composition comprising tetracyclic compounds and orally administrable formulation comprising it

专利摘要:
COMPOSITION UNDERSTANDING TETRACYCLIC COMPOUNDS. The present invention relates to a composition that comprises the substance represented by the formula. (l) a pharmaceutically acceptable carrier and dissolution aid is useful for improving the solubility, oral absorption capacity and / or blood absorption capacity of water-soluble or water-insoluble tetracyclic compounds having an ALK inhibitory activity that are useful as a prophylactic and / or therapeutic agent for cancer, depression and cognitive function disorder.
公开号:BR112013003879B1
申请号:R112013003879-9
申请日:2011-08-19
公开日:2020-12-22
发明作者:Kentaro Furumoto；Koji Shiraki；Tomoaki Hirayama
申请人:Chugai Seiyaku Kabushiki Kaisha；
IPC主号:

专利说明:

TECHNICAL FIELD
[0001] The present invention relates to a composition of a tetracyclic compound having an ALK inhibitory activity and, in particular, to a composition for oral administration. PREVIOUS TECHNIQUE
[0002] Anaplastic Lymphoma Kinase (ALK) is one of the receptor-type tyrosine kinases belonging to an insulin receptor family (Non-Patent Documents Nos. 1 and 2). ALK gene alteration is reported to cause abnormal kinase production fused to another gene.
[0003] Examples of disorders accompanied with ALK abnormality include cancer and cancer metastasis (Non-Patent Document 1 and Patent Document 1), depression and cognitive function disorder (Non-Patent Document 2). In this way, an ALK inhibitor will provide pharmaceutical products that are effective for treating and preventing disorders.
[0004] Such pharmaceutical products need to be developed in the form of an orally administrable formulation. However, the developmental property of an orally administrable formulation depends on the level of bioavailability of a pharmaceutical compound. As a factor that affects bioavailability, water solubility of a pharmaceutical compound can be considered. In general, when a compound that is poorly soluble in water or insoluble in water is orally administered, it shows poor bioavailability. Improving an oral absorption capacity by increasing the bioavailability of an active ingredient is also important in terms of obtaining a stable display of the pharmaceutical effect of the active ingredient. Patent Document 2 discloses a composition which comprises a poorly water-soluble ingredient such as steroids, sodium lauryl sulfate and an organic polymer for improving the solubility and oral absorption capacity of a poorly water-soluble ingredient, which is obtained through wet granulation in the presence of water.
[0005] So far, for example, tricyclic compounds (Patent Document 2) or similar have been reported as an ALK inhibiting substance.
[0006] However, the tetracyclic compounds that are represented by Formula (I) that follows or salts thereof are not described in any document.
[0007] However, ellipticin derivatives are known as a tetracyclic compound (Non-Patent Document 3).
[0008] Although the tetracyclic compounds used in the present invention have excellent ALK inhibitory activity, due to their property of poorly soluble in water or insoluble in water, further studies have been needed to develop them in the form of orally administrable formulation. DOCUMENT LISTING [Patent Document 1] JP2009100783 (A) [Patent Document 2] Japanese Patent Application Open to Public Inspection (JP-A) No. 2008-280352 [Non-Patent Document] [Non-Patent Document 1] Nature, Vol. 448, pages 561-566, 2007 [Non-Patent Document 2] Neuropsychofarmacology, Vol. 33, pages 685-700, 2008 [Non-Patent Document 3] Current Medication Chemistry: Anti-Cancer Agents, Vol. 4 , Edition No. 2, pages 149-172, 200 SUMMARY OF THE PRESENT INVENTION Problems to be Solved by the Present Invention
[0009] The inventors of the present invention studied extensively to solve the problems described above and, as a result, unexpectedly found that by allowing a dissolution aid to co-exist with a poorly soluble or water-insoluble substance represented by Formula (I) , solubility of the substance can be significantly improved. The inventors carried out additional studies based on these findings and then ended the present invention. Means to Solve Problems
[00010] Specifically, the present invention relates to the following. [1] A composition comprising a substance represented by Formula (I), a pharmaceutically acceptable carrier and a dissolution aid,
on what,
[00011] A1, A2, A3, A4, A7, A8, A9 and A10 all represent C, or any of A2, A3, A4, A7, A8 and A9 represents N (with the proviso that when it represents N , no substituting groups exist therefore) and the rest represent C; A5 is selected from NR5, O and S; R1 and R10 each independently represent [1] a hydrogen atom, [2] a cyano group, [3] a halogen atom or [4] a 4 to 10 membered heterocycloalkyl group that can be replaced by group (s) 4- to 10-membered heterocycloalkyl; R2 is selected from the group consisting of: (1) a hydrogen atom, (2) a C1-8 alkyl group, (3) a C2-8 alkenyl group, (4) a C2-8 alkynyl group, (5) a cyano group, (6) a halogen atom, (7) a (C1-8alkyl) m2-amino group that can be replaced by C1-8 alkylsulfonyl group (s), m2: 0 ~ 2, and (8) a nitro group; R3 is selected from the group consisting of: (1) a hydrogen atom, (2) a C1-8 alkyl group that can be replaced by [1] halogen atom (s), [2] hydroxy group (s) or [3] C1-8 alkoxy group (s), (3) a C6-10 aryl group, (4) a cyano group, (5) a C1-8 alkanoyl group that can be replaced by C6-10 group (s) aryl, (6) a (C1-8 alkyl) m3a-aminocarbonyl group that can be substituted by one or more R3A, R3A: [1] a C6-10 aryl group, [2] a C1-8 alkoxy group, [3 ] a 5- to 14-membered heteroaryl group or [4] a C6-10 aryl sulfonyl group, m3a: 0 ~ 2, (7) a hydroxycarbonyl group, (8) a C1-8 alkoxycarbonyl group that can be replaced by [1 ] hydroxy group (s) or [2] C1-8 alkoxy group (s), (9) a halogen atom, (10) a (C1-8 alkyl) m3b-amino group that can be replaced by group (s) C6-10 aryl, m3b: 0 ~ 2, (11) a C1-8 alkylcarbonyl (C0-8 alkyl) amino group that can be replaced by [1] C6-10 aryl group (s) or [2] group (s ) C6-10 aryloxy, (12) a C6-10 aryl group carbonyl (C0-8 alkyl) amino which can be substituted by C1-8 alkyl group (s) which can be substituted by halogen atom (s), (13) a (C1-8 alkyl) m3c-aminocarbonyl (C0-) group 8 alkyl) amino that can be substituted by C6-10 aryl group (s), m3c: 0 ~ 2, (14) a nitro group, (15) a hydroxy group, (16) a C1-8 alkoxy group that can be replaced by one or more R3B, R3B: [1] a hydroxy group, [2] a C1-8 alkoxy group, [3] a C6-10 aryl (C0-8 alkyl) aminocarbonyl group, [4] a group (C1 -8 alkyl) m3d- amino or [5] a halogen atom, m3d: 0 ~ 2, (17) a 4- to 10-membered heterocycloalkyloxy group, (18) a 5- to 14-membered heteroaryloxy group, (19) one (C1-8 alkyl) m3e-aminocarbonyloxy group that can be replaced by C6-10 aryl m3e group (s): 0 ~ 2, (20) a 4 to 10 membered nitrogen-containing heterocycloalkylcarbonyl group, (21) a C1- group 8 alkylsulfonyloxy that can be substituted by halogen atom (s), (22) a C1-8 alkylthio group, (23) a C1-8 alkylsulfonyl group which and can be replaced by C6-10 aryl group (s), (24) a 5- to 14-membered heteroaryl group that can be replaced by C1-8 alkyl group (s) which can be replaced by C1-8 group (s) alkoxy, (25) a C1-8 alkoxycarbonyl (C0-8 alkyl) amino group that can be replaced by C1-8 alkoxy group (s), (26) a C6-10 aryloxycarbonyl (C0-8 alkyl) amino group that can substituted by C1-8 alkyl group (s) which can be substituted by halogen atom (s), (27) a C6-10 aryl (C0-8 alkyl) aminocarbonyl (C0-8 alkyl) amino group which can be substituted with one or more R3C, R3C: [1] a C1-8 alkyl group that can be replaced by halogen atom (s) or [2] a C1-8 alkoxy group, (28) a C3-8 cycloalkyl group (C0 -8 alkyl) aminocarbonyloxy, and (29) a C6-10 aryl (C0-8 alkyl) aminocarbonyloxy group that can be substituted by substituent group (s) selected from the group consisting of [1] a C1-8 group alkyl and [2] a C1-8 alkoxy group; R4 is selected from the group consisting of: (1) a hydrogen atom, (2) a C1-8 alkyl group that can be replaced by halogen atom (s), (3) a C2-8 alkenyl group, (4 ) a C2-8 alkynyl group, (5) a C3-8 cycloalkyl group, (6) a cyano group, (7) an aminocarbonyl group, (8) a (C1-8 alkyl) m4a-aminocarbonyl group, m4a: 1 ~ 2, (9) a hydroxycarbonyl group, (10) a C1-8 alkoxycarbonyl group, (11) a halogen atom, (12) a (C1-8 alkyl) m4b-amino group, m4b: 0 ~ 2, ( 13) a hydroxy group, and (14) a C1-8 alkoxy group that can be substituted by hydroxy group (s); R5 is selected from the group consisting of: (1) a hydrogen atom, (2) a C1-8 alkyl group that can be replaced by one or more R5A, R5A: [1] a hydroxycarbonyl group, [2] a group C1-8 alkoxycarbonyl, [3] a hydroxy group, [4] a C1-8 alkoxy group, [5] a (C1-8 alkyl) m5-amino group, [6] a C6-10 aryl group or [7] a C1-8 alkylthio group, m5: 0 ~ 2, (3) a C2-8 alkenyl group, (4) a C2-8 alkynyl group, (5) a C3-8 cycloalkyl group, and (6) a C1 group -8 alkylsulfonyl; R6 and R6 'are each independently selected from the group consisting of: (8) a C1-8 alkyl group that can be replaced by halogen atom (s), (9) a C2-8 alkenyl group, and (10) a C2-8 alkynyl group; or R6 and R6 'are attached to the carbon atoms to which they are attached to form: (11) a C3-8 cycloalkyl group, or (12) a 4 to 10 membered heterocycloalkyl group that can be replaced by group (s) C1-8 alkyl C6-10 aryl sulfonyl that can be substituted by C1-8 alkyl group (s); R7 is selected from the group consisting of: (1) a hydrogen atom, (2) a halogen atom, (3 ) a C1-8 alkoxy group that can be substituted by one or more R7A, R7A: [1] a (C1-8 alkyl) m7a-amino group, [2] a hydroxy, [3] a 4 to 10 heterocycloalkyl group members that can be substituted by C1-8 alkyl group (s), m7a: 0 ~ 2, (4) a C1-8 alkylsulfonyl group, (5) a nitro group, and (6) a hydroxyl group; R8 is selected from the group consisting of: (1) a hydrogen atom, (2) a C1-8 alkyl group that can be replaced by one or more R8A, R8A: [1] a 4 to 10 membered heterocycloalkyl group that can be replaced by one or more R8A1, [2] a (C1-8 alkyl) m8a amino group that can be replaced by a halogen atom and [3] a hydroxy group, m8a: 0 ~ 2, R8A1: [1 ] a C1-8 alkyl group, [2] a C1-8 alkylsulfonyl group, [3] a (C1-8 alkyl) m8b-aminosulfonyl group, [4] an oxo group, [5] a C1-8 alkoxycarbonyl or [ 6] a C1-8 alkoxycarbonyl (C0-8 alkyl) aminosulfonyl, m8b: 0 ~ 2, (3) a C2-8 alkenyl group, (4) a 4- to 10-membered heterocycloalkyl group that can be substituted by one or more R8B, R8B: <1> a C1-8 alkyl group that can be substituted by one or more R8B1, <2> a C2-8 alkenyl group, <3> a C2-8 alkynyl group, <4> a C3- group 8 cycloalkyl which can be substituted by [1] cyano group (s) or [2] C1-8 alkyl group (s), <5> a heterocycloalkyl group a of 4 to 10 members that can be substituted by one or more R8B2, <6> a C1-8 alkoxy group that can be substituted by substituent group (s) selected from the group consisting of [1] a C1 group -8 alkoxy and [2] a C3-8 cycloalkyl group, <7> a C1-8 alkoxycarbonyl group, <8> a C1-8 alkylsulfonyl group, <9> a 5 to 14 membered heteroarylsulfonyl group, <10> one oxo group, <11> a cyano group, <12> a C1-8 alkanoyl group that can be substituted by one or more R8B3, <13> a C3-8 cycloalkylcarbonyl group, <14> a group (C1-8 alkyl) m8c-aminosulfonyl, <15> a C1-8 alkylsulfonyl (C0-8 alkyl) amino group, <16> a m8d-amino (C1-8 alkyl) group that can be substituted by one or more R8B4, <17> a group hydroxy, <18> a (C1-8 alkyl) m8e-aminocarbonyl group or <19> a C1-8 alkoxycarbonyl (C0-8 alkyl) amino m8c group: 0 ~ 2 m8d: 0 ~ 2 m8e: 0 ~ 2 R8B1: [1] a C3-8 cycloalkyl group, [2] a hydroxy group or [3] a C1-8 alkoxy group (s), R8B2: [1] a halogen atom, [2] a C1-8 alkyl group, [3] an oxo group, [4] a hydroxy group or [5] a deuterium atom, R8B3: a (C1-8 alkyl) m8f-amino, m8f: 0 ~ 2, R8B4 group : [1] a C3-8 cycloalkyl group or [2] a hydroxy group, (5) a 5- to 14-membered heteroaryl group that can be replaced by a C1-8 alkyl group, (6) a (C1-8 group) alkyl) m8g-aminocarbonyl that can be substituted by one or more R8C, m8g: 0 ~ 2, R8C: [1] a hydroxy group, [2] a (C1-8 alkyl) m8h-amino group that can be substituted by group (s) substituent (s) selected from the group consisting of <1> a (C1-8 alkyl) m8i-aminosulfonyl group, <2> a -C1-8 alkylsulfonyl group, <3> a C1-8 alkoxycarbonyl group and < 4> a C1-8 alkoxycarbonyl (C0-8 alkyl) aminosulfonyl group, [3] a C1-8 alkylsulfonyl group or [4] a C1-8 alkoxy group that can be replaced by a hydroxy group, m8h: 0 ~ 2, m8i: 0 ~ 2, (7) a 4- to 10-membered heterocycloalkyl (C0-8 alkyl) aminocarbonyl group that can be replaced by oxo group (s), (8) a hetero group 4- to 10-membered nitrogen-containing rocycloalkylcarbonyl that can be replaced by one or more R8D, R8D: [1] a C1-8 alkyl group that can be replaced by one or more R8D1, [2] a hydroxy group, [3] one C1-8 alkylsulfonyl group or [4] a C1-8 alkoxycarbonyl group, R8D1: [1] a hydroxyl group, or [2] a C1-8 alkoxy group, (9) a hydroxycarbonyl group, (10) a C0- 8 (C0-8 alkyl) aminocarbonyl alkoxy which can be substituted by hydroxy group (s), (11) a halogen atom, (12) a (C1-8 alkyl) m8j-amino group that can be substituted by one or more R8H, m8j: 0 ~ 2, R8H: [1] a hydroxy group or [2] a 4- to 10-membered heterocycloalkyl group, (13) a hydroxyl group, (14) a C1-8 alkoxy group that can be substituted by one or more R8E, R8E: <1> a hydroxy group, <2> halogen atom, <3> a hydroxycarbonyl group, <4> a C1-8 alkoxycarbonyl group, <5> a heterocycloalkylcarbonyl group containing 4 to 10 nitrogen members that can be replaced by one or more R8E1, <6> a m8k1-amino (C1-8 alkyl) group that can be replaced by one or more R8E2, m8k1: 0 ~ 2, <7> a 4 to 10 membered heterocycloalkyl group that can be substituted by one or plus R8E3, <8> a 5- to 14-membered heteroaryl group, <9> a m8k2-aminocarbonyl (C1-8 alkyl) group that can be replaced by one or more R8E6, m8k2: 0 ~ 2, <10> a group C1-8 alkoxy that can be substituted by one or more R8E7, <11> a C1-8 alkylthio group, <12> a C1-8 alkylsulfinyl group, <13> a C1-8 alkylsulfonyl group, R8E1: <1> one C1-8 alkoxycarbonyl group, <2> a C1-8 alkanoyl group, <3> a C1-8 alkylsulfonyl group, <4> a (C1-8 alkyl) m8k3-aminosulfonyl group, m8k3: 0 ~ 2, or <5 > a 4- to 10-membered heterocycloalkyl group, R8E2: <1> a hydroxy group, <2> a C1-8 alkoxycarbonyl group that can be replaced by halogen atom (s), <3> a C3-8 cycloalkyl group that can be replaced by C1-8 alkyl group (s) which can be replaced by hydroxy group (s), <4> u m C1-8 alkanoyl group that can be substituted by substituent group (s) selected from the group consisting of [1] a m8k4-amino (C1-8 alkyl) group and [2] a halogen atom (s) , m8k4: 0 ~ 2, <5> a (C1-8 alkyl) m8k5-aminocarbonyl group, m8k5: 0 ~ 2, <6> a C1-8 alkylsulfonyl group, <7> a heterocycloalkylsulfonyl group containing 4 to 10 nitrogen members that can be substituted by C1-8 alkyl group (s), <8> a m8k6-aminosulfonyl (C1-8 alkyl) group that can be replaced by C1-8 alkoxycarbonyl group (s), m8k6: 0 ~ 2, or R8E3: <1> a C1-8 alkyl group that can be substituted by substituent group (s) selected from the group consisting of [1] a hydroxy group and [2] a C1-8 alkylcarbonyloxy group, <2> a C1-8 alkylcarbonyloxy group, <3> a hydroxy group, <4> a C3-8 cycloalkyl group, <5> a C1-8 alkoxy group, <6> a C1-8 alkoxycarbonyl group, <7> a C1 group -8 alkylsulfonyl, <8> a m8k8 (C1-8 alkyl) m8k8-aminocarbonyl group: 0 ~ 2, <9> a C1-8 alkyl group oyl that can be substituted by hydroxy group (s), <10> an oxo group, or <11> a 4- to 10-membered heterocycloalkyl group that can be substituted by a substituent group (s) selected from the group (s) consisting of [1] a C1-8 alkanoyl group, [2] a C1-8 alkoxycarbonyl group and [3] a C1-8 alkylsulfonyl group, R8E6: <1> a C2-8 alkenylcarbonyloxy group, <2> a group hydroxy, <3> a cyano group, <4> a m8k9-amino (C1-8 alkyl) group that can be replaced by m8k9: 0 ~ 2 hydroxy group (s), <5> a C1-8 alkoxy group that can be substituted be substituted by hydroxy group (s), <6> a C1-8 alkylcarbonyloxy group, <7> a 4 to 10 membered heterocycloalkyl group that can be substituted by C1-8 alkyl group (s), or <8> a group 5 to 14 membered heteroaryl, R8E7: <1> a hydroxy group, or <2> a C1-8 alkoxy group that can be replaced by hydroxy group (s), (15) a 4 to 10 membered heterocycloalkyloxy group that can be replaced by one or more R8F, R8F: <1> a C1-8 alkyl group the one that can be replaced by one or more R8F1, <2> a C3-8 cycloalkyl group, <3> a C1-8 alkanoyl group that can be replaced by halogen atom (s), <4> a C1-8 group alkylcarbonyloxy, <5> a C1-8 alkoxycarbonyl group, <6> a 4 to 10 membered heterocycloalkyl group that can be substituted by one or more R8F2, <7> a C1-8 alkyl sulfonyl group, <8> a hydroxy group , or [9] a C6-10 aryl group, R8F1: [1] a hydroxy group, [2] a C1-8 alkoxy group or [3] a halogen atom, R8F2: [1] a heterocycloalkyl group from 4 to 10 members, [2] a C1-8 alkoxycarbonyl group or [3] a C1-8 alkylsulfonyl group, (16) a 5 to 14 membered heteroaryloxy group, (17) a 4 to 10 membered heterocycloalkylcarbonyloxy group, (18) a (C1-8 alkyl) m8l1-aminosulfonyloxy group, m8l1: 0 ~ 2, (19) a C1-8 alkylthio group that can be replaced by [1] (C1-8 alkyl) m8l2-amino group (s), [2] hydroxy group (s) or [3] hydroxycarbonyl group (s), m8l2: 0 ~ 2, (20) a C1-8 alkylsulfonium group la which can be replaced by one or more R8G, R8G: [1] a hydroxycarbonyl group, [2] a hydroxy group or [3] a (C1-8 alkyl) m8l3-amino group, m8l3: 0 ~ 2, (21 ) a 4- to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy group that can be replaced by a C1-8 alkyl group (s), (22) a C2-8 alkenyloxy group, and (23) a C1-8 alkylsulfonyloxy group that can be substituted by halogen atom (s); R9 is selected from the group consisting of: (1) a hydrogen atom, (2) a C1-8 alkyl group that can be replaced by one or more R9A, R9A: [1] a C3-8 cycloalkyl group, [2 ] a 4- to 10-membered heterocycloalkyl group that can be substituted by one or more R9A1, [3] a hydroxy group, [4] a C1-8 alkoxy group or [5] a hydroxycarbonyl group, R9A1: [1] a group C1-8 alkyl, [2] a C3-8 cycloalkyl group or [3] a 4- to 10-membered heterocycloalkyl group, (3) a C2-8 alkenyl group that can be substituted by one or more R9B, R9B: [1 ] a (C1-8 alkyl) m9a-amino group, [2] a 4- to 10-membered heterocycloalkyl group that can be substituted by one or more R9B1, R9B1: [1] a C3-8 cycloalkyl group or [2] one 4- to 10-membered heterocycloalkyl group, m9a: 0 ~ 2, (4) a C2-8 alkynyl group that can be substituted by one or more R9C, R9C: [1] a C1-8 alkoxy group, [2] a group (C1-8 alkyl) m9b-amino which can be substituted by C6-10 aryl group (s), [3] a heterocyclic group 4- to 10-membered loalkyl that can be substituted by one or more R9C1, [4] a C3-8 cycloalkyl group, [5] a hydroxy group, [6] a hydroxycarbonyl group or [7] a C1-8 alkyloxycarbonyl group, m9b: 0 ~ 2, R9C1: [1] a C3-8 cycloalkyl group, [2] a 4- to 10-membered heterocycloalkyl group or [3] an oxo group, (5) a C3-8 cycloalkyl group, (6) a 4 to 10 membered heterocycloalkyl group that can be substituted by one or more R9D, R9D: [1] a C1-8 alkyl group that can be replaced by 4 to 10 membered heterocycloalkyl group (s), [2] a group C3-8 cycloalkyl, [3] a 4- to 10-membered heterocycloalkyl group or [4] a C1-6 alkylsulfonyl group or [5] a C1-8 alkoxycarbonyl group, (7) a C6-10 aryl group that can be substituted with one or more R9E, R9E: [1] a halogen atom, [2] a hydroxy group, [3] a hydroxycarbonyl group or [4] a C1-8 alkyl group that can be replaced by hydroxy group (s) or [5] a C1-8 alkoxy group, (8) a 5 to 1 heteroaryl group 4 members that can be replaced by C1-8 alkyl group (s), (9) a cyano group, (10) a C1-8 alkanoyl group, (11) a 4 to 10 membered nitrogen-containing heterocycloalkylcarbonyl group per C1-8 alkyl group (s), (12) a halogen atom, (13) a (C1-8 alkyl) m9c-amino group that can be replaced by one or more R9F, m9c: 0 ~ 2, (14 ) a C1-8 alkylcarbonyl (C0-8 alkyl) amino group that can be replaced by m9d-amino (C1-8 alkyl) group, m9d: 0 ~ 2, (15) a C1-8 alkylsulfonyl group (C0 -8 alkyl) amino, (16) a (C1-8 alkyl) m9e-aminosulfonyl (C0-8 alkyl) amino group, m9e: 0 ~ 2, (17) a nitro group, (18) a hydroxy group, (19 ) a C1-8 alkoxy group that can be substituted by one or more R9G, R9G: [1] a hydroxy group, [2] a hydroxycarbonyl group, [3] a C6-10 aryl group that can be substituted by group (s ) C1-8 alkoxy, [4] a (C1-8 alkyl) m9g1-amino group, [5] a C1-8 alkoxy group that can be replaced by one or more R9G1, [6] a heteroar group 5 to 14 membered group or [7] a 4 to 10 membered heterocycloalkyloxy group that can be substituted by C1-8 alkyl group (s), m9g1: 0 ~ 2, R9G1: [1] a C1-8 alkoxy group or [2] a hydroxycarbonyl group, (20) a 4 to 10 membered heterocycloalkyloxy group that can be replaced by [1] 4 to 10 membered heterocycloalkyl group (s) or [2] C1-8 alkoxycarbonyl group (s), ( 21) a C1-8 alkylsulfonyloxy group that can be substituted by halogen atom (s), (22) a C1-8 alkylthio group that can be substituted by (C1-8alkyl) m9f-amino group, m9f: 0 ~ 2, (23) a C1-8 alkylsulfonyl group that can be substituted by (C1-8alkyl) m9g-amino group, m9g: 0 ~ 2, (24) a (C1-8alkyl) m9h-aminosulfonyl group, m9h: 0 ~ 2, (25) a 4- to 10-membered nitrogen-containing heterocycloalkylsulfonyl group that can be replaced by C1-8 alkyl group (s), and (26) a hydroxycarbonyl group, (2) The composition according to [ 1] above, where the dissolution aid is a surfactant, (3) The composition according to [2] above, where the surfactant is a non-ionic or an anionic surfactant, (4) The composition according to [2] or [3] above, in which the surfactant is selected from a group consisting of sulfate monoalkyl, polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, sodium lauromacrogol, sodium sulfussuccinate dihydrate, sodium sulfur sulfate sulfate sodium and a mixture thereof, [4-1] The composition according to [2] or [3] above, in which the surfactant is selected from a group consisting of monoalkyl sulfate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene 60 hydrogenated castor oil, polyoxyl 35 castor oil, sodium dioctyl sulfosuccinate, sodium lauroilsarcosine, sodium dodecylbenzene sulfonate and a mixture thereof, [4-2] The composition according to [2 ] to [4] above, where the surfactant is selected from a group consisting of sodium lauryl sulphate, sodium tetradecyl sulphate, sodium hexadexyl sulphate, sodium octadecyl sulphate and a mixture thereof, [4-3] The composition according to [2] to [4 ] above, where the surfactant is a mixture of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) glycol, [4-4] The composition according to [2] to [4] above, where the surfactant is sodium lauryl sulfate, [4-5] The composition according to [2] to [4-4] above, where the content of the surfactant is 0.5 to 25 parts by weight, [4-6] The composition of according to [2] to [4] above, where the content of the surfactant is 1.5 to 15 parts by weight, (5) The composition according to [2] to [4-6] above, where the composition it further comprises an organic polymer. (6) The composition according to [5] above, in which the organic polymer is selected from the group consisting of a synthetic resin, a water-soluble polymer, a gastric-soluble polymer, an enteric-soluble polymer and a mixture thereof, (7) The composition according to [5] above, in which the organic polymer is a synthetic resin, [7-1] The composition according to [6] above, in which the water soluble polymer is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, propylene glycol alginate ester, sodium caseinate, a polymer of carboxyvinyl, powdered agar, guar gum, copolividone, hydroxyethylmethyl cellulose or polyvinyl alcohol, the gastric soluble polymer is an alkylmethacrylate E amino dimethylamine copolymer or dimethylamino acetate. polyvinylacetal and enteric soluble polymer is LD methacrylic acid copolymer, purified shellac, carboxymethyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, meta acid copolymer chrylic S, casein or zein, [7-2] The composition according to [6] above, wherein the water-soluble polymer is propylene glycol alginate ester, sodium caseinate, a carboxyvinyl polymer, powdered agar, guar gum, copolividone, hydroxyethylmethyl cellulose or polyvinyl alcohol, the gastric soluble polymer is amino alkyl methacrylate copolymer or polyvinylacetal diethylaminoacetate and the enteric soluble polymer is LD methacrylic acid copolymer, cellulose acetate, acetyl acetate and cellulose hydroxypropylmethyl cellulose, methacrylic acid copolymer S, casein or zein, [7-3] The composition according to [6] above, in which the organic polymer is selected from a group consisting of casein, sodium caseinate, polystyrene sulfonate sodium, polyvinylacetal diethylaminoacetal, carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, methacrylic acid S copolymer and a mixture their, [7-4] The composition according to [5] to [7-3] above, in which the surfactant is selected from sodium lauryl sulfate and the organic polymer is selected from polystyrene sodium sulfonate, [7 -5] The composition according to [5] to [7-3] above, wherein the surfactant is a mixture of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) glycol and the organic polymer is selected from polystyrene sulfonate sodium, [7-6] The composition according to [7] above, wherein the synthetic resin is sodium polystyrene sulfonate or a vinyl acetate resin, [7-7] The composition according to [5] a [7-6] above, where the content of the organic polymer is 1 to 20 parts by weight, [7-8] The composition according to [5] to [7-6] above, where the content of the organic polymer is 2 to 10 parts by weight, (8) The composition according to [2] to [7-5] above, wherein the composition comprises one or more additives which are selected from the following additive group A:
[00012] Additive A: citric acid, fumaric acid, DL-malic acid, adipic acid, succinic acid, tartaric acid, lactic acid, maleic acid, sulfuric acid, phosphoric acid, sodium dehydroacetate, sodium stearyl fumarate, L ester -stearic sorbate, L-aspartic acid, skimmed milk powder, aluminum lactate, ascorbic acid palmitate, aluminum sulphate, monobasic calcium phosphate or tryptophan acetyl, [8-2] The composition according to [8] above, wherein the additive group A is citric acid, fumaric acid, DL-malic acid, adipic acid, succinic acid, tartaric acid, lactic acid, maleic acid, phosphoric acid, sodium dehydroacetate, sodium stearyl fumarate, L- ester stearic ascorbate, L-aspartic acid, skimmed-milk powder or monobasic calcium phosphate, [8-3] The composition according to [8] above, wherein the additive selected from additive group A is sodium dehydroacetate or milk in skim powder, [8-4] The composition according to [8] to [8-3] above, where the total content of one or more additives that are selected from additive group A is 1 to 20 parts by weight, (9) The composition according to [1] to [8-4] above, where the water solubility of the substance is less than 100 μg / mL at 25 ° C, [9-1] The composition according to [1], characterized by the fact that the dissolution aid is selected from the following group: Group:
[00013] citric acid, sodium stearyl fumarate, LD methacrylic acid copolymer, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, stearic L-ascorbate ester, L-aspartic acid, adipic acid, copolymer amino alkyl methacrylate E, propylene glycol alginate ester, casein, sodium caseinate, a carboxyvinyl polymer, carboxymethylethyl cellulose, powdered agar, guar gum, succinic acid, copolividone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate , zein, skimmed-milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbic acid palmitate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60 , polyoxyl 35 castor oil, sodium polystyrene sulfonate, polyvinylacetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer o S, sulfuric acid, aluminum sulfate, phosphoric acid, monobasic calcium phosphate, sodium dodecylbenzene sulfonate, a vinyl pyrrolidone copolymer. vinyl acetate, sodium lauroilsarcosine, sodium tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate . [9-2] The composition according to [1], characterized by the fact that the dissolution aid is selected from the group that follows Group:
[00014] citric acid, LD methacrylic acid copolymer, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbate ester, stearic acid, adipic acid, propylene glycol alginate ester , sodium caseinate, carboxymethylethyl cellulose, succinic acid, copolividone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, ascorbic acid palmitate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, polyoxyethylene hydrogenated oil 60 polyoxyl 35 castor, sodium polystyrene sulfonate, polyvinylacetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, sodium dodecylbenzene sulfonate, a pyrrolidone vinyl copolymer. vinyl acetate, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate and sodium octadecyl sulfate, [9-3] The composition according to [1], characterized by the fact that the dissolution aid is selected from the group that Group follows:
[00015] citric acid, LD methacrylic acid copolymer, sodium laurel sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate ester, sodium caseinate, carboxymethyl ethyl cellulose , succinic acid, copolividone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, aluminum sulfuric acid, polyacrylic acid sulfate, S a vinyl pyrrolidone copolymer. vinyl acetate and sodium decyl sulfate. [9-4] The composition according to [1], in which the dissolution aid that is selected from the group that follows is used to improve the solubility of a substance of formula (I). Group:
[00016] citric acid, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium stearyl fumarate, LD methacrylic acid copolymer, methyl cellulose, sodium lauryl sulfate, purified shellac, sodium dehydroacetate, fumaric acid, DL malic acid, L ester - stearic ascorbate, L-aspartic acid, adipic acid, amino alkyl methacrylate copolymer E, propylene glycol alginate ester, casein, sodium caseinate, a carboxyvinyl polymer, carboxymethyl ethyl cellulose, powdered agar, guar gum, succinic acid, copolivone , cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, skimmed milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbic acid palmitate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose (105) polyoxyethylene succinate ) polyoxypropylene (5) glycol, polyoxyethylene 60 hydrogenated castor oil, polyoxyl 35 castor oil, sodium polystyrene sulfonate, diethylaminoa polyvinylacetal ketate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, phosphoric acid, monobasic calcium phosphate, sodium dodecylbenzene sulfonate, a pyrrolidone vinyl copolymer. vinyl acetate, sodium lauroilsarcosine, sodium tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate , [9-5] The composition according to [1], in which the dissolution aid that is selected from the group that follows is used to improve the solubility of a substance of formula (I). Group:
[00017] citric acid, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, LD methacrylic acid copolymer, methyl cellulose, sodium lauryl sulfate, purified shellac, sodium dehydroacetate, fumaric acid, DL malic acid, stearic L-ascorbate ester, L- aspartic, adipic acid, propylene glycol alginate ester, casein, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copolividone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, ascorbic acid palmitate, hydroxyethylmethyl cellulose, succinate succinate hydroxypropylmethyl cellulose acetate, polyoxyethylene 60 hydrogenated castor oil, polyoxy 35 castor oil, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, dodecylb a vinyl pyrrolidone copolymer. vinyl acetate, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate and sodium octadecyl sulfate, [9-6] The composition according to [1], in which the dissolution aid that is selected from the group below is used to improve the solubility of a substance of formula (I). Group:
[00018] citric acid, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, LD methacrylic acid copolymer, methyl cellulose, sodium lauryl sulfate, purified shellac, sodium dehydroacetate, fumaric acid, DL malic acid, L-aspartic acid, adipic acid, propylene glycol alginate ester, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copolividone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, polyacetyl acetyl acetate, diethyl acetate, ethylene acetyl acetate copolymer of methacrylic acid S, sulfuric acid, aluminum sulfate, a vinyl pyrrolidone copolymer. vinyl acetate and sodium decyl sulfate, (10) The composition according to [1] to [9-3] above, where A1 to A4, A6 and A7 are a carbon atom, A5 is NH, R3 is cyan, R6 and R6 'are both methyl for the substance, [10-1] The composition according to [1] to [10] above, where A1 to A4, A6 and A7 are a carbon atom, A5 is NH, R3 is cyan, R8 is a 4 to 10 membered heterocycloalkyl group or a 4 to 10 membered heterocycloalkyl group that can be replaced by a C3-8 cycloalkyl group for the substance, (11) Composition according to any one of [1] to [9-6] , in which the substance is selected from the group consisting of 9- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 9-cyclopropylethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) - 11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-bromo-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 9-bromo-8- (4-cyclopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-chloro-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6,9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3- carbonitrile; 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 9-ethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethynyl-6,6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) - 6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-ethynyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (1-isopropyl-piperidin-4-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (2-tert-butylamino-ethoxy) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethynyl-8- (4-methanesulfonyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; and 9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile, [11-1] The composition according to any one of [1] to [8], wherein the substance is selected from the group consisting of (i) 6,6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl ) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile, (ii) 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6 -dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile, (iii) 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxy-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile, [11-2] The composition according to [1] to [11] above, characterized by the fact that the content of the substance is 1 to 50 parts by weight. [11-3] The composition according to [1] to [11-1] above, characterized by the fact that the substance content is 3 to 30 parts by weight, [11-4] The composition according to [2 ] to [8] above, where the weight ratio between the substance and the surfactant is 1: 0.01 to 1:25, [11-5] The composition according to [2] to [8] above, in that the weight ratio between the substance and the surfactant is 1: 0.05 to 1: 1, [11-6] The composition according to [9] to [11-5] above, where the weight ratio between the substance and the organic polymer is 1: 0.02 to 1:20, [11-7] The composition according to [9] to [11-6] above, where the weight ratio between the substance and the polymer organic is 1: 0.25 to 1: 1, [11-8] The composition according to [8] to [11-7] above, in which the weight ratio between the substance and the total amount of one or more additives selected from additive group A is 1: 0.02 to 1:20. The present invention further includes the following aspects. [12] A pharmaceutical formulation comprising the composition according to [1] to [11-8], [13] The pharmaceutical formulation according to [12] above, which is an orally administrable formulation, [14] The pharmaceutical formulation according to [12] above, where the orally administrable formulation is a solid formulation, and [15] The pharmaceutical formulation according to [13] above, where the orally administrable formulation is a tablet, a capsule, a granule, powder, a pill, a water-soluble or insoluble liquid or a suspension for oral administration, [16] 1] A dissolution aid consisting of a substance selected from the group that follows for use in improving the solubility of a substance of Formula ( I): Group I:
[00019] citric acid, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium stearyl fumarate, LD methacrylic acid copolymer, methyl cellulose, sodium lauryl sulfate, purified shellac, sodium dehydroacetate, fumaric acid, malic acid DL, L ester - stearic ascorbate, L-aspartic acid, adipic acid, amino alkyl methacrylate copolymer E, propylene glycol alginate ester, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, powdered agar, guar gum, succinic acid, copolividone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, skimmed milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbic acid palmitate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate (105) polyoxypropylene (5) glycol, polyoxyethylene 60 hydrogenated castor oil, polyoxyl 35 castor oil, sodium polystyrene sulfonate, diethylaminoacetate polyvinylacetal, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, phosphoric acid, monobasic calcium phosphate, sodium dodecylbenzene sulfonate, a pyrrolidone vinyl copolymer. vinyl acetate, sodium lauroilsarcosine, sodium tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate , [16-2] A dissolution aid consisting of a substance selected from the group that follows for use in improving the solubility of a substance of Formula (I). Group:
[00020] citric acid, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, LD methacrylic acid copolymer, methyl cellulose, sodium lauryl sulfate, purified shellac, sodium dehydroacetate, fumaric acid, DL malic acid, stearic L-ascorbate ester, L- aspartic, adipic acid, propylene glycol alginate ester, casein, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copolividone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, ascorbic acid palmitate, hydroxyethylmethyl cellulose, succinate succinate hydroxypropylmethyl cellulose acetate, polyoxyethylene 60 hydrogenated castor oil, polyoxy 35 castor oil, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, dodecylb a vinyl pyrrolidone copolymer. vinyl acetate, acetyl tryptophan, sodium tetradecyl sulfate and sodium octadecyl sulfate, [16-3] A dissolution aid consisting of a substance selected from the group that follows for use in improving the solubility of a substance of Formula (I) . Group:
[00021] citric acid, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, LD methacrylic acid copolymer, methyl cellulose, sodium lauryl sulfate, purified shellac, sodium dehydroacetate, fumaric acid, DL malic acid, L-aspartic acid, adipic acid, propylene glycol alginate ester, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copolividone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, polyacetyl acetyl acetate, diethyl acetate, ethylene acetyl acetate copolymer of methacrylic acid S, sulfuric acid, aluminum sulfate, a vinyl pyrrolidone copolymer. vinyl acetate and sodium decyl sulfate. EFFECT OF THE INVENTION
[00022] The composition of the present invention improves the solubility, oral absorption capacity and / or blood absorption capacity of tetracyclic compounds poorly soluble in water or insoluble in water having an ALK inhibitory activity which are useful as a prophylactic agent and / or therapeutic for cancer, depression and cognitive function disorder. BRIEF DESCRIPTION OF THE DRAWINGS
[00023] Figure 1 is a graph to compare the effect of the additive amount of sodium lauryl sulfate on the solubility of compound F6-20.
[00024] Figure 2 is a graph to illustrate the effect of various cellulose polymers on the solubility of the hydrochloride salt of Compound F6-20.
[00025] Figure 3 is a graph to illustrate the effect of the additive amount of hydroxypropyl cellulose on the solubility of the hydrochloride salt of Compound F6-20.
[00026] Figure 4 is a graph to illustrate the solubility of the hydrochloride salt of Compound F6-20 when sodium lauryl sulfate and hydroxypropyl cellulose are mixed.
[00027] Figure 5 is a graph to compare the effect of the manufacturing method on the solubility of the hydrochloride salt of Compound F6-20.
[00028] Figure 6 is a graph to illustrate the effect of the additive amount of sodium lauryl sulfate on the solubility of Compound F6-20 mesylate salt.
[00029] Figure 7 is a graph to illustrate the solubility of Compound F6-20 mesylate salt when sodium lauryl sulfate and hydroxypropyl cellulose are mixed.
[00030] Figure 8 is a graph to illustrate the effect of SLS and polyvinyl pyrrolidone on the solubility of Compound B4-8 hydrochloride salt crystal.
[00031] Figure 9 is a graph to illustrate the effect of SLS and polyvinyl pyrrolidone on the solubility of Compound B4-8 mesylate salt crystal.
[00032] Figure 10 is a graph to illustrate the effect of SLS and HPC on the solubility of the sulfate salt crystal of Compound B4-8.
[00033] Figure 11 is a graph to illustrate the effect of SLS and HPC on the solubility of Compound B4-8 L-tartrate salt crystal.
[00034] Figure 12 is a graph to illustrate the effect of SLS and HPC on the crystal solubility of Compound B4-8 phosphate salt.
[00035] Figure 13 is a graph to illustrate the effect of polyoxyethylene (105) polyoxypropylene (5) glycol on the solubility of Compound F6-4 hydrochloride salt crystal.
[00036] Figure 14 is a graph to illustrate the effect of polyoxyethylene (105) polyoxypropylene (5) glycol on the solubility of the mesylate salt crystal of Compound F6-4.
[00037] Figure 15 is a graph to illustrate the effect of SLS on the solubility of the hydrochloride salt crystal of Compound F6-17.
[00038] Figure 16 is a graph to illustrate the effect of SLS on the solubility of the mesylate salt crystal of Compound F6-17.
[00039] Figure 17 is a graph to illustrate the effect of SLS and polyvinyl pyrrolidone on the solubility of the mesylate salt crystal of Compound F6-17.
[00040] Figure 18 is a graph to illustrate the effect of SLS on the solubility of the compound F6-17 maleate salt crystal.
