JP6553748B2 - 縮合環化合物、医薬組成物およびその使用 - Google Patents
縮合環化合物、医薬組成物およびその使用 Download PDFInfo
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- JP6553748B2 JP6553748B2 JP2017560857A JP2017560857A JP6553748B2 JP 6553748 B2 JP6553748 B2 JP 6553748B2 JP 2017560857 A JP2017560857 A JP 2017560857A JP 2017560857 A JP2017560857 A JP 2017560857A JP 6553748 B2 JP6553748 B2 JP 6553748B2
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- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims description 540
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- 125000000217 alkyl group Chemical group 0.000 claims description 174
- 125000003545 alkoxy group Chemical group 0.000 claims description 97
- -1 -SH Chemical group 0.000 claims description 80
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 75
- 150000003839 salts Chemical class 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 239000001257 hydrogen Substances 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 49
- 150000002431 hydrogen Chemical class 0.000 claims description 44
- 206010028980 Neoplasm Diseases 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 229910052727 yttrium Inorganic materials 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims description 26
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims description 25
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 24
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 24
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 22
- 150000001356 alkyl thiols Chemical class 0.000 claims description 22
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 12
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- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
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- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 244000131360 Morinda citrifolia Species 0.000 claims 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 235000017524 noni Nutrition 0.000 claims 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 345
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 315
- 230000015572 biosynthetic process Effects 0.000 description 230
- 238000003786 synthesis reaction Methods 0.000 description 229
- 239000000243 solution Substances 0.000 description 226
- 238000005481 NMR spectroscopy Methods 0.000 description 178
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 136
- 239000007787 solid Substances 0.000 description 125
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 120
- 229910052938 sodium sulfate Inorganic materials 0.000 description 119
- 235000011152 sodium sulphate Nutrition 0.000 description 119
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
- 239000012074 organic phase Substances 0.000 description 106
- 239000012267 brine Substances 0.000 description 104
