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JP-7855637-B2 - BCL6 inhibitors

JP7855637B2JP 7855637 B2JP7855637 B2JP 7855637B2JP-7855637-B2

Inventors

  • ベンジャミン・リチャード・ベレニー
  • クワイ・ミン・ジャック・チュン
  • オーウェン・アレクサンダー・デイビス
  • スウェン・ヘルダー
  • ローズマリー・ハックベイル
  • ギャビン・コリー
  • ミルコ・メニコーニ
  • アルフィー・ブレナン
  • マシュー・ガース・ロイド

Assignees

  • キャンサー・リサーチ・テクノロジー・リミテッド
  • ジ・インスティテュート・オブ・キャンサー・リサーチ：ロイヤル・キャンサー・ホスピタル

Dates

Publication Date
20260508
Application Date
20240521
Priority Date
20180413

Claims (15)

  1. Compound represented by formula (III-a): Equation (III-a) (In the formula: Z is a ( 1-2C ) alkylene group selected from (-CH2-), ( -CH2CH2- ), ( -CF2CH2 ) or (-CH(Me) CH2- ), W is selected from the group consisting of NO2 , halogens, and OTf; X1 is selected from N or CR a , where Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or NR b R c , where R b and R c are independently selected from hydrogen or (1-2C) alkyl, respectively; X2 is selected from N, CH, CF, CCl, or C-CH3; R1 is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent or O, C(O), C(O)O or C(O)N(R e ), where R e is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally further substituted with one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-4C) alkyl. Selected from; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and/or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, where Ru and R v are independently selected from hydrogen or (1-2C)alkyl; R 31 is hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or a group of the following formula: Y 5 - L 5 - Z 5 (In the formula: Y5 is either absent or selected from C(O)O or C(O)N( Rw ), where Rw is selected from hydrogen or (1-2C) alkyl; L 5 is absent or (1-2C)alkylene; and Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2 , cyano, nitro, or hydroxy. Selected from; or R 30 and R 31 are bonded together with the carbon atoms to which they are bonded to form a 4- to 6-membered carbon ring or heterocycle).
  2. The compound according to claim 1, wherein W is NO 2 .
  3. The following (R)-2-cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; and, A compound according to claim 1 or 2, selected from the group consisting of (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.
  4. The compound according to any one of claims 1 to 3, wherein the compound is (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one.
  5. A method for producing a compound represented by formula (III-a) from a compound represented by formula (IV), The manufacturing method includes performing an intramolecular cyclization reaction on a compound represented by formula (IV) to obtain a compound represented by formula (III-a), (wherein, Z is a ( 1-2C ) alkylene group selected from (-CH2-), ( -CH2CH2- ), ( -CF2CH2 ) or (-CH(Me) CH2- ), W is selected from the group consisting of NO2 , halogens, and OTf; Y is a halogen, X1 is selected from N or CR a , where Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or NR b R c , where R b and R c are independently selected from hydrogen or (1-2C) alkyl, respectively; X2 is selected from N, CH, CF, CCl, or C-CH3; R1 is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent or O, C(O), C(O)O or C(O)N(R e ), where R e is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally further substituted with one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-4C) alkyl. Selected from; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and/or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, where Ru and R v are independently selected from hydrogen or (1-2C)alkyl; R 31 is hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or a group of the following formula: Y 5 - L 5 - Z 5 (In the formula: Y5 is either absent or selected from C(O)O or C(O)N( Rw ), where Rw is selected from hydrogen or (1-2C) alkyl; L 5 is absent or (1-2C)alkylene; and Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2 , cyano, nitro, or hydroxy. Selected from; or R 30 and R 31 are bonded together with the carbon atoms to which they are bonded to form a 4- to 6-membered carbon ring or heterocycle).
  6. The compound represented by formula (III-a) is the following (R)-2-cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; and, The method for producing the product according to claim 5, selected from the group consisting of (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.
  7. Compound represented by formula (II): (In the formula: X1 is selected from N or CR a , where Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or NR b R c , where R b and R c are independently selected from hydrogen or (1-2C) alkyl, respectively; X2 is selected from N, CH, CF, CCl, or C-CH3; R1 is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent or O, C(O), C(O)O or C(O)N(R e ), where R e is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally further substituted with one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-4C) alkyl. Selected from; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and/or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, where Ru and R v are independently selected from hydrogen or (1-2C)alkyl; R 31 is hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or a group of the following formula: Y 5 - L 5 - Z 5 (In the formula: Y5 is either absent or selected from C(O)O or C(O)N( Rw ), where Rw is selected from hydrogen or (1-2C) alkyl; L 5 is absent or (1-2C)alkylene; and Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2 , cyano, nitro, or hydroxy. Selected from; or R 30 and R 31 are bonded together with the carbon atoms to which they are bonded to form a 4- to 6-membered carbon ring or heterocycle; and, Ring A is a six- or seven-membered heterocycle, which, in addition to substituents R 30 and R 31 , is further optionally substituted with one or more substituents selected from oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH₂ , cyano, or hydroxy.
