JP6671359B2 - スルホキシイミン基を含むフッ素化ベンゾフラニル−ピリミジン誘導体 - Google Patents
スルホキシイミン基を含むフッ素化ベンゾフラニル−ピリミジン誘導体 Download PDFInfo
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- JP6671359B2 JP6671359B2 JP2017519840A JP2017519840A JP6671359B2 JP 6671359 B2 JP6671359 B2 JP 6671359B2 JP 2017519840 A JP2017519840 A JP 2017519840A JP 2017519840 A JP2017519840 A JP 2017519840A JP 6671359 B2 JP6671359 B2 JP 6671359B2
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000006490 viral transcription Effects 0.000 description 1
- 208000006542 von Hippel-Lindau disease Diseases 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
・改善された活性および/または効力、
・各治療ニーズに応じた有用なキナーゼ選択性プロファイル、
・改善された副作用プロファイル、例えば、より少ない望ましくない副作用がより少ないこと、副作用の強さがより低いこと、または(細胞)毒性の低下、
?水および体液での溶解度などの改善された物理化学特性、
?例えば用量低減または投与計画の容易化などを可能とする改善された薬物動態特性、
・例えば合成経路の短縮または精製の容易化による原体製造の容易化
のような1以上の利点を提供する、疾患、例えば過剰増殖疾患、ウィルス疾患および/または心疾患の治療に使用される選択的CDK9阻害剤が現在も必要とされている。
R1は、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ヘテロアリール−、フェニル−C1−C3−アルキル−およびヘテロアリール−C1−C3−アルキル−から選択される基を表し、
前記基は、ヒドロキシ、シアノ、ハロゲン、ハロ−C1−C3−アルキル−、C1−C6−アルコキシ−、C1−C3−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、−OP(O)(OH)2、−C(O)OH、−C(O)NH2の群から選択される同一または異なって1個もしくは2個もしくは3個の置換基で置換されていても良く;
R2は、下記の基:
R3、R4は互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、−SF5、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R5は、水素原子、シアノ、−C(O)R9、−C(O)OR9、−S(O)2R9、−C(O)NR10R11、−P(O)(OR12)2、−CH2OP(OR12)2、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−またはヘテロアリール−基は、同一であるか異なって、ハロゲン、ヒドロキシ、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く;
R6、R7は互いに独立に、水素原子、フッ素原子、塩素原子、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R8a、R8bは互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R9は、C1−C6−アルキル−、ハロ−C1−C3−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−およびヘテロアリール−から選択される基を表し、
前記基は、同一であるか異なって、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く;
R10、R11は互いに独立に、水素原子、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−およびヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−またはヘテロアリール−基は、同一であるか異なって、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成しており;
R12は、水素原子、C1−C4−アルキル−およびベンジル−から選択される基を表す。
R1が、C1−C6−アルキル−、C3−C5−シクロアルキル−から選択される基を表し、
前記基が、ヒドロキシ、ハロ−C1−C2−アルキル−、C1−C3−アルコキシ−、C1−C2−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、環状アミン類、−OP(O)(OH)2、−C(O)OH、−C(O)NH2の群から選択される1個の置換基で置換されていても良く;
R2が、下記の基:
R3が、水素原子、フッ素原子または塩素原子、−SF5基、C1−C3−アルキル−基またはフルオロ−C1−C3−アルキル−基を表し;
R4が、水素原子またはフッ素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−S(O)2R9、−C(O)NR10R11、−P(O)(OR12)2、−CH2OP(OR12)2、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−またはヘテロアリール−基が、同一であるか異なって、ハロゲン、ヒドロキシ、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く;
R6、R7が互いに独立に、水素原子、フッ素原子、塩素原子、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R8a、R8bが互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R9が、C1−C6−アルキル−、ハロ−C1−C3−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−およびヘテロアリール−から選択される基を表し、