[00041] Figure 19 is a graph to illustrate the effect of SLS and polyvinyl pyrrolidone on the solubility of Compound F6-17 L-tartrate salt crystal.
[00042] Figure 20 is a graph to illustrate the effect of SLS on the solubility of the citrate salt crystal of Compound F6-17.
[00043] Figure 21 is a graph to illustrate the effect of SLS on the solubility of the malate salt crystal of Compound F6-17.
[00044] Figure 22 is a graph to illustrate the effect of SLS on the solubility of the hydrochloride salt crystal of Compound F5-46.
[00045] Figure 23 is a graph to illustrate the effect of SLS on the solubility of the mesylate salt crystal of Compound F5-46.
[00046] Figure 24 is a graph to illustrate the effect of SLS on the solubility of the hydrochloride salt crystal of Compound F5-51.
[00047] Figure 25 is a graph to illustrate the effect of SLS on the solubility of the mesylate salt crystal of Compound F5-51.
[00048] Figure 26 is a graph to illustrate the effect of SLS, polyoxyethylene (105) polyoxypropylene (5) glycol and poly (sodium 4-styrene sulfonate) on the solubility of the hydrochloride salt crystal of Compound F6-20.
[00049] Figure 27 is a graph to illustrate the effect of a combination of SLS and polyoxyethylene (105) polyoxypropylene (5) glycol on the solubility of the hydrochloride salt crystal of Compound F6-20.
[00050] Figure 28 is a graph to illustrate the effect of a combination of SLS and poly (sodium 4-styrene sulfonate) on the solubility of the hydrochloride salt crystal of Compound F6-20.
[00051] Figure 29 is a graph to illustrate the effect of a combination of SLS, polyoxyethylene (105) polyoxypropylene (5) glycol and poly (sodium 4-styrene sulfonate) on the solubility of the hydrochloride salt crystal of Compound F6- 20.
[00052] Figure 30 is a graph to illustrate the effect of quantity of SLS on the solubility of the hydrochloride salt formulation of Compound F6-20 containing polyoxyethylene (105) polyoxypropylene (5) glycol and poly (4-styrene sulfonate) sodium). MODE FOR CARRYING OUT THE INVENTION
[00053] The term "pharmaceutically acceptable carrier" as used in the present application means one or more acceptable solid or liquid fillers / diluents or encapsulating substances that are suitable for administration to a mammal. The term "acceptable", as used herein, means that the ingredients of the composition are capable of being miscible with the object compound, and with each other, in a way that there is no interaction that would substantially reduce the pharmaceutical effectiveness of the composition under situations common use. Pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration preferably to an animal, more preferably a mammal being treated.
[00054] The "dissolution aid" used in the present invention includes a surfactant, an organic polymer and a pH adjusting agent, etc., and specific examples thereof are the substances given in Table 2 below. Preferred examples thereof include casein, sodium caseinate, skimmed milk powder, sodium lauryl sulfate (below, also referred to as SLS), sodium dioctyl sulfosuccinate, polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol , polyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacrogol, sodium lauroilsarcosinate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate , sodium octyl sulfate, sodium decyl sulfate and sodium dodecylbenzene sulfonate.
[00055] In accordance with the present invention, the dissolution aid can be used in combination of two or more types that are mixed in an appropriate ratio.
[00056] Particularly preferred is a surfactant.
[00057] In the present invention, when two or more dissolution aids are used as a combination, preferred examples of the dissolution aids combination include a combination of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) glycol and a combination of sodium lauryl sulfate and sodium polystyrene sulfonate. More preferred examples include a combination of sodium lauryl sulfate, sodium polystyrene sulfonate and polyoxyethylene (105) polyoxypropylene (5) glycol.
[00058] Examples of sodium polystyrene sulfonate include CAS (Chemical Abstract) registration number 9080-79-9 (a cation exchange resin in which a sulfonic acid group attached to a styrene and divinyl benzene copolymer is present in the form of a sodium, as defined in the Japanese Pharmacopoeia, revised ed. 15) and poly (sodium 4-styrene sulfonate) [CAS number 25704-18-1, a homopolymer obtained through the polymerization of sodium 4-ethylene benzene sulfonate] and poly (sodium 4-styrene sulfonate) is preferable.
[00059] The term "surfactant" indicates a substance that has both a hydrophilic group and a hydrophobic group in a molecule. The surfactant includes an ionic surfactant and a nonionic surfactant.
[00060] The ionic surfactant means an ionic surfactant that dissociates to give an ion (that is, an atom or an atomic group having a charge) when it is dissolved in water. Depending on the ion charge generated, the ionic surfactant is further classified into an anionic surfactant, a cationic surfactant and an amphoteric surfactant. According to the present invention, a nonionic surfactant and an anionic surfactant are preferable.
[00061] Examples of the nonionic surfactant include sugar ester type surfactant such as sorbitan fatty acid ester (C12-18), POE sorbitan fatty acid ester (C12-18) and sucrose fatty acid ester; fatty acid ester type such as POE fatty acid ester (C12-18), POE resin acid ester and POE fatty acid diester (C12-18); alcohol type such as POE alkyl ether (C12-18); alkyl phenol type surfactant such as (C8-12) alkyl ether POE, dialkyl ether (C8-12) phenyl POE and alkyl (C8-12) ether formalin condensate POE; polyoxyethylene block polymer-type surfactant. polyoxypropylene such as polyoxyethylene block polymer. polyoxypropylene and (C12-18) polyoxyethylene alkyl block polymer ether. polyoxypropylene; alkylamine type such as POE alkylamine (C12-18) and POE fatty acid amide (C12-C18); bisphenol-type surfactant such as POE fatty acid bisphenyl ether; polyaromatic type surfactant such as benzylphenyl (or phenylphenyl) ether POA and styrylphenyl (or phenylphenyl) ether POA; surfactant based on silicone and fluorine type ether and POE ester, and; plant oil type surfactant such as POE castor oil and hydrogenated POE castor oil. Preferred examples include polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene 60 halogenated castor oil, polyoxyl 35 castor oil and lauromacrogol.
[00062] Examples of the anionic surfactant include sulfate-type surfactant such as alkyl sulfate (C12-18, Na, NH4, alkanolamine), POE alkyl ether sulfate (C12-18, Na, NH4, alkanolamine), ether sulfate alkylphenyl POE (C12-18, NH4, alkanolamine, Ca), benzyl ether sulfate (or styryl) phenyl (or phenylphenyl) (Na, NH4, alkanolamine), polyoxyethylene and polyoxypropylene block polymer sulfate (Na, NH4 , alkanolamine); sulfonate-type surfactant such as paraffin (alkane) sulfonate (C12-22, Na, Ca, alkanolamine), AOS (C14-16, Na, alkalnolamine), dialkylsulfosuccinate (C8-12, Na, Ca, Mg), alkylbenzene sulfonate (C12 , Na, Ca, Mg, NH4, alkylamine, alkanol, amine, cyclohexylamine), mono or dialkyl (C3-6) naphthalene sulfonate (Na, NH4, alkanolamine, Ca, Mg), naphthalene sulfonate condensate. formalin (Na, NH4), alkyl (C8-12) diphenyl ether disulfonate (Na, NH4), lignin sulfonate (Na, Ca), alkyl (C8-12) ether sulfonate POE (Na) and semi- alkyl acid ester (C12-18) sulfosuccinic ether (Na); carboxylic acid type surfactant such as fatty acid salt (C12-18, Na, K, NH4, alkanolamine), N-methyl fatty acid sarcosinate (C12-18, Na), and resin acid salt (Na, K); and phosphate-type surfactant such as (C12-18) alkyl phosphate POE (Na, alkanolamine), mono or dialkyl (C8-12) phenyl ether (Na, alkanolamine), benzyl (or styrene) phosphate phenyl (or phenylphenyl) side POE (Na, alkanolamine), polyoxyethylene block polymer. polyoxypropylene (Na, alkanolamine), phosphatidylcholine. phosphatidyl ethanolimine (lecithin) and (C8-12) alkyl phosphate. Preferred examples include monoalkyl sulfate such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate, sodium dioctyl sulfosuccinate, sodium lauroilsarcosine and sodium dodecylbenzene sulfonate.
[00063] The organic polymer indicates a substance having a molecular weight of at least 10,000 and the skeleton composed mainly of a carbon. The organic polymer includes a protein derived from an animal or a plant, polysaccharides, synthetic resin and the like.
[00064] Specific examples of the organic polymer include polysaccharides such as hydroxypropyl cellulose (referred to below as HPC), hydroxypropyl methyl cellulose, methyl cellulose, propylene glycol alginate ester, powdered agar, guar gum, zein and hydroxyethyl methyl cellulose, such a synthetic resin as a carboxyvinyl polymer, polyvinyl alcohol or vinyl acetate resin, and sodium polystyrene sulfonate and phosphorous protein such as casein and sodium caseinate.
[00065] Among organic polymers, those having a water solubility of 1 g / 100 g or greater are called water-soluble polymer. Specific examples thereof include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, propylene glycol alginate ester, sodium caseinate, a carboxyvinyl polymer, powdered agar, guar gum, copolividone, hydroxyethylmethyl cellulose and polyvinyl alcohol.
[00066] Among the organic polymers, those soluble under acidic conditions of pH 1.2 to 3.5, which is the pH of gastric juice, are called gastric soluble polymer, while those rapidly soluble in enteric pH of 6 to 8 are called soluble enteric polymer. Examples of the gastric soluble polymer include amino alkyl methacrylate E copolymer and polyvinylacetal dimethylaminoacetate and examples of the enteric soluble polymer include LD methacrylic acid copolymer (emulsion), methacrylic acid S copolymer, purified shellac, cellulose acetate, cellulose, cellulose acetate cephalate), hydroxypropylmethyl cellulose acetate succinate, casein and zein.
[00067] The pH adjusting agent indicates a substance that controls the pH of a solution with the addition of an acidic agent or an alkaline agent in order to improve the solubility of a poorly water-soluble substance. The pH adjusting agent is appropriately selected according to the property of a substance to be dissolved. For example, in the case of a substance poorly soluble in basic water, an acidic agent is added to adjust the pH to be acidic and improve solubility.
[00068] Examples of the pH adjusting agent include adipic acid, citric acid, trisodium citrate, gluconic acid, sodium gluconate, glucono deltalactone, potassium gluconate, succinic acid, monosodium succinate, disodium succinate, sodium acetate, L-tartaric acid , Potassium hydrogen L-tartrate, sodium L-tartrate, DL-tartaric acid, DL potassium hydrogen tartrate, sodium DL-tartrate, sodium hydrogen carbonate, potassium carbonate (anhydrous), sodium carbonate, carbon dioxide , lactic acid, sodium lactate, glacial acetic acid, disodium dihydrogen phosphate, fumaric acid, monosodium fumarate, DL-malic acid, DL-malate sodium, phosphoric acid, monobasic potassium phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and disodium hydrogen phosphate.
[00069] Preferred examples include an acidic agent such as adipic acid, citric acid, gluconic acid, glucono deltalactone, succinic acid, L-tartaric acid, DL-tartaric acid, carbon dioxide, lactic acid, glacial acetic acid, fumaric acid, DL-malic acid and phosphoric acid.
[00070] It is particularly preferable that the formulation of the present invention comprises a dissolution aid which is selected from casein, sodium caseinate, skimmed milk powder, sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and octadecyl sulfate sodium.
[00071] The term "orally administrable formulation" indicates a formulation that can be administered orally. Oral administration means that the formulation is swallowed to enter a gastrointestinal tract, and the active ingredient is absorbed mainly in an intestinal tract.
[00072] Specific examples of the orally administrable formulation include a solid formulation such as a tablet, a capsule, a liquid, powder, a lozenge, a chewable formulation, granules, a gel formulation, a film formulation and a well spray formulation as a liquid formulation. Examples of the liquid formulation include a suspension, a liquid, a syrup and an elixir. These formulations can be used as a filler for a soft or hard capsule, and as a carrier, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or suitable oil, and one or more emulsifying agent and / or suspending agent are generally used. In addition, the liquid formulation can be prepared, for example, by dissolving solid state pharmaceutical formulation, for example, an individually packaged pharmaceutical formulation, in water, etc.
[00073] In the present application, the term "poorly soluble in water or insoluble in water" indicates that the solubility in water is less than 100 μg / mL, preferably less than 10 μg / mL at 25 ° C, for example. Solubility can be determined according to a method well known in the art.
[00074] In the present application, the expression "water solubility is improved" indicates that the solubility in FaSSIF, which is the simulated intestinal fluid in a human fasted state, is improved. Specifically, it indicates that the solubility is significantly increased (p <0.05) when a T test is performed for a comparative example. Similarly, the expression "water solubility is improved in a significant sense" indicates that solubility is increased in a significant sense (p <0.01) when a significant difference test is performed. Similarly, the expression "water solubility is improved in a particularly significant sense" indicates that the solubility is increased in a significant sense (p <0.001) when a significant difference test is performed.
[00075] In the present application, the term "ALK" indicates a "receptor-type tyrosine kinase which means anaplastic lymphoma kinase and belongs to an insulin receptor family".
[00076] In this application, the "substance" represented by Formula (I) or specific chemical name means a compound represented by a certain structure, its salts or solvates or prodrugs.
[00077] According to the present invention, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. According to the present invention, when the halogen atom is a substituent group for an aromatic carbon ring, an aromatic heterocycle and the like, the preferred halogen atom includes a fluorine atom, a chlorine atom and a bromine atom. According to the present invention, when the halogen atom is a substituent group for an alkyl group or a group comprising alkyl as at least a part of the group (e.g., alkoxy, alkenyl, unsaturated carbocycle, unsaturated heterocycle and the like) , the preferred halogen atom includes a fluorine atom. Specific examples of the same include a trifluoromethyl group, a pentafluorethyl group, a heptafluorpropyl group, a nonafluorbutyl group, a trifluoromethoxy group, a pentafluorethoxy group, a heptafluorpropoxy group, a heptafluorutyl group, a trifluorylpropyl group, a trifluoryl group nonafluorpentanoíla group.
[00078] The group "C1-8 alkyl" means a monovalent group that is derived by removing any of the hydrogen atoms from a linear or branched aliphatic hydrocarbon having 1 to 8 carbon atoms. Especially, examples of the same include a methyl group, an ethyl group, an isopropyl group, a butyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a group isopentyl, a 2,3-dimethyl propyl group, a hexyl group, a 2,3-dimethyl hexyl group, a 1,1-dimethyl pentyl group, a heptyl group and an octyl group. Preferably, it is a C1-6 alkyl group, more preferably a C1-5 alkyl group, even more preferably a C1-4 alkyl group and even more preferably a C1-3 alkyl group.
[00079] The "substitutable C1-8 alkyl group" means an unsubstituted C1-8 alkyl group or a C1-8 alkyl group of which at least one hydrogen atom in the alkyl group is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl group can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C1-8 alkyl group that can be substituted by certain 1 to 3 substituent groups.
[00080] The group "C2-8 alkenyl" means a monovalent group in which at least one double bond (two adjacent SP2 carbon atoms) is comprised of a linear or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms. Specific examples of the C2-8 alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group (including both cis and trans), a group 3-butenyl, a pentenyl group and a hexenyl group. Preferably, it is a C2-6 alkenyl group, more preferably a C2-5 alkenyl group, even more preferably a C2-4 alkenyl group and even more preferably a C2-3 alkenyl group.
[00081] The "substitutable C2-8 alkenyl group" means the unsubstituted C2-8 alkenyl group as defined above or a C2-8 alkenyl group of which at least one hydrogen atom in the alkenyl group is replaced by a certain substituting group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the individually bonded carbon atom can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C2-8 alkenyl group that can be substituted by 1 to 3 certain substituent groups. More preferably, there are 1 to 3 substituent groups for a C2-6 alkenyl group and a C2-5 alkenyl group and 1 to 2 substituent groups for a C2-3 alkenyl group.
[00082] The "C2-8 alkynyl group" means a monovalent group in which at least one triple bond (two adjacent SP carbon atoms) is comprised of a linear or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms. Specific examples of the C2-8 alkynyl group include an ethynyl group, a 1-propynyl group, a propargyl group and a 3-butynyl group. Preferably, it is a C2-6 alkynyl group, more preferably a C2-5 alkynyl group, even more preferably a C2-4 alkynyl group and even more preferably a C2-3 alkynyl group.
[00083] The "substitutable C2-8 alkynyl group" means the unsubstituted C2-8 alkynyl group as defined above or a C2-8 alkynyl group of which at least one hydrogen atom in the alkynyl group is replaced by a certain substituting group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the individually bonded carbon atom can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C2-8 alkynyl group that can be substituted by certain 1 to 3 substituent group. More preferably, there are 1 to 3 substituent groups for a C2-6 alkynyl group and a C2-5 alkynyl group and 1 to 2 substituent groups for a C2-3 alkynyl group.
[00084] The "C3-8 cycloalkyl group" means an aliphatic hydrocarbon group in cyclic form. Preferably, it includes a C3-6 cycloalkyl group. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloeptyl group and a cyclooctyl group. Preferably, it is a C3-6 cycloalkyl group.
[00085] The "substitutable C3-8 cycloalkyl group" means the unsubstituted C3-8 cycloalkyl group as defined above or a C3-8 cycloalkyl group of which at least one or more hydrogen atoms are replaced by a certain group substituent. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C3-8 cycloalkyl group that can be substituted by certain 1 to 3 substituent groups.
[00086] The "4 to 10 membered heterocycloalkyl group" means a saturated or partially unsaturated heterocyclic group consisting of 4 to 10 ring constituent atoms and comprises 1 to 3 heteroatoms which are selected from O, S and N. The heterocycloalkyl group it may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl group. Specific examples thereof include an oxetanyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a pyrrolidine group, a pyrrolidinyl group, a piperidine group, a piperidinyl group, a piperazine group, a piperazine group, a morpholine group morpholinyl group, a tetrahydrothiopyranyl group, a thiomorpholine group, an imidazolidinyl group, a 1,3-dioxadinyl group, a tetrahydropyranyl group, a 1,3-dioxadinyl group, a 1,2,3,6-tetrahydropyridinyl group, a group 1 -oxa-8-aza-spiro [4,5] decanyl and a 1,4-dioxa-8-aza-spiro [4,5] decanyl group. Preferably, it is a 4- to 8-membered heterocycloalkyl group, more preferably, a 4- to 6-membered heterocycloalkyl group.
[00087] The "substituted 4-10 membered heterocycloalkyl group" means the unsubstituted 4-10 membered heterocycloalkyl group as defined above or a 4-10 membered heterocycloalkyl group of which at least one hydrogen atom in the group heterocycloalkyl is substituted by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a 4- to 10-membered heterocycloalkyl group that can be substituted by 1 to 4 certain substituent groups. More preferably, there are 1 to 4 substituent groups for a 4- to 8-membered heterocycloalkyl group and there are 1 to 3 substituent groups for a 4- to 6-membered heterocycloalkyl group. When the substituting group is an oxo group, two oxo groups can be attached to the same sulfur atom. When a quaternary ammonium salt is formed, two alkyl groups can bond to the nitrogen atom.
[00088] The "C6-10 aryl group" means a monovalent aromatic hydrocarbon ring. Specific examples of the C6-10 aryl group include a phenyl group, a 1-naphthyl group and a 2-naphthyl group.
[00089] The "substitutable C6-10 aryl group" means the unsubstituted C6-10 aryl group described above or a C6-10 aryl group of which at least one hydrogen atom is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C6-10 aryl group that can be substituted by certain 1 to 3 substituent groups.
[00090] The "5- to 14-membered heteroaryl group" means a cyclic aromatic group comprising one or more heteroatoms between 5 to 14 ring constituent atoms. The cycle can be a monocyclic or bicyclic heteroaryl group fused to a benzene ring or a monocyclic heteroaryl ring. Specific examples of this include a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isooxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidyl group, a pyridininyl group, a triazinyl group, a benzofuranyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzoxoxylol group , a benzoimidazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a cinolinyl group, a quinazolinyl group, a quinoxalinyl group, a benzodioxolyl group, an indolizinyl group, an imidazopyridyl group and the like . Preferably, it is a 5- to 6-membered heteroaryl group.
[00091] The "substituted 5-14 membered heteroaryl group" means the unsubstituted 5-14 membered heteroaryl group as defined above or a 5-14 membered ring heteroaryl group of which at least one hydrogen atom in the heteroaryl group it is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a 5- to 14-membered heteroaryl group that can be substituted by certain 1 to 3 substituted groups. More preferably, there are 1 to 3 substituent groups or 1 to 2 substituent groups for a 5- to 6-membered heteroaryl group.
[00092] The "C1-8 alkanoyl group" means a C1-8alkyl-C (O) - group, wherein the C1-8alkyl group is as defined above. Especially, examples of the same include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and a hexanoyl group. Preferably, it is a C1-6 alkanoyl group and, more preferably, a C1-3 alkanoyl group.
[00093] The "substitutable C1-8 alkanoyl group" means the unsubstituted C1-8 alkanoyl group as defined above or a C1-8 alkanoyl group of which at least one hydrogen atom in the alkanoyl group is replaced by a certain substituting group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C1-8 alkanoyl group that can be substituted by certain 1 to 3 substituent groups. More preferably, there are 1 to 2 substituent groups for a C1-6 alkanoyl group and a C1-3 alkanoyl group.
[00094] The "C3-8 cycloalkylcarbonyl group" means a C3-8 cycloalkyl-C (O) - group, wherein the C3-8 cycloalkyl group is as defined above. Specific examples thereof include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a cycloeptylcarbonyl group and a cyclooctylcarbonyl group.
[00095] The "4 to 10 membered heterocycloalkylcarbonyl group" means a 4 to 10 membered heterocycloalkyl-CO- group and it contains 4 to 10 membered heterocycloalkyl as defined above.
[00096] The "C3-8 cycloalkyl (C0-8alkyl) aminocarbonyloxy group" means a C3-8 cycloalkyl-NHC (O) O- group or a C3-8 cycloalkyl-N (C1-8alkyl) C (O) O group -, in which the C3-8 cycloalkyl group is as defined above. Specific examples thereof include a cyclopropylaminocarbonyloxy group, a cyclobutylaminocarbonyloxy group, a cyclopentylaminocarbonyloxy group, a cyclohexylaminocarbonyloxy group, a cyclopropyl (N-methyl) aminocarbonyloxy group and a cyclobutyl (N-methyl) aminocarbonyloxy group.
[00097] The "(C1-8alkyl) x-aminocarbonyl group", (where x represents the symbol as defined in the claims) means an NH2C (O) - group, a (C1-8alkyl) NC (O) group - or a (C1-8alkyl) 2N-C (O) - group. Specific examples thereof include an N-methyl-aminocarbonyl group, N-ethyl-aminocarbonyl group, an N-n-butyl-aminocarbonyl group and an N, N-dimethyl-aminocarbonyl group.
[00098] The "substitutable (C1-8alkyl) x-aminocarbonyl group" means an unsubstituted (C1-8alkyl) x-aminocarbonyl group or group in which at least one hydrogen atom of the nitrogen atom or portion alkyl is replaced by a certain substituent group. When there are two or more substituting groups, each substituting group can be the same or different from each other.
[00099] The "C6-10 aryl (C0-8alkyl) aminocarbonyl group" means a C6-10 aryl-NHC (O) group - or a C6-10 aryl-N (C1-8alkyl) -C (O) group - . Specific examples thereof include a phenyl-NHC (O) group and a phenyl- (N-methyl) -aminocarbonyl group. C6-10 aryl and C1-8alkyl are as defined above. Specific examples thereof include a phenylaminocarbonyl group and a phenyl (N-methyl) aminocarbonyl group.
[000100] The "4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl group" means a carbonyl group to which a 4- to 10-membered nitrogen-containing heterocycloalkyl group is attached. Here, the 4- to 10-membered nitrogen-containing heterocycloalkyl group (a 4- to 10-membered nitrogen-containing heterocycloalkyl group) means a heterocycloalkyl group consisting of 4 to 10 ring constituent atoms and comprises at least one nitrogen atom as a heteroatom. Preferably, it is attached to the carbonyl group by means of a nitrogen atom which is comprised in the heterocycloalkyl ring. Specific examples of the heterocycloalkyl group include a pyrrolidinyl group, an imidazolidinyl group, a morpholino group, a piperazine group and a piperidine group. For the 4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl group, examples of the same include a pyrrolidinocarbonyl group, a piperidinocarbonyl group, a piperazinocarbonyl group and a morpholinocarbonyl group.
[000101] The "4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl group" means the 4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl group or the group in which at least one hydrogen atom of the heterocycloalkyl moiety is replaced by a certain group substituent. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the heterocycloalkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a 4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl group that can be substituted by certain 1 to 3 substituent groups.
[000102] "4 to 10 membered heterocycloalkyl (C0-8alkyl) aminocarbonyl group" means 4 to 10 membered NHC (O) heterocycloalkyl group or 4 to 10 membered N (C1-8alkyl) C (O) heterocycloalkyl group . Specific examples thereof include an oxetan-3-yl amide group and a (1,1-dioxo-tetrahydrothiophen-3-yl) -amide group.
[000103] The "4 to 10 membered heterocycloalkylaminocarbonyl group that can be substituted by one or more oxo group" means the 4 to 10 membered heterocycloalkylaminocarbonyl group or the group in which the heterocycloalkyl portion is replaced by at least one oxo group .
[000104] The "C6-10 arylsulfonyl group" means a C6-10 aryl-S (O) 2- group, wherein the C6-10 aryl group is as defined above. Specific examples thereof include a phenylsulfonyl group.
[000105] The "5-14 membered heteroaryl sulfonyl group" means a 5-14 membered heteroaryl-S (O) 2- group, wherein the 5-14 membered heteroaryl group is as described above. Specific examples thereof include an imidazole sulfonyl group.
[000106] The "C1-8 alkyl C6-10 arylsulfonyl group" means a C1-8 alkyl-C6-10 aryl-S (O) 2- group, wherein the C1-8 alkyl and C6-10 aryl groups conform defined above. Specific examples thereof include a 4-methyl-phenylsulfonyl group.
[000107] The "(C1-8alkyl) x-amino group" (where x represents the symbol as defined in the claims) means an amino group, an NH (C1-8alkyl) group or an NH (C1-8alkyl) 2- group . Specific examples thereof include amino, methylamino, ethylamino, butylamino, isopropylamino, dimethylamino and diethylamino. Preferably, it is a C1-3 alkylamino group.
[000108] The "substitutable (C1-8alkyl) x-amino group" means the unsubstituted (C1-8alkyl) x-amino group or the group in which at least one hydrogen atom of the nitrogen atom or portion alkyl is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other.
[000109] The "C1-8alkylcarbonyl (C0-8alkyl) amino group" means a C1-8alkyl-C (O) -NH- group or a C1-8alkyl-C (O) -N (C1-8alkyl) group -, wherein C1-8alkyl is as defined above. Specific examples thereof include a methylcarbonylamino group, an ethylcarbonylamino group, a propylcarbonylamino group and a butylcarbonylamino group.
[000110] The "substitutable C1-8alkylcarbonyl (C0-8alkyl) amino group" means the unsubstituted C1-8alkylcarbonyl (C0-8alkyl) amino group or the group in which at least one hydrogen atom in the terminal alkyl portion of the C1-8 alkylcarbonyl (C0-8 alkyl) amino group is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl group can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C1-8 alkylcarbonyl (C0-8alkyl) amino group that can be substituted by certain 1 to 3 substituent groups.
[000111] The "C6-10 arylcarbonyl (C0-8alkyl) amino group" means a C6-10 aryl-C (O) -NH- group or a C6-10 aryl-C (O) -N (C1-8alkyl) group ) -, in which the C6-10 aryl group and the C1-8alkyl group are as defined above. Specific examples thereof include a phenylcarbonylamino group.
[000112] The "substitutable C6-10 arylcarbonyl (C0-8alkyl) amino group" means the unsubstituted C6-10 arylcarbonyl (C0-8alkyl) amino group or the group in which at least one hydrogen atom of the aryl moiety of the C6-10 arylcarbonyl (C0-8alkyl) amino group is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C6-10 arylcarbonyl (C0-8 alkyl) amino group that can be substituted by 1 to 3 substituent groups.
[000113] The "(C1-8alkyl) x-aminocarbonyl (Co-8alkyl) amino group" (where x represents the symbol as defined in the claims) means an NH2C (O) NH- group, a (C1-8alkyl) NHC group (O) NH-, an NH2C (O) N (C1-8alkyl) group - or a (C1-8alkyl) NHC (O) N (C1-8alkyl) group -, where the C1-8alkyl group is as defined above . Specific examples thereof include aminocarbonyl (N-methyl) amino and (N-methyl) aminocarbonyl (N'-methyl) amino.
[000114] The "substitutable (C1-8alkyl) x-aminocarbonyl (C0-8alkyl) amino group" means the unsubstituted (C1-8alkyl) x-aminocarbonyl (C0-8alkyl) amino group or (C1- 8alkyl) x-aminocarbonyl (C0-8alkyl) amino wherein at least one hydrogen atom of the nitrogen atom or the alkyl portion of the (C1-8 alkyl) x-aminocarbonyl (C0-8 alkyl) amino group is replaced by a certain substituting group. Preferably, it is a (C1-8alkyl) x-aminocarbonyl (Co-8alkyl) amino group that can be replaced by a phenyl group.
[000115] The "(C1-8alkyl) x aminosulfonyl (C0-8alkyl) amino group" (where x represents the symbol as defined in the claims) means an NH2S (O) 2NH- group, an NH (C1-8alkyl) group - S (O) 2NH-, an N (C1-8alkyl) 2-S (O) 2NH- group, an NH2S (O) 2N (C1-8alkyl) - group, an NH (C1-8alkyl) -S (O ) 2 (C1-8alkyl) N- or an N (C1-8alkyl) 2-S (O) 2 (C1-8alkyl) N- group, where C1-8alkyl is as defined above. Specific examples thereof include a methylaminosulfonylamino group and a dimethylaminomethylsulfonylamino group.
[000116] The "C1-8 alkoxy group" means a C1-8alkyl-O- group. Specific examples of the same include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a tert-butoxy group, a 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-butyloxy group, 3-methyl-1-butyloxy group, 2-methyl-2-butyloxy group, 3 group -methyl-2-butyloxy, a 2,2-dimethyl-1-propyloxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, a group 3 -methyl-1-pentyloxy, a 4-methyl-1-pentyloxy group, a 2-methyl-2-pentyloxy group, a 3-methyl-2-pentyloxy group, a 4-methyl-2-pentyloxy group, a group 2 -methyl-3-pentyloxy, a 3-methyl-3-pentyloxy group, a 2,3-dimethyl-1-butyloxy group, a 3,3-dimethyl-1-butyloxy group, a 2,2-dimethyl-1 group -butoxy, a 2-ethyl-1-butyloxy group, a 3,3-dimethyl-2-butyloxy group, a 2,3-dimethyl-2-butyloxy group and a 1-methyl-cyclopropylmethoxy group. Preferably, it is a C1-6 alkoxy group. Most preferably, it is a C 1-5 alkoxy group. Even more preferably, it is a C1-4 alkoxy group and even more preferably it is a C1-3 alkoxy group.
[000117] The "substitutable C1-8 alkoxy group" means an unsubstituted C1-8 alkoxy group or the group in which at least one hydrogen atom of an alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C1-8 alkoxy group that can be substituted by 1 to 3 certain substituent groups. More preferably, there are 1 to 3 substituent groups for a C1-6 alkoxy group and a C1-4 alkoxy group or 1 to 2 substituent groups for a C1-3 alkoxy group.
[000118] The "C1-8 alkoxycarbonyl group" means a C1-8alkyl-O-C (O) group - wherein the C1-8alkyl group is as defined above. Specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group and an i-propoxycarbonyl group. Preferably, it is a C1-6 alkoxycarbonyl group, and more preferably a C1-3 alkoxycarbonyl group.
[000119] The "substitutable C1-8 alkoxycarbonyl group" means the unsubstituted C1-8 alkoxycarbonyl group or the group in which at least one hydrogen atom of the C1-8 alkoxycarbonyl group is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl portion of the alkoxycarbonyl group can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C1-8 alkoxycarbonyl group that can be substituted by certain 1 to 3 substituent groups.
[000120] The "C0-8 alkoxy (C0-8alkyl) aminocarbonyl group" means an HO-NH-C (O) - group, a C1-8alkyl-NH-C (O) group -, an HO-N group ( C1-8alkyl) -C (O) - or a C1-8alkyl-N (C1-8alkyl) -C (O) - group, wherein the C1-8 alkoxy group and the C1-8 alkyl group are as defined above. Specific examples thereof include a methoxyminocarbonyl group, an ethoxyminocarbonyl group, an n-propoxy aminocarbonyl group and an i-propoxy aminocarbonyl group. Preferably, it is a C1-6 alkoxyminocarbonyl group. Most preferably, it is a C1-3 alkoxyminocarbonyl group.
[000121] The "C0-8 alkoxy (C0-8alkyl) aminocarbonyl group that can be substituted" means the unsubstituted hydroxyminocarbonyl group, a C1-8 alkoxyminocarbonyl group or a hydroxy (C1-8alkyl) aminocarbonyl group or the group in which at least at least one hydrogen atom of the alkyl portion of the C1-8 alkoxy (C1-8 alkyl) aminocarbonyl group is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C1-8 alkoxyminocarbonyl group that can be substituted by certain 1 to 3 substituent groups.
[000122] The "4 to 10 membered heterocycloalkyloxy group" means a 4 to 10 membered heterocycloalkyl-O- group having the 4 to 10 membered heterocycloalkyl defined above.
[000123] The "substituted 4 of 10 membered heterocycloalkyloxy group" means the unsubstituted 4- to 10-membered heterocycloalkyloxy group as defined above or a 4- to 10-membered heterocycloalkyloxy group in which at least one hydrogen atom of the portion heterocycloalkyl is substituted by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the heterocycloalkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a 4- to 10-membered heterocycloalkyloxy group that can be substituted by 1 to 3 certain substituent groups.
[000124] The "C6-10 aryloxy group" means a C6-10 aryl-O- group, wherein the C6-10 aryl group is as defined above.
[000125] The "5 to 14 membered heteroaryloxy group" means a 5 to 14 membered heteroaryl-O- group having the 5 to 14 membered heteroaryl described above. Specific examples thereof include a pyrimidinyloxy group.
[000126] The "C1-8alkylcarbonyloxy group" means a C1-8alkyl-C (O) -O- group having the C1-8alkyl described above. Specific examples thereof include a methylcarbonyloxy group, an ethylcarbonyloxy group and a propylcarbonyloxy group.
[000127] The "C2-8 alkenylcarbonyloxy group" means a C2-8 alkenyl-C (O) -O- group having the C2-8 alkenyl described above. Specific examples thereof include a 2-methyl-2-butenoyloxy group.
[000128] The "4-10 membered heterocycloalkylcarbonyloxy group" means a 4-10 membered heterocycloalkyl-C (O) -O- group having the 4-10 membered heterocycloalkyl described above.
[000129] The "(C1-8alkyl) x-aminocarbonyloxy group" (where x represents the symbol as defined in the claims) means an NHC (O) -O- group, an N (C1-8alkyl) C (O) - group O- or an N (C1-8alkyl) 2C (O) -O- group. Specific examples thereof include a methylaminocarbonyloxy group, an ethylaminocarbonyloxy group and a propylaminocarbonyloxy group.
[000130] The "substitutable (C1-8alkyl) x-aminocarbonyloxy group" means an unsubstituted (C1-8alkyl) x-aminocarbonyloxy group or the group in which at least one hydrogen atom in the nitrogen atom of the alkyl portion is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other.
[000131] The "heterocycloalkylsulfonyl group containing 4 to 10 membered nitrogen" means the heterocycloalkyl-S (O) 2- group containing 4 to 10 membered nitrogen. Specific examples of the same include a morpholino-sulfonyl group.
[000132] The "4- to 10-membered nitrogen-containing heterocycloalkylsulfonyl group" means the 4- to 10-membered nitrogen-containing heterocycloalkylsulfonyl group or the group in which at least one hydrogen atom of the 4-membered nitrogen-containing heterocycloalkyl group to 10 members is replaced by a certain substitution group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a 4- to 10-membered nitrogen-containing heterocycloalkylsulfonyl that can be substituted by certain 1 to 3 substituent groups.
[000133] The "4- to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy group" means a 4- to 10-membered nitrogen-heterocycloalkyl-S (O) 2-O- group. Specific examples thereof include a morphorino-sulfonyloxy group and a piperazine-sulfonyloxy group.
[000134] The "substituted 4 to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy group" means the unsubstituted 4 to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy group or the group in which at least one hydrogen atom of the 4-membered heterocycloalkyl nitrogen to 10 members is replaced by a certain substitution group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a 4- to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy that can be substituted by certain 1 to 3 substituent groups.
[000135] The "C1-8alkylsulfonyloxy group" means a C1-8alkyl-S (O) 2-O- group, and C1-8alkyl is as defined above.
[000136] The "substitutable C1-8alkylsulfonyloxy group" means the unsubstituted C1-8alkylsulfonyloxy group or the group in which at least one hydrogen atom of the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl moiety can be replaced by a cyclic substituent group through a spiro bond. Preferably, it is a C1-8 alkylsulfonyloxy group that can be substituted by certain 1 to 3 substituent groups. Specific examples thereof include a trifluoromethylsulfonyloxy group.
[000137] The "(C1-8alkyl) x-aminosulfonyloxy group" (where x represents the symbol as defined in the claims) means an NH2S (O) 2- group, an N (C1-8alkyl) S (O) 2- group or an N (C1-8alkyl) 2S (O) 2- group. Specific examples thereof include an N-methylaminosulfonyloxy group.
[000138] The "C1-8alkylthio group" means a C1-8alkyl-S- group, wherein the C1-8alkyl group is as defined above. Examples of the same include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, tert-butylthio, n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio, 1- ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3-ethylbutylthio and 2-ethylbutylthio and the like. Preferably, it is a C1-6alkylthio group and more preferably a C1-3alkylthio group.
[000139] The "substitutable C1-8alkylthio group" means the unsubstituted C1-8alkylthio group or the group in which at least one hydrogen atom of the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the alkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a C1-8 alkylthio group that can be substituted by certain 1 to 3 substituent groups.
[000140] The "C1-8alkylsulfonyl group" means a C1-8alkyl-S (O) 2- group, wherein the C1-8alkyl group is as defined above. Specific examples thereof include a methylsulfonyl group, an ethylsulfonyl group and an n-propylsulfonyl group. Preferably, it is a C1-6 alkylsulfonyl group and more preferably a C1-3 alkylsulfonyl group.
[000141] The "C1-8alkylsulfinyl group" means a C1-8alkyl-S (O) - group, wherein the C1-8alkyl group is as defined above. Specific examples thereof include a methylsulfinyl group, an ethylsulfinyl group and an n-propylsulfinyl group. Preferably, it is a C1-6alkylsulfinyl group and more preferably a C1-3alkylsulfinyl group.
[000142] The "substitutable C1-8alkylsulfonyl group" means the unsubstituted C1-8alkylsulfonyl group or the group in which at least one hydrogen atom of the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C1-8 alkylsulfonyl group that can be substituted by certain 1 to 3 substituent groups.
[000143] The "substitutable C1-8alkylsulfinyl group" means the unsubstituted C1-8alkylsulfinyl group described above wherein at least one hydrogen atom of the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C1-8alkylsulfinyl group that can be substituted by certain 1 to 3 substituent groups.
[000144] The "4-10 membered heterocycloalkylsulfonyl group" means a 4-10 membered heterocycloalkyl-S (O) 2 group having the 4-10 membered heterocycloalkyl defined above.
[000145] The "substituted 4- to 10-membered heterocycloalkylsulfonyl group" means the 4- to 10-membered unsubstituted heterocycloalkylsulfonyl group described above or the group in which at least one hydrogen atom of the heterocycloalkyl portion is replaced by a certain group substituent. When two or more substituting groups are present, each substituting group can be the same or different from each other. In addition, the heterocycloalkyl moiety can be replaced by a cyclic substituent group via a spiro bond. Preferably, it is a 4- to 10-membered heterocycloalkylsulfonyl group that can be substituted by certain 1 to 3 substituent groups.
