of tris(dibenzylideneacetone)dipalladium (7.33 mg, 0.008 mmol) and 2-di-tert-butylphosphino-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 a nitrogen atmosphere. Ethyl 5-bromonicotinate (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 short plug of Celite. The filtrate was dried and evaporated. The crude product was purified by flash chromatography to give the pure compound. 1H NMR (400 MHz, 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).

[0097] The following intermediates were prepared from the starting materials indicated in the table following the procedure described for Intermediate 22. TIFF0007824953000039.tif75164

[0098] Intermediate 25: 6-Benzylpyrazine-2-carboxylate methyl ester [ka] To a mixture of methyl 6-chloropyrazine-2-carboxylate (0.173 g, 1.00 mmol), potassium phosphate (0.637 g, 3.00 mmol), dicyclohexylphosphino-2,6-dimethoxybiphenyl (0.041 g, 0.10 mmol), and palladium acetate (0.011 g, 0.05 mmol) in degassed THF (10 mL) under a nitrogen atmosphere was added B-benzyl-9-borabicyclo[3.3.1]nonane (0.5 M in THF, 2.5 mL, 5.0 mmol). The mixture was stirred at 65 °C until the reaction was complete. The cooled mixture was diluted with DCM and filtered through a short plug of Celite. The filtrate was washed with 5% aqueous Na2CO3, water, and brine, dried, and evaporated. The crude product was purified by flash chromatography to give 0.16 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ9.14 (d, 1H), 8.57 (d, 1H), 7.23-7.37 (m, 5H), 4.31 (s, 2H), 4.05 (s, 3H).

[0099] Example 1 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methanone (Compound 1) [ka] a) (5-Bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (3) Methyl 5-bromonicotinate (8.0 g, 37.0 mmol) was treated with 4-dihydro-2H-benzo[b][1,4]oxazine (7.5 g, 56.0 mmol) in the presence of triethylamine (11.0 g, 15 mL, 0.11 mmol), trimethylaluminum (28.0 mL, 2 M in toluene, 56.0 mmol) in 40 mL of toluene at 25° C. for 16 hours. Purification by Combiflash chromatography gave 9.5 g of the title compound. 1 H-NMR (400 MHz, 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.

[0100] b) (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methanone (Compound 1) To a solution of methyl (5-bromopyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (200 mg, 0.627 mmol) in a mixture of 2.5 mL of ethanol, 10 mL of toluene, and 2.5 mL of water, 3-(trifluoromethoxy)phenyl)boronic acid (142 mg, 0.689 mmol) and sodium carbonate (133 mg, 1.25 mmol) were added under an inert atmosphere. The reaction mixture was degassed for 10 minutes, after which bis(triphenylphosphine)palladium(II) dichloride was added. Degassing was continued for another 10 minutes. The resulting reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction as indicated by TLC, the mixture was filtered through a bed of Celite. The resulting filtrate was diluted with water (10 mL) and EtOAc (21 mL) and extracted with EtOAc (3 x 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 Combiflash chromatography using 5-40% EtOAc in heptane as the eluent to give 0.08 g of the title compound. 1 H NMR (400 MHz, 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 (dd, 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.

[0101] Example 2 (7-Fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (Compound 2) [ka] a) Methyl 5-(4-fluorophenyl)nicotinate (3) Methyl 5-bromonicotinate (2.0 g, 9.3 mmol) was treated with (4-fluorophenyl)boronic acid (1.4 g, 10.0 mmol) in the presence of sodium carbonate (2.0 g, 19.0 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.65 g, 0.93 mmol) in 40 ml of DME and 20 ml of water at 90° C. for 4 hours. Purification by Combiflash chromatography using 5-30% EtOAc in heptane as the eluent gave 1.7 g of the title compound. 1 H-NMR (400 MHz, 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.

[0102] b) (7-Fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (Compound 2) Methyl 5-(4-fluorophenyl)nicotinate (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 the presence of TEA (0.36 mL, 2.59 mmol) and trimethylaluminum (0.65 mL, 2.0 M in toluene, 1.30 mmol) in 8 mL of toluene for 16 h at 25° C. Purification by Combiflash chromatography using 5-25% EtOAc in heptane as eluent gave 0.235 g of the title compound. 1 H NMR (400 MHz, DMSO-d6)δ: 8.99 (d, 1H), 8.69 (s, 1H), 8.22 (s, 1H), 7.00 - 7.90 (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.

[0103] Example 3 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (Compound 3) [ka] a) 3-bromo-4-methyl-5-phenylpyridine (3) 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 of DME and 30 ml of water at 90° C. for 6 hours. Purification by Combiflash using 5-30% EtOAc in heptane as the eluent gave 3.1 g of the title compound. 1 H-NMR (400 MHz, 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.