前記基が、同一であるか異なって、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く;
R10、R11が互いに独立に、水素原子、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、ベンジル−、フェニル−およびヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、ベンジル−、フェニル−またはヘテロアリール−基が、同一であるか異なって、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成しており;
R12が、水素原子およびC1−C2−アルキル−から選択される基を表す、一般式(I)の化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
R1が、C1−C6−アルキル−、C3−C5−シクロアルキル−から選択される基を表し、
前記基が、ヒドロキシ、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、環状アミン類、−OP(O)(OH)2の群から選択される1個の置換基で置換されていても良く;
R2が、下記の基:
R3が、水素原子、フッ素原子または塩素原子、−SF5基、C1−C3−アルキル−基またはフルオロ−C1−C3−アルキル−基を表し;
R4が、水素原子またはフッ素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11、−P(O)(OR12)2、−CH2OP(OR12)2、C1−C3−アルキル−から選択される基を表し、
前記C1−C3−アルキル基が、−NH2、アルキルアミノ−、ジアルキルアミノ−および環状アミン類から選択される1個の置換基で置換されていても良く;
R6、R7がは互いに独立に、水素原子、フッ素原子および塩素原子から選択される基を表し;
R8a、R8bが互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、メチル−、メトキシ−、ハロメチル−、フルオロメトキシ−から選択される基を表し;
R9が、C1−C3−アルキル−、ハロ−C1−C3−アルキル−、およびベンジル−基から選択される基を表し、そのフェニル−基が、同一または異なって、ハロゲン、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−の群から選択される1個もしくは2個の置換基で置換されていても良く;
R10、R11が互いに独立に、水素原子、C1−C3−アルキル−、ベンジル−から選択される基を表し、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成しており;
R12が、水素原子およびメチル−から選択される基を表す、一般式(I)の化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
R1が、C1−C6−アルキル−基を表し、
前記基が、C1−C3−アルコキシ、−NH2、アルキルアミノ−、ジアルキルアミノ−および環状アミン類の群から選択される1個の置換基で置換されていても良く;
R2が、下記の基:
R3が、水素原子、フッ素原子または塩素原子または−SF5、メチル−、エチル−またはトリフルオロメチル−基を表し;
R4が、水素原子またはフッ素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11から選択される基を表し;
R6、R7が互いに独立に、水素原子、フッ素原子および塩素原子から選択される基を表し;
R9が、C1−C3−アルキル−基、ベンジル−基、またはトリフルオロメチル−を表し;
R10、R11が互いに独立に、水素原子、C1−C2−アルキル−から選択される基を表す、一般式(I)の化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
R3が、水素原子またはフッ素原子またはメチル−または−SF5基を表し;
R4が、水素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11から選択される基を表し;
R6が、水素原子、フッ素原子および塩素原子から選択される基を表し、
R7が、水素原子を表し;
R9が、メチル−、エチル−またはトリフルオロメチル−基を表し;
R10が、C1−C3−アルキル−基を表し;
R11が、水素原子を表す、一般式(I)の化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
R3が、水素原子またはフッ素原子またはメチル−または−SF5基を表し;
R4が、水素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11から選択される基を表し;
R6が、水素原子およびフッ素原子から選択される基を表し、
R7が、水素原子を表し;
R9が、メチル−、エチル−またはトリフルオロメチル−基を表し;
R10が、C1−C2−アルキル−基を表し;
R11が、水素原子を表す、一般式(I)の化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
R3が、水素原子またはフッ素原子またはメチル−または−SF5基を表し;
R4が、水素原子を表し;
R5が、水素原子およびシアノ基から選択される基を表す、一般式(I)の化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
前記基が、ヒドロキシ、シアノ、ハロゲン、ハロ−C1−C3−アルキル−、C1−C6−アルコキシ−、C1−C3−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、−OP(O)(OH)2、−C(O)OH、−C(O)NH2の群から選択される同一または異なって1個もしくは2個もしくは3個の置換基で置換されていても良い、式(I)の化合物に関するものである。