[000146] The "(C1-8alkyl) x-aminosulfonyl group" (where x represents the symbol as defined in the claims) means an NH2-S (O) 2- group, a C1-8alkylamino-S (O) 2 group -or a (C1-8alkyl) 2 amino- S (O) 2- group, where C1-8alkyl is as defined above. Specific examples thereof include an aminosulfonyl group, a methylaminosulfonyl group and a dimethylaminosulfonyl group.
[000147] The "substitutable (C1-8alkyl) x-aminosulfonyl group" means the unsubstituted aminosulfonyl group or the group in which at least one hydrogen atom in the nitrogen atom or in the alkyl portion is replaced by a certain group substituent. When two or more substituting groups are present, each substituting group can be the same or different from each other.
[000148] The "C1-8 alkoxycarbonyl (C0-8alkyl) amino group" means a C1-8 alkoxy-C (O) -NH- group or a C1-8 alkoxy-C (O) -N (C1-8alkyl) group ) -, in which the C1-8 alkoxy group and (C1-8alkyl) are as defined above. Specific examples thereof include a methoxycarbmamoyl group and an N-ethylcarbonyl-N-methylamino group.
[000149] The "substitutable C1-8 alkoxycarbonyl (C0-8alkyl) amino group" means the unsubstituted C1-8 alkoxycarbonyl (C0-8alkyl) amino group or the C1-8 alkoxycarbonyl (C0-8alkyl) amino group in that at least one hydrogen atom in the nitrogen atom or in the alkyl moiety can be replaced by a certain substituent group. Preferably, it is a C1-8 alkoxycarbonyl (C0-8alkyl) amino group that can be substituted by certain 1 to 3 substituent groups.
[000150] The "C1-8 alkoxycarbonyl (C0-8alkyl) aminosulfonyl group" means a C1-8 alkoxy-C (O) -NHS (O) 2- group or a C1-8 alkoxy- C (O) -N group (C1-8alkyl) S (O) 2-, where C1-8 alkoxy and C1-8alkyl are as defined above. Specific examples thereof include a methoxycarbonylaminosulfonyl group and an ethoxycarbonyl-N-methylaminosulfonyl group.
[000151] The "C6-10 aryloxycarbonyl (C0-8alkyl) amino group" means a C6-10 aryl-OC (O) -NH- group or a C6-10 aryl-OC (O) -N (C1-8alkyl) group ) -, in which the C6-10 aryl and C1-8alkyl groups are as defined above. Specific examples thereof include a phenyloxycarbonylamino group and an N-methyl-N-phenyloxycarbonyl-amino group.
[000152] The "substitutable C6-10 aryloxycarbonyl (C0-8alkyl) amino group" means the unsubstituted C6-10 aryloxycarbonyl (C0-8alkyl) amino group or the C6-10 aryloxycarbonyl (C0-8alkyl) amino group in that at least one hydrogen atom in the nitrogen atom or in the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C6-10 aryloxycarbonyl (C0-8 alkyl) amino group that can be substituted by certain 1 to 3 substituent groups.
[000153] The "C6-10 aryl (C0-8alkyl) aminocarbonyl (C0-8alkyl) amino group" means a C6-10 aryl-NH-C (O) -NH group, a C6-10 aryl- N (C1 group) -8alkyl) -C (O) -NH or a C6-10 aryl-N (C1-8alkyl) group -C (O) -N (C1-8alkyl) -, in which the C6-10 aryl and C1-8alkyl groups are as defined above. Specific examples thereof include a phenylaminocarbonylamino group and a phenylaminocarbonyl (N-methyl) amino group.
[000154] The "C6-10 aryl (C0-8alkyl) aminocarbonyl (C0-8alkyl) amino group that can be substituted" means the C6-10 aryl (C0-8alkyl) aminocarbonyl (C0-8alkyl) amino group which is unsubstituted or the C6-10 aryl (C0-8alkyl) aminocarbonyl (C0-8alkyl) amino group in which at least one hydrogen atom in the nitrogen atom or in the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C6-10 aryl (C0-8 alkyl) aminocarbonyl (C0-8 alkyl) amino group that can be substituted by certain 1 to 3 substituent groups.
[000155] The "C6-10 aryl (C0-8alkyl) aminocarbonyloxy group" means a C6-10 aryl-NH-C (O) -O- group or a C6-10 aryl-N (C1-8alkyl) -C group (O) -O-, in which the C6-10 aryl and C1-8alkyl group are as defined above. Specific examples thereof include a phenylaminocarbonyloxy group and a phenyl (N-methyl) aminocarbonyloxy group.
[000156] The "substitutable C6-10 aryl (C0-8alkyl) aminocarbonyloxy group" means the unsubstituted C6-10 aryl (C0-8alkyl) aminocarbonyloxy group or C6-10 aryl (C0-8alkyl) aminocarbonyloxy group in that at least one hydrogen atom in the nitrogen atom or in the alkyl moiety is replaced by a certain substituent group. When two or more substituting groups are present, each substituting group can be the same or different from each other. Preferably, it is a C6-10 aryl (C0-8 alkyl) aminocarbonyloxy group that can be substituted by certain 1 to 3 substituent groups.
[000157] The "C1-8alkylsulfonyl (C0-8alkyl) amino group" means a C1-8alkyl-S (O) 2-NH- group or a C1-8alkyl-S (O) 2-N (C1-8alkyl) group -, where the C1-8 alkyl group is as defined above. Specific examples thereof include a methylsulfonylamino group, an ethylsulfonylamino group and a methylsulfonyl (N-methyl) amino group.
[000158] The "C2-8 alkenyloxy group" means a C2-8 alkenyl-O- group, wherein the C2-8 alkenyl group is as defined above. Specific examples of the C2-8 alkenyloxy group include a vinyloxy group and an aryloxy group.
[000159] Preferred examples of the substance represented by Formula (I) include a substance in which A1 to A4 and A6 to A7 are a carbon atom, R3 is cyano and A5 is NH.
[000160] More preferred examples of the substance represented by Formula (I) include a substance in which A1 to A4 and A6 to A7 are a carbon atom, R3 is cyano, A5 is NH, R8is a 4- to 10-membered heterocycloalkyl group or a heterocycloalkyl group 4 to 10 members that can be replaced by a C3-8 cycloalkyl group.
[000161] Specific examples of the preferred substance represented by Formula (I) include 9- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 9-cyclopropylethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) - 11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-bromo-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 9-bromo-8- (4-cyclopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-chloro-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6,9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3- carbonitrile; 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 9-ethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethynyl-6,6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) - 6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-ethynyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (1-isopropyl-piperidin-4-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (2-tert-butylamino-ethoxy) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethynyl-8- (4-methanesulfonyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; and 9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile.
[000162] Specific examples of the most preferred substance represented by Formula (I) include (i) 6,6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6,11 -dihydro-5H-benzo [b] carbazol-3-carbonitrile, (ii) 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [b] carbazol-3-carbonitrile, (iii) 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6,6-dimethyl-11-oxo-6 , 11-dihydro-5H-benzo [b] carbazol-3-carbonitrile or (iv) 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) - 11- oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile or the salts thereof.
[000163] Method for producing the substances used in the present invention REPRESENTATIVE PRODUCTION METHOD
[000164] The substances represented by Formula (I) of the present invention can be produced using the method described below, for example. However, the method of producing the compounds used in the present invention is not limited to the same. Also, depending on the need, the order of the reaction step such as the introduction of a substituent group, etc., can be changed. Although the compounds used in the present invention are new compounds that have not yet been described in the literature, the compounds can be produced according to a chemical method that is well known in the art. In addition, For the reaction compounds that are used for production, commercially available ones can be used or they can be produced according to a method that is generally known in the art depending on the need.
[000165] In the reaction schemes that follow showing the reaction step, A1 to A10 and R1 to R10 are as defined in Formula (I). PR1 to PR10 are equal to R1 to R10 which are defined in Formula (I) or represent a group that can be converted to R1 to R10 according to the modification or deprotection of a functional group.
[000166] Other abbreviated symbols described in the reaction schemes that follow have the general meanings that can be understood by one skilled in the art. PRODUCTION METHOD I
[000167] This is one of the methods for producing the skeleton of Formula (I) in which A5 is N and R5 is H.
(The symbols that are included in the formula have the meanings as defined above. P represents a protection group, and for the production methods described below, when a defined group is subjected to unwanted chemical modification under a condition for implementation of the method, the desired compound can be produced using means such as protecting and deprotecting a functional group, etc., using a suitable protecting group). Step I-1
[000168] It is an alkylation step of a cyclic ketone derivative Ia. The step can be carried out by reacting cyclic ketone derivative Ia with an alkylating agent corresponding to R6 and R6 'in the presence of a base. For example, it can be performed in view of the method described in the Journal of the American Chemical Society, 115 (23), 10628-36; 1993 and Organic Letters, 9 (24), 5027-5029; 2007, etc. The reaction is carried out in a solvent under the condition of a reaction temperature of -20 ° C to the boiling point of the solvent, in the presence or absence of a catalyst. When R6 and R6 'are atomic groups other than a hydrogen atom, the reaction order can be optionally selected, and separation and purification can be carried out at each stage or the reaction can be carried out continuously.
[000169] Examples of the alkylating agent include an alkyl halide such as MeI, ethyl iodide, 2-iodopropane, 1,4-dibromobutane, 1,1'-oxybis (2-bromoethane) and the like, dimethyl sulfate and sulfonic acid ester such as dimethyl sulfuric acid methylmethanesulfonate, methyl tosylate and methyltrifluoromethanesulfonate. Preferably, it is an alkyl halide such as MeI and the like. For the catalyst, examples of it include a phase transfer catalyst such as tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate. Preferably, it is tetrabutylammonium hydrogen sulfate. Examples of the base include an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, calcium hydride and the like or an organic base such as t-BuOK, t-BuONa, pyridine, TEA (trifluoroacetic acid), DIPEA (N, N-diisopropylethylamine), LDA (lithium diisopropylamide), LiHMDS (lithium hexamethyl disilazide) and n-BuLi. Preferably, it is potassium hydroxide, potassium tert-butoxy or sodium tert-butoxy. For the solvent, examples of the same include toluene, xylene, n-hexane, cyclohexane, DMF (N, N-dimethylformamide), DMA (N, N-dimethyl acetamide), EtOAc, DMSO (dimethyl sulfoxide), dichloromethane, carbon tetrachloride, THF (tetrahydrofuran), dioxane, acetonitrile, water, methanol, ethanol and a mixture of them. Preferably, it is a water-THF or THF mixture solvent. Step I-2
[000170] It is the synthesis of carbazole Id skeleton according to Fischer method. This step is generally carried out using cyclic ketone Ib in the presence of hydrazine compound Ic and an acid in a solvent or using an acid as a solvent under the condition of a reaction temperature of 0 ° C to the boiling point of the solvent, and also can be performed in view of the method described in the Journal of Heterocyclic Chemistry, 28 (2), 321-3; 1991 and Bioorganic & Medicinal Chemistry Letters (2008), 18 (24), 6479-6481, In addition, when the reaction proceeds slowly, a zinc chloride catalyst and the like can also be used in view of the reaction condition described in Organic Letters (2006), 8 (3), 367-370, The reaction includes a phenyl hydrazone production step and a sigmatropic recombination step. Separation and purification can be carried out at each stage or the reaction can be carried out continuously. In addition, according to the aryl hydrazine structure, which is a reaction material for this reaction step, the mixture of a position isomer can be obtained as a reaction product. Such a position isomer can be separated from one another or used as a mixture for the next reaction step.
[000171] For the acid used for the reaction, examples of the same include formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, TFA, hydrochloric acid, sulfuric acid and pyridinium p-toluenesulfonate. Preferably, it is acetic acid, sulfuric acid or TFA. For the solvent, examples of it include toluene, xylene, NMP (N-methyl pyrrolidone), DMF, DMA, DMSO, sulfolane, dioxane, DME (dimethoxyethane), TFE (trifluorethanol), diethylene glycol, triethylene glycol and a mixture thereof . Step I-3
[000172] It is a benzyl oxidation step at position 11 of carbazole skeleton Id. This step is performed by applying an oxidizing agent to a substrate in a solvent in the presence or absence of a catalyst under the condition of a temperature of -20 ° C reaction to the boiling point of the solvent. For the reaction condition, the method described in the Journal of Medicinal Chemistry, 51 (13), 3814-3824; 2008, etc. can be considered.
[000173] For the oxidizing agent and catalyst used for the reaction, DDQ, peracid such as mCPBA and the like, cerium (IV) ammonium nitrate (CAN), permanganate such as potassium permaganate, barium permaganate and similare, sodium chloride, hydrogen peroxide or N-hydroxyphthalimide and the like can be used alone or in a combination thereof. Preferably, it is DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) or N-hydroxyphthalimide. For the solvent used for the reaction, examples of the same include water, tert-butanol, acetonitrile, THF, dichloromethane, ethyl acetate and a mixture thereof. Preferably, it is THF.
[000174] According to the present invention, examples of the salts of the compounds which are represented by formula (I) include hydrochloric acid salt, hydrobromic acid salt, iodridic acid salt, phosphoric acid salt, phosphonic acid salt, salt sulfuric acid salt, sulfonic acid salt such as methanesulfonic acid salt, p-toluenesulfonic acid salt and the like, carboxylic acid salt such as acetic acid salt, citric acid salt, malic acid salt, tartaric acid salt, succinic acid salt, salicylic acid salt and the like, or alkali metal salt such as sodium salt, potassium salt and the like, alkaline earth metal salt such as magnesium salt, calcium salt and the like, ammonium salt such such as ammonium salt, alkyl ammonium salt, dialkyl ammonium salt and trialkyl ammonium salt, tetraalkyl ammonium salt. Preferred examples thereof include hydrochloride salt and methane sulfonate salt.
[000175] These salts are produced by bringing the compounds described above in contact with an acid or a base that can be used for the production of a pharmaceutical product.
[000176] According to the present invention, the compounds which are represented by formula (I) or salts thereof can be an anhydride or a solvate such as a hydrate and the like. Here, the term "solvate" indicates a phenomenon by which molecules of solute or ions contained in a solution strongly attract neighboring solvent molecules to form a gigantic group of molecules. When the solvent is water, it is called "hydrate." The solvate can be either a hydrate or a non-hydrate. For the non-hydrate, alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide and the like can be used.
[000177] The compounds of the present invention and salts thereof can be present in various forms of tautomer, for example, enol and imine forms, keto and enamine forms and a mixture thereof. In a solution, a tautomer is present as a mixture of the tautomeric set. In the case of solid form, a type of tautomer is usually present in a dominant ratio. In this regard, even if only one type of tautomer is described, the present invention will include all types of tautomers of the compounds of the present invention.
[000178] The present invention includes all types of stereoisomers of the compounds represented by Formula (I) (e.g., enantiomer, diastereomer (including cis and trans geometric isomer)), isomer racemate and a mixture thereof. For example, compounds having formula (I) of the present invention can have one or more asymmetric centers, and the present invention includes a racemic mixture, a diastereomer and enantiomer mixture of such a compound.
[000179] When the compounds of the present invention are obtained in free form, the compounds can be converted into a salt, hydrate or solvate thereof which can be formed from the compounds according to a method generally known in the art.
[000180] Furthermore, when the compounds of the present invention are obtained in the form of a salt, hydrate or solvate of the compounds, the compounds can be converted to free form according to a method generally known in the art.
[000181] In addition, the substances used in the present invention can be administered in the prodrug form of the compounds having Formula (I). Here, the term "prodrug" indicates derivatives of compounds having Formula (I) that can be converted to compounds having Formula (I) or pharmaceutically acceptable salts thereof after administration by enzymatic or non-enzymatic degradation under a condition physiological. The prodrug can be inactive form when it is administered to a patient. However, in living organisms, it converts to compounds having Formula (I) and present here in active form.
[000182] For example, the prodrug converts to the desired drug form at a specific pH or by an enzymatic action. Typical prodrug is a compound having a hydrolyzable ester residue that produces a free acid in living organisms. Examples of such a hydrolyzable ester residue include a residue having a carboxyl moiety of which the free hydrogen (for example, a free hydrogen in a carboxyl group when Y in formula (I) has a carboxyl group) is replaced by a C1-4 group alkyl, a C2-7 alkanoyloxymethyl group, a 1- (alkanoyloxy) ethyl group having 4 to 9 carbon atoms, a 1-methyl-1- (alkanoyloxy) -ethyl group having 5 to 10 carbon atoms, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, a 1- (alkoxycarbonyloxy) ethyl group having 4 to 7 carbon atoms, a 1- methyl-1- (alkoxycarbonyloxy) ethyl group having 5 to 8 carbon atoms, an N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, a 1- (N- (alkoxycarbonyl) amino) ethyl group having 4 to 10 carbon atoms, a 3-phthalidyl group, a 4-crotonolactonyl group, a y-butyrolacton-4-yl group , a di-N, N- (C1-2) alkylamino (C2-3) alkyl group (e.g., N, N-dimethylaminoethyl group), a carbamoyl (C1-2) alkyl group, an N, N- group di (C1-2) alkylcarbamoyl- (C1-2) alkyl, a piperidino (C2-3) alkyl group, a pyrrolidine (C2-3) alkyl group, or a morpholino (C2-3) alkyl group, but not limited to they.
[000183] The formulation of the present invention is produced according to a method well known in the art using additives such as a filler, a lubricating agent, a coating agent, a binding agent, a disintegrating agent, a stabilizing agent, a flavoring agent or a diluent.
[000184] Examples of the filler include starch such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol and sorbitol; and anhydrous dibasic calcium phosphate, microcrystalline cellulose, precipitated calcium carbonate and calcium silicate. Preferred examples of the filler include starch such as potato starch and corn starch, lactose hydrate, microcrystalline cellulose and anhydrous dibasic calcium phosphate.
[000185] For the formulation of the present invention, lactose hydrate and microcrystalline cellulose are preferably used as a filler. Here, the amount of lactose hydrate used is preferably 5 to 60 parts by weight and, more preferably, 10 to 50 parts by weight with respect to 100 parts by weight of the formulation. In addition, the amount of microcrystalline cellulose used is preferably 5 to 60 parts by weight and, more preferably, 10 to 50 parts by weight with respect to 100 parts by weight of the formulation.
[000186] Examples of the disintegrating agent include the compounds mentioned above as a charge above, and chemically modified starch and cellulose such as sodium Croscarmellose, sodium starch glycolate and cross-linked polyvinyl pyrrolidone. Specific examples of disintegrating agent include sodium starch glycolate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium Croscarmellose, crospovidone, lower substituted hydroxypropyl cellulose and hydroxypropyl starch. The amount of disintegrating agent used is preferably 0.5 to 25 parts by weight and more preferably 1 to 15 parts by weight with respect to 100 parts by weight of the formulation.
[000187] Examples of the linker include polyvinyl pyrrolidone, Macrogol and the compounds mentioned above as a charge above. Specific examples of the binding agent include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, povidone (polyvinyl pyrrolidone) and gum arabic powder. The amount of the binding agent used is preferably 0.1 to 50 parts by weight and more preferably 0.5 to 40 parts by weight with respect to 100 parts by weight of the formulation.
[000188] For the lubricating agent, suitable examples thereof include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and sodium stearyl fumarate.
[000189] As the surfactant or an emulsifying agent, examples of the same include polysorbate 80, polyoxol 40 and lauromacrogol.
[000190] As the coloring agent, any of those that can be used in a pharmaceutical product can be used. Examples of these include a food coloring such as Food Yellow No. 5 (Sunset yellow, US Food Yellow No. 6), Food Red No. 2 and Food Blue No. 2, Food Lake coloring and iron trioxide.
[000191] As a stabilizing agent, examples thereof include paraoxy benzoic acid esters such as methyl paraben, propyl paraben and the like; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol and the like; benzalkonium chloride; phenols such as phenol, cresol and the like; thimerosal; dehydroacetic acid; and sorbic acid.
[000192] As a flavoring agent, examples of it include a sweetener, an acidic flavoring agent, a flavoring agent and the like that are generally used in the art.
[000193] With respect to the fluidizing agent, it is used for the purpose of improving the fluidity of mixed powder or granules, and representative examples include talc, light anhydrous silicic acid, that is, silicon dioxide and hydrated silicon dioxide. Here, light anhydrous silicic acid is only required to contain hydrated silicon dioxide (SiO2 • nH2O) (n represents an integer) as a main ingredient and specific examples thereof include SYLYSIA 320 (trademark, manufactured by FUJI SILYSIA CHEMICAL LTD.) and AEROSIL 200 (registered trademark, manufactured by Nippon Aerosil Co., Ltd.).
[000194] Suitable examples of preservatives include paraoxy benzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
[000195] Suitable examples of the antioxidant include sulfite salt and ascorbic acid.
[000196] These additives can be used in combination of two or more types that are mixed in an appropriate ratio.
[000197] Still, as a solvent to produce a liquid formulation, examples of the same include ethanol, phenol, chlorocresol, purified water and distilled water.
[000198] The solid formulation of the present invention can be produced by mixing the substance used for the present invention with a dissolution aid and a pharmaceutically acceptable carrier, and carrying out a production method generally performed in the art. Preferably, it is produced according to the production method described below. 1) The substance used for the present invention is mixed with ingredients such as additive, filler, disintegrating agent and lubricating agent that are selected from additive group A, and then filled into a capsule or subjected to compression molding to produce the solid formulation of the present invention. 2) The substance used for the present invention is mixed with ingredients such as additive, filler and binding agent that are selected from additive group A, and then granulated with the addition or spray of a solvent (eg, purified water, ethanol or its mixture, and the like). To the granulate obtained, an adequate amount of a lubricating agent and, if necessary, a disintegrating agent, etc., is added and mixed, and then the mixture is filled into a capsule or subjected to compression molding to produce the solid formulation of the present invention. 3) The substance used for the present invention is mixed with ingredients such as additive and filler that are selected from additive group A, and then granulated while adding or spraying a liquid that is obtained by dispersing or dissolving a binding agent. and, if necessary, other additives for a solvent (for example, purified water, ethanol or a mixture thereof and the like). For the granulate obtained, an appropriate amount of a lubricating agent and, if necessary, a disintegrating agent, etc., is added and mixed, and then the mixture is filled into a capsule or subjected to compression molding to produce the solid formulation of the present invention.
[000199] It is also possible to obtain a sugar-coated pellet or a film-coated pellet using a more suitable coating agent.
[000200] Examples of a sugar base material include sugars or sugar alcohols such as white sugar and erythritol. In addition, one type or a combination of two or more types that are selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan and carnauba wax and the like can be used.
[000201] As a coating agent, examples thereof include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax and paraffin.
[000202] Examples of the base material for enteric film coating include cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethyl ethyl cellulose and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (registered trademark), Evonik Degussa Co., Ltd.), LD methacrylic acid copolymer [Eudragit L-30 D55 (registered trademark), Evonik Degussa Co., Ltd.] , methacrylic acid copolymer S [Eudragit S (registered trademark) and Evonik Degussa Co., Ltd.]; and natural products such as shellac.
[000203] Examples of the base material for extended release film coating include cellulose polymers such as ethyl cellulose; acrylate polymers such as amino alkyl methacrylate copolymer RS [Eudragit RS (trademark); Evonik Degussa Co., Ltd.], suspension of ethyl methacrylate ethylacrylate copolymer [Eudragit NE (registered trademark), Evonik Degussa Co., Ltd.]; and cellulose acetate.
[000204] The base material for coating can be used in combination of two or more types that are mixed in an appropriate ratio.
[000205] If necessary, a water-soluble substance and a plasticizer, etc., can be added to the coating agent to control the dissolution rate. Examples of the water-soluble substance include at least one selected from water-soluble polymers such as hydroxypropylmethyl cellulose, sugar alcohols such as mannitol, sugars such as white sugar and anhydrous maltose and surfactants such as sucrose fatty acid ester, polyoxyethylene polyoxypropylene glycol , polysorbate and sodium lauryl sulfate. Examples of the plasticizer that can be used include acetylated monoglyceride, trimethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain fatty acid triglyceride, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate, dibutyl adipate, acid oleic and oleanolic acid.
[000206] Also, as a method for coating a tablet with a coating layer, a method generally used in the field can be used and examples of it include coating with pan coating, fluid coating, tipping coating and coating with fluid tipping. In addition, the coating liquid used for such a method is obtained by mixing the base coating material as described above with the talc and the solvent (preferably ethanol or a mixture of ethanol and water). In addition, the concentration of solids in the coating liquid is within the range of 5 to 15% by weight with respect to the total mass of the coating liquid.
[000207] The method comprises a step of administering a pharmaceutically effective amount of a pharmaceutical composition containing the substance used in the present invention disclosed to an individual who is in need of treatment or in a condition having a disorder or symptom.
[000208] The substance used in the present invention has excellent ALK inhibitory activity and has excellent stability in a body and excellent solubility in water and is therefore useful as a prophylactic or therapeutic agent (in particular, a therapeutic agent) for a proliferative disorder. The compounds of the present invention or their pharmaceutically acceptable salts are useful as a prophylactic or therapeutic agent (in particular, a therapeutic agent) for disorders including leukemia (acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphatic leukemia and chronic lymphatic leukemia, etc.), malignant lymphoma (Hodgkin's lymphoma and Non-Hodgkin's lymphoma, etc.) and various cancers such as brain tumor, neuroblastoma, neuroglioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, cancer colorectal, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant myeloma, kidney cancer, pelvis-ureter renal cancer, urinary bladder cancer, ovarian cancer , uterine cancer, testicular cancer and prostate cancer. In addition, the compounds of the present invention are useful as a prophylactic or therapeutic agent (in particular, a therapeutic agent) for infiltration and metastasis of solid tumors. In addition, the substance used in the present invention is effective as a prophylactic or therapeutic agent for other disorders related to ALK, for example, depression and cognitive function disorder.
[000209] When the pharmaceutical composition of the present invention is used as an ALK inhibitor or a prophylactic or therapeutic agent for a proliferative disorder or depression and cognitive function disorder, the method of administration includes rectal, parenteral (intravenous, intramuscular and subcutaneous) administrations ), intracisternal, intravaginal, intraperitoneal, intravesical, topical (drops, powder, ointment, gel or cream) and inhalation (oral or nasal spray), etc. Examples of the form of administration include a tablet, a capsule, granules, powder, a pill, an aqueous or non-aqueous oral solution and suspension, and a non-oral solution that is filled into a container suitable for a small divided dose. In addition, the formulation can be adapted for various methods of administration including a release control regimen such as subcutaneous implantation, etc.
[000210] Preferably, it is an oral administration of a tablet, capsule, granules, powder, pill or the like.
[000211] The formulation of the present invention is produced according to a method well known in the art through the use of additives such as a filler, a lubricating agent (i.e., coating agent), a binding agent, a disintegrating agent , a stabilizing agent, a flavoring agent, a diluent and the like.
[000212] When the pharmaceutical composition of the present invention is used as an ALK inhibitor, or a prophylactic or therapeutic agent for a proliferative disorder or depression and cognitive function disorder, the amount used of the compounds of the present invention or their pharmaceutically acceptable salts varies depending on symptoms, age, body weight, relative health condition, presence of other medication and method of administration, etc.
[000213] When the pharmaceutical composition of the present invention is used as an ALK inhibitor or a prophylactic or therapeutic agent for a proliferative disorder or depression and cognitive function disorder, the amount used of the compounds of the present invention or its pharmaceutically acceptable salts or solvates of them varies depending on the symptoms, age, body weight, relative health condition, presence of other medication and method of administration, etc. For a patient (i.e., warm-blooded animal, in particular human), the generally effective amount is, in terms of the active ingredient (i.e., the compounds of the present invention that are represented by Formula (I)), preferably 0.001 to 1000 mg per kg body weight per day and more preferably 0.01 to 300 mg per kg body weight per day for an orally administrable formulation, for example. The daily dosage is preferably in the range of 1 to 800 mg for an adult patient with normal body weight. In the case of a parenteral formulation, it is preferably 0.001 to 1000 mg per kg of body weight per day and more preferably 0.01 to 300 mg per kg of body weight per day. It is preferably administered once or, in a divided dose, several times a day, depending on the symptoms.
[000214] Furthermore, the pharmaceutical composition of the present invention can be combined with other chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeting agents or the like.
[000215] Examples of "chemotherapeutic agents" include an alkylating agent, a platinum formulation, a metabolic antagonist, a topoisomerase inhibitor, an anti-cancer antibiotic substance and a plant-derived anticancer agent, etc. Examples of the "alkylating agent" include mustard nitrogen, mustard nitrogen N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacharbazine, ranacustazine estramustine sodium, triethylene melamine, carmustine, lomustine, streptozocin, pipobroman, etoglucide, altretamine, ambamustine, dibrospid hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trosulfone, trosulfine, trophosamine Examples of the "platinum formulation" include carboplatin, cisplatin, miboplatin, nedaplatin and oxaliplatin. Examples of the "metabolic antagonist" include mercaptopurine, riboside 6-mercaptopurine, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ochosphate, ancitabine hydrochloride, 5-FU-based pharmaceutical agents (e.g., fluoruracil, tegafururine, UFT, , galocitabine and emitefur, etc.), aminopterin, calcium leucovorin, tabloid, butocin, calcium folinate, calcium levofolinate, cladribine, emitefur, fludarabine, gemcitabine, hydrocicarbamide, pentostatin, pyridoxine ,idoxuridine, tiaxuridine, amboxyazurine, tiaxuridine, tiaxururine and tiaxurazine Topoisomerase I inhibitor (for example, irinotecan and topotecan, etc.), topoisomerase II inhibitor (for example, sobuzoxane, etc.). Examples of "anti-cancer antibiotic material" include anthracycline-based anti-cancer agent (doxorubicin hydrochloride, daunorubicin hydrochloride, acrarubicin hydrochloride, pyrarubicin hydrochloride and epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, chromomycin A3 bleomycin, bleomycin sulfate, peplomycin sulfate, neocarzinostatin, mitramycin, sarcomycin, carzinophylline, mitotam, zorubicin hydrochloride, mitoxantrone hydrochloride and idarubicin hydrochloride, etc. Examples of the "plant-derived anticancer agent" include vinccalcaloid anticancer agent (vinblastine sulfate, vincristine sulfate and vindecine sulfate), taxane anticancer agent (paclitaxel and docetaxel, etc.), etoposide, etoposide phosphate, teniposide and vinorrelbine.
[000216] Examples of "therapeutic hormonal agents" include pharmaceutical agents based on adrenocortical hormone (for example, dexamethasone, prednisolone, betamethasone and triamcinolone, etc.). Of these, prednisolone is preferable.
[000217] Examples of the "immunotherapeutic agents (BRM)" include picibanil, crestine, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, lymphotoxin, BCG vaccine, Corynebacterium parum , levamisole, polysaccharide K and procodazole.
[000218] "Molecular targeting agents" include a "pharmaceutical agent that inhibits the function of a cell proliferating factor and its receptor" or similar. Examples of the "cell proliferation factor" can be any substance if it alone can promote proliferation of a cell and a peptide having a molecular weight of 20,000 or less is included that exhibits its activity in low concentration through binding to a receptor. Specific examples of the same include (1) EGF (epidermal growth factor) or a substance that has substantially the same activity [eg EGF, heregulin (HER2 ligand), etc.], (2) insulin or a substance that has substantially the same activity [for example, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.], (3) FGF (fibroblast growth factor) or a substance that has substantially the same activity [for example , Acid FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, etc.], (4) VEGF (vascular endothelial growth factor), (5) other factors of cell proliferation [for example, CSF (factor colony stimulation), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF ( hepatocyte growth factor), etc.], etc.
[000219] The "receptor for cell proliferation factor" can be any receptor if only it has an ability to bind to the cell proliferation factor described above. Specific examples thereof include an EGF receptor, heregulin receptor (HER2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, HGF receptor (c-met), VEGF receptor and SCF receiver (c-kit). Examples of "pharmaceutical agents that inhibit cell proliferation factor activity" include herceptin (HER2 antibody), GLEEVEC (c-kit, abl inhibitor) and Iressa (GF receptor inhibitor).
[000220] Also, a pharmaceutical agent that inhibits the activity of a plurality of cell proliferation factors even as a simple formulation or a pharmaceutical agent that blocks the cellular signal produced by the cell proliferation factor are also included.
[000221] In addition to the pharmaceutical agents described above, L-asparaginase, aceglaton, procarbazine hydrochloride, protoporphyrin complex • cobalt, mercury hematoporphyrin • sodium, differentiation promoting agent (eg retinoid, vitamin D, etc.), angiogenesis inhibitor and α-blocker (eg, tamsulosin hydrochloride, etc.), etc. can also be used.
[000222] Among the above, preferred examples of a concomitant remedy include a platinum complex (for example, carboplatin, cisplatin and oxaliplatin, etc.), taxane-based pharmaceutical agents (for example, paclitaxel and docetaxel), topoisomerase I inhibitor ( eg irinotecan and topotecan, etc.), vinorelbine, gemcitabine, an anti-cancer antibiotic material (eg mitomycin C) and a molecular targeting agent (eg VEGF inhibitor), etc. In addition, they can be used in combination with combination therapy for said pharmaceutical agents. For example, coadministration with combination therapy such as cisplatin and vinblastine and mitonicin C, cisplatin and vinorelbine, cisplatin and paclitaxel, cisplatin and gemcitabine and carboplatin and paclitaxel, etc., can be mentioned.
[000223] The time for administration of the solid formulation of the present invention and a pharmaceutical agent for co-administration is not limited. They can be administered to an individual or simultaneously or at intervals of time. In addition, the solid formulation of the present invention and a pharmaceutical agent for co-administration can be administered to an individual in the form of a single formulation comprising both. For example, there is multidrug combination therapy through which a plurality of pharmaceutical agents are instilled over a period of 3 to 6 months and a method of ingesting an oral formulation for approximately two years.
[000224] Also, in order to prevent recurrence caused by metastasis through inhibiting cancer cells already spreading or to limit an area for operation, a preoperative adjuvant therapy such as "chemical therapy" can be performed before the operation is performed .
[000225] Also, when topical treatment such as surgery or radiation is not sufficient, in order to prevent recurrence caused by metastasis by inhibiting the growth of remaining cancer cells, a post-operative adjuvant therapy such as "chemical therapy" can be fulfilled.
[000226] However, the anticancer agent used in combination also exhibits its activity on normal cells as well as cancer cells, thereby showing a side effect. Representative examples of the side effect include nausea, vomiting, lack of appetite, stomatitis, diarrhea or constipation and dysgeusia due to mucosal disease in the digestive organ and reduction in leukocyte • erythrocyte • blood platelet, affects and reduced immunity due to bone marrow disorder. In this way, a pharmaceutical agent for reducing a side effect such as these can also be used in combination. Examples of the same include an anti-hemetic pharmaceutical agent that can effectively inhibit nausea (eg, granisetron hydrochloride salt) or a pharmaceutical agent to promote recovery from a bone marrow disorder (eg, erythropoietin, G-SCF and GM -CSF).
[000227] The dosage of the pharmaceutical agent for co-administration can be appropriately selected with reference to the dosage that is clinically used. In addition, the mixing ratio between the solid formulation of the present invention and the pharmaceutical agent for coadministration can be appropriately selected depending on the individual for administration, route of administration, disease to be treated, symptoms and combination, etc. When the subject for administration is a human, the pharmaceutical agent for co-administration can be used in an amount of 0.01 to 100 parts by weight with respect to 1 part by weight of the solid formulation. Example
[000228] Below, the present invention will be explained in more detail in view of the examples and test examples that follow. However, the present invention is not limited by these examples. NMR analysis
[000229] NMR analysis was performed using JNM-EX270 (270 MHz, manufactured by JEOL), JNM-GSX400 (400 MHz, manufactured by JEOL) or 400 MR (400 MHz, manufactured by Varian). NMR data were expressed in ppm (parts per million; δ), while being compared with the deuterium blocking signal obtained from a sample solvent. Mass spectrometry
[000230] The measurement was performed using JMS-DX303 or JMS-SX / SX102A (both manufactured by JEOL).
[000231] Mass spectrometry data equipped with high performance liquid chromatography (LC-MS).
[000232] The measurement was performed using Micromass (ZMD, manufactured by Micromass) equipped with 996-600E gradient high performance liquid chromatography (manufactured by Waters) or Micromass (ZQ, manufactured by Micromass) equipped with high performance liquid chromatography of gradient 2525 Waters (manufactured by Waters).
[000233] One of the following conditions that are described in Table 1 below was taken as a condition for high performance liquid chromatography. Table 1