[0104] b) 4-methyl-5-phenylnicotinate (4) To a solution of 3-bromo-4-methyl-5-phenylpyridine (2.8 g, 11.0 mmol) in MeOH:DMSO (1:1) was added triethylamine (7.8 mL, 56.0 mmol). The reaction mixture was degassed with argon for 10 minutes, after which palladium(II) acetate (0.51 g, 2.3 mmol), 1,3-bis(diphenylphosphino)propane (0.93 g, 2.3 mmol), and CO gas were added. The resulting reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction 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 CombiFlash chromatography using 5–40% EtOAc in heptane as the eluent to give 2.3 g of the title compound. 1 H-NMR (400 MHz, 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.

[0105] c) (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (compound 3) 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 the presence of triethylamine (0.93 mL, 6.60 mmol) and trimethylaluminum (1.65 mL, 2.0 M in toluene, 3.30 mmol) in 12 mL of toluene at 100 °C for 16 h. Purification by Combiflash chromatography using 5-40% EtOAc in heptane as eluent gave 0.05 g of the title compound. Rf (50% EtOAc / heptane) = 0.2. 1H NMR (400 MHz, 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.

[0106] Example 4 (3,4-Dihydroquinolin-1(2H)-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (Compound 4) [ka] 4-Methyl-5-phenylnicotinate (500 mg, 2.20 mmol) was treated with 1,2,3,4-tetrahydroquinoline (440 mg, 3.30 mmol) in the presence of triethylamine (0.93 mL, 6.60 mmol) and trimethylaluminum (1.65 mL, 2.0 M in toluene, 3.30 mmol) in 15 mL of toluene at 100 °C for 16 h. Purification by Combiflash chromatography using 5-30% EtOAc in heptane as eluent gave 0.15 g of the title compound. Rf (50% EtOAc / heptane) = 0.2. 1 H NMR (400 MHz, 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.

[0107] Example 5 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methanone (Compound 5) [ka] a) 3-bromo-5-(4-fluorophenyl)-4-methylpyridine (3) 3,5-Dibromo-4-methylpyridine (5.0 g, 0.02 mol) was treated with (4-fluorophenyl)boronic acid (3.0 g, 0.02 mol), NaCO (6.0 g, 0.06 mol), and Pd(PPh)Cl (1.0 g, 2.0 mmol) in 60 ml of DME and 30 ml of water at 100 °C for 16 h. Purification by Combiflash chromatography using 5-40% ethyl acetate in heptane as eluent gave 4.2 g of the title compound. 1 H-NMR (400 MHz, 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.

[0108] b) Methyl 5-(4-fluorophenyl)-4-methylnicotinate (4) 3-Bromo-5-(4-fluorophenyl)-4-methylpyridine (5.0 g, 0.02 mol) in 60 ml of DMSO and 60 ml of MeOH was treated with triethylamine (8.0 g, 11 ml, 79.0 mmol), palladium(II) acetate (0.71 g, 3.2 mmol), 1,3-bis(diphenylphosphino)propane (1.3 g, 3.2 mmol), and CO gas at 100° C. for 16 h. Purification by Combiflash chromatography using 10-40% ethyl acetate in heptane as the eluent gave 3.2 g of the title compound. 1H-NMR (400 MHz, 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.

[0109] c) (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methanone (Compound 5) 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 the presence of triethylamine (0.68 mL, 4.89 mmol) and trimethylaluminum (1.22 mL, 2.0 M in toluene, 2.45 mmol) in 10 mL of toluene at 95° C. for 18 hours. Purification by Combiflash chromatography using 5-40% ethyl acetate in heptane as eluent gave 0.118 g of the title compound. 1 H NMR (400 MHz, 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.

[0110] Example 6 (4-Amino-5-phenylpyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (Compound 6) [ka] a) 3-bromo-5-phenylpyridin-4-amine (3) 3,5-Dibromopyridin-4-amine (6.0 g, 24.0 mmol) was treated with phenylboronic acid (3.2 g, 26.0 mmol), NaCO (5.0 g, 48.0 mmol), and Pd(PPh)Cl (1.7 g, 2.4 mmol) in 12 ml of DME and 6 ml of water at 90 °C for 4 h. Purification by Combiflash chromatography using 5-40% ethyl acetate in heptane as eluent gave 3.6 g of the title compound. 1 H-NMR (400 MHz, 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.

[0111] b) Methyl 4-amino-5-phenylnicotinate (4) 3-Bromo-5-phenylpyridin-4-amine (2.8 g, 11.0 mmol) in 50 ml of MeOH and 50 ml of DMSO 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(diphenylphosphino)propane (1.9 g, 4.5 mmol) and CO gas at 80° C. for 12 hours. Purification by Combiflash chromatography using 10-40% ethyl acetate in heptane as the eluent gave 1.6 g of the title compound. 1 H-NMR (400 MHz, 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.

[0112] c) (4-amino-5-phenylpyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 6) Methyl 4-amino-5-phenylnicotinate (500 mg, 2.19 mmol) was treated with 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 in toluene, 3.29 mmol) in 20 mL of toluene at 100 °C for 16 h. Purification by Combiflash chromatography using 5-30% ethyl acetate in heptane as eluent afforded 0.025 g of the title compound. (NMR / MS data in Table 2). 1 H NMR (400 MHz, 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.