前記基が、ヒドロキシ、シアノ、ハロゲン、ハロ−C1−C2−アルキル−、C1−C3−アルコキシ−、C1−C2−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類の群から選択される同一または異なって1個もしくは2個もしくは3個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記基が、ヒドロキシ、ハロ−C1−C2−アルキル−、C1−C3−アルコキシ−、C1−C2−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、環状アミン類、−OP(O)(OH)2、−C(O)OH、−C(O)NH2の群から選択される1個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記基が、ヒドロキシ、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、環状アミン類、−OP(O)(OH)2の群から選択される1個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記基が、ヒドロキシまたはメトキシ−の群から選択される1個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記基が、C1−C3−アルコキシ、−NH2、アルキルアミノ−、ジアルキルアミノ−および環状アミン類の群から選択される1個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記基が、C1−C3−アルコキシ、−NH2、アルキルアミノ−、ジアルキルアミノ−、および環状アミン類の群から選択される1個の置換基で置換されていても良い式(I)の化合物に関するものである。
R6、R7が互いに独立に、水素原子、フッ素原子、塩素原子、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し、
R8a、R8bが互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表す式(I)の化合物に関するものである。
R6、R7が互いに独立に、水素原子、フッ素原子または塩素原子から選択される基を表し、
R8a、R8bが互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、メチル−、メトキシ−、ハロメチル−、フルオロメトキシ−から選択される基を表す式(I)の化合物に関するものである。
R6、R7が互いに独立に、水素原子、フッ素原子または塩素原子から選択される基を表す式(I)の化合物に関するものである。
R6が、水素、フルオロまたは塩素原子から選択される基を表し、
R7が水素を表す式(I)の化合物に関するものである。
R6が、水素およびフッ素原子から選択される基を表し、
R7が水素を表す式(I)の化合物に関するものである。
前記C1−C6−アルキル、C3−C7−シクロアルキル−、複素環−、フェニル−またはヘテロアリール−基が、同一であるか異なって、ハロゲン、ヒドロキシ、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記C1−C3−アルキル−基が−NH2、アルキルアミノ−、ジアルキルアミノ−、および環状アミン類から選択される1個の置換基によって置換されていても良い式(I)の化合物に関するものである。
前記基が、同一であるか異なって、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良い式(I)の化合物に関するものである。
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−またはヘテロアリール基が、同一であるか異なって、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される1個、2個もしくは3個の置換基で置換されていても良く、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成している式(I)の化合物に関するものである。
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成している式(I)の化合物に関するものである。
・(rac)−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミド;
・[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー1;
・[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー2;
・(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)−メチル]フェニル}−ピリミジン−2−アミン;
・5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー1;
・5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー2;
・(rac)−[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド;
・[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー1;
・[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー2;
・(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;
・5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー1;
・5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー2;
・(rac)−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド;
・[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー1;
・[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー2;
・(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−メチル−5−[(S−メチルスルホンイミドイル)−メチル]フェニル}ピリミジン−2−アミン;