[000234] Commercially available reagents were used without further purification. The ambient temperature indicates the temperature range of about 20 to 25 ° C. The entire non-aqueous reaction was carried out in an anhydrous solvent under an atmosphere of nitrogen or argon. For concentration under reduced pressure or removal of a solvent by distillation, a rotary evaporator was used.
[000235] Below, production examples for the substances that are used in the present invention as represented by Formula (I) are given. Reference Example 1 Compound J2 6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

[000236] Under the same conditions as the method for synthesis of compound B1 (7-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 209 g, 1.18 mol), hydrogen sulfate tetrabutylammonium (40 g, 0.118 mol) and methyl iodide (162 g, 2.60 moles) were suspended in THF (500 ml) at room temperature, while stirring, the mixture was added with 50% aqueous potassium hydroxide solution ( 400 g) for 5 minutes Reflux occurred as the internal temperature rapidly increased Once the internal temperature had stopped rising, stirring was continued for 45 minutes The reaction solution was diluted with distilled water (1 L) and extracted twice with CPME (1.5L). The combined organic layer was washed (1 L x 3 distilled water), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was recrystallized with MeOH (1 L) and distilled water (500 ml) to obtain Compound B1 (7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one) as a needle-like crystal colorless (177 g, 73%) and the title compound was synthesized from 6-methoxy-3,4-dihydro-1H-naphthalene-2-one and iodomethane. LCMS: m / z 205 [M + H] + HPLC retention time: 1.54 minutes (analysis condition S) Reference example 2 Compound J3-1 9-Methoxy-6,6-dimethyl-6,11- dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000237] With the same conditions as the synthesis of Compound E2-1 (6-bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (7.89 g , 27.85 mmoles) and 3-hydrazino-benzonitrile (4.45 g, 1.2 eq.) Were dissolved in TFA (250 mL) and stirred at 100 ° C for 2 hours TFA was removed by concentration under pressure After that, the residues were added with saturated aqueous NaHCO3 solution (500 mL) and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried over sodium sulfate. After filtering the drying agent, the residues obtained after concentration under reduced pressure were added with ethyl acetate, stirred at room temperature and the precipitated solid was filtered through the concentration of the filtrate under reduced pressure, compound E2-1 (9-bromo-8-methoxy-6.6 -dimethyl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile) (yellowish white powder, 2.65 g) was obtained as a mixture with Compound E2-2 (9-bromo-8 -methoxy-6,6-dimethyl-6, 11-dihydro-5H-benzo [b] carbazol-1-carbonitrile), the title compound was synthesized from Compound J2 and 3-hydrazino-benzonitrile. LCMS: m / z 303 [M + H] +
[000238] HPLC retention time: 2.73 minutes (analysis condition S) Reference example 3 Compound J3-2 9-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo [b ] carbazol-1-carbonitrile