[0113] Example 7 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methanone (Compound 7) [ka] a) 3-chloro-5-(4-fluorophenyl)pyridazine (3) 3,5-Dichloropyridazine (3.0 g, 20.1 mmol) was treated with (4-fluorophenyl)boronic 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 of toluene and 10 mL of water at 80 °C for 16 h. Purification by Combiflash chromatography using 5-40% ethyl acetate in heptane as eluent gave 1.0 g of the title compound. Rf (70% EtOAc / heptane) = 0.4. 1H-NMR (400 MHz, DMSO-d6)δ: 9.68 (d, 1 H), 8.29 (d, 1 H), 8.09 (dt, 2H), 7.43 (dd, 2H). MS (ESI) m / z [M+1]+: 209.02.

[0114] b) methyl 5-(4-fluorophenyl)pyridazine-3-carboxylate (4) 3-Chloro-5-(4-fluorophenyl)pyridazine (850 mg, 4.07 mmol) was treated with triethylamine (1.14 mL, 8.15 mmol), PdCl(dppf) (298 mg, 0.407 mmol) and CO gas in 50 mL of MeOH at 100° C. for 16 h. Purification by Combiflash chromatography using 10-40% ethyl acetate in heptane as eluent gave 0.87 g of the title compound. 1 H-NMR (400 MHz, DMSO-d6): δ9.86 (d, 1 H), 8.45 (d, 1 H), 8.11 (dd, 2H), 7.44 (dd, 2H), 3.99 (s, 3H). MS (ESI) m / z [M+1]+: 233.02.

[0115] c) (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methanone (Compound 7) Methyl 5-(4-fluorophenyl)pyridazine-3-carboxylate (500 mg, 2.15 mmol) was treated with 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 in toluene, 3.23 mmol) in 15 mL of toluene at 100 °C for 16 h. Purification by Combiflash chromatography using 5-40% ethyl acetate in heptane as eluent gave 0.142 g of the title compound. Rf (50% EtOAc / heptane) = 0.2.

[0116] Example 8 (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 8) [ka] a) (6-Bromopyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (3) Methyl 5-(4-fluorophenyl)pyridazine-3-carboxylate (20 mg, 0.086 mmol) was treated with 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 in toluene, 0.129 mmol) in 5 mL of toluene at 100° C. for 16 h. Purification by Combiflash chromatography using 20-60% ethyl acetate in heptane as eluent afforded 0.025 g of the title compound. Rf (50% EtOAc / heptane) = 0.2. Yield: 70%. 1 H-NMR (400 MHz, 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.

[0117] b) (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 8) (6-Bromopyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (500 mg, 1.56 mmol) was treated with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (383 mg, 1.56 mmol), sodium carbonate (331 mg, 3.12 mmol), and Pd(PPh)Cl (110 mg, 0.156 mmol) in 2.5 mL of ethanol, 10 mL of toluene, and 2.5 mL of water at 90 °C for 16 h. Purification by Combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent gave 0.3 g of the title compound. 1 H NMR (400 MHz, 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 / z 359.15.

[0118] Example 9 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)methanone (Compound 9) [ka] (6-Bromopyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (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(PPh)Cl (110 mg, 0.156 mmol) in 0.63 mL of ethanol, 2.5 mL of toluene, and 0.63 mL of water at 90 °C for 16 h. Purification by Combiflash chromatography using 0-35% ethyl acetate in heptane as the eluent gave 0.4 g of the title compound. 1 H NMR (400 MHz, DMSO-d6)δ9.37 (s, 1H), 8.96 (s, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.65 (t, 1H), 7.48 (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.

[0119] Example 10 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-phenylpyridin-3-yl)methanone (Compound 10) [ka] 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 RT 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 H NMR (chloroform-d, 400 MHz) 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).

[0120] Example 11 (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (Compound 11) [ka] A mixture of 5-phenylnicotinoyl chloride (0.1 g, 0.46 mmol), 1,2,3,4-tetrahydro-1,6-naphthyridine (61.6 mg, 0.46 mmol) in DCM (5 ml) was cooled to 0 °C, and then EtN (0.2 ml, 1.38 mmol) was added. The mixture was stirred at RT for 12 h. Water (10 ml) was added, followed by extraction with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound. 1H NMR (DMSO-d6, 600 MHz)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) + .

[0121] The following compounds were prepared according to the procedures described above. Compound numbers, characterising data, starting materials, reaction conditions (example numbers cited) and purification methods are given in the table.