・(rac)−{[3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−(ペンタフルオロ−λ6−スルファニル)ベンジル](メチル)オキシド−λ6−スルファニリデン}シアナミド、および
・(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)メチル]−5−(ペンタフルオロ−λ6−スルファニル)フェニル}ピリミジン−2−アミン;
から選択される化合物ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩である。
本発明はさらに、下記式(6)の化合物(R1、R2、R3およびR4は本発明による式(I)の化合物について定義の通りである。)ならびにそれのエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩に関するものである。
(1)いずれかの薬剤単独の投与と比較して、腫瘍増殖の低下においてより良好な効力を生じるか、さらに腫瘍を排除する;
(2)投与される化学療法剤の量をより少なくする;
(3)単剤化学療法およびある種の他の併用療法で認められるものより有害な薬理的合併症をより少なくして、患者において良好に耐容される化学療法を提供する;
(4)哺乳動物、特にヒトにおける、より広範な異なる癌タイプの治療を提供する;
(5)治療を受ける患者の中でより高い応答率を提供する;
(6)標準的化学療法治療と比較して、治療を受ける患者の中でのより長い生存期間を提供する;
(7)腫瘍進行に要する時間を延長する;および/または、
(8)他の癌薬剤組み合わせが拮抗効果を生じる既知の場合と比較して、単独で使用される薬剤と少なくとも同じほど良好な効力および耐容性結果を生じるのに役立つ。
以下の試験および実施例でのパーセントは、別段の断りがない限り、重量%であり、部は重量部である。液/液溶液の溶媒比、希釈比および濃度データは、各場合で体積基準である。
・平均値は、算術平均値とも称され、得られた値の合計を試験回数によって割った値を表し、
・中央値は、昇順または降順で順位付けされた場合の値群の中央の数を表す。データセットにおける値の数が奇数である場合、中央値はその中央の値である。データセットにおける値の数が偶数である場合、中央値は二つの中央の値の算術平均である。
本発明の化合物のCDK9/CycT1阻害活性を、下記の段落に記載のCDK9/CycT1 TR−FRETアッセイを用いて定量した。
酵素および試験化合物の前インキュベーション後の高ATP濃度での本発明の化合物のCDK9/CycT1阻害活性を、下記の段落に記載のCDK9/CycT1 TR−FRETアッセイを用いて定量した。
本発明の化合物のCDK2/CycE阻害活性を、下記の段落に記載のCDK2/CycE TR−FRETアッセイを用いて定量した。
2mMアデノシン三リン酸(ATP)での本発明の化合物のCDK2/CycE阻害活性を、下記の段落に記載のCDK2/CycE TR−FRET(TR−FRET=時間分解蛍光エネルギー転移)アッセイを用いて定量した。
培養した腫瘍細胞(NCI−H460、ヒト非小細胞肺癌腫細胞、ATCC HTB−177;A2780、ヒト卵巣癌細胞、ECACC#93112519;DU145、ホルモン非依存性ヒト前立腺癌細胞、ATCC HTB−81;HeLa−MaTu−ADR、多剤耐性ヒト頸部癌腫細胞、EPO−GmbH、Berlin;Caco−2、ヒト結腸直腸癌細胞、ATCC HTB−37;B16F10マウス黒色腫細胞、ATCC CRL−6475)を、5000細胞/ウェル(DU145, HeLa−MaTu−ADR)、3000細胞/ウェル(NCI−H460, HeLa−MaTu, HeLa)、1500細胞/ウェル(Caco−2)または1000細胞/ウェル(B16F10)の密度で、10%ウシ胎仔血清を補充した各増殖培地200μLに96ウェルマルチタイタープレートに蒔いた。24時間後、一方のプレート(ゼロポイントプレート)の細胞を、クリスタルバイオレット(下記参照)によって染色し、他方のプレートの培地を新鮮な培養培地(200μL)によって置き換え、それに試験物質を各種濃度で添加した(0μM、ならびに0.001から10μMの範囲で;溶媒ジメチルスルホキシドの最終濃度は0.5%であった)。その細胞を、試験物質の存在下で4日間培インキュベートした。細胞をクリスタルバイオレットで染色することで、細胞増殖を求めた。15分室温にて11%グルタルアルデヒド溶液20μL/測定点を加えることで細胞を固定した。その固定細胞の水による洗浄サイクルを3回行った後に、当該プレートを室温で乾燥させた。0.1%クリスタルバイオレット溶液(pH3.0)100μL/測定点を加えることで、細胞を染色した。染色細胞の水による洗浄サイクルを3回行った後、プレートを室温にて乾燥させた。10%酢酸溶液100μL/測定点を加えることで染料を溶解させた。消失を、波長595nmの測光法によって消光を測定した。ゼロポイントプレートの消光値(=0%)と未処理(0μm)細胞の消光値(=100%)に対して測定値を正規化することでパーセント単位での細胞数の変化を計算した。4パラメータ適合によって、IC50値(50%最大効果での阻害濃度)を求めた。
Caco−2細胞(DSMZ Braunschweig, Germanyから購入)を、4.5×104細胞/ウェルの密度にて24ウェルインサートプレート(孔径0.4μm)に接種し、15日間にわたり10%ウシ胎仔血清、1%GlutaMAX(100倍、GIBCO)、100U/mLペニシリン、100μg/mLストレプトマイシン(GIBCO)および1%非必須アミノ酸(100倍)を補充したDMEM培地で増殖させた。細胞を、37℃で湿度5%CO2雰囲気に維持した。培地は2から3日ごとに交換した。透過アッセイを行う前に、培地を、FCSを含まないhepes−カーボネート輸送緩衝液(pH7.2)に換えた。単層の完全性を評価するために、経上皮電気抵抗(TEER)を測定した。試験化合物を、DMSOに予め溶解させて、輸送緩衝液中最終濃度2μMで先端(apical)区画または側底(basolateral)区画に加えた。37℃でインキュベーションの2時間前後に、サンプルを両方の区画から採取した。化合物含有量の分析を、メタノールによる沈澱後に、LC/MS/MS分析によって行った。透過率(Papp)を、先端から側底方向(A→B)と側底から先端方向(B→A)で計算した。その見かけの透過率は、下記の等式を用いて計算した。