[000239] Compound J3-2 was obtained as a by-product of the synthesis of compound J3-1. LCMS: m / z 303 [M + H] +
[000240] HPLC retention time: 2.67 minutes (analysis condition S) Production example 1 Compound J4 9-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000241] Under the same conditions as the method for synthesis of Compound A4, the title compound was synthesized from Compound J3-1 and compound J3-2 (mixture).
[000242] 1H-NMR (DMSO-d6) δ: 12.79 (1 H, s), 8.33 (1 H, d, J = 8.2 Hz), 8.02 (1 H, s), 7.81 (1 H, d, J = 8.6 Hz), 7.69 (1 H, d, J = 3.0 Hz), 7.63 (1 H, dd, J = 8.3, 1 , 4 Hz), 7.28 (1 H, dd, J = 8.7, 3.0 Hz), 3.87 (3 H, s), 1.74 (6 H, s). LCMS: m / z 317 [M + H] +
[000243] HPLC retention time: 2.25 minutes (analysis condition S) Production example 2 Compound J5 9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000244] Under the same conditions as the method for synthesis of compound A6, the title compound was synthesized from compound J4.
[000245] 1H-NMR (DMSO-d6) δ: 12.75 (1 H, s), 9.77 (1 H, s), 8.32 (1 H, dd, J = 8.2, 0, 7 Hz), 8.01 (1 H, s), 7.68 (1 H, d, J = 8.6 Hz), 7.62 (1 H, dd, J = 8.2, 1.4 Hz ), 7.58 (1H, d, J = 2.8 Hz), 7.10 (1 H, dd, J = 8.6, 2.8 Hz), 1.72 (6 H, s). LCMS: m / z 303 [M + H] +
[000246] HPLC retention time: 1.75 minutes (analysis condition S) Production example 3 Compound J6 3-Cyano-6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-9-yl ester of trifluoromethanesulfonic acid

[000247] Under the same conditions as the method for synthesis of compound B1, the title compound was synthesized from Compound J5.
[000248] 1H-NMR (DMSO-d6) δ: 12.95 (1 H, s), 8.31 (1 H, d, J = 8.2 Hz), 8.15 (2 H, m), 8.05 (1 H, s), 7.87 (1 H, dd, J = 9.0, 2.7 Hz), 7.65 (1 H, d, J = 8.2 Hz), 1, 80 (6 H, s). LCMS: m / z 435 [M + H] +
[000249] HPLC retention time: 2.75 minutes (analysis condition S) Production example 4 Compound J7-4 9- (4-Isopropyl-piperazin-1-yl) -6,6-dimethyl-11 -oxo -6.11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000250] Under the same conditions as the method for synthesis of compound B2-10, (3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] - carbazol-8 -il) trifluoro-methane sulfonic acid ester (Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane (1 mL), added with thiomorpholine 1,1-dioxide (19 mg, 2 eq.) , Pd2dba3 (6.3 mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) And K3PO4 (29 mg, 2 eq.) And stirred at 100 ° C all night and day whole. The reaction solution was poured into water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate / hexane) to obtain Compound B2-10 (8- (1,1 - dioxothiomorpholino) -6,6-dimethyl-11 -oxo- 6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (white powder, 2.1 mg, 7%)), the title compound was synthesized from Compound J6 and 1-isopropyl-piperazine.
[000251] 1H-NMR (270 MHz, DMSO-d6) δ: 12.80 (1 H, s), 8.33 (1 H, d, J = 7, 6 Hz), 8.02 (1 H, s), 7.66 (3 H, m), 7.33 (1 H, d, J = 8.2 Hz), 3.21 (4 H, broad), 2.66 (5 H, m), 1.72 (6 H, s), 1.02 (6 H, d, J = 6.3 Hz). LCMS: m / z 413 [M + H] + HPLC retention time: 1.38 minutes (analysis condition S) Reference example 4 Compound A2 7-Methoxy-1,1-dimethyl-3,4-di- hydro-1H-naphthalen-2-one

[000252] 7-Methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 209 g, 1.18 mol), tetrabutylammonium hydrogen sulfate (40 g, 0.118 mol) and iodide methyl (162 g, 2.60 mol) were suspended in THF (500 ml) at room temperature. With stirring, the mixture was added with 50% aqueous potassium hydroxide solution (400 g) over 5 minutes. The reflux occurred as the internal temperature rapidly increased. As soon as the internal temperature stopped rising, stirring was continued for 45 minutes. The reaction solution was diluted with distilled water (1 L) and extracted twice with CPME (1.5 L). The combined organic layer was washed (1 L x 3 distilled water), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was recrystallized from MeOH (1 L) and distilled water (500 ml) to obtain the title compound as a colorless needle-like crystal (177 g, 73%).
[000253] 1H-NMR (400 MHz, CDCh) δ: 1.43 (6 H, s), 2.65 (2 H, t, 12 Hz), 3, 02 (2 H, t, 12 Hz), 3.79 (3 H, s), 6, 74 (1 H, m), 6, 87 (1 H, m), 7, 24 (1 H, m). LCMS: m / z 205 [M + H] + Reference example 5 Compound A3-1, Compound A3-2 3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo [b] carbazole 1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo [b] carbazole

[000254] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 66.2 g, 324 mmol) and 3-bromophenylhydrazine hydrochloric acid salt ( 71.0 g, 318 mmol) were dissolved in AcOH (350 ml) and refluxed with stirring for 6 hours. The reaction solvent was removed by distillation under reduced pressure to obtain the crude product as a mixture of the title compounds A3-1 and A3-2. Production example 5 Compound A4 3-Bromo-8-methoxy-6,6-dimethyl- 5,6-dihydrobenzo [b] carbazole-11-one

[000255] The crude product obtained from the above (i.e. mixture of A3-1 and A3-2) was dissolved in a mixture solvent of THF (450 ml) and distilled water (50 ml), added once with DDQ ( 115 g, 509 mmol) and then stirred at room temperature for 1 hour. The reaction mixture was diluted with CPME (3L) and the organic layer was washed three times with 0.5 N aqueous sodium hydroxide solution (1 L) and twice with distilled water (1 L) in order and dried over sulfate anhydrous sodium. The organic layer was concentrated to 500 ml under reduced pressure. The precipitated product was collected by filtration and washed with a small amount of CPME to obtain the title compound as a yellow crystal (48 g, 40%).
[000256] 1H-NMR (400 MHz, DMSO-d6) δ: 1, 73 (6 H, s), 3, 90 (3 H, s), 7, 06-7, 09 (1 H, m), 7, 32-7, 38 (2 H, m), 7, 65-7, 66 (1 H, m), 8, 09- 8.17 (2 H, m), 12, 32 (1 H, s broad). LCMS: m / z 370, 372 [M + H] + Production example 6 Compound A5-2 8-Methoxy-6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000257] 3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo [b] carbazole-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper cyanide (I) (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml), followed by stirring at 170 ° C for 17 hours. The reaction mixture was suspended in ethyl acetate (500 ml) and distilled water (200 ml). Insoluble matter was removed by filtration through Celite and washed with ethyl acetate (300 mL x 2). The organic layer was washed once with an aqueous solution of disodium EDTA (200 ml) and twice with saturated brine (200 ml) in order and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to produce a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (6.58 g, 73%).
[000258] 1H-NMR (400 MHz, DMSO-d6) δ: 1.71 (6 H, s), 3.89 (3 H, s), 7.07-7.09 (1 H, m), 7.34 (1 H, s), 7.58-7.60 (1 H, m), 7.99 (1 H, s), 8.14 - 8.16 (1 H, m), 8, 30-8.32 (1 H, m), 12.32 (1 H, wide s), LCMS: m / z 317 [M + H] + HPLC retention time: 2.56 minutes (U analysis condition ) Production example 7 Compound A6 8-Hydroxy-6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000259] 8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (Compound A5-2, 6.58 g, 20.8 mmol) was dissolved in pyridine hydrochloric acid salt (25.0 g) and stirred at 170 ° C for 13 hours. The reaction mixture was partitioned between ethyl acetate (400 ml) and distilled water (400 ml), and the aqueous layer was extracted once more with ethyl acetate (400 ml). The combined organic layer was washed twice with distilled water (100 ml) and once with saturated brine (100 ml) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to produce a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (5.91 g, 93%).
[000260] 1H-NMR (400 MHz, DMSO-d6) δ: 1.73 (6 H, s), 6.87-6.90 (1 H, m), 7.11 (1 H, s), 7.57-7.59 (1 H, m), 7.97 (1 H, s), 8.04-8.06 (1H, m), 8.29-8.31 (1 H, m) , 10.27 (1 H, s), 12.66 (1 H, s wide), LCMS: m / z 303 [M + H] + Production Example 8 Compound B1 3-cyano-6,6-dimethyl- 11 -oxo-6,11 -dihydro-5H-benzo [b] carbazol-8-yl ester of trifluoromethanesulfonic acid

[000261] 8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL), added with anhydrous trifluoromethanesulfonic acid (0.758 mL, 3 eq.) And stirred at room temperature for 30 minutes. The reaction solution was added to the water and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the target compound (white powder, 641 mg, 81%).
[000262] 1H-NMR (400 MHz, DMSO-d6) δ: 12.89 (1 H, wide s), 8.36 (1 H, d, J = 8.8 Hz), 8.31 (1 H , dd, J = 8.1, 0.7 Hz), 8.11 (1 H, d, J = 2.3 Hz), 8.04 (1 H, dd, J = 1.5, 0.7 Hz), 7.65-7.60 (2 H, m), 1.76 (6 H, s) LCMS: m / z 435 [M + H] + HPLC retention time: 3.10 minutes (condition analysis U) Production example 9 Compound B2-22-1 4- (3-cyano-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo acid tert-butyl ester [b ] carbazol-8-yl) -3,6-dihydro-2H-pyridine-1-carboxylic

[000263] A 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yl ester of trifluoromethanesulfonic acid (Compound B1, 7 , 80 g, 18.0 mmol), 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -3,6-dihydro tert-butyl ester -2H-pyridine-1-carboxylic (6.11 g, 19.8 mmol, 1.1 eq.), Pd (PPh3) 2Cl2 (630 mg, 0.898 mmol, 0.05 eq.) And sodium carbonate (5 , 71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and water (25 ml) were added. The mixture was subjected to reduced pressure under ultrasonic treatment, followed by nitrogen filling. This procedure was repeated five times to remove air. After further stirring at 80 ° C for 2 hours under a nitrogen atmosphere, the mixture was cooled to room temperature, added with water (250 ml) and further stirred for 30 minutes. The precipitates were filtered and washed with water (50 ml). They were also washed with CH3CN (50 ml) to obtain the target compound as a crude product (gray powder, 7.54 g, 90%). LCMS: m / z 468 [M + H] + HPLC retention time: 2.90 minutes (analysis condition S) Production example 10 Compound B3-13-1 4- (3-cyano acid tert-butyl ester) -6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-8-yl) -piperidine-1-carboxylic