[0122] Purification method used: a) Crystallization b) Column chromatography c) Precipitation in aqueous media d) Semi-preparative HPLC e) Crushing f) Salt formation TIFF0007824953000052.tif242164 TIFF0007824953000053.tif234164 TIFF0007824953000054.tif239164 TIFF0007824953000055.tif240164 TIFF0007824953000056.tif245164 TIFF0007824953000057.tif234164 TIFF0007824953000058.tif209164 TIFF0007824953000059.tif215164 TIFF0007824953000060.tif217164 TIFF0007824953000061.tif234164 TIFF0007824953000062.tif240164 TIFF0007824953000063.tif204164 TIFF0007824953000064.tif204164

[0123] Example 12 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methanone (Compound 73) [ka] To a mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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)methanone (0.112 g, 0.35 mmol), and cesium carbonate (0.319 g, 0.98 mmol) in degassed DME-water (2.5:1, 3.5 mL) under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (0.040 g, 0.035 mmol) was added. The mixture was stirred at 90 °C until the reaction was complete. The cooled reaction mixture was diluted with EtOAc and filtered through a short plug of Celite. The filtrate was washed with water and brine, dried, and evaporated. The crude material was purified by reverse phase flash chromatography to give 0.083 g of the title compound. 1 H NMR (400 MHz, 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).

[0124] Example 13 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone (Compound 74) [ka] 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)methanone (0.128 g, 0.40 mmol), sodium tert-butoxide (0.050 g, 0.52 mmol), tris(dibenzylideneacetone)dipalladium (0.018 g, 0.020 mmol), and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.025 g, 0.10 mmol) in dry toluene (1.5 ml) under a nitrogen atmosphere was stirred at 100° C. until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a short plug of Celite. The filtrate was evaporated. The crude product was purified by reverse-phase flash chromatography to give 0.046 g of the title compound. 1 H NMR (400 MHz, 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), 6.91 (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).

[0125] Example 14 2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methanone (Compound 75) [ka] The compound was prepared according to the procedure of Example 13, starting 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)methanone (0.112 g, 0.35 mmol). Yield 0.028 g. 1 H NMR (400 MHz, 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).

[0126] Example 15 (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidin-1-yl)pyrazin-2-yl)methanone (Compound 76) [ka] A mixture of (6-chloropyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (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 reverse-phase flash chromatography to give the pure compound. 1H NMR (400 MHz, 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).

[0127] The following compounds were prepared according to the procedure of Example 15. Compound numbers, characterizing data, deviating reaction conditions and starting materials are indicated in the table. TIFF0007824953000069.tif116164

[0128] Example 16 1-(3,4-Dihydroquinolin-1(2H)-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (Compound 79) [ka] To a mixture of 2-(5-bromopyridin-3-yl)-1-(3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (0.116 g, 0.35 mmol), 4-fluorobenzeneboronic acid (0.059 g, 0.42 mmol), and sodium carbonate (0.104 g, 0.98 mmol) in degassed DME-water (6:1, 1.75 ml) under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol) was added. The mixture was stirred at 90 °C until the reaction was complete. The cooled mixture was diluted with EtOAc and filtered through a short plug of Celite. The filtrate was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give the pure compound. 1H NMR (400 MHz, CDCl3):δ8.66 (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).

[0129] The following compounds were prepared according to the procedure of Example 16. Compound numbers, characterizing data and starting materials are given in the table. TIFF0007824953000071.tif110164

[0130] Example 17 (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanone (Compound 82) [ka] 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 bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (0.071 g, 0.277 mmol) in dry toluene (0.5 ml) was stirred at 120 °C until the reaction was complete. The cooled mixture was quenched with 2 M aqueous HCl and then extracted with DCM. The organic phase was dried and evaporated. The crude material was purified by reverse-phase flash chromatography to give the pure compound. 1H NMR (600 MHz, d6-DMSO):δ8.91 (d, 1H9, 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).

[0131] The following compounds were prepared according to the procedure of Example 17. Compound numbers, characterizing data and starting materials are given in the table. TIFF0007824953000073.tif146164

[0132] Example 18 1-(2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (Compound 86) [ka] a) 2-(5-(4-fluorophenyl)pyridin-3-yl)acetic acid [ka] To a mixture of 5-bromo-3-pyridineacetic acid (0.216 g, 1 mmol), 4-fluorobenzeneboronic acid (0.175 g, 1.25 mmol), and cesium carbonate (0.912 g, 2.80 mmol) in degassed DME-water (3:1, 8 ml) under a nitrogen atmosphere was added 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 short plug of Celite. The phases were separated, and the pH of the aqueous phase was adjusted to 6 with 2 M aqueous NaOH. The aqueous phase was extracted with EtOAc. The organic phase was dried and evaporated to give 0.10 g of the title compound. 1H NMR (400 MHz, 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).

[0133] b) 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (compound 85) [ka] The compound was prepared following the procedure for Intermediate 19, starting 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). The crude product was purified by reverse-phase flash chromatography. Yield: 0.039 g. 1 H NMR (400 MHz, CDCl3):δ8.70 d (1H), 8.40 (br s, 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).

[0134] Example 19 (3,4-Dihydroquinolin-1(2H)-yl)(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methanone (Compound 87) [ka] a) (6-Bromopyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone [ka] The compound was prepared following the procedure of Example 17, starting with methyl 6-bromopyrazine-2-carboxylate (0.217 g, 1.00 mmol) and 1,2,3,4-tetrahydroquinoline (0.126 ml, 1.00 mmol). The crude product was purified by flash 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).