式中、Vrは受け取りチャンバでの培地体積であり、Poはt=0時の供与チャンバでの試験薬剤のピーク面積もしくはピーク高さ測定値であり、Sは単層の表面積であり、P2は、2時間のインキュベーション後の受け取りチャンバ内の試験薬剤の測定ピーク面積であり、tはインキュベーション時間である。Papp B−AをPapp A−Bで割ることで、側底(B):先端(A)の流出比を計算した。さらに、化合物回収率を計算した。
式(I)の化合物の一般的合成
本発明による式(I)の4−(ベンゾフラン−7−イル)−置換5−フルオロ−ピリミジン誘導体およびそれの下位集合、例えば式(7)、(8)および(10)の化合物の合成は、下記図式1および2に従って行うことができる。
化学についての説明と下記の実施例で使用される略称:
CDCl3(重クロロホルム);cHex(シクロヘキサン);d(二重線);DCM(ジクロロメタン);DIPEA(ジイソプロピルエチルアミン);DME(1,2−ジメトキシエタン)、DMF(ジメチルホルムアミド);DMSO(ジメチルスルホキシド);eq(当量);ES(エレクトロスプレー);EtOAc(酢酸エチル);EtOH(エタノール);iPrOH(イソプロパノール);mCPBA(メタクロロ過安息香酸)、MeCN(アセトニトリル)、MeOH(メタノール);MS(質量分析);NBS(N−ブロモコハク酸イミド)、NMP(1−メチルピロリジン−2−オン)、NMR(核磁気共鳴);p(五重線);Pd(dppf)Cl2([1,1′−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)のジクロロメタンとの錯体);iPrOH(イソプロパノール);q(四重線);RT(室温);s(一重線);sat. aq.(飽和水溶液);SiO2(シリカゲル);TFA(トリフルオロ酢酸);TFAA(無水トリフルオロ酢酸)、THF(テトラヒドロフラン);tr(三重線)。
(rac)−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−λ4−スルファニリデン]−シアナミド(483mg;1.14mmol;中間体1.5)のアセトン(24.4mL)中溶液を撹拌しながら、それに室温で過マンガン酸カリウム(368mg;2.28mmol)を加えた。バッチを50℃で1時間撹拌した。バッチを濃縮し、残留物をシリカゲルでのカラムクロマトグラフィー(ヘキサン/酢酸エチル)によって精製して、所望の生成物を得た(267mg;0.59mmol)。
[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミドのエナンチオマー
(rac)−[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド
(rac)−[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−ベンジル)(メチル)−λ4−スルファニリデン]シアナミド
(rac)−[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−λ4−スルファニリデン]シアナミド(1.68g;3.69mmol;中間体7.4)を用い、実施例1の製造において記載のものと同様の条件下で実施例7を製造した。バッチをシリカゲルでのカラムクロマトグラフィー(ヘキサン/酢酸エチル)によって精製して、標題化合物を得た(1.01g;2.07mmol)。
[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミドのエナンチオマー
5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミンのエナンチオマー
(rac)−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド
rac−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)(メチル)−λ4−スルファニリデン]シアナミド
rac−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)(メチル)−λ4−スルファニリデン]シアナミド(310mg;0.71mmol;中間体13.4)を用い、実施例1の製造において記載のものと同様の条件下で実施例13を製造した。バッチをシリカゲルでのカラムクロマトグラフィー(ヘキサン/酢酸エチル)によって精製して、標題化合物を得た(190mg;0.42mmol)。
[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミドのエナンチオマー
(rac)−{[3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−(ペンタフルオロ−λ6−スルファニル)ベンジル](メチル)オキシド−λ6−スルファニリデン}シアナミド
5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(メチルスルファニル)メチル]−5−(ペンタフルオロ−λ6−スルファニル)フェニル}ピリミジン−2−アミン
(rac)−[3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−(ペンタフルオロ−λ6−スルファニル)ベンジル](メチル)−λ4−スルファニリデン]シアナミド
(rac)−[3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−(ペンタフルオロ−λ6−スルファニル)ベンジル](メチル)−λ4−スルファニリデン]シアナミド(205mg;0.373mmol;中間体17.7)を用い、実施例1の製造において記載のものと同様の条件下で実施例17を製造した。バッチをシリカゲルでのクロマトグラフィー(ヘキサン/酢酸エチル)によって精製して、標題化合物を得た(120mg;0.21mmol)。
(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)メチル]−5−(ペンタフルオロ−λ6−スルファニル)フェニル}ピリミジン−2−アミン
表2:本発明による化合物のCDK9およびCDK2の阻害
IC50(最大効果の50%での阻害濃度)値を、nM単位で示しており、「n.t.」は、個々のアッセイで、その化合物について試験を行っていないことを意味する。
2:CDK9:材料および方法の方法1a下に記載のCDK9/CycT1キナーゼアッセイ
3:材料および方法の方法2a.下に記載のCDK2:CDK2/CycEキナーゼアッセイ