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 104
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 88
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- 238000000034 method Methods 0.000 description 82
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- 238000004128 high performance liquid chromatography Methods 0.000 description 64
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 63
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- 238000000926 separation method Methods 0.000 description 45
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 25
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- 239000007858 starting material Substances 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 21
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- 125000005647 linker group Chemical group 0.000 description 9
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- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 6
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- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 5
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Description
式(I)の化合物および/またはその異性体、プロドラッグ、安定同位体誘導体、および/またはその薬学的に許容される塩を提供する;
nは1、2または3であり、tは1または2であり; UはN、CまたはCR4であり、結合αは単結合または二重結合であり; UがN、またはCR4でる場合、結合αは単結合であり、UがCの場合、結合αは二重結合であり;
A環は5員複素芳香環であり; Z、Z1、Z2、Z3、Z4は独立してNまたはCであり、およびZ3およびZ4は同時にNではなく;
B環はベンゼンまたは5もしくは6員の複素芳香環であり;
結合αが単結合である場合、A1は-(CR9R9a)m-または-C2-4アルケニル-であり、mは0、1、2または3であり;
結合αが二重結合の場合、A1は-CR9(CR9R9a)m-であり、mは0、1、2または3であり;
R9は、独立して水素、ハロゲン、置換または非置換アルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アルコキシであり; R9aは独立して水素、重水素、ハロゲン、置換または非置換アルキルであり; または、R9およびR9aは、それらが結合している炭素原子と一緒になって、3〜8員環のモノシクロアルキル環を形成し;
A2は、-C(=R7)(CR5R5a)m-、-(CR5R5a)m-、-(C=R7)O-、-(CR5R5a)mO-または-S(O)0-2(CR5R5a)m-であり; ここでmは0、1、2または3であり; R5およびR5aは、独立して水素、ヒドロキシル、ハロゲン、アルキル、アミノ、-SR6、-OR6、-NR6R6a、-NR6S(O)2R6a、-S(O)2NR6R6a、-(CH2)rS(O)0-2CH3、-OS(O)3H、-OP(O)(O-R6)2、-OC(O)R6、-OC(O)NR6R6a、-C(O)NR6R6a、-(CH2)rC(O)OH、-(CH2)rOH、-(CH2)rNR6R6aまたは-(CH2)rC(O)NR6R6aであり; rは、1〜8の範囲の整数であり;
R1は、水素、ハロゲン、ヒドロキシル、アルキル、アルコキシ、アルキルチオール、ハロアルキル、ハロアルコキシ、アミノ、C2-6 アルキニル、C2-6 アルケニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、-SH、-CN、-NO2、-OC(O)R6、-OC(O)OR6、-OC(O)NR6R6a、-C(O)OR6、-C(O)R6、-C(O)NR6R6a、-NR6R6a、-NR6C(O)R6a、-NR6C(O)OR6a、-NR6C(O)NR6R6a、-(CH2)rNR6R6a、-NR6S(O)2R6a、-S(O)0-2R6または-S(O)2NR6R6aであり; rは1〜8の範囲の整数であり;
R2は、水素、ハロゲン、ヒドロキシル、アルキル、アルコキシ、アルキルチオール、ハロアルキル、ハロアルコキシ、アミノ、C2-6 アルキニル、C2-6 アルケニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、-SH、-CN、-NO2または-NR6R6aであり;
R6およびR6aは、独立して水素、アルキル、ハロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、ヘテロシクロアルキルアルキル、シクロアルキルアルキル、アリールアルキルまたはヘテロアリールアルキルであり、R6およびR6aは、それらが結合している炭素原子と一緒になって、3〜8員環モノヘテロシクロアルキル環を形成し;
いくつかの実施形態において、R6およびR6aは、独立して水素、C1-4 アルキル、ハロ-C1-4アルキル、C3-8シクロアルキル、5〜8員環ヘテロシクロアルキル、C6-10 アリール、5〜6員環ヘテロアリール、5〜8員環ヘテロシクロアルキル-C1-4 アルキル、C3-8シクロアルキル-C1-4 アルキル、C6-10アリール-C1-4アルキル、または5〜6員環ヘテロアリール-C1-4アルキル、またはそれらが結合している炭素原子と一緒になって、3〜8員環モノヘテロシクロアルキル環を形成し;