[0135] b) (3,4-Dihydroquinolin-1(2H)-yl)(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methanone (compound 86) [ka] The compound was prepared following the procedure for Intermediate 22, starting from (6-bromopyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (0.080 g, 0.251 mmol) and 3,5-dimethylpyrazole (0.024 g, 0.251 mmol). The crude product was purified by reverse-phase flash chromatography to give 0.012 g of the title compound. 1 H NMR (400 MHz, 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 (brs, 3H). LC-MS: m / z 334.7 (M+H).

[0136] Example 20 (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanone (Compound 88) [ka] A mixture of (5-bromopyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (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 short plug of Celite. The filtrate was washed with aqueous NH4Cl-NH3 (4:1), water, and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 0.016 g of the title compound. 1 H NMR (400 MHz, 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).

[0137] Example 21 1-((5-(4-fluorophenyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroquinoline (Compound 89) [ka] To a mixture of 1,2,3,4-tetrahydroquinoline (0.050 ml, 0.40 mmol) and acetic acid (0.25 ml) in 1,2-dichloroethane (1.0 ml) was added 5-(4-fluorophenyl)nicotinaldehyde (0.089 g, 0.44 mmol) dissolved in 1,2-dichloroethane (1.0 ml). The mixture was stirred at RT for 6 h. Sodium triacetoxyborohydride (0.1287 g, 0.88 mmol) was added, and the mixture was stirred at RT overnight. The mixture was diluted with DCM and basified with saturated aqueous 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 reverse-phase flash chromatography to give the pure compound. 1 H NMR (400 MHz, 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).

[0138] The following compounds were prepared according to the procedure of Example 21. Compound numbers, characterizing data and starting materials are shown in the table. TIFF0007824953000082.tif93164

[0139] Abbreviation DCM - dichloromethane DIPEA - N,N-Diisopropylethylamine DME - Dimethoxyethane DMF - N,N-dimethylformamide DMSO - Dimethyl Sulfoxide dppp - 1,3-bis(diphenylphosphino)propane HPLC - High Performance Liquid Chromatography LC-MS - Liquid Chromatography-Mass Spectrometry PdCl2(dppf) - [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2- Palladium(II) acetate Pd2(dba)3- Tris(dibenzylideneacetone)dipalladium PdCl2(PPh3)2- Bis(triphenylphosphine)palladium(II) dichloride Q-PHOS - 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene RT - room temperature STB - Sodium tert-butoxide STAB - Sodium triacetoxyborohydride TEA - Triethylamine T3P - Propylphosphonic Anhydride THF - tetrahydrofuran TLC - Thin Layer Chromatography TMA - Trimethylamine

[0140] experiment Experiment 1. CYP11A1 Inhibition The ability of test compounds to inhibit pregnenolone biosynthesis was measured by enzyme-linked immunosorbent assay (ELISA) to detect pregnenolone (Abnova Pregnenolone ELISA Kit, KA1912). The human adrenocortical carcinoma cell line NCI-H295R, which has been shown to express all key steroidogenic enzymes, was used as the enzyme source. The half maximal inhibitory concentration (IC) of test compounds for CYP11A1 inhibition was determined. 50To determine the activity of pregnenolone in cells, cells were treated with increasing concentrations of test compounds for 24 hours. The final DMSO concentration was 0.4%. Media samples were diluted 1:6, and pregnenolone levels were measured 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 tested in duplicate at 10 concentrations.

[0141] The compounds of the present invention were screened using the above assays, and the IC 50 The values ​​are listed in Table 1 below, where "A" indicates an IC of less than 50 nM. 50 "B" indicates IC values ​​in the range of 51-200 nM 50 values ​​are shown, and "C" is the IC in the range of 201-2500 nM. 50 Indicates the value.