4:材料および方法の方法1a.および2a.による選択性CDK9対CDK2:IC50(CDK2)/IC50(CDK9)
5:材料および方法の方法1b.下に記載の高ATPCDK9:CDK9/CycT1キナーゼアッセイ
6:材料および方法の方法2b.下に記載の高ATPCDK2:CDK2/CycEキナーゼアッセイ
7:材料および方法の方法1b.および2b.による選択性高ATPCDK9対高ATPCDK2:IC50(高ATPCDK2)/IC50(高ATPCDK9)
2:HeLa細胞増殖の阻害
3:HeLa−MaTu−ADR細胞増殖の阻害
4:NCI−H460細胞増殖の阻害
5:DU145細胞増殖の阻害
6:Caco−2細胞増殖の阻害
7:B16F10細胞増殖の阻害
8:A2780細胞増殖の阻害
9:MOLM−13細胞増殖の阻害
前記細胞系は、表3aに示した下記の適応症を表すものである。
Claims (21)
- 一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。
[式中、
R1は、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ヘテロアリール−、フェニル−C1−C3−アルキル−およびヘテロアリール−C1−C3−アルキル−から選択される基を表し、
前記基は、ヒドロキシ、シアノ、ハロゲン、ハロ−C1−C3−アルキル−、C1−C6−アルコキシ−、C1−C3−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、−OP(O)(OH)2、−C(O)OH、−C(O)NH2の群から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く;
R2は、下記の基:
を表し;
R3、R4は互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、−SF5、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R5は、水素原子、シアノ、−C(O)R9、−C(O)OR9、−S(O)2R9、−C(O)NR10R11、−P(O)(OR12)2、−CH2OP(OR12)2、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−またはヘテロアリール−基は、ハロゲン、ヒドロキシ、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く;
R6、R7は互いに独立に、水素原子、フッ素原子、塩素原子、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R8a、R8bは互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R9は、C1−C6−アルキル−、ハロ−C1−C3−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−およびヘテロアリール−から選択される基を表し、
前記基は、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く;
R10、R11は互いに独立に、水素原子、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−およびヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−またはヘテロアリール−基は、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成しており;
R12は、水素原子、C1−C4−アルキル−およびベンジル−から選択される基を表す。] - R1が、C1−C6−アルキル−、C3−C5−シクロアルキル−から選択される基を表し、
前記基が、ヒドロキシ、ハロ−C1−C2−アルキル−、C1−C3−アルコキシ−、C1−C2−フルオロアルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、環状アミン類、−OP(O)(OH)2、−C(O)OH、−C(O)NH2の群から選択される1個の置換基で置換されていても良く;
R2が、下記の基:
を表し;
R3が、水素原子、フッ素原子または塩素原子、−SF5基、C1−C3−アルキル−基またはフルオロ−C1−C3−アルキル−基を表し;
R4が、水素原子またはフッ素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−S(O)2R9、−C(O)NR10R11、−P(O)(OR12)2、−CH2OP(OR12)2、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−またはヘテロアリール−基が、ハロゲン、ヒドロキシ、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く;
R6、R7が互いに独立に、水素原子、フッ素原子、塩素原子、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R8a、R8bが互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、C1−C3−アルキル−、C1−C3−アルコキシ−、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される基を表し;
R9が、C1−C6−アルキル−、ハロ−C1−C3−アルキル−、C3−C7−シクロアルキル−、複素環−、フェニル−、ベンジル−およびヘテロアリール−から選択される基を表し、
前記基が、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く;
R10、R11が互いに独立に、水素原子、C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、ベンジル−、フェニル−およびヘテロアリール−から選択される基を表し、
前記C1−C6−アルキル−、C3−C7−シクロアルキル−、複素環−、ベンジル−、フェニル−またはヘテロアリール−基が、ハロゲン、ヒドロキシ、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、アセチルアミノ−、N−メチル−N−アセチルアミノ−、環状アミン類、ハロ−C1−C3−アルキル−、C1−C3−フルオロアルコキシ−から選択される同一または異なる1個、2個もしくは3個の置換基で置換されていても良く、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成しており;