[000264] 4- (3-cyano-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-8-yl) -3,6 tert-Butyl ester -dihydro-2H-pyridine-1-carboxylic (Compound B2-22-1, 16.2 g, 34.6 mmol) was dissolved in THF (800 ml) and methanol (230 ml), added with 10% by weight of Pd / C (3.2 g) and stirred under a hydrogen atmosphere for 19 hr. The solid was filtered through Celite, eluted with a mixing solvent (400 ml; THF / methanol = 4/1) and concentrated under reduced pressure. The residues were dissolved in ethyl acetate (400 ml) and then washed with 1% aqueous solution of N-acetylcysteine, saturated aqueous NaHCO3 solution and saturated brine. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the title compound as a crude product (white powder, 14.0 g, 86%). LCMS: m / z 470 [M + H] + HPLC retention time: 2.88 minutes (analysis condition S) Production example 11 Compound B3-13-2 6,6-Dimethyl-11 -oxo-8- piperidin-4-yl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000265] Under the same conditions as the method for synthesis of compound A8-1 (THF (0.5 ml) and TFA (0.5 ml) were added to 4- (3-cyano-6 acid tert-butyl ester), 6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yloxy) -piperidine-1-carboxylic (Compound A7-1, 35 mg, 0.072 mmol) and the mixture was stirred at room temperature until Compound A7-1 disappeared.The reaction solution was concentrated under reduced pressure and the residue was desalted using PL StratoSpheres (trademark) anion exchange resin PL-HCO3 MP to obtain Compound A8-1 ( 37 mg, 76%)), the title compound was synthesized from Compound B3-13-1. LCMS: m / z 370 [M + H] + HPLC retention time: 1.30 minutes (analysis condition S) (Production example 12) Compound B4-8 6,6-Dimethyl-8- (1 -oxetan- 3-yl-piperidin-4-yl) -11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000266] Under the same conditions as the method for synthesis of compound B3-32 (morpholine (6 μl, 1.5 eq.) And sodium triacetoxy borohydride (81 mg, 2.0 eq.) Were added to the THF solution ( 1 ml) of Compound B2-29: 8-formyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] -carbazol-3-carbonitrile (30 mg, 0.095 mmol) and stirred at room temperature for 1 hour The reaction solution was filtered to remove insoluble matter Residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain Compound B3-32 (6.6-dimethyl -8-morpholin-4-ylmethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile) (19 mg, 50%)), the title compound was synthesized from Compound B3-13-2 and oxetan-3-one.
[000267] 1H-NMR (400 MHz, DMSO-d6) δ: 12.74 (1 H, s), 8.32 (1 H, d, 7.9 Hz), 8.13 (1 H, d, 7.9 Hz), 8.00 (1 H, s), 7.74 (1 H, s), 7.61 (1 H, d, 9.8 Hz), 7.40 (1 H, d, 7.9 Hz), 4.56 (2 H, t, 6.7 Hz), 4.46 (2 H, t, 6.1 Hz), 3.46-3.39 (1 H, m), 2.85-2.82 (2 H, m), 2.71-2.64 (1 H, m), 1.92-1.86 (2 H, m), 1.82-1.79 ( 4 H, m), 1.77 (6 H, s) LCMS: m / z 426 [M + H] + HPLC retention time: 1.53 minutes (S analysis condition) Compound B4- sulfate salt 8
[000268] 6,6-Dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile it was dissolved at 80 ° C in a mixture of 5 w / v DMA and 1.4 w / v 2N sulfuric acid. After cooling to room temperature, 15 w / v acetone was added in drops and the precipitated solids were filtered and dried to obtain 6,6-dimethyl-8- (1-oxetan-3-yl-piperidinyl) sulfuric acid salt 4-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile.
[000269] 1H-NMR (400 MHz, DMSO-d6) δ: 12.81 (1H, s), 10.26 (1H, broad s), 8.33 (1H, d, 8.3Hz), 8, 21 (1H, d, 8.3Hz), 8.04 (1H, s), 7.75 (1H, s), 7.63 (1H, d, 8.3Hz), 7.41 (1H, d, 8.3Hz), 4.85-4.70 (4H, m), 4.50-4.40 (1H, wide s), 3.60-3.00 (6H, wide m), 2.20- 2.10 (2H, m), 2.05-1.90 (2H, m), 1.79 (6H, s) LCMS: m / z 426 [M + H] + Hydrochloride salt B4-8
[000270] B4-8 was dissolved in 5 w / v dimethyl sulfoxide and 0.41 w / v aqueous hydrochloric acid solution (6 N) and then the dissolved solution was subjected to freeze drying. To the freeze-dried product, a mixture of 3.7 w / v water and 1.3 w / v acetonitrile was added. After stirring at room temperature all night and all day, the precipitated crystals were filtered and dried to give the B4-8 monohydrochloride salt. B4-8 mesylate salt
[000271] B4-8 was dissolved in 4 w / v of dimethyl sulfoxide and 1.2 v / w of aqueous solution of mesyl acid (2 N) and then the dissolved solution was subjected to freeze drying. To the freeze-dried product, 0.1 v / w of water and 5 v / w of ethyl acetate were added. After stirring at room temperature all night and all day, the precipitated crystals were filtered and dried to give the B4-8 monomesylate salt. B4-8 L-tartrate salt
[000272] B4-8 and L-tartaric acid, which is added in an amount of 0.81 times the weight of B4-8, were dissolved in 10 v / w tetrahydrofuran and 2 w / v water at 80 ° C The dissolved solution was added with 30 v / w of ethanol. The mixture was stirred at room temperature all night and all day and the precipitated crystals were filtered and dried to give the B4-8 hemi-L-tartrate salt. The obtained B4-8 hemi-L-tartrate salt. was sprayed using a jet grinder. B4-8 phosphate salt
[000273] B4-8 was dissolved in 14 v / w of N, N-dimethylacetamide and 5.9 v / w of aqueous phosphoric acid solution (2 N) under reflux with heating. The dissolved solution was added with 43 v / w of ethanol. The mixture was stirred at room temperature all night and all day and the precipitated crystals were filtered and dried to give the B4-8 monophosphate salt. The obtained B4-8 monophosphate salt was sprayed using a jet grinder. Production example 13 Compound F5-22 6,6-Dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11 -oxo-9-prop-1-inyl-6,11 -di- hydro-5H-benzo [b] carbazol-3-carbonitrile

[000274] The compound E4-2-1 (9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), bis (acetonitrile) dichloropalladium (II) (1.64 mg, 0.05 eq.), Xphos (9.05 mg, 0.15 eq.), cesium carbonate (185 mg, 4.5 eq.) and 3-methyl-1-butin-1-ol (18.6 μl, 1.5 eq.) were dissolved in acetonitrile and stirred at 85 ° C for 2 hours The reaction solution was poured into water and then extracted with ethyl acetate The organic layer was washed with aqueous sodium chloride solution and dried over sodium sulfate The drying agent was removed by filtration and the residue obtained after concentration under reduced pressure was purified by HPLC and under the same conditions as in the method for the synthesis of Compound E4-2-1 (9- (3-hydroxy-3-methyl-but-1-ynyl) -8-methoxy- 6 , 6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile) (brown solid, 21.3 mg, 42%)), the title compound was synthesized from of compound F4-3 and kickback.
[000275] 1H-NMR (400 MHz, CD3OD) δ: 8.37 (1 H, d, J = 8.2 Hz), 8.18 (1 H, s), 7.84 (1 H, s) , 7.53 (1 H, d, J = 8.2 Hz), 7.19 (1 H, s), 4.70-4.77 (2 H, m), 4.62-4.68 ( 2 H, m), 3.57-3.63 (1 H, m), 3.38-3.45 (4 H, m), 2.54-2.61 (4 H, m), 2, 10 (3 H, s), 1.79 (6 H, s) LCMS: m / z 465 [M + H] + HPLC retention time: 1.90 minutes (U analysis condition) Production example 14 Compound F5-25 9-Cyclopropylethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) - 11 -oxo-6,11-dihydro-5H-benzo [b] carbazole -3-carbonitrile

[000276] Under the same conditions as the method for synthesis of compound E4-2-1, the title compound was synthesized from compound F4-3 and ethynylcyclopropane.
[000277] 1H-NMR (270 MHz, DMSO-d6) δ: 12.74 (1 H, broad s), 8.32 - 8.29 (1 H, d, 8.08 Hz), 8.05 ( 1 H, s), 8.00 (1 H, s), 7.62-7.58 (1 H, m), 7.21 (1 H, s), 4.62-4.57 (2 H , m), 4.51-4.47 (2 H, m), 3.53-3.48 (1 H, m), 3.34 (4 H, m), 2.46 (4 H, m ), 1.76 (6 H, s), 1.64-1.58 (1 H, m), 0.97-0.89 (2 H, m), 0.76-0.70 (2 H , m) LCMS: m / z 491 [M + H] + Reference example 6 Compound E1 6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

[000278] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH3CN (40 mL), added with NBS (1.92 g, 1.1 eq.) and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was added to the water (40 ml) and the precipitated solid was filtered to obtain the title compound (white powder, 2.55 g, 92%). 1H-NMR (270 MHz, CDCl3) δ: 7.36 ( 1 H, s), 6.84 (1 H, s), 3.91 (3 H, s), 3.02 (2 H, t, J = 6.8 Hz), 2.66 (2 H, t, J = 6.8 Hz), 1.42 (6 H, s). LCMS: m / z 283, 285 [M + H] + HPLC retention time: 2.67 minutes (analysis condition S) Reference example 7 Compound E2-1 9-Bromo-8-methoxy-6,6- dimethyl-6,11 -dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000279] 6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound E1, 7.89 g, 27.85 mmol) and 3-hydrazine -benzonitrile (4.45 g, 1.2 eq.) were dissolved in TFA (250 ml) and stirred at 100 ° C for 2 hours. TFA was removed by concentration under reduced pressure and the residues were added with saturated aqueous NaHCO3 solution (500 ml), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was filtered off (Compound E2-2). The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with E2-2 (yellowish white powder, 2.65 g). LCMS: m / z 381, 383 [M + H] + HPLC retention time: 3.03 minutes (analysis condition S) Production example 15 Compound E3-1-1 9-Bromo-8-methoxy-6.6 -dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000280] Under the same conditions as the method for synthesis of compound A4, the title compound was synthesized from compound E2-1.
[000281] 1H-NMR (270 MHz, DMSO-d6) δ: 12.82 (1 H, s), 8.30 (2 H, s + d), 8.03 (1 H, s), 7, 61 (1 H, dd, J = 8.2, 1.4 Hz), 7.49 (1 H, s), 4.04 (3 H, s), 1.81 (6 H, s). LCMS: m / z 395, 397 [M + H] + HPLC retention time: 2.77 minutes (analysis condition S) Production example 16 Compound E3-2 9-Bromo-8-hydroxy-6,6- dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000282] 9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (Compound E3-1-1, 1, 0 g, 2.53 mmol) was dissolved in NMP (10 ml), added with NaOMe (683 mg, 5 eq.) And 1-dodecanethiol (3.0 ml, 5 eq.) And stirred at 160 ° C for 1 hour. The reaction solution was added to the 0.5 N aqueous hydrochloric acid solution and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH and the remaining solid after dissolution was filtered to obtain the title compound (yellow powder, 1.88 g, 65%).
[000283] 1H-NMR (400 MHz, DMSO-d6) δ: 12.77 (1 H, s), 11.13 (1 H, d, J = 2.4 Hz), 8.31 (1 H, dd, J = 7.9, 2.4 Hz), 8.25 (1 H, d, J = 3.0 Hz), 8.01 (1 H, s), 7.61 (1 H, d, J = 7.9 Hz), 7.28 (1 H, d, J = 2.4 Hz), 1.74 (6H, s). LCMS: m / z 381, 383 [M + H] + HPLC retention time: 2.40 minutes (analysis condition S) Production example 17 Compound F2 9-bromo-3-cyano-6,6-dimethyl- 11 -oxo-6,11 -dihydro-5H-benzo [b] carbazol-8-yl trifluoromethanesulfonic acid ester

[000284] Under the same conditions as the method for synthesis of compound B1, the title compound synthesized from compound E3-2.
[000285] 1H-NMR (270 MHz, DMSO-d6) δ: 12.99 (1 H, s), 8.51 (1 H, s), 8.31 (1 H, dd, J = 8.2 , 0.7 Hz), 8.17 (1 H, s), 8.07 (1 H, s), 7.67 (1 H, dd, J = 8.2, 1.4 Hz), 1, 81 (6 H, s). LCMS: m / z 513, 515 [M + H] + HPLC retention time: 3.13 minutes (analysis condition S) Production example 18 Compound F3-9 9-Bromo-6,6-dimethyl-11 - oxo-8-piperazin-1-yl-6,11 -dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000286] Under the same conditions as the method for synthesis of Compound B2-1, Compound B2-1 (3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b ] carbazol-8-yl ester of trifluoromethane sulfonic acid) (Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml) and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at 120 ° C for 3 hours. After cooling to room temperature, purification was performed by HPLC to give Compound B2-1 (8- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11 -oxo-6,11 -di- hydro-5H-benzo [b] carbazol-3-carbonitrile) (white powder, 12.8 mg, 34%)) and the title compound was synthesized from compound F2 and piperazine.
[000287] 1H-NMR (DMSO-d6) δ: 8.30-8.24 (2 H, m), 8.00 (1 H, s), 7.63-7.58 (1 H, m) , 7.37 (1 H, s), 3.10-3.01 (4 H, m), 2.91-2.85 (4 H, m), 1.76 (6 H, s) LCMS: m / z 449, 451 [M + H] + HPLC retention time: 1.45 minutes (analysis condition S) Production example 19 Compound F4-3 9-Bromo-6,6-dimethyl-8- (4 -oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000288] Under the same conditions as Compound B3-32, the title compound was synthesized from compound F3-9 and 1-oxetan-3-one.
[000289] 1H-NMR (270 MHz, DMSO-d6) δ: 12.83 (1 H, broad s), 8.31-8.32 (1 H, m), 8.27-8.29 (1 H, m), 8.01-8.04 (1 H, m), 7.59-7.64 (1 H, m), 7.48 (1 H, s), 4.59 (2 H, dd, J = 6.3, 6.3 Hz), 4.48 (2 H, dd, J = 6.3, 6.3 Hz), 3.52 (1 H, t, J = 6.3 Hz ), 3.12-3.25 (4 H, m), 2.44-2.54 (4 H, m), 1.78 (6 H, s). LCMS: m / z 505, 507 [M + H] + HPLC retention time: 1.45 minutes (analysis condition S) Hydrochloride salt of compound F4-3
[000290] 9-Bromo-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole -3-carbonitrile was added with 1.05 eq. of 6N hydrochloric acid and DMSO and dissolved in them. After freeze drying, the mixture was crystallized from ethanol comprising 25% water to obtain 9-bromo-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-) monohydrochloride salt il) -11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile.
[000291] 1H-NMR (270 MHz, DMSO-d6) δ: 12.91 (1 H, wide s), 11.70 (1 H, wide s), 8.32-8.29 (2 H, m ), 8.04 (1 H, s), 7.64-7.62 (1 H, m), 7.52 (1 H, s), 4.89-4.62 (4 H, wide m) , 3.66-3.39 (1 H, m), 3.31 3.05 (8 H, wide m), 1.81 (6 H, s) LCMS: m / z 505, 507 [M + H] + Production example 20 Compound F4-9 9-Bromo-8- (4-cyclopropyl-piperazin-1-yl) -6,6-dimethyl-11 -oxo- 6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000292] Under the same conditions as the method for synthesis of compound B3-32, the title compound was synthesized from compound F3-9 and (1-ethoxy-cyclopropoxy)-trimethylsilane.
[000293] 1H-NMR (270 MHz, DMSO-d6) δ: 8.22-8.30 (2 H, m), 8.00 (1 H, s), 7.56 (1 H, d, J = 7.9 Hz), 7.43 (1 H, s), 3.30 (1 H, d, J = 5.8 Hz), 3.11 (4 H, s), 2.75 (4 H , s), 1.75 (6H, s), 0.47 (2 H, d, J = 5.8 Hz), 0.34 (2H, d, J = 5.8 Hz) LCMS: m / z 489, 491 [M + H] + HPLC retention time: 1.68 minutes (analysis condition S) Reference example 8 Compound I1-1 6-Chloro-7-methoxy-1,1-dimethyl-3,4 -di-hydro-1H-naphthalen-2-one

[000294] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3.37 g, 16.5 mmol) was dissolved in CH3CN (82 ml) , added with NCS (2.42 g, 1.1 eq.) and stirred at 90 ° C for 1.5 hr. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed and the target compound was obtained after concentration under reduced pressure (yellow oily substance, 4.45 g).
[000295] 1H-NMR (400 MHz, CDCh) δ: 7.16 (1 H, s), 6.85 (1 H, s), 3.90 (3 H, s), 3.00 (2 H , t, J = 6.8 Hz), 2.65 (2 H, t, J = 6.8 Hz), 1.42 (6 H, s). LCMS: m / z 239 [M + H] + HPLC retention time: 2.80 minutes (U analysis condition) Reference example 9 Compound I1-2 9-Chlorine-8-methoxy-6,6-dimethyl-6 , 11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000296] 6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound I1-1, 4.45 g, 16.5 mmol) and 3 hydrazinobenzonitrile (2.63 g, 1.2 eq.) was dissolved in TFA (91 ml) and stirred at 90 ° C for 3 hours. According to the concentration under reduced pressure, TFA was removed and the residues were added with saturated aqueous NaHCO3 solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with I1-3 (red powder, 6.46 g). Preparation example 21 Compound I3 9-Chloro-8-methoxy-6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000297] Under the same conditions as the method for synthesis of Compound A4, the title compound was synthesized from Compound I1-2.
[000298] 1H-NMR (400 MHz, DMSO-d6) δ: 12.79 (1 H, s), 8.27-8.31 (1 H, m), 8.12 (1 H, s), 8.00-8.02 (1 H, m), 7.58-7.63 (1 H, m), 7.51 (1 H, s), 4.03 (3 H, s), 1, 80 (6 H, s). LCMS: m / z 351 [M + H] + HPLC retention time: 2.87 minutes (U analysis condition) Production example 22 Compound I4 9-Chloro-8-hydroxy-6,6-dimethyl-11 - oxo-6,11 -dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000299] Under the same conditions as the method for synthesis of Compound E3-2, (9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile (Compound E3-1-1, 1.0 g, 2.53 mmol) was dissolved in NMP (10 mL), added with NaOMe (683 mg, 5 eq.) and 1-dodecanethiol (3, 0 mL, 5 eq.) And stirred at 160 ° C for 1 hour. The reaction solution was poured into aqueous 0.5 N hydrochloric acid solution and then extracted with ethyl acetate. The organic layer was washed with brine and dried The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH, the remaining solid after dissolution was filtered to obtain Compound E3-2 (9-bromo-8-hydroxy) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile) (yellow powder, 1.88 g, 65%)) and the title compound was synthesized from Compound I3, LCMS: m / z 337 [M + H] + HPLC retention time: 2.47 minutes (U analysis condition) Exe production model 23 Compound I59-chloro-3-cyano-6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yl trifluoromethanesulfonic acid ester

[000300] Under the same conditions as the method for synthesis of compound B1, the title compound was prepared from Compound I4. LCMS: m / z 469 [M + H] + HPLC retention time: 3.40 minutes (U analysis condition) Production example 24 Compound I6-4 9zCloroz6J6zdimetil∑8∑ (4zmorfoljn∑4∑il∑piperidiMj-il ) ∑1 ^ oXo∑ 6.11 -dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000301] Under the same conditions as the method for synthesis of compound B2-1, the title compound was synthesized from compound I5 and 4-piperidin-4-yl-morpholine.
[000302] 1H-NMR (400 MHz, DMSO-d6) δ: 12.75 (1 H, s), 8.28 (1 H, d, 8.0 Hz), 8.07 (1 H, s) , 8.00 (1 H, s), 7.59 (1 H, d, 8.0 Hz), 7.41 (1 H, s), 3.55-3.62 (4 H, m), 3.47-3.56 (4H, m), 2.75-2.86 (2 H, m), 2.45-2.55 (4 H, m), 2.28-2.39 (1 H, m), 1.86-1.96 (2 H, m), 1.76 (6 H, s), 1.52-1.66 (2 H, m) LCMS: m / z 489 [M + H] + HPLC retention time: 1.97 minutes (analysis condition U) Production example 25 Compound F5-44 8- (4-Cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11 -oxo -9-prop-1-inyl-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000303] Under the same conditions as the method for synthesis of compound E4-2-1, the title compound was synthesized from compound F4-10 under a brine gas atmosphere.
[000304] 1H-NMR (400 MHz, DMSO-d6) δ: 12.71 (1 H, s), 8.30 (1 H, d, 7.9 Hz), 8.06 (1 H, s) , 8.00 (1 H, s), 7.59 (1 H, d, 7.9 Hz), 7.20 (1 H, s), 2.75-2.83 (1 H, m), 2.40-2.48 (4 H, m), 2.11 (3 H, s), 1.97-2.06 (2 H, m), 1.76 (6 H, s), 1, 62-1.71 (2 H, m) LCMS: m / z 463 [M + H] + HPLC retention time: 2.80 minutes (W analysis condition) Production example 26 Compound F3-11 9-Bromo -6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000305] Under the same conditions as the method for synthesis of compound B2-1, the title compound was synthesized from compound F2 and 4-piperidin-4-ylmorpholine.
[000306] 1H-NMR (DMSO-d6) δ: 8.30-8.24 (2 H, m), 8.00 (1 H, s), 7.59 (1 H, d, J = 8, 2 Hz), 7.42 (1 H, s), 3.66-3.45 (6 H, m), 2.80 (2 H, t, J = 11.1 Hz), 2.38-2 , 28 (1 H, m), 1.96-1.87 (2 H, m), 1.75 (6 H, s), 1.66-1.56 (2 H, m) LCMS: m / z 533, 535 [M + H] + HPLC retention time: 1.53 minutes (analysis condition S) Production example 27 Compound F5-51 6,6,9-Trimethyl-8- (4-morpholin-4 -yl-piperidin-1-yl) -11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000307] Under the same conditions as the method for synthesis of compound F5-47 under a nitrogen atmosphere, to the solution of N, N-dimethyl formamide (1.5 ml) of 9-bromo-8- (4-cyclobutyl-piperazin- 1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (Compound F4-10, 50 mg, 0.099 mmol), trimethyl boroxin ( 12 mg, 0.1 eq.), Triphenylphosphine palladium tetracis (39 mg, 0.2 eq.) And potassium carbonate (41 mg, 3.0 eq.) Were added and the mixture was stirred at 100 ° C for 24 hours. At the end of the reaction, distilled water was poured into the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate / methanol) to obtain Compound F5-47 (8- (4-cyclobutyl- piperazin-1-yl) - 6,6,9-trimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (25 mg, 58%)), the title compound was synthesized from Compound F3-11.
[000308] 1H-NMR (270 MHz, DMSO-d6) δ: 12.70 (1 H, wide s), 8.33 - 8.30 (1 H, d, 8.08 Hz), 8.00 ( 1 H, s), 7.95 (1 H, s), 7.61-7.58 (1 H, m), 7.28 (1 H, s), 3.60 (4 H, m), 3.32-3.26 (2 H, m), 2.79-2.69 (2 H, m), 2.32 (3 H, s), 1.95-1.90 (2 H, m ), 1.74 (6 H, s), 1.65-1.52 (2 H, m), LCMS: m / z 469 [M + H] + Methanesulfonic acid salt of compound F5-51
[000309] 6,6,9-Trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3 -carbonitrile was added with 1.05 eq. of 2N methane sulfonic acid and DMSO and dissolved in them. After freeze drying, the mixture was crystallized from ethanol to give 6,6,9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) - 11-oxo-6 methanesulfonic acid salt, 11-dihydro-5H-benzo [b] carbazole-3-carbonitrile.
[000310] 1H-NMR (270 MHz, DMSO-d6) δ: 12.72 (1 H, wide s), 9.60 (1 H, wide s), 8.33-8.31 (1 H, d , 9.8 Hz), 8.01 (1 H, s), 7.99 (1 H, s), 7.61-7.59 (1 H, m), 7.31 (1 H, s) , 4.07-4.04 (2 H, m), 3.73-3.67 (2 H, m), 3.55-3.40 (8 H, m), 3.32-3.26 (1 H, m), 2.70-2.60 (2 H, m), 2.34 (3 H, s), 2.30 (3 H, s), 1.95-1.90 (2 H, m), 1.75 (6 H, s) LCMS: m / z 469 [M + H] + F5-51 hydrochloride salt
[000311] F5-51 was dissolved in 5 v / w of dimethyl sulfoxide and 0.37 v / w of aqueous hydrochloric acid solution (6 N) and then the dissolved solution was subjected to freeze drying. To the freeze-dried product, 5 v / w of ethanol was added. The precipitated crystals were filtered and dried to give the hydrochloride salt F5- 51. Production example 28 Compound F6-4 9-Ethyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1- il) -11 -oxo-6,11 - dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000312] Under the same conditions as the method for synthesis of compound B3-13-1, the title compound was synthesized from compound F5-16.
[000313] 1H-NMR (400 MHz, DMSO-d6) δ: 12.70 (1 H, broad s), 8.29 (1 H, d, 8.0 Hz), 8.03-7.94 ( 2H, m), 7.59-7.55 (1 H, m), 7.38 (1 H, s), 4.59-4.47 (4 H, m), 3.53-5.47 (1 H, m), 3.03-2.97 (2 H, m), 2.73-2.62 (2 H, m), 1.74 (6 H, s), 1.29-1 , 98 (3 H, m) LCMS: m / z 455 [M + H] + HPLC retention time: 1.92 minutes (U analysis condition) Hydrochloric acid salt of compound F6-4
[000314] 9-Ethyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6,11- dihydro-5H-benzo [b] carbazole -3-carbonitrile was added with 1.05 eq. of 6N hydrochloric acid and DMSO and dissolved in them. After freeze-drying, the mixture was crystallized from ethanol containing 25% water to give sodium chloride hydrochloride.
[000315] 9-ethyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6,11- dihydro-5H-benzo [b] carbazole -3-carbonitrile.
[000316] 1H-NMR (270 MHz, DMSO-d6) δ: 12.83 (1 H, wide s), 11.59 (1 H, wide s), 8.33-8.31 (1 H, m ), 8.09 (1H, s), 8.02 (1 H, s), 7.63- 7.61 (1 H, m), 7.39 (1 H, s), 4.91-4 , 60 (4 H, wide m), 3.58-3.40 (1 H, m), 3.31-3.05 (8 H, wide m), 2.73 (2 H, q,, J = 7.3), 1.81 (6 H, s), 1.29 (3 H, t, J = 7.3) LCMS: m / z 455 [M + H] + F6-4 mesylate salt
[000317] F6-4 was dissolved in 5 v / w of dimethyl sulfoxide and 1.2 v / w of aqueous solution of mesyl acid (2 N) and then the dissolved solution was subjected to freeze drying. To the freeze-dried product, a mixture of 3.89 v / w of water and 1.3 w / v of ethanol was added. The precipitated crystals were filtered and dried to give the F6-4 mesylate salt. Production example 29 Compound F5-49 9-Ethinyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11 -oxo- 6,11-dihydro-5H- benzo [b] carbazole-3-carbonitrile