[0142] [Table 1]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, B is one of the following groups: 【Chemistry 2】 When B is group (1) or (2), A is a 3- to 10-membered carbocyclyl or a 4- to 12-membered heterocyclyl containing 1-4 heteroatoms selected from O, N, and S; C is one of the following groups: 【Transformation 3】 G 1 is CH 2 , NH or O; G 2 and G 3 is independently CH or N; Z is -C(O)-, -SO 2 -, -C 1-3 Alkyl- or -CH 2 -C(O)-; L is a bond, -C 1-7 Alkyl- or -C 1-7 alkenyl-; R 1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, nitro, halogen C 1-7 Alkyl, hydroxy C 1-7 Alkyl, —O-halogen C 1-7 Alkyl or -X-NR 6 R 7 and R 2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R 3 is hydrogen, C 1-7 alkyl or amino; R 4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or —C(O)—O—C 1-7 is alkyl; R 5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R 6 and R 7 are independently hydrogen or C 1-7 is alkyl; When B is group (3), A is one of the following groups: 【Chemistry 4】 However, when C is ring (3'), A is not ring (2'') or ring (7''); C is one of the following groups: 【Transformation 5】 G 1 is CH 2 , NH or O; G 2 and G 3 is independently CH or N; Z is -C(O)-, -SO 2 -, -C 1-3 Alkyl- or -CH 2 -C(O)-; L is a bond, -C 1-7 Alkyl- or -C 1-7 alkenyl-; R 1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy, halogen C 1-7 Alkyl, hydroxy C 1-7 Alkyl, —O-halogen C 1-7 Alkyl, —X—NR 6 R 7 and R 2 is hydrogen, hydroxy, C 1-7 is alkyl or halogen; R 3 is hydrogen, C 1-7 alkyl or amino; R 4 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy C 1-7 Alkyl, halogen C 1-7 Alkyl or —C(O)—O—C 1-7 is alkyl; R 5 is hydrogen, halogen, C 1-7 Alkoxy or C 1-7 is alkyl; X is a bond or C 1-7 is alkyl; R 6 and R 7 are independently hydrogen or C 1-7 is alkyl, However, the compound of formula (I) (7-Methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidin-1-yl)pyrazin-2-yl)methanone; (8-fluoro-3,4-dihydro-3-hydroxymethyl-1(2H)-quinolinyl)(6-(1-pyrrolidinyl)-2-pyrazinyl)methanone; (3,4-Dihydro-3-methoxy-1(2H)-quinolinyl)(6-phenyl-4-pyridazinyl)methanone; (6-fluoro-3,4-dihydro-4-methyl-1(2H)-quinoxaquinyl)(5-phenyl-3-pyridinyl)methanone; (3,4-dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(3,4-dihydro-1(2H)-quinolinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methanone; (6,8-difluoro-3,4-dihydro-1(2H)-quinolinyl)(5-(4-(dimethylamino)phenyl)-3-pyridinyl)methanone; (3,4-dihydro-1(2H)-quinolinyl)(5-(1-pyrrolidinyl)-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(octahydro-4H-1,4-benzoxazin-4-yl)methanone; (5-(4-methoxyphenyl)-3-pyridinyl)(octahydro-4H-1,4-benzoxazin-4-yl)methanone; (2,3-dihydro-1H-indol-1-yl)(5-phenyl-3-pyridinyl)methanone; [3,4-dihydro-3-(hydroxymethyl)-1(2H)-quinolinyl][6-(1-pyrrolidinyl)-2-pyrazinyl]methanone; (3,4-Dihydro-1(2H)-quinoxalinyl)[6-(1-pyrrolidinyl)-2-pyrazinyl]methanone; or (3,4-Dihydro-3-isopropyl-1(2H)-quinoxalinyl)[6-(1-pyrrolidinyl)-2-pyrazinyl]methanone isn't it).

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

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

4. The compound according to any one of claims 1 to 3, wherein L is a bond.

5. The compound according to any one of claims 1 to 4, wherein group C is (1').

6. G 1 is CH 2 or O.

7. G 2 is N and G 3 The compound according to claim 5 or 6, wherein is CH.

8. G 2 is CH and G 3 The compound according to claim 5 or 6, wherein is N.

9. R 1 But hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, hydroxy C 1-7 Alkyl or halogen C 1-7 The compound according to any one of claims 1 to 8, which is alkyl.

10. R 2 is hydrogen, hydroxy, C 1-7 The compound according to any one of claims 1 to 9, wherein the aryl group is alkyl or halogen.

11. R 3 The compound according to any one of claims 1 to 10, wherein is hydrogen.

12. R 4 But hydrogen, C 1-7 Alkyl, halogen or —C(O)—O—C 1-7 The compound according to any one of claims 1 to 11, which is alkyl.

13. R 5 The compound according to any one of claims 1 to 12, wherein is hydrogen.

14. When B is group (3), A is one of the following groups: 【Transformation 6】 The compound according to any one of claims 1 to 13.

15. When B is group (1) or (2), A is one of the following groups: 【Transformation 7】 The compound according to any one of claims 1 to 14.

16. A is one of the following groups: 【Transformation 8】 16. The compound of claim 15.

17. The compound according to any one of claims 1 to 16, represented by formula (IA) or a pharmaceutically acceptable salt thereof: 【Chemistry 9】 (In the formula, D is N or CH; G is CH 2 , NH or O; M is CH or N; R 1 is hydrogen, C 1-7 Alkyl, C 1-7 alkoxy or halogen; R 2 is hydrogen or halogen; R 3 is hydrogen or C 1-7 is alkyl; R 4 is hydrogen, C 1-7 Alkyl, halogen or —C(O)—O—C 1-7 is alkyl; A is one of the following groups: 【Chemistry 10】 However, the compound of formula (I) (3,4-dihydro-1(2H)-quinolinyl)(5-phenyl-3-pyridinyl)methanone; (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(3,4-dihydro-1(2H)-quinolinyl)methanone; or (5-(2,3-dihydro-5-benzofuranyl)-3-pyridinyl)(7-fluoro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methanone isn't it).