R3は、置換または非置換アルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、置換または非置換トリシクロアルキル、または置換または非置換架橋ヘテロシクロアルキルであり; Uが、CまたはCR4の場合が提供され、B環は、ベンゼンであり、R3は置換または非置換C9-20シクロアルキル、置換または非置換架橋トリシクロアルキル、または置換または非置換架橋ヘテロシクロアルキルであり;
R4は、水素、重水素、ハロゲン、-CN、-C(O)OH、テトラゾール、置換または非置換アルキル、置換または非置換アルコキシである)
1)式(IA)の化合物および/またはその薬学的に許容される塩、
2)式(IB)の化合物および/またはその薬学的に許容される塩、
3)式(IC)の化合物および/またはその薬学的に許容される塩、
4)式(ID)の化合物および/またはその薬学的に許容される塩、
Y、Y1、XおよびX1は、独立してCまたはNであり; pは1または2であり;
Z、Z1、Z2、Z3、Z4、R1、R2、U、結合α、A1、A2、R10およびnはその各実施形態を含む式(I)についての記載と同じであり;
式(I)について記載したように、Y、Y1、X、X1、p(式(IA)〜(ID)について説明したように)、Z、Z1、Z2、Z3、Z4、R1、R2、U、結合α、A1、A2、R10、nおよびtは、式(IA)〜(ID)の範囲内である)
である。
1)式(IA-1)の化合物および/またはその薬学的に許容される塩、または
2)式(IB-1)の化合物および/またはその薬学的に許容される塩、
XおよびX1は、独立してCまたはNであり; pは1又は2であり、
R1、R2、R4、R10、A1、A2およびnは、それぞれの実施形態を含む式(I)について記載したものと同じである)
である。
1)式(IE)の化合物および/または薬学的に許容される塩、または
2)式(IF)の化合物および/または薬学的に許容される塩、
XおよびX1は独立してCまたはNであり;
R1、R2、R4、R10、A1、A2およびnは、そのそれぞれの実施形態を含む式(I)について記載したものと同じであり、
である。
R1、A1、A2およびR10はそのそれぞれの実施形態を含む式(I)について記載したものと同じであり、
である。
1)式(IG)の化合物および/またはその薬学的に許容される塩、または
2)式(IH)の化合物および/またはその薬学的に許容される塩、
Y、Y1、XおよびX1は、独立してCまたはNであり;
R1、R4、A1、A2、R10およびnは、そのそれぞれの実施形態を含む式(I)について記載したものと同じである)
である。
1)式(IJ)の化合物および/またはその薬学的に許容できる塩、または
2)式(IK)の化合物および/またはその薬学的に許容できる塩、
Y、Y1、XおよびX1は独立してCまたはNであり;
Z、Z1、Z2、Z3、Z4、R1、R2、R3、R5、nおよびtは、そのそれぞれの実施形態を含む式(I)について記載したものと同じであり、
「*」で標識された単結合の立体異性の構造は、それぞれ(S、S)、(S、R)、(R、S)、(R、R)である)
である。
ビンブラスチンアナログ(例えば、ビンブラスチン、ビンクリスチンおよびビンデジシン)、タキサンアナログ(例えば、パラタキセルおよびドセタキセル)およびエリブリンメシレートを含む抗微小管剤から選択される。
葉酸拮抗体、ピリミジンアナログ、プリンアナログおよびアデノシンデアミナーゼ阻害剤; 例えば、メトトレキサート、5-フルオロウラシル、フロクスウリジン、シタラビン、6-メルカプトプリン、6-チオグアニン、リン酸フルダラビン、ペントスタチンおよびゲムシタビンなどの代謝拮抗剤から選択される。
方法1:
方法2:
以下の実施例は、本開示における化合物および調製方法を説明する役割を果たすが、実施例は、本開示の範囲を限定するものとみなされるべきではない。下記化合物において、飽和炭素における
方法A: 28〜72% (v/v%)移動相Aおよび72〜28% (v/v%)移動相B;
方法B: 25〜75% (v/v%)移動相Aおよび75〜25% (v/v%)移動相B;
方法C: 30〜60% (v/v%)移動相Aおよび70〜40% (v/v%)移動相B;
方法D: 30〜70% (v/v%)移動相Aおよび70〜30% (v/v%)移動相B;
方法E: 30〜60% (v/v%)移動相Aおよび70〜40% (v/v%)移動相B;
方法F: 20〜50% (v/v%)移動相Aおよび80〜50% (v/v%)移動相B;
方法G: 95〜60% (v/v%)移動相Aおよび5〜40% (v/v%)移動相B;
方法H: 60〜95% (v/v%)移動相Aおよび40〜5% (v/v%)移動相B;
方法I: 35〜60% (v/v%)移動相Aおよび65〜40% (v/v%)移動相B;
方法J: 75〜70% (v/v%)移動相Aおよび25〜30% (v/v%)移動相B;
方法K: 18〜82% (v/v%)移動相Aおよび82〜18% (v/v%)移動相B;
方法L: 20〜80% (v/v%)移動相Aおよび80〜20% (v/v%)移動相B;
方法M: 65〜80% (v/v%)移動相Aおよび35〜20% (v/v%)移動相B;
方法N: 5〜33%(v/v%)移動相Aおよび95〜67% (v/v%)移動相B。
TLCはYantai Huanghai HSGF254またはQingdao GF254シリカゲルプレートであった。
中間体1:2-(1-トリチル-1H-イミダゾール-4-イル)ベンズアルデヒド(1.1)の合成
実施例1: 化合物1の合成
次いで、混合物に水(10mL)を加え停止させ、酢酸エチル(10mL×3)で抽出した。合わせた有機相をブラインで洗浄し、硫酸ナトリウムで乾燥し、濾過し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:石油エーテル= 9:1)で精製して、化合物76(160mg、収率:40%)をオフホワイトの固体として得た。
トリホスゲン(217mg、0.73mmol)のジクロロメタン溶液(2mL)に、上記溶液を注射器で滴下した。得られた混合物を室温で2時間撹拌して、4-イソシアナトテトラヒドロ-2H-ピラン(54.1)のジクロロメタン溶液を得た。これは、次のステップに直接用いることができる。