[000318] Under the same conditions as the method for synthesis of compound F5-43, the title compound was synthesized from compound F3-11. LCMS: m / z 479 [M + H] + HPLC retention time: 1.90 minutes (U analysis condition) Production example 30 Compound F6-20 9-Ethyl-6,6-dimethyl-8- (4 -morfolin-4-yl-piperidin-1-yl) -11 -oxo- 6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000319] Under the same conditions as the method for synthesis of Compound B3-13-1, the title compound was synthesized from Compound F5-49.
[000320] 1H-NMR (400MHz, DMSO-D6) δ: 12.70 (1H, s), 8.32 (1H, d, J = 7.9 Hz), 8.04 (1H, s), 8 .00 (1H, s), 7.61 (1H, d, J = 8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m), 3.27- 3.18 (2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H, m), 1.96-1.87 (2H, m), 1, 76 (6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J = 7.3 Hz) LCMS: m / z 483 [M + H] + Retention time HPLC: 1.98 minutes (U condition analysis) Compound F6-20 hydrochloride salt
[000321] 9-Ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole -3-carbonitrile was dissolved in a mixture of 10 v / w of methyl ethyl ketone, 4 v / w of water and 3 v / w of acetic acid at 60 ° C. To the dissolved solution, 1 v / w of hydrochloric acid (2 N) was added. After stirring at 60 ° C for 30 minutes, 25 v / w of ethanol was added in drops. The precipitated solid was filtered and dried to give 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-di monohydrochloride salt -hydro-5H-benzo [b] carbazol-3-carbonitrile. 9-Ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo monohydrochloride salt [b] carbazol-3-carbonitrile obtained was sprayed using a jet grinder.
[000322] 1H-NMR (400MHz, DMSO-D6) δ: 12.78 (1H, s), 10.57 (1H, broad s), 8.30 (1H, J = 8.4 Hz), 8, 05 (1H, s), 7.99 (1H, s), 7.59 (1H, d, J = 7.9 Hz), 7.36 (1H, s), 4.02-3.99 (2H , m), 3.84-3.78 (2H, m), 3.51-3.48 (2H, m), 3.15-3.13 (1H, s), 2.83-2.73 (2H, s), 2.71-2.67 (2H, s), 2.23-2.20 (2H, m), 1.94-1.83 (2H, m), 1.75 (6H , s), 1.27 (3H, t, J = 7.5 Hz) FABMS: m / z 483 [M + H] + F6-20 mesylate salt
[000323] F6-20 was dissolved in 33 v / w of dimethyl acetamide at 90 ° C. The dissolved solution was added with 1.2 v / w of aqueous solution of mesyl acid (2 N) and 168 v / w of acetate of ethyl followed by stirring for 4 hours. The precipitated crystals were filtered and dried to give the F6-20 monomesylate salt. The obtained F6-20 monomesylate salt was sprayed using a jet grinder. Production example 31 Compound F5-16 9-Ethinyl-6J6-dimethyl-8- (4-oxetan∑3-yl-piperaziMj: yl) ∑1 ^ oxo- 6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000324] Under the same conditions as the method for synthesis of compound F5-43, the title compound was synthesized from compound F4-3.
[000325] 1H-NMR (270 MHz, DMSO-d6) δ: 12.77 (1 H, broad s), 8.31 (1 H, d, J = 8.2 Hz), 8.16 (1 H , s), 8.02 (1 H, s), 7.61 (1 H, dd, J = 8.2, 1.3 Hz), 7.27 (1 H, s), 4.59 (2 H, dd, J = 6.6, 6.6 Hz), 4.51 (1 H, s), 4.49 (2 H, dd, J = 6.6, 6.6 Hz), 3.51 (1 H, t, J = 6.6 Hz), 3.35-3.43 (4 H, m), 2.43-2.50 (4H, s), 1.78 (6 H, s) . LCMS: m / z 451 [M + H] + HPLC retention time: 1.40 minutes (analysis condition S) Production example 32 Compound F6-17 8- (4-Cyclobutyl-piperazin-1-yl) - 9-ethyl-6,6-dimethyl-11-oxo-6,11 - dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000326] Under the same conditions as the method for synthesis of compound B3-13-1, the title compound was synthesized from compound F5-43.
[000327] 1H-NMR (400 MHz, DMSO-d6) δ: 12.80 (1 H, s), 8.32 (1 H, d, 7.9 Hz), 8.10 (1 H, s) , 8.02 (1 H, s), 7.62 (1 H, d, 7.9 Hz), 7.38 (1 H, s), 3.78-3.88 (1 H, m), 3.79-3.89 (1 H, m), 3.48-3.54 (2 H, m), 3.40-3.47 (2 H, m), 3.30-3.39 ( 2 H, m), 3.02-3.24 (4 H, m), 2.73 (2 H, q, 7.3 Hz), 2.30-2.41 (2 H, m), 2 , 17-2,26 (2 H, m), 1,71-1,86 (8 H, m), 1,29 (3 H, t, 7.3 Hz) LCMS: m / z 453 [M + H] + HPLC retention time: 2.76 minutes (analysis condition W) Methanesulfonic acid salt of compound F6-17
[000328] 8- (4-Cyclobutyl-piperazin-1-yl) -9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile it was dissolved at room temperature and added with 6 v / w of DMF and added in drops with 1.05 eq. of an aqueous solution of methane sulfonic acid (2 M). The resulting solution was added dropwise to 60 w / v acetonitrile. The precipitated solid was filtered and dried to give 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6.6 monomethanesulfonic acid salt - dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile.
[000329] 1H-NMR (400 MHz, DMSO-d6) δ: 12.75 (1 H, s), 8.31 (1 H, J = 8.4 Hz), 8.07 (1 H, s) , 8.01 (1 H, s), 7.59 (1 H, d, J = 7.9 Hz), 7.38 (1 H, s), 3.58-2.84 (10 H, m ), 2.71 (2 H, q, J = 7.5 Hz), 2.34 (3 H, s), 2.20 - 2.04 (4 H, m), 1.76-1.68 (8 H, m), 1.26 (3 H, t, J = 7.5 Hz) FABMS: m / z 453 [M + H] + F6-17 hydrochloride salt
[000330] F6-17 was dissolved in 5 v / w of dimethyl sulfoxide and 0.39 v / w of aqueous hydrochloric acid solution (6 N), and then the dissolved solution was subjected to freeze drying. To the freeze-dried product, a mixture of 4.0 v / w of water and 1.3 v / w of ethanol was added. The precipitated crystals were filtered and dried to give the hydrochloride salt of F6-17. F6-17 maleate salt
[000331] A mixture containing F6-17 and maleic acid, which is added in an amount of 0.38 times the weight of F6-17, was dissolved in 10 v / w of dimethyl acetamide at 80 ° C. The dissolved solution was cooled to room temperature and added in drops with a mixture of 5.8 v / w acetone and 5.8 w / v water followed by stirring at room temperature. 3.5 v / w of water was added more in drops and the precipitated crystals were filtered and dried to give the maleate salt of F6-17, L-tartrate salt of F6-17
[000332] A mixture containing F6-17 and L-tartaric acid, which is added in an amount of 0.51 times the weight of F6-17, was dissolved in 6 v / w of dimethyl acetamide at 80 ° C. The solution dissolved was cooled to room temperature and added in drops with 37 v / w of acetonitrile followed by stirring at room temperature all night and all day. The precipitated crystals were filtered and dried to give the tartrate salt of F6-17. The obtained F6-17 tartrate salt was sprayed using a jet grinder. F6-17 citrate salt
[000333] A mixture containing F6-17 and citric acid, which is added in an amount of 0.50 times the weight of F6-17, was dissolved in 6 v / w of dimethyl acetamide at 80 ° C. The dissolved solution was cooled to room temperature and added in drops with 12 v / w acetonitrile. The precipitated crystals were filtered and dried to give the citrate salt of F6-17. The citrate salt of F6-17 obtained was sprayed using a jet grinder. F6-17 malate salt
[000334] A mixture containing F6-17 and L-malic acid, which is added in an amount of 0.46 times the weight of F6-17, was dissolved in 8 v / w of dimethyl acetamide at 80 ° C. The solution dissolved was cooled to room temperature and added in drops with 62 v / w acetonitrile. The precipitated crystals were filtered and dried to give the malate salt of F6-17. Production example 33 Compound F3-2 9-Bromo-6,6-dimethyl-11 -oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) - 6,11-dihydro-5H- benzo [b] carbazole-3-carbonitrile

[000335] Under the same conditions as the method for synthesis of Compound B2-1, the title compound was synthesized from compound F2 and 4-pyrrolidin-1-yl-piperidine. LCMS: m / z 517, 519 [M + H] + HPLC retention time: 1.70 minutes (analysis condition S) Production example 34 Compound F5-4 9-Ethinyl-6,6-dimethyl-11 - oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) - 6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000336] Under the same conditions as the method for synthesis of compound E4-2-1, Compound E4-2-2 (9- (3-hydroxy-3-methyl-but-1-ynyl) -8-methoxy-6 , 6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (Compound E4-2-1, 21.3 mg, 0.05 mmol) and sodium hydride (3.2 mg, 1.5 eq.) Were dissolved in THF and the mixture was stirred overnight at 50 ° C. Water was added to the reaction solution and the residues obtained after concentration under reduced pressure were purified by HPLC to obtain Compound E4-2-2 (9-ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile) (brown solid, 9.6 mg, 31%)), the title compound was synthesized from Compound F3-2,
[000337] 1H-NMR (270 MHz, DMSO-d6) δ: 8.29 (1 H, d, J = 8.2 Hz), 8.14 (1 H, s), 8.00 (1 H, s), 7.58 (1 H, dd, J = 8.1, 1.3 Hz), 7.24 (1H, s), 4.50 (1 H, s), 3.70-3.83 (2 H, m), 3.34-3.48 (1 H, m), 2.83-2.98 (2 H, m), 2.45-2.58 (2 H, m), 2 , 10-2.23 (2 H, m), 1.90-2.03 (2 H, m), 1.76 (6 H, s), 1.51-1.74 (6 H, m) . LCMS: m / z 463 [M + H] + HPLC retention time: 1.60 minutes (analysis condition S) Production example 35 Compound B2-4 6,6-Dimethyl-11 -oxo-8- (4 -pyrrolidin-1-yl-piperidin-1-yl) -6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000338] Under the same conditions as the method for synthesis of compound B2-1, the title compound was synthesized from compound B1 and 4-pyrrolidin-1-yl-piperidine.
[000339] 1H-NMR (270 MHz, DMSO-d6) δ: 8.30 (1 H, d, 8.1 Hz), 8.01 (1 H, d, 8.7 Hz), 7.97 ( 1 H, s), 7.56 (1 H, d, 8.6 Hz), 7.20 (1 H, s), 3.94 - 3.90 (2 H, m), 3.30-3 , 28 (4 H, m), 2.95 (2 H, t, 11.8 Hz), 2.24-2.20 (1 H, m), 1.95-1.91 (2 H, m ), 1.75 (6 H, s), 1.70-1.66 (4 H, m), 1.54-1.52 (2 H, m) LCMS: m / z 439 [M + H] + Production example 36 Compound F5-43 8- (4-Cyclobutyl-piperazin-1-yl) -9-Ethinyl-6,6-dimethyl-11 -oxo- 6,11 -dihydro-5H-benzo [b ] carbazole-3-carbonitrile

[000340] Under nitrogen atmosphere, to the suspension of MeCN (8 ml) of 9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-di - hydro-5H-benzo [b] carbazol-3-carbonitrile (Compound F4-10, 200 mg, 0.397 mmol), ethinyltriisopropylsilane (268 mg, 3.0 eq.), 2-dicyclohexylphosphino-2 ', 4' , 6'-triisopropylbiphenyl (Xphos) (39 mg, 0.2 eq.), Pd (CH3CN) 2Cl2 (11 mg, 0.1 eq.) And cesium carbonate (518 mg, 4.0 eq.) Were added and the mixture was stirred and heated under reflux until the reaction was complete. After completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate / methanol) to obtain 8- (4-cyclobutyl-piperazin-1-yl) -6 , 6-dimethyl-11-oxo-9 - [(triisopropylsilanyl) -ethynyl] -6.11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (179 mg, 74%). To the THF solution (6 ml) of the obtained compound (179 mg, 0.295 mmol), 1 M THF solution (710 μl) of tetrabutylammonium fluoride was added and the mixture was stirred until the reaction was complete. After the completion of the reaction, ethyl acetate was added to the reaction solution, which was then washed with distilled water and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were washed with a mixture solvent of ethanol and distilled water to obtain the title compound (67 mg, 92%).
[000341] 1H-NMR (400 MHz, DMSO-d6) δ: 12.85 (1 H, s), 8.31 (1 H, d, 7.9 Hz), 8.20 (1 H, s) , 8.03 (1 H, s), 7.62 (1 H, d, 7.9 Hz), 7.35 (1 H, s), 4.62 (1 H, s), 3.94- 4.03 (2 H, m), 3.79-3.89 (1 H, m), 3.48-3.54 (2 H, m), 3.27-3.38 (2 H, m ), 2.96-3.16 (2 H, m), 2.30-2.41 (2 H, m), 2.16-2.26 (2 H, m), 1.72-1, 85 (8 H, m) LCMS: m / z 449 [M + H] + HPLC retention time: 2.69 minutes (W analysis condition) Production example 37 Compound F6-18 8- (4-Cyclobutyl- piperazin-1-yl) -6,6-dimethyl-11 -oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000342] Under the same conditions as the method for synthesis of Compound B3-13-1, the title compound was synthesized from compound F5-44.
[000343] 1H-NMR (400 MHz, DMSO-d6) δ: 12.69 (1 H, s), 8.31 (1 H, d, 7.9 Hz), 8.01 (1 H, s) , 7.99 (1 H, s), 7.60 (1 H, d, 7.9 Hz), 7.39 (1 H, s), 2.92-3.02 (4 H, m), 2.75-2.84 (1 H, m), 2.65 (2 H, t, 7.3 Hz), 2.38-2.48 (4 H, m), 1.96-2.06 (2 H, m), 1.78-1.87 (2 H, m), 1.75 (6 H, s), 1.62-1.73 (4 H, m), 0.97 (3 H, t, 7.3 Hz) LCMS: m / z 467 [M + H] + HPLC retention time: 2.96 minutes (W analysis condition) Production example 38 Compound B4-7 8- (1 - Isopropyl-piperidin-4-yl) -6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000344] Under the same conditions as the method for synthesis of Compound B3-32, the title compound was synthesized from compound B3-13-2 and acetone.
[000345] 1H-NMR (400 MHz, DMSO-d6) δ: 12.77 (1 H, s), 8.32 (1 H, d, 7.9 Hz), 8.13 (1 H, d, 7.9 Hz), 8.01 (1 H, s), 7.73 (1 H, s), 7.61 (1H, d, 9.1 Hz), 7.39 (1 H, d, 9 , 8 Hz), 2.93 (2 H, d, 11.0 Hz), 2.77-2.71 (1 H, m), 2.67-2.62 (1 H, m), 2, 25 (2 H, t, 10.1 Hz), 1.80-1.73 (10 H, m), 1.02 (6 H, d, 6.7 Hz) LCMS: m / z 412 [M + H] + HPLC retention time: 1.60 minutes (analysis condition S) Production example 39 Compound B2-1 8- (4-Isopropyl-piperazin-1-yl) -6,6-dimethyl-11 -oxo -6.11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000346] 3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yl ester of trifluoromethanesulfonic acid (Compound B1, 40 mg, 0 , 0921 mmol) was dissolved in NMP (1 ml) and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at 120 ° C for 3 hours. After cooling to room temperature, purification was performed by HPLC to obtain the target compound (white powder, 12.8 mg, 34%).
[000347] 1H-NMR (270 MHz, DMSO-d6) δ: 8.30 (1 H, d, 8.1 Hz), 8.03 (1 H, d, 8.6 Hz), 7.98 ( 1 H, s), 7.56 (1 H, d, 8.6 Hz), 7.21 (1 H, s), 7.04 (1 H, d, 9.1 Hz), 3.40- 3.37 (4 H, m), 2.73-2.65 (1 H, m), 2.61-2.58 (4 H, m), 1.75 (6 H, s), 1, 02 (6 H, d, 6.6 Hz) LCMS: m / z 413 [M + H] + Production example 40 Compound F3-10 4- (9-bromo-3-cyano-6) tert-Butyl ester , 6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yl) -piperazine-1-carboxylic

[000348] Under the same conditions as the method for synthesis of Compound B2-1, the title compound was synthesized from Compound F2 and piperazine-1-carboxylic acid tert-butyl ester. LCMS: m / z 549, 551 [M + H] + HPLC retention time: 4.61 minutes (analysis condition W) Preparation example 41 Compound F5-15-1 tert-Butyl acid ester 4- (3 -cyano-9-cyclopropyl-6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yl) -piperazine-1-carboxylic

[000349] Under the same conditions as the method for synthesis of Compound E4-7-1 (a 9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [ b] carbazole-3-carbonitrile (Compound E3-1-1, 300 mg, 0.759 mmol), 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan- tert-butyl ester) 2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic (282 mg, 0.911 mmol, 1.2 eq.), Pd (PPh3) 2Cl2 (26.6 mg, 0.0379 mmol, 0.05 eq.) And sodium carbonate (241 mg, 2.28 mmoles, 3.0 eq.), DME (5 ml) and water (1 ml) were added.The mixture was subjected to reduced pressure under ultrasonication, followed by nitrogen filling.This procedure was repeated five times to remove air.The mixture was stirred at 80 ° C for 80 minutes under a nitrogen atmosphere. Pd (PPh3) 2Cl2 (26.6 mg, 0.0379 mmol, 0.05 eq.) Was added and the mixture was stirred further at 80 ° C for 20 minutes, then the mixture was cooled to room temperature and added with water and ethyl acetate. Insoluble matter was filtered through Celi you. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to obtain Compound E4-7-1 (acid tert-butyl ester (4- (3-cyano-8-methoxy-6,6-dimethyl- 11 -oxo-6,11 -dihydro-5H-benzo [b] carbazol-9-yl) -3,6-dihydro-2H-pyridine-1-carboxylic) as a crude product (gray powder)) , the title compound was synthesized from Compound F3-10 and potassium cyclopropyltrifluorborate.
[000350] 1H-NMR (400 MHz, DMSO-d6) δ: 8.55 (1 H, s), 8.28-8.25 (1 H, m), 7.98-7.95 (1 H , m), 7.62 (1 H, s), 7.32 (1 H, s), 3.56-3.53 (4 h, m), 3.09-3.07 (4 H, m ), 2.22-2.18 (1 H, m), 1.73 (6 H, br s), 1.44 (9 H, s), 1.08-1.05 (2 H, m) , 0.77-0.76 (2 H, m) LCMS: m / z 511 [M + H] + HPLC retention time: 4.50 minutes (analysis condition W) Production example 42 Compound F5-15 -2 9-Cyclopropyl-6,6-dimethyl-11 -oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000351] Under the same conditions as the method for synthesis of compound A8-1, the title compound was synthesized from compound F5-15-1. LCMS: m / z 411 [M + H] + HPLC retention time: 2.67 minutes (analysis condition W) Production example 43 Compound F5-46 8- (4-Cyclobutyl-piperazin-1-yl) - 9-cyclopropyl-6,6-dimethyl-11 - oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000352] Under the same conditions as the method for synthesis of compound B3-32, the title compound was synthesized from compound F5-15-2 and cyclobutanone.
[000353] 1H-NMR (400 MHz, DMSO-d6) δ: 8.23 (1 H, d, 8 Hz), 7.92 (1 H, wide s), 7.59 (1 H, s), 7.47 (1 H, wide d, 8 Hz), 7.28 (1 H, s), 3.12 (4 H, wide s), 2.80 (1 H, dddd, 8, 8, 8, 8 Hz), 2.20-2.13 (1 H, m), 2.01 (2 H, broad s), 1.86-1.68 (10 H, m), 1.05 (2 H, d, 8 Hz), 0.76 (2 H, d, 4 Hz) LCMS: m / z 465 [M + H] + HPLC retention time: 2.79 minutes (W analysis condition) Hydrochloride salt of compound F5-46
[000354] 8- (4-Cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile was added with 1.05 eq. of 6N hydrochloric acid and DMO and dissolved in them. After freeze drying, the mixture was crystallized from ethanol containing 25% water to give 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6-dimethyl-11- hydrochloride salt oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile.
[000355] 1H-NMR (400 MHz, DMSO-d6) δ: 12.81 (1 H, s), 10.64 (1 H, broad s), 8.32-8.29 (1 H, m) , 8.01 (1 H, s), 7.67 (1 H, s), 7.61-7.60 (1 H, m), 7.33 (1 H, s), 4.00-3 , 39 (6 H, m), 3.28-3.02 (3 H, m), 2.45-2.05 (5 H, m), 1.83-1.77 (8 H, m) , 1.09-1.07 (2 H, m), 0.81-0.80 (2 H, m) LCMS: m / z 465 [M + H] + F5-46 mesylate salt
[000356] F5-46 was dissolved in 5 v / w of dimethyl sulfoxide and 1.1 v / w of aqueous solution of mesyl acid (2 N) and then the dissolved solution was subjected to freeze drying. To the freeze-dried product, 5 v / w benzyl alcohol was added. The precipitated crystals were filtered and dried to give the mesylate salt of F5-46. Production example 44 Compound A7-24 8- (2-Bromo-ethoxy) -6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000357] Under the same conditions as compound A7-1 (8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile (Compound A6, 30 mg, 0.099 mmol) was dissolved in THF (1 mL), added with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 eq.), Triphenylphosphine (52 mg, 2 eq.) and diisopropyl azo dicarboxylate (43 μL, 2 eq.) in order, and stirred at room temperature for 4 hours. The reaction solution was poured into water and then extracted with ethyl acetate. The organic layer was washed with brine and The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate / hexane) to obtain Compound A7-1 tert- (4- (3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-8-yloxy) -piperidin-1-carboxylic acid butyl ester ( 37 mg, 76%)), the title compound was synthesized from Compo A6 and 2-bromoethanol.
[000358] 1H-NMR (270 MHz, DMSO-d6) δ: 12.75 (1 H, broad s), 8.32 (1 H, d, J = 8.2 Hz), 8.17 (1 H , d, J = 8.6 Hz), 8.01 (1 H, s), 7.61 (1 H, dd, J = 8.2, 1.4 Hz), 7.40 (1 H, d , J = 2.2 Hz), 7.12 (1 H, dd, J = 8.6, 2.2 Hz), 4.50 (2 H, t, J = 5.3 Hz), 3.88 (2 H, t, J = 5.3 Hz), 1.77 (6 H, s). LCMS: m / z 409, 411 [M + H] + HPLC retention time: 2.48 minutes (analysis condition S) Production example 45 Compound A8-10 8- (2-tert-Butylamino-ethoxy) - 6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000359] Under the same synthetic conditions as Compound A7-17, (8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile ( Compound A6, 25 mg, 0.083 mmol) was dissolved in N, N-dimethylacetamide (1 ml), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) And cesium carbonate (54 mg, 2 eq.) In order and stirred at 100 ° C for 4 hours The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by column chromatography of amino silica gel (ethyl acetate / hexane) to obtain Compound A7-17 (8-2-diethylamino-ethoxy) -6,6-dimethyl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile (11 mg, 32%), the title compound was synthesized from Compound A7-24 and tert-butyl amine.
[000360] 1H-NMR (400 MHz, DMSO-d6) δ: 12.71 (1 H, s), 8.32 (1 H, d, 7.9 Hz), 8.15 (1 H, d, 9.1 Hz), 8.07 (1 d, 1.8 Hz), 7.60 (1 H, dd, 1.8, 7.9 Hz), 7.35 (1 H, d, 2.4 Hz), 7.09 (1 H, dd, 2.4, 9.1 Hz), 4.16 (2 H, t, 6.1 Hz), 2.91 (2 H, t, 6.1 Hz ), 1.77 (6 H, s), 1.08 (9 H, s) LCMS: m / z 402 [M + H] + HPLC retention time: 2.55 minutes (W analysis condition) Example production 46 Compound F3-3 9-Bromo-8- (4-methanesulfonyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole -3-carbonitrile

[000361] Under the same conditions as the method for synthesis of Compound B2-1, the title compound was synthesized from Compound F2 and 1-methanesulfonylpiperazine. LCMS: m / z 527, 529 [M + H] + HPLC retention time: 2.48 minutes (analysis condition S) Production example 47 Compound F5-1 9-Ethinyl-8- (4-methanesulfonyl-piperazin -1-yl) -6,6-dimethyl-11 - oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000362] Under the same conditions as the method for synthesis of compound F5-43, the title compound was synthesized from compound F3-3.
[000363] 1H-NMR (270 MHz, DMSO-d6) δ: 12.78 (1 H, s), 8.31 (1 H, dd, J = 8.1, 0.7 Hz), 8.19 (1 H, s), 8.02 (1 H, dd, J = 1.4, 0.7 Hz), 7.61 (1 H, dd, J = 8.2, 1.4 Hz), 7 , 33 (1 H, s), 4.55 (1 H, s), 3.43 (4 H, br), 2.98 (3 H, s), 1.79 (6 H, s). LCMS: m / z 473 [M + H] + HPLC retention time: 2.27 minutes (analysis condition S) Production example 48 Compound F4-10 9-Bromo-8- (4-cyclobutyl-piperazin-1 -yl) -6,6-dimethyl-11 -oxo- 6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile

[000364] Under the same conditions as the method for synthesis of compound B3-32, the title compound was synthesized from compound F3-9 and cyclobutanone.
[000365] 1H-NMR (400 MHz, DMSO-d6) δ: 8.23-8.29 (2 H, m), 8.00 (1 H, s), 7.55 (1 H, d, 7 , 9 Hz), 7.45 (1 H, s), 4.04-4.15 (1 H, m), 3.10-3.20 (4 H, m), 2.39-2.48 (4 H, m), 1.97-2.06 (2 H, m), 1.78-1.88 (2 H, m), 1.77 (6 H, s), 1.61 , 72 (2 H, m) LCMS: m / z 503, 505 [M + H] + HPLC retention time: 2.78 minutes (analysis condition W) Production example 49 Compound F6-8 6,6-Dimethyl -8- (4-oxetan-3-yl-piperazin-1-yl) -11 -oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000366] Under the same conditions as the method for synthesis of compound B3-13-1, the title compound was synthesized from compound F5-22.
[000367] 1H-NMR (270 mHz DMSO-d6) δ: 12.75 (1 H, s), 8.30 (1 H, d, J = 8.2 Hz), 8.01-7.97 ( 2H, m), 7.59 (1 H, d, J = 7.1 Hz), 7.38 (1H, s), 4.51 (4 H, dt, J = 27.7, 6.3 Hz ), 3.55-3.49 (1 H, m), 3.02-2.96 (4 H, m), 2.63 (2 H, t, J = 7.3 Hz), 2.47 -2.41 (4 H, m), 1.73 (6 H, s), 1.70-1.61 (2 H, m), 0.94 (3 H, t, J = 7.4 Hz ). LCMS: m / z 469 [M + H] + HPLC retention time: 1.57 minutes (analysis condition S) Production example 50 Compound F3-4 9-Bromo-6,6-dimethyl-8-morpholin- 4-yl-11 -oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000368] Under the same conditions as the method for synthesis of compound B2-1, the title compound was synthesized from compound F2 and morpholine. LCMS: m / z 450, 452 [M + H] + HPLC retention time: 2.65 minutes (analysis condition S) Production example 51 Compound F5-5 9-Ethinyl-6,6-dimethyl-8- morfolin-4-yl-11 -oxo-6,11 -dihydro-5H-benzo [b] carbazol-3-carbonitrile