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

19. (2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methanone (Compound 1); (7-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 2); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (compound 3); (3,4-Dihydroquinolin-1(2H)-yl)(4-methyl-5-phenylpyridin-3-yl)methanone (compound 4); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)-4-methylpyridin-3-yl)methanone (Compound 5); (4-amino-5-phenylpyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 6); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridazin-3-yl)methanone (Compound 7); (6-(benzo[d]oxazol-6-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 8); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)methanone (compound 9); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-phenylpyridin-3-yl)methanone (compound 10); (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 11); (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 12); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)methanone (compound 13); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-methoxyphenyl)pyrazin-2-yl)methanone (compound 14); (3,4-Dihydroquinolin-1(2H)-yl)(6-phenylpyrazin-2-yl)methanone (compound 15); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 16); (5-(4-chlorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 17); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methanone (compound 18); (5-(3,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 19); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyrazin-2-yl)methanone (compound 20); (6-(4-fluorophenyl)pyrazin-2-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone (compound 21); (6-(4-fluorophenyl)pyrazin-2-yl)(2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (compound 22); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methanone (compound 23); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 24); (3,4-Dihydroquinolin-1(2H)-yl)(6-(3-methoxyphenyl)pyrazin-2-yl)methanone (compound 25); (6-(4-fluorophenyl)pyrazin-2-yl)(3-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 26); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-hydroxyphenyl)pyridin-3-yl)methanone (compound 27); (5-(2,4-difluorophenyl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 28); (6-(2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 29); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methanone (compound 30); (5-(4-fluorophenyl)pyridin-3-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone (compound 31); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-nitrophenyl)pyridin-3-yl)methanone (compound 32); (5-(cyclohex-1-en-1-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 33); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(5-(4-methoxyphenyl)pyridin-3-yl)methanone (compound 34); Ethyl 4-(6-(4-fluorophenyl)pyrazine-2-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Compound 35); 1-(5-phenylnicotinoyl)-2,3-dihydroquinolin-4(1H)-one (compound 36); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(6-phenylpyrazin-2-yl)methanone (compound 37); (3,4-Dihydroquinolin-1(2H)-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methanone (compound 38); (5-(1H-pyrrol-1-yl)pyridin-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 39); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-fluorophenyl)pyridazin-4-yl)methanone (compound 40); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(2-fluorophenyl)pyridin-3-yl)methanone (compound 41); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(5-(4-fluorophenyl)pyridin-3-yl)methanone (compound 42); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)methanone (compound 43); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methanone (compound 44); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanone (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)methanone (compound 48); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6′-fluoro-[3,3′-bipyridin]-5-yl)methanone (compound 49); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(3-methoxyphenyl)pyridin-3-yl)methanone (compound 50); (3,4-Dihydroquinolin-1(2H)-yl)(5-(1-phenylvinyl)pyridin-3-yl)methanone (compound 51); (3,4-Dihydroquinolin-1(2H)-yl)(6-phenylpyridazin-4-yl)methanone (compound 52); (6-Methoxy-3,4-dihydroquinolin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 53); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methanone (compound 54); (5-(4-fluorophenyl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 55); (5-(4-fluorophenyl)pyridin-3-yl)((4aS,8aS)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 56); (5-(4-fluorophenyl)pyridin-3-yl)((4aR,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 57); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-fluoro-3-nitrophenyl)pyridin-3-yl)methanone (compound 58); (5-Methoxy-3,4-dihydroquinolin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 59); (5-(4-fluorophenyl)pyridin-3-yl)(indolin-1-yl)methanone (compound 60); (3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 61); [3,4′-bipyridin]-5-yl(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 62); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanone (compound 63); (6-(4-fluorophenyl)pyridazin-4-yl)(2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (compound 64); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(4-(hydroxymethyl)phenyl)pyridin-3-yl)methanone (compound 65); (5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 66); Methyl 1-(5-phenylnicotinoyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (Compound 67); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-((dimethylamino)methyl)phenyl)pyridin-3-yl)methanone (compound 68); (7-Methoxy-3,4-dihydroquinolin-1(2H)-yl)(5-phenylpyridin-3-yl)methanone (compound 69); [3,3′-bipyridin]-5-yl(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 70); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(p-tolyl)pyridin-3-yl)methanone (compound 71); (5-(2,3-dihydrobenzofuran-6-yl)pyridin-3-yl)(octahydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 72); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methanone (compound 73); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone (compound 74); 2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methanone (compound 75); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(pyrrolidin-1-yl)pyrazin-2-yl)methanone (compound 76); (6-(3,3-difluoroazetidin-1-yl)pyrazin-2-yl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone (compound 77); (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-yl)(6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (compound 78); 1-(3,4-dihydroquinolin-1(2H)-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (compound 79); 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-methoxyphenyl)pyridin-3-yl)ethan-1-one (compound 80); 4-((5-phenylpyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 81); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methanone (compound 82); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-methyl-1H-imidazol-1-yl)pyrazin-2-yl)methanone (compound 83); (3,4-Dihydroquinolin-1(2H)-yl)(6-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl)methanone (compound 84); (6-benzylpyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone (compound 85); 1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(5-(4-fluorophenyl)pyridin-3-yl)ethan-1-one (compound 86); (3,4-Dihydroquinolin-1(2H)-yl)(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazin-2-yl)methanone (compound 87); (3,4-Dihydroquinolin-1(2H)-yl)(5-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methanone (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)indoline (compound 90); 19. The compound of any one of claims 1 to 18, which is: or a tautomer or a pharmaceutically acceptable salt thereof.