  8. The following (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-ethyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,3,3,7-tetramethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-2',3'-dimethyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepino[2,3-c]quinoline]-6(7H)-one; (2S,4S)-10-amino-2,4,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-7'-methyl-3',4,4',5-tetrahydro-1'H,2H--spiro[furan-3,2'-[1,4]oxazepino[2,3-c]quinoline]-6'(7'H)-one; 10-amino-2-(difluoromethyl)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one, A compound according to claim 7, selected from the group consisting of the following.
  9. The compound according to claim 7 or claim 8, wherein the compound is (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H) -one .
  10. A method for producing a compound represented by formula (II) from a compound represented by formula (III), The manufacturing method includes a reduction reaction of the W group of formula (III) to obtain a compound represented by formula (II), (wherein, W is NO. 2 ; X1 is selected from N or CR a , where Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or NR b R c , where R b and R c are independently selected from hydrogen or (1-2C) alkyl, respectively; X2 is selected from N, CH, CF, CCl, or C-CH3; R1 is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent or O, C(O), C(O)O or C(O)N(R e ), where R e is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally further substituted with one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-4C) alkyl. Selected from; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and/or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, where Ru and R v are independently selected from hydrogen or (1-2C)alkyl; R 31 is hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or a group of the following formula: Y 5 - L 5 - Z 5 (In the formula: Y5 is either absent or selected from C(O)O or C(O)N( Rw ), where Rw is selected from hydrogen or (1-2C) alkyl; L 5 is absent or (1-2C)alkylene; and Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2 , cyano, nitro, or hydroxy. Selected from; or R 30 and R 31 are bonded together with the carbon atoms to which they are bonded to form a 4- to 6-membered carbon ring or heterocycle; and, Ring A is a six- or seven-membered heterocycle, which, in addition to substituents R 30 and R 31 , is further optionally substituted with one or more substituents selected from oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH₂ , cyano, or hydroxy.
  11. The manufacturing method according to claim 10, wherein the reduction reaction of the W group includes (1) a hydrogenation reaction in the presence of a metal catalyst; (2) a reaction using tin(II) chloride; or (3) a reaction using iron or zinc metal.
  12. A method for producing a compound represented by formula (II) from a compound represented by formula (III), The manufacturing method includes reacting a compound represented by formula (III) under conditions for W group amination to obtain a compound represented by formula (II), (wherein, W is a halogen or OTf; X1 is selected from N or CR a , where Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or NR b R c , where R b and R c are independently selected from hydrogen or (1-2C) alkyl, respectively; X2 is selected from N, CH, CF, CCl, or C-CH3; R1 is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent or O, C(O), C(O)O or C(O)N(R e ), where R e is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally further substituted with one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-4C) alkyl. Selected from; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and/or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, where Ru and R v are independently selected from hydrogen or (1-2C)alkyl; R 31 is hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or a group of the following formula: Y 5 - L 5 - Z 5 (In the formula: Y5 is either absent or selected from C(O)O or C(O)N( Rw ), where Rw is selected from hydrogen or (1-2C) alkyl; L 5 is absent or (1-2C)alkylene; and Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2 , cyano, nitro, or hydroxy. Selected from; or R 30 and R 31 are bonded together with the carbon atoms to which they are bonded to form a 4- to 6-membered carbon ring or heterocycle; and, Ring A is a six- or seven-membered heterocycle, which, in addition to substituents R 30 and R 31 , is further optionally substituted with one or more substituents selected from oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH₂ , cyano, or hydroxy.
  13. The manufacturing method according to claim 12, wherein the amination conditions include amination using a metal catalyst.
  14. The compound represented by formula (II) is the following (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-ethyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,3,3,7-tetramethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-2',3'-dimethyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepino[2,3-c]quinoline]-6(7H)-one; (2S,4S)-10-amino-2,4,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-7'-methyl-3',4,4',5-tetrahydro-1'H,2H--spiro[furan-3,2'-[1,4]oxazepino[2,3-c]quinoline]-6'(7'H)-one; 10-amino-2-(difluoromethyl)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one, A manufacturing method according to any one of claims 10 to 13, selected from the group consisting of the following:
  15. The production method according to any one of claims 10 to 14, wherein the compound represented by formula (II) is (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.