[000369] Under the same conditions as the method for synthesis of compound E4-2-1 and compound E4-2-2, the title compound was synthesized from Compound F3-4.
[000370] 1H-NMR (400 MHz, DMSO-d6) δ: 12.82 (1 H, s), 8.31 (1 H, d, J = 7.9 Hz), 8.18 (1 H, s), 8.02 (1 H, s), 7.61 (1 H, d, J = 7.9 Hz), 7.28 (1 H, s), 4.53 (1 H, s), 3.80 (4 H, s), 3.36 (4 H, s), 1.79 (6 H, s). LCMS: m / z 396 [M + H] + HPLC retention time: 2.32 minutes (S analysis condition) Examples 1 to 269: Ultramicro scale dissolution test Materials
[000371] Materials for Compound F6-20 (free form) were produced according to the method described in Production Example 30 and used. Additives shown in Table 2 were used as additives for the formulation. Composition preparation
[000372] For Examples 1 to 269, compound F6-20 was dissolved in DMSO to the concentration of 0.5 mg / ml and added with hydrochloric acid in the same molar equivalent as Compound F6-20. Then, several dissolution aids that were dissolved or dispersed in the solvent shown in Table 2 were added to Compound F6-20 to have a 100% by weight ratio. The resultant was freeze-dried to obtain a mixture of Compound F6-20 and various dissolution aids. Table 2 Dissolution aids and solvents for dissolving them
















Comparative example 1
[000373] For Comparative Example 1, Compound F6-20 was dissolved in DMSO to the concentration of 0.5 mg / ml, added with hydrochloric acid in the same molar equivalent as Compound F6-20 and freeze dried. Test example 1
[000374] To Nos. 1 to 269 and Comparative Example 1, FaSSIF (Fasted state simulated intestinal fluid. E. Galia et al., Pharma Res. 15: 698Y705 (1998)), which are simulated fasting human intestinal fluids, was added and stirred with a shaker ( trade name: Bio Shaker, manufactured by TAITEC) with an agitation rate of 200 rpm. After stirring for 10 minutes and 240 minutes, respectively, the concentration was measured with high performance liquid chromatography (trademark: UFLC, manufactured by Shimadzu).
[000375] As a result, as shown in Table 3, it was found that the solubility of Compound F6-20 was significantly increased for citric acid (Example 6), hydroxypropyl cellulose (Example 16), hydroxypropyl methyl cellulose (Example 17), sodium stearyl fumarate (Example 18), LD methacrylate copolymer (Example 22), methyl cellulose (Example 23), sodium lauryl sulfate (Example 24), polyoxyl 40 stearate (Example 38), purified shellac (Example 39), dehydroacetate sodium (Example 44), fumaric acid (Example 46), DL-malic acid (Example 57), L-ascorbate ester stearic (Example 58), L-aspartic acid (Example 59), adipic acid (Example 66), copolymer amino alkyl methacrylate E (Example 67), propylene glycol alginate ester (Example 73), casein (Example 81), sodium caseinate (Example 82), a carboxyvinyl polymer (Example 85), carboxymethyl cellulose (Example 86), powdered agar (Example 88), guar gum (Example 90), succinic acid (Example 106), cop olividone (Example 107), cellulose acetate phthalate (Example 112), tartaric acid (Example 113), sodium dioctyl sulfosuccinate (Example 117), zein (Example 128), skimmed milk powder (Example 136), sorbitan trioleate ( Example 147), lactic acid (Example 148), aluminum lactate (Example 149), ascorbic acid palmitate (Example 152), hydroxyethyl methyl cellulose (Example 154), hydroxypropyl methyl cellulose acetate succinate (Example 156), polyoxyethylene (105) polyoxypropylene (5) glycol (Example 176), polyoxyethylene 60 hydrogenated castor oil (Example 182), polyoxol 35 castor oil (Example 185), poly (sodium 4-styrene sulfonate), (Example 186), polyvinyl acetal diethylaminoacetate (Example 190), polyvinyl alcohol (Example 191), maleic acid (Example 200), methacrylate copolymer S (Example 206), lauromacrogol (Example 216), sulfuric acid (Example 219), aluminum sulfate (Example 220), phosphoric acid (Example 223), monobasic calcium phosphate (Exe example 230), sodium dodecylbenzene sulfonate (Example 240), vinyl pyrrolidone copolymer • vinyl acetate (Example 241), sodium lauroylsarcosine (Example 245), tryptophan acetyl (Example 253), sodium methyl sulfate (Example 260), sodium ethyl sulfate (Example 261), sodium butyl sulfate (Example 262), sodium octyl sulfate (Example 263), sodium decyl sulfate (Example 264), sodium tetradecyl sulfate (Example 265), sodium hexadecyl sulfate ( Example 266) and sodium octadecyl sulfate (Example 267).
[000376] Among them, the effect was notable for citric acid (Example 6), hydroxypropyl cellulose (Example 16), hydroxypropylmethyl cellulose (Example 17), LD methacrylate copolymer (Example 22), methyl cellulose (Example 23), lauryl sulfate sodium (Example 24), purified shellac (Example 39), sodium dehydroacetate (Example 44), fumaric acid (Example 46), DL-malic acid (Example 57), stearic L-ascorbate ester (Example 58) , L-aspartic acid (Example 59), adipic acid (Example 66), propylene glycol alginate ester (Example 73), casein (Example 81), sodium caseinate (Example 82), carboxymethylethyl cellulose (Example 86), acid succinic (Example 106), copolividone (Example 107), sodium dioctyl sulfosuccinate (Example 117), lactic acid (Example 148), aluminum lactate (Example 149), ascorbic acid palmitate (Example 152), hydroxyethyl methyl cellulose (Example 154) ), hydroxypropylmethyl cellulose acetate succinate (Example 156), hydrogenated castor oil d and polyoxyethylene 60 (Example 182), polyoxol 35 castor oil (Example 185), sodium poly (4-styrene sulfonate) (Example 186), polyvinylacetal diethylaminoacetate (Example 190), polyvinyl alcohol (Example 191), copolymer of methacrylate S (Example 206), lauromacrogol (Example 216), sulfuric acid (Example 219), aluminum sulfate (Example 220), sodium dodecylbenzene sulfonate (Example 240), vinyl pyrrolidone copolymer • vinyl acetate (Example 241), tryptophan acetyl (Example 253), sodium decyl sulfate (Example 264), sodium tetradecyl sulfate (Example 265) and sodium octadecyl sulfate (Example 267).
[000377] Among them, the effect was particularly noticeable for citric acid (Example 6), hydroxypropyl cellulose (Example 16), hydroxypropylmethyl cellulose (Example 17), LD methacrylate copolymer (Example 22), methyl cellulose (Example 23), lauryl sodium sulfate (Example 24), purified shellac (Example 39), sodium dehydroacetate (Example 44), fumaric acid (Example 46), malic acid DL (Example 57), L-aspartic acid (Example 59), acid adipic (Example 66), propylene glycol alginate ester (Example 73), sodium caseinate (Example 82), carboxymethylethyl cellulose (Example 86), succinic acid (Example 106), copolividone (Example 107), sodium dioctyl sulfosuccinate ( Example 117), lactic acid (Example 148), aluminum lactate (Example 149), hydroxyethyl methyl cellulose (Example 154), hydroxypropyl methyl cellulose acetate succinate (Example 156), sodium poly (4-styrene sulfonate) (Example 186) , polyvinylacetal diethylaminoacetate (Example 190), methacr copolymer S-ilate (Example 260), sulfuric acid (Example 219), aluminum sulfate (Example 220), vinyl pyrrolidone copolymer • vinyl acetate (Example 241) and sodium decyl sulfate (Example 264). Table 3 Effect of various auxiliaries of dissolution on the solubility of the hydrochloride salt of Compound F6-20 (* p <0.05, ** p <0.01, *** p <0.001)



















Examples 270 to 281 Materials
[000378] Crystal hydrochloride salt of Compound F6-20 was obtained according to the method generally known in the art (for example, the method described in Production Example 30). For Examples 270 to 281, crystal hydrochloride salt of Compound F6-20 was prepared according to the dry mixing method using agate pestle with the formula shown in Tables 4 to 8. Sodium lauryl sulfate passed with 100 mesh was used. For Comparative Example 2, crystal hydrochloride salt of Compound F6-20 and lactose were mixed with each other in a weight ratio of 1: 9,
[000379] Test example 2 (small scale dissolution test)
[000380] For the small scale dissolution test (R. Takano et al., Pharm. Res. 23: 1144-1156 (2006)), a small scale dissolution tester (Vankel Technologies, Inc.) was used and the solubilities in FaSSIF were determined at 37 ° C with a paddle agitation rate of 50 rpm. For each test sample, after passing 5, 10, 15, 20, 25, 30, 45, 60, 120 and 240 minutes, the concentration of Compound F6-20 in FaSSIF was measured using high performance liquid chromatography. Examples 270 to 272
[000381] Using Examples 270 to 272 shown in Table 4 and Comparative Example 2 above, the effect of the amount of SLS addition on crystal solubility of the hydrochloride salt of Compound F6-20 was determined. As a result, it was found that the solubility of Compound F6-20 is improved according to the amount of sodium lauryl sulfate addition as shown in Figure 1.Table 4
Examples 273 to 275
[000382] Using Examples 273 to 275 shown in Table 5 and Comparative Example 2 above, the effect of various cellulose polymers on the solubility of the hydrochloride salt crystal of Compound F6-20 was determined. As a result, it was found that, among the various cellulose polymers, HPC exhibits the most excellent effect on improving the solubility of Compound F6-20 as shown in Figure 2, although it is light. Table 5
Examples 276 to 278
[000383] Using Examples 276 to 278 shown in Table 6 and Comparative Example 2 above, the effect of the additive amount of HPC on the solubility of the hydrochloride salt crystal of Compound F6-20 was determined. As a result, it was found that Examples 276 to 278 have greater solubility than Comparative Example 2 as shown in Figure 3. In this way, at least through the addition of HPC in an amount of 25 to 100% by weight compared to the Compound F6-20, solubility enhancing effects can be obtained. Table 6
Example 279
[000384] Using Example 279 shown in Table 7, the solubility of the hydrochloride salt crystal of Compound F6-20 when SLS and HPC were added to it was determined. As a result, as illustrated in Figure 4, it was found that the solubility was greater than in Example 276 in which only HPC was added, and the greater solubility was maintained compared to Example 270 in which only SLS was added. Table 7
Examples 280 to 281
[000385] Using Examples 280 to 281 shown in Table 8 and Comparative Example 2 above, effect of the difference in the manufacturing method on the solubility of the hydrochloride salt crystal of Compound F6-20 was determined. For the dry mixing method, the hydrochloride salt crystal of Compound F6-20 and each ingredient of the formula were mixed using agate pestle. For the wet granulation method, dissolution aids other than magnesium stearate and Compound F6-20 were mixed using agate pestle. After adding water in drops, the wet powder was subjected to granulation using a 850 μm sieve mesh. After drying at 60 ° C for 3 hours, particle size regulation was performed using a 850 μm mesh again. As a result, it was found that there is no significant difference in the solubility of the hydrochloride salt crystal of Compound F6-20 between different production methods, as shown in Figure 5. That is, it was shown that the effect of improving solubility through SLS and polymer does not depend on the production method. Table 8
Examples 282 to 284
[000386] For Examples 282 to 284 and comparative example 3, crystal mesylate salt of Compound F6-20 was used in the preparation of the Compound according to the dry production method using agate pestle with the formula shown in Table 9 For Comparative Example 3, crystal of Compound F6-20 mesylate salt and lactose were mixed with each other in a 1: 9 weight ratio.
[000387] The effect of the amount of SLS addition on the solubility of the mesylate salt crystal of Compound F6-20 was determined. As a result, it was found that the solubility of the mesylate salt of Compound F6-20 is improved according to the amount of addition of sodium lauryl sulfate as shown in Figure 6. Table 9
Example 285
[000388] The solubility of the mesylate salt crystal of Compound F6-20 in the case when SLS and HPC were added using Example 285 shown in Table 10 and Comparative Example 3 above was determined. As a result, it was found that high solubility was obtained by adding SLS and HPC, as shown in Figure 7. Table 10
Examples 286 to 298
[000389] For Comparative Example 4 and Examples 286 to 298, the effect of various dissolution aids on the solubility of Compound B4-8 (Production example 12) was determined in the same way as in Examples 1 to 269. The results are shown in Table 11. Table 11 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound B4-8

Examples 299 to 311
[000390] For Comparative Example 5 and Examples 299 to 311, the effect of various dissolution aids on the solubility of Compound F4-3 (Production example 19) was determined in the same way as in Examples 1 to 269. The results are shown in Table 12. Table 12 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F4-3

Examples 312 to 324
[000391] For Comparative Example 6 and Examples 312 to 324, the effect of various dissolution aids on the solubility of Compound F4-9 (Production example 20) was determined in the same way as for Examples 1 to 269. The results are shown in Table 13. Table 13 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F4-9

Examples 325 to 337
[000392] For Comparative Example 7 and Examples 325 to 337, the effect of various dissolution aids on the solubility of Compound F6-4 (Production example 28) was determined in the same way as in Examples 1 to 269. The results are shown in Table 14. Table 14 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F6-4

Examples 338 to 350
[000393] For Comparative Example 8 and Examples 338 to 350, the effect of various dissolution aids on the solubility of Compound F5-43 (Production example 46) was determined in the same way as in Examples 1 to 269. The results are shown in Table 15, Table 15 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F5-43


Examples 351 to 363
[000394] For Comparative Example 9 and Examples 351 to 363, the effect of various dissolution aids on the solubility of Compound F6-17 (Production example 32) was determined in the same way as in Examples 1 to 269. The results are shown in Table 16. Table 16 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F6-17

Examples 364 and 376
[000395] For Comparative Example 10 and Examples 364 to 376, the effect of various dissolution aids on the solubility of Compound F5-46 (Production example 43) was determined in the same way as in Examples 1 to 269. The results are shown in Table 17. Table 17 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F5-46

Examples 377 to 389
[000396] For Comparative Example 11 and Examples 377 to 389, the effect of various dissolution aids on the solubility of Compound F6-18 (Production example 37) was determined in the same way as in Examples 1 to 269. The results are shown in Table 18. Table 18 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F6-18

Examples 390 to 402
[000397] For Comparative Example 12 and Examples 390 to 402, the effect of various dissolution aids on the solubility of Compound F5-51 (Production example 27) was determined in the same way as for Examples 1 to 269. The results are shown in Table 19. Table 19 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F5-51

Examples 403 to 415
[000398] For Comparative Example 13 and Examples 403 to 415, the effect of various dissolution aids on the solubility of Compound I6-4 (Production example 24) was determined in the same manner as in Examples 1 to 269. The results are shown in Table 20. Table 20 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound I6-4

Examples 416 to 418
[000399] With Examples 416 to 418 shown in Table 21, the effect of SLS and polyvinyl pyrrolidone on the solubility of the hydrochloride salt crystal of Compound B4-8 was determined based on a small scale dissolution test. For Comparative Example 14, the hydrochloride salt crystal of Compound B4-8 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 8. Table 21
Examples 419 to 421
[000400] With Examples 419 to 421 shown in Table 22, the effects of SLS and polyvinyl pyrrolidone on the solubility of Compound B4-8 mesylate salt crystal was determined based on a small scale dissolution test. For Comparative Example 15, the crystal of Compound B4-8 mesylate salt and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 9. Table 22
Examples 422 to 424
[000401] With Examples 422 to 424 shown in Table 23, the effect of SLS and HPC on the crystal solubility of the sulfate salt of Compound B4-8 was determined based on the small scale dissolution test. For Comparative Example 16, the crystal of the sulfate salt of Compound B4-8 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 10. Table 23
Examples 425 to 427
[000402] With Examples 425 to 427 shown in Table 24, the effect of SLS and HPC on the solubility of Compound B4-8 L-tartrate salt crystal was determined based on a small scale dissolution test. For Comparative Example 17, the crystal of Compound B4-8 L-tartrate salt and lactose were mixed in a 1: 9 weight ratio. The results shown in Figure 11. Table 24
Examples 428 to 429
[000403] With Examples 428 to 429 shown in Table 25, the effect of SLS and HPC on solubility of Compound B4-8L L-phosphate salt crystal was determined based on the small scale dissolution test. For Comparative Example 18, the crystal of the phosphate salt of Compound B4-8 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 12. Table 25
Example 430
[000404] With Example 430 shown in Table 26, the effect of polyoxyethylene (105) polyoxypropylene (5) glycol on the solubility of the hydrochloride salt crystal of Compound F6-4 was determined based on a small scale dissolution test . For Comparative Example 19, the hydrochloride salt crystal of Compound F6-4 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 13. Table 26
Example 431
[000405] With Example 431 shown in Table 27, the effect of polyoxyethylene (105) polyoxypropylene (5) glycol on the crystal solubility of the mesylate salt of Compound F6-4 was determined based on a small scale dissolution test . For Comparative Example 20, the crystal of Compound F6-4 mesylate salt and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 14, Table 27
Example 432
[000406] With Example 432 shown in Table 28, the effect of SLS on the solubility of the hydrochloride salt crystal of Compound F6-17 was determined based on the small scale dissolution test. For Comparative Example 21, the hydrochloride salt crystal of Compound F6-17 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 15, Table 28
Examples 433 to 435
[000407] With Examples 433 to 435 shown in Table 29, the effect of SLS on the solubility of Compound F6-17 mesylate salt crystal was determined based on the small scale dissolution test. For Comparative Example 22, the crystal of the mesylate salt of Compound F6-17 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 16. Table 29
Examples 436 to 437
[000408] With Examples 436 to 437 shown in Table 30 and Comparative Example 22, the effect of SLS and polyvinyl pyrrolidone on the crystal solubility of Compound F6-17 mesylate salt was determined based on a dissolution test of small scale. The results are shown in Figure 17. Table 30
Example 438
[000409] With Example 438 shown in Table 31, the effect of SLS on the crystal solubility of the compound F6-17 maleate salt was determined based on a small scale dissolution test. For Comparative Example 23, the crystal of Compound F6-17 maleate salt and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 18. Table 31
Examples 439 to 440
[000410] With Examples 439 to 440 shown in Table 32, the effect of SLS and polyvinylpyrrolidone on the crystal solubility of Compound F6-17 L-tartrate salt was determined based on a small scale dissolution test. For Comparative Example 24, the crystal of Compound F6-17 L-tartrate salt and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 19. Table 32
Examples 441 to 443
[000411] With Examples 441 to 443 shown in Table 33, the effect of SLS on the crystal solubility of the citrate salt of Compound F6-17 was determined based on a small scale dissolution test. For Comparative Example 25, the crystal of Compound F6-17 citrate salt and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 20. Table 33
Examples 444 to 446
[000412] With Examples 444 to 446 shown in Table 34, the effect of SLS on the crystal solubility of the compound F6-17 malate salt was determined based on a small scale dissolution test. For Comparative Example 26, the crystal of Compound F6-17 malate salt and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 21. Table 34
Example 447
[000413] With Example 447 shown in Table 35, the effect of SLS on crystal solubility of the hydrochloride salt of Compound F5-46 was determined based on a small scale dissolution test. For Comparative Example 27, the crystal of the hydrochloride salt of Compound F5-46 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 22. Table 35
Example 448
[000414] With Example 448 shown in Table 36, the effect of SLS on crystal solubility of the mesylate salt of Compound F5-46 was determined based on small scale dissolution test. For Comparative Example 28, the crystal of the mesylate salt of Compound F5- 46 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 23. Table 36
Example 449
[000415] With Example 449 shown in Table 37, the SLS feat on crystal solubility of the hydrochloride salt of Compound F5-51 was determined based on the small scale dissolution test. For Comparative Example 29, the hydrochloride salt crystal of Compound F5-51 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 24. Table 37
Example 450
[000416] With Example 450 shown in Table 38, the effect of SLS on crystal solubility of the mesylate salt of Compound F5-51 was determined based on a small scale dissolution test. For Comparative Example 30, the crystal of the mesylate salt of Compound F5-51 and lactose were mixed in a 1: 9 weight ratio. The results are shown in Figure 25. Table 38
Example for producing a formulation
[000417] Each component described in Tables 39 to 41 (except the lubricating agent) was added to a high speed mixing granulator for pre-mixing. The resulting mixture was sprayed with purified water and granulated under stirring. After drying under vacuum, dry powder was obtained. The dry powder was then granulated using a granulator. The granule powder obtained and the lubricating agent were mixed with each other with a type V mixer to obtain powder mixture, which was then filled into a capsule to produce a capsule formulation containing 20 mg of active ingredient per capsule. Table 39

Table 40

Table 41
Examples 451 to 453
[000418] For Examples 451 to 453, preparation was carried out using crystal hydrochloride salt of Compound F6-20 according to the dry production method using agate pestle with the formula shown in Table 42. Comparative Example 31 was prepared by mixing crystal of the hydrochloride salt of Compound F6-20 with lactose.
[000419] Effect of SLS, polyoxyethylene (105) polyoxypropylene (5) glycol and poly (sodium 4-styrene sulfonate) on the solubility of the hydrochloride salt crystal of Compound F6-20 was determined. As a result, as shown in Figure 26, it was evident that the solubility of the hydrochloride salt crystal of Compound F6-20 is improved by the addition of SLS and sodium poly (4-styrene sulfonate). It was also evident that the initial solubility of the crystal of the hydrochloride salt of Compound F6-20 is improved by the addition of polyoxyethylene (105) polyoxypropylene (5) glycol.
[000420] For sodium poly (4-styrene sulfonate), the compound from Sigma Chemical Company was used (ie product number 243051). Table 42
Example 454 to 457
[000421] With Examples 454 to 457 shown in Table 43, the effect of a combination of SLS and polyoxyethylene (105) polyoxypropylene (5) glycol on the crystal solubility of the hydrochloride salt of Compound F6-20 was determined. As a result, as shown in Figure 27, it was evident that the solubility of the hydrochloride salt crystal of Compound F6-20 improved by SLS is further increased by the addition of at least 1% polyoxyethylene (105) polyoxypropylene (5) glycol formulation, especially in the initial phase. Table 43
Example 458 to 460
[000422] With Examples 458 to 460 shown in Table 44, the effect of a combination of SLS and poly (sodium 4-styrene sulfonate) on the crystal solubility of the hydrochloride salt of Compound F6-20 was determined. As a result, as shown in Figure 28, it was evident that the effect of improving the solubility of the crystal of the hydrochloride salt of Compound F6-20 by SLS is further increased depending on the amount of addition of sodium poly (4-styrene sulfonate) .
[000423] For poly (sodium 4-styrene sulfonate), the compound from Sigma Chemical Company was used (ie, product number 243051). Table 44

Examples 461 to 465
[000424] With Examples 461 to 465 shown in Table 45, the effect of a combination of SLS, polyoxyethylene (105) polyoxypropylene (5) glycol and poly (4-styrene sodium sulfonate) on the solubility of the hydrochloride salt crystal Compound F6-20 was determined. As a result, as shown in Figure 29, it was evident that the crystal solubility of the hydrochloride salt of Compound F6-20 is improved by combining SLS, polyoxyethylene (105) polyoxypropylene (5) glycol and poly (4-styrene sulfonate) sodium).
[000425] For poly (sodium 4-styrene sulfonate), the compound from Sigma Chemical Company was used (i.e., product number 243051). Table 45

Examples 446 and 467
[000426] With Examples 466 and 467 shown in Table 46, the effect of the amount of SLS on the solubility of the crystal formulation of the hydrochloride salt of Compound F6-20 containing polyoxyethylene (105) polyoxypropylene (5) glycol and poly (4 -styrene sodium sulfonate) was determined. As a result, as shown in Figure 30, it was evident that the solubility of the crystal formulation of the hydrochloride salt of Compound F6-20 containing polyoxyethylene (105) polyoxypropylene (5) glycol and poly (sodium 4-styrene sulfonate) remained the same even when the amount of SLS has been cut in half.
[000427] For poly (sodium 4-styrene sulfonate), the compound from Sigma Chemical Company was used (ie, product number 243051). Table 46

权利要求:
Claims (12)
[0001]
1. Composition, characterized by the fact that it comprises a substance represented by Formula (I), a pharmaceutically acceptable carrier and a dissolution aid,
[0002]
2. Composition, according to claim 1, characterized by the fact that said dissolution aid is a surfactant.
[0003]
3. Composition, according to claim 2, characterized by the fact that said surfactant is a nonionic or anionic surfactant.
[0004]
4. Composition according to claim 2 or 3, characterized in that said surfactant is selected from the group consisting of monoalkyl sulphate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, sodium dioctyl sulfosuccinate, sodium lauroylsarcosine, sodium dodecylbenzene sulfonate and a mixture thereof.
[0005]
Composition according to any one of claims 2 to 4, characterized in that said composition further comprises an organic polymer.
[0006]
6. Composition according to claim 5, characterized in that said organic polymer is selected from a group consisting of a synthetic resin, a water-soluble polymer, a gastric soluble polymer, an enteric soluble polymer and a mixture of themselves.
[0007]
7. Composition according to claim 5, characterized by the fact that said organic polymer is a synthetic resin.
[0008]
8. Composition according to any one of claims 2 to 7, characterized in that said composition further comprises one or more additives that are selected from the following additive group A: additive A: Additive A: citric acid, acid fumaric acid, DL-malic acid, adipic acid, succinic acid, tartaric acid, lactic acid, maleic acid, sulfuric acid, phosphoric acid, sodium dehydroacetate, sodium stearyl fumarate, L-ascorbate ester, stearic acid, L-aspartic acid, milk skimmed-milk powder, aluminum lactate, ascorbic acid palmitate, aluminum sulfate, monobasic calcium phosphate or tryptophan acetyl.
[0009]
Composition according to any one of claims 1 to 8, characterized in that the said water solubility of the substance is less than 100 μg / mL at 25 ° C.
[0010]
10. Composition according to any one of claims 1 to 8, characterized in that A1 to A4, A6 and A7 are a carbon atom, A5 is NH, R3 is cyan, R6 and R6 'are both methyl for the substance.
[0011]
11. Composition according to any one of claims 1 to 8, characterized in that said substance is selected from 9- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo- 6.11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 6.6- dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo [b] carbazole- 3-carbonitrile; 9-cyclopropylethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) - 11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6.7- dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-bromo-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 9-bromo-8- (4-cyclopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-chloro-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6,9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3- carbonitrile; 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 9-ethynyl-6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo- 6,11-dihydro-5H-benzo [b] carbazole-3- carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethynyl-6,6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) - 6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; 6,6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-ethynyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (1-isopropyl-piperidin-4-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-isopropyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 8- (2-tert-butylamino-ethoxy) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 9-ethynyl-8- (4-methanesulfonyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile; 9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile; 6,6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-propyl-6,11-dihydro-5H-benzo [b] carbazol-3- carbonitrile; and 9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo [b] carbazol-3-carbonitrile.
[0012]
12. Orally administrable formulation, characterized in that it comprises the composition as defined in any one of claims 1 to 11.

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-08-13| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2020-02-27| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-09-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-22| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/08/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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JP2010185385|2010-08-20|

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JP2010185385|2010-08-20|

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PCT/JP2011/068735|WO2012023597A1|2010-08-20|2011-08-19|Composition containing tetracyclic compound|

---