20. A medicament comprising the compound according to any one of claims 1 to 19.

21. A medicament for the treatment of a steroid receptor dependent condition or disease, comprising a compound according to any one of claims 1 to 19, or a compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 11】 (In the formula, A is a 3- to 10-membered carbocyclyl or a 4- to 12-membered heterocyclyl containing 1-4 heteroatoms selected from O, N, and S; B is the following group 【Chemistry 12】 Either C is the following group 【Chemistry 13】 is one of: G 1 is CH 2 , NH or O; G 2 and G 3 are independently CH or N; Z is —C(O)—, —SO 2 —, —C 1-3 alkyl- or —CH 2 —C(O)—; L is a bond, —C 1-7 alkyl- or —C 1-7 alkenyl-; R 1 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, hydroxy, nitro, halogenC 1-7 alkyl, hydroxyC 1-7 alkyl, —O-halogenC 1-7 alkyl or —X—NR 6 R 7 ; R 2 is hydrogen, hydroxy, C 1-7 alkyl or halogen; R 3 is hydrogen, C 1-7 alkyl or amino; R 4 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, hydroxy, hydroxyC 1-7 alkyl, halogenC 1-7 alkyl or —C(O)—O—C 1-7 alkyl; R 5 is hydrogen, halogen, C 1-7 alkoxy or C 1-7 alkyl; X is a bond or C 1-7 alkyl; R 6 and R 7 are independently hydrogen or C 1-7 alkyl).

22. The pharmaceutical agent according to claim 21, wherein the steroid receptor-dependent symptom or disease is cancer.

23. The pharmaceutical composition according to claim 22, wherein the steroid receptor-dependent condition or disease is prostate cancer or breast cancer.

24. The method according to any one of claims 20 to 23, wherein the compound of formula (I) is administered in addition to a glucocorticoid and / or a mineralocorticoid, and optionally one or more anticancer agents.

25. A pharmaceutical comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is administered in addition to a glucocorticoid and / or a mineralocorticoid, and optionally one or more anticancer agents. 【Chemistry 14】 (In the formula, A is a 3- to 10-membered carbocyclyl or a 4- to 12-membered heterocyclyl containing 1-4 heteroatoms selected from O, N, and S; B is the following group 【Chemistry 15】 Either C is the following group 【Chemistry 16】 is one of: G 1 is CH 2 , NH or O; G 2 and G 3 are independently CH or N; Z is —C(O)—, —SO 2 —, —C 1-3 alkyl- or —CH 2 —C(O)—; L is a bond, —C 1-7 alkyl- or —C 1-7 alkenyl-; R 1 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, hydroxy, nitro, halogenC 1-7 alkyl, hydroxyC 1-7 alkyl, —O-halogenC 1-7 alkyl or —X—NR 6 R 7 ; R 2 is hydrogen, hydroxy, C 1-7 alkyl or halogen; R 3 is hydrogen, C 1-7 alkyl or amino; R 4 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, hydroxy, hydroxyC 1-7 alkyl, halogenC 1-7 alkyl or —C(O)—O—C 1-7 alkyl; R 5 is hydrogen, halogen, C 1-7 alkoxy or C 1-7 alkyl; X is a bond or C 1-7 alkyl; R 6 and R 7 are independently hydrogen or C 1-7 alkyl).

26. The compound of formula (I) - nonsteroidal androgen receptor antagonists; - steroidogenesis inhibitors; - chemotherapeutic agents; - antiestrogens; - epigenetic modulators; - mTOR inhibitors; - AKT inhibitors; - radiopharmaceuticals; - GnRH / LHRH analogues; - PI3K inhibitors; and -CDK4 / 6 inhibitors The pharmaceutical composition according to any one of claims 20 to 25, which is administered simultaneously, separately or consecutively in addition to one or more anticancer drugs selected from the group consisting of:

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 together with a pharmaceutically acceptable carrier.

28. A compound according to any one of claims 1 to 19; - glucocorticoids, - mineralocorticoids, - nonsteroidal androgen receptor antagonists, -steroidogenesis inhibitors, -chemotherapeutic agents, - anti-estrogens, - epigenetic modulators, - mTOR inhibitors; - AKT inhibitors; - radiopharmaceuticals); - GnRH / LHRH analogues; - PI3K inhibitors; and -CDK4 / 6 inhibitors and at least one additional active ingredient selected from the list consisting of:

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