R12が、水素原子およびC1−C2−アルキル−から選択される基を表す、請求項1に記載の一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。 - R1が、C1−C6−アルキル−、C3−C5−シクロアルキル−から選択される基を表し、
前記基が、ヒドロキシ、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−、環状アミン類、−OP(O)(OH)2の群から選択される1個の置換基で置換されていても良く;
R2が、下記の基:
を表し;
R3が、水素原子、フッ素原子または塩素原子、−SF5基、C1−C3−アルキル−基またはフルオロ−C1−C3−アルキル−基を表し;
R4が、水素原子またはフッ素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11、−P(O)(OR12)2、−CH2OP(OR12)2、C1−C3−アルキル−から選択される基を表し、
前記C1−C3−アルキル基が、−NH2、アルキルアミノ−、ジアルキルアミノ−および環状アミン類から選択される1個の置換基で置換されていても良く;
R6、R7は互いに独立に、水素原子、フッ素原子および塩素原子から選択される基を表し;
R8a、R8bが互いに独立に、水素原子、フッ素原子、塩素原子、臭素原子、シアノ、メチル−、メトキシ−、ハロメチル−、フルオロメトキシ−から選択される基を表し;
R9が、C1−C3−アルキル−、ハロ−C1−C3−アルキル−、およびベンジル−基から選択される基を表し、そのフェニル−基が、ハロゲン、C1−C3−アルキル−、C1−C3−アルコキシ−、−NH2、アルキルアミノ−、ジアルキルアミノ−の群から選択される同一または異なる1個もしくは2個の置換基で置換されていても良く;
R10、R11が互いに独立に、水素原子、C1−C3−アルキル−、ベンジル−から選択される基を表し、または
R10およびR11が、それらが結合している窒素原子とともに、環状アミンを形成しており;
R12が、水素原子およびメチル−から選択される基を表す、請求項1に記載の一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。 - R1が、C1−C6−アルキル−基を表し、
前記基が、C1−C3−アルコキシ、−NH2、アルキルアミノ−、ジアルキルアミノ−および環状アミン類の群から選択される1個の置換基で置換されていても良く;
R2が、下記の基:
を表し;
R3が、水素原子、フッ素原子または塩素原子または−SF5、メチル−、エチル−またはトリフルオロメチル−基を表し;
R4が、水素原子またはフッ素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11から選択される基を表し;
R6、R7が互いに独立に、水素原子、フッ素原子および塩素原子から選択される基を表し;
R9が、C1−C3−アルキル−基、ベンジル−基、またはトリフルオロメチル−を表し;
R10、R11が互いに独立に、水素原子、C1−C2−アルキル−から選択される基を表す、請求項1に記載の一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。 - R1が、C1−C3−アルキル−基を表し;
R2が、下記の基:
を表し;
R3が、水素原子またはフッ素原子またはメチル−または−SF5基を表し;
R4が、水素原子を表し;
R5が、水素原子、シアノ、−C(O)R9、−C(O)OR9、−C(O)NR10R11から選択される基を表し;
R6が、水素原子およびフッ素原子から選択される基を表し、
R7が、水素原子を表し;
R9が、メチル−、エチル−またはトリフルオロメチル−基を表し;
R10が、C1−C2−アルキル−基を表し;
R11が、水素原子を表す、請求項1に記載の一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。 - R5が、水素原子およびシアノ基から選択される基を表す、請求項1から6のいずれか1項に記載の一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。
- R3が、水素原子またはフッ素原子またはメチル−または−SF5基を表し;
R4が、水素原子を表す、請求項1から7のいずれか1項に記載の一般式(I)の化合物または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。 - (rac)−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミド;
[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー1;
[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー2;
(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)−メチル]フェニル}−ピリミジン−2−アミン;
5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー1;
5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー2;
(rac)−[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド;
[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー1;
[(3−フルオロ−5−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}ベンジル)(メチル)−オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー2;
(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;
5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー1;