Description

This invention relates to certain compounds that function as inhibitors of BCL6 (B-cell lymphoma 6) activity. The invention also relates to processes for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders such as cancer, and other diseases or conditions associated with BCL6 activity. BCL6 is a zinc finger transcriptional repressor that plays a crucial role in germinal center formation and development, where somatic mutations and rearrangements of immunoglobulin genes occur in B cells, resulting in antibody diversity against various foreign antibodies (Dent et al., Science, 1997, 276, 589-592). BCL6 promotes the proliferation of antibody-producing B cells by suppressing genes involved in DNA damage response, cell cycle arrest, and apoptosis. BCL6 mediates this repression by recruiting corepressor proteins SMRT, NCoR, and BCoR to an expanded groove motif formed along the dimer interface of the BCL6 BTB (BR-C, Ttk, and Bab) domain (Ahmad et al., Mol Cell, 2003, 12, 1551-1564; Ghetu et al., Mol Cell, 2008, 29, 384-391). Genetic upregulation of the BCL6 gene, observed in many lymphomas, leads to the proliferation of malignant B cells (Hatzi & Melnick, Trends Mol Med, 2014, 20, 343-352). Therefore, there is a need to develop drugs that inhibit the tumorigenic effects of BCL6 by selectively binding to the BTB domain and preventing corepressor recruitment, or by binding to the BTB domain and inducing proteolysis (Kerres et al. Cell Rep., 2017, 20, 2860-2875). According to a first aspect of the present invention, the compounds defined above in this specification, or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided. A further aspect of the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate (in a mixture thereof), and a pharmaceutically acceptable diluent or carrier. A further aspect of the present invention provides a method for inhibiting BCL6 kinase enzyme activity in vitro or in vivo, the method comprising the step of contacting cells with an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. A further aspect of the present invention provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising the step of contacting cells with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. A further aspect of the present invention provides a method for treating a disease or disorder related to BCL6 activity, which is to be performed in a patient requiring such treatment, the method comprising the step of administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. A further aspect of the present invention provides a method for treating a proliferative disorder, to be performed in a patient requiring such treatment, the method comprising the step of administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. A further aspect of the present invention provides a method for treating cancer in a patient requiring such treatment, the method comprising the step of administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Further aspects of the present invention provide compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in therapeutic purposes. Further aspects of the present invention provide compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in treating proliferative conditions. Further aspects of the present invention provide compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of cancer. In certain embodiments, cancer is human cancer. Further aspects of the present invention provide compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in inhibiting BCL6 activity. Further aspects of the present invention provide compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in treating diseases or disorders associated with BCL6 activity. Further aspects of the presen