5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−フルオロ−5−[(S−メチルスルホンイミドイル)−メチル]−フェニル}−ピリミジン−2−アミン;エナンチオマー2;
(rac)−[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド;
[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー1;
[(3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−メチルベンジル)−(メチル)オキシド−λ6−スルファニリデン]シアナミド;エナンチオマー2;
(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−メチル−5−[(S−メチルスルホンイミドイル)−メチル]フェニル}ピリミジン−2−アミン;
(rac)−{[3−{[5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)ピリミジン−2−イル]アミノ}−5−(ペンタフルオロ−λ6−スルファニル)ベンジル](メチル)オキシド−λ6−スルファニリデン}シアナミドおよび
(rac)−5−フルオロ−4−(4−フルオロ−1−ベンゾフラン−7−イル)−N−{3−[(S−メチルスルホンイミドイル)メチル]−5−(ペンタフルオロ−λ6−スルファニル)フェニル}ピリミジン−2−アミン
から選択される請求項1に記載の化合物、または該化合物のエナンチオマー、ジアステレオマー、塩、溶媒和物もしくは溶媒和物の塩。 - 過剰増殖性障害、ウィルス誘発感染疾患および/または心血管疾患の治療および/または予防に使用するための請求項1から10のいずれか1項に記載の一般式(I)の化合物。
- メラノーマ、子宮頸癌、肺癌、卵巣癌、前立腺癌、結腸直腸癌または白血病の治療および/または予防に使用するための請求項1から10のいずれか1項に記載の一般式(I)の化合物。
- 過剰増殖性障害、ウィルス誘発感染疾患および/または心血管疾患の治療および/または予防のための医薬製造における請求項1から10のいずれか1項に記載の一般式(I)の化合物の使用。
- 肺癌、前立腺癌、子宮頸癌、結腸直腸癌、メラノーマ、卵巣癌または白血病の治療および/または予防のための医薬製造における請求項1から10のいずれか1項に記載の一般式(I)の化合物の使用。
- 非小細胞肺癌、ホルモン非依存性ヒト前立腺癌、子宮頸癌、多剤耐性ヒト子宮頸癌、結腸直腸癌、メラノーマ、卵巣癌または急性骨髄性白血病の治療および/または予防のための医薬製造における請求項1から10のいずれか1項に記載の一般式(I)の化合物の使用。
- 少なくとも1以上の別の有効成分と組み合わせた請求項1から10のいずれか1項に記載の化合物を含む組み合わせ医薬。
- 不活性で無毒性の医薬として好適な補助剤と組み合わせて請求項1から10のいずれか1項に記載の化合物を含む医薬組成物。
- 過剰増殖性障害、ウィルス誘発感染疾患および/または心血管疾患の治療および/または予防のための請求項16に記載の組み合わせ医薬。
- 過剰増殖性障害、ウィルス誘発感染疾患および/または心血管疾患の治療および/または予防のための請求項17に記載の医薬組成物。
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EP2755948B1 (en) * | 2011-09-16 | 2016-05-25 | Bayer Intellectual Property GmbH | Disubstituted 5-fluoro pyrimidine derivatives containing a sulfoximine group |
US20150259300A1 (en) | 2012-10-18 | 2015-09-17 | Bayer Pharma Aktiengesellschaft | 4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amines containing a sulfone group |
TW201418243A (zh) * | 2012-11-15 | 2014-05-16 | Bayer Pharma AG | 含有磺醯亞胺基團之n-(吡啶-2-基)嘧啶-4-胺衍生物 |
US9499492B2 (en) * | 2012-11-15 | 2016-11-22 | Bayer Pharma Aktiengesellschaft | 4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amines containing a sulfoximine group |
KR102242871B1 (ko) | 2012-11-15 | 2021-04-20 | 바이엘 파마 악티엔게젤샤프트 | 술폭시민 기를 함유하는 5-플루오로-n-(피리딘-2-일)피리딘-2-아민 유도체 |
JP6371385B2 (ja) | 2013-07-04 | 2018-08-08 | バイエル ファーマ アクチエンゲゼルシャフト | スルホキシイミン置換5−フルオロ−n−(ピリジン−2−イル)ピリジン−2−アミン誘導体およびそのcdk9キナーゼ阻害薬としての使用 |
CN106232596A (zh) | 2014-03-13 | 2016-12-14 | 拜耳医药股份有限公司 | 含有砜基团的5‑氟‑n‑(吡啶‑2‑基)吡啶‑2‑胺衍生物 |
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CN107001341A (zh) | 2017-08-01 |
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WO2016059086A1 (en) | 2016-04-21 |
EP3207038B1 (en) | 2018-08-22 |
JP2017535532A (ja) | 2017-11-30 |
CA2964696C (en) | 2022-09-06 |
EP3207038A1 (en) | 2017-08-23 |
CA2964696A1 (en) | 2016-04-21 |
US9884849B2 (en) | 2018-02-06 |
CN107001341B (zh) | 2020-08-07 |
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