実施例1: IDO1酵素アッセイ
各ウェルは100μLの培養培地を含み、続いてIFN-γおよび試験化合物を特定濃度(10μM〜1Nmの濃度範囲で、培養培地の最終容量が、200μLになるように)を加え、IFN-γをIDO1発現を誘導するために用いた。インキュベーション後、140μLの上清を96ウェルプレートに移した。6.1 N TCA(10μL)を加えた後、プレートを50℃で30分間連続してインキュベートし、IDOによって産生されたN-ホルミルキヌレニンをキヌレニンに加水分解した。次いで、反応溶液を2500rpmで10分間遠心分離して沈殿物を除去した。次いで、100μL/ウェルの上清を別の96ウェルプレートに移した。100μLの2%(w/v)4-N、N-ジメチルアミノベンズアルデヒド酢酸溶液を加え、室温で10分間インキュベートした。キヌレニン由来の黄色は、マイクロプレートリーダー(TECAN Infinite M1000 Pro)を用いて480nmでの吸光度を測定することによって記録した。
Ref.A: (1R、4r)-4-((R)-2-((S)-6-フルオロ-5H-イミダゾ[5,1-a]イソインドール-5-イル)-1-ヒドロキシエチル)シクロヘキサノール
Ref.B: 4-アミノ-N-(3-クロロ-4-フルオロフェニル)-N'-ヒドロキシ-1,2,5-オキサジアゾール-3-カルボキシミドアミド
Claims (11)
- 式(I)の化合物;
nは1、2または3であり; tは2であり; UはCR4であり、結合αは単結合であり;
A環は、5員環ジアザアリールであり; 及び
Z1及びZ4は、Nであり; Z、Z2及びZ3は、Cであり;
B環はベンゼン、ピリジン、またはピリミジンであり;
A1は、-CH 2 であり;
R9は、独立して水素であり;
R9aは、独立して水素、または重水素であり;
A2は、-CH(OH)-、-CH(OPO 3 H 2 )-、
R5およびR5aは、独立して水素、ヒドロキシル、-SR6、-OR6、-OP(O)(O-R6)2、または-OC(O)R6であり;
R1は、水素、ハロゲン、ヒドロキシル、C1-3アルキル、C1-3アルコキシ、C1-3アルキルチオール、ハロ-C1-3アルキル、ハロ-C1-3アルコキシ、アミノ、C2-6アルキニル、C2-6アルケニル、-SH、-CN、-NO2、-OC(O)R6、-C(O)OR6、-C(O)R6、-C(O)NR6R6a、または-NR6R6aであり;
R2は、-OH、-SH、-NH2、水素、ハロゲン、C1-3アルキル、C1-3アルコキシ、C1-3アルキルチオール、またはハロ-C1-3アルキルであり;
R3は、置換または非置換架橋C7-10トリシクロアルキル、または置換または非置換架橋7〜10員環ヘテロシクロアルキルであり; ここで、置換架橋C7-10トリシクロアルキル、または置換架橋7〜10員環ヘテロシクロアルキルは、一つまたはそれ以上のR10によって置換され;
R4は、水素、フッ素、ヒドロキシル、C1-4アルキル、またはC1-4アルコキシであり;
R10は、独立して、-NO2、-CN、-OH、-NH2、-SH、ハロゲン、置換または非置換C1-4アルキル、置換または非置換C1-4アルコキシ、置換または非置換C6-10アリール、置換または非置換5〜10員環ヘテロアリール、置換または非置換C3-8シクロアルキル、置換または非置換5〜8員環ヘテロシクロアルキル、置換または非置換C2-6アルキニル、置換または非置換C2-6アルケニル、-L-R8、-O-L-R8、-N(R8)-L-R8b、-L-OR8b、-L-OC(O)R8b、-L-OC(O)NR8R8b、-L-OP(O)(O-R8)2、-L-S(O)2NR8R8b、-L-S(O)0-2R8b、-L-S(O)2N(R8)C(O)NR8R8b、-L-C(O)OR8b、-L-C(O)R8b、-L-C(=R7)NR8R8b、-L-NR8R8b、-L-N(R8)C(O)OR8b、-L-N(R8)C(=R7)R8b、-L-N(R8)C(=R7)NR8R8b、-L-N(R8)S(O)1-2R8b、または-L-N(R8)S(O)1-2NR8R8bであり; ここで、置換C1-4アルキル、置換C1-4アルコキシ、置換C3-8シクロアルキル、置換5〜8員環ヘテロシクロアルキル、置換C6-10アリール、置換5〜10員環ヘテロアリール、置換C2-6アルケニル、または置換C2-6アルキニルが、任意の位置で1〜3のR13によって置換され;
R13は、F、Cl、Br、-OH、-SH、-CN、-NO2、-NH2、C1-4アルキルチオール、C3-8シクロアルキル、-C(O)NR6R6a、-OC(O)R6、-OC(O)OR6、-OC(O)NR6R6a、-C(O)OR6、-C(O)R6、-C(O)NR6R6a、-NR6R6a、-NR6C(O)R6a、-NR6C(O)R6a、-NR6C(O)OR6a、-NR6C(O)NR6R6a、-NR6C(O)NR6R6a、-NR6S(O)2R6a、-NR6S(O)2NR6R6a、-S(O)0-2R6、-S(O)2NR6R6a、-(CH2)rNR6R6a、C1-4アルキル、C1-4アルコキシ、フェニル、5〜6員環ヘテロアリール、C3-8シクロアルキル、又は5〜8員環ヘテロシクロアルキルであり;
Lは、結合またはL1であり、ここで、L1は、-(CR8R8a)rであり; またはR8およびR8aが、それらが結合している炭素原子と一緒になって3〜8員環のモノシクロアルキル環を形成し;
R8は、独立して、水素、C1-4アルキル、C1-4アルコキシ、C3-8シクロアルキル、5〜8員環ヘテロシクロアルキル、C6-10アリール、または5〜10員環ヘテロアリールであり;
R8aは、水素、ハロゲン、ヒドロキシル、アミノ、C1-4アルキル、C1-4アルコキシ、C3-8シクロアルキル、5〜8員環ヘテロシクロアルキル、C6-10アリール、5〜10員環ヘテロアリール、C3-8シクロアルキル-C1-4アルキル、5〜8員環ヘテロシクロアルキル-C1-4アルキル、C6-10アリール-C1-4アルキル、および5〜6員環ヘテロアリール-C1-4アルキルから選択され;
R8bは、水素、置換または非置換C1-4アルキル、置換または非置換C1-4アルコキシ、置換または非置換C3-8シクロアルキル、置換または非置換5〜8員環ヘテロシクロアルキル、置換または非置換C6-10アリール、置換または非置換5〜10員環ヘテロアリール、置換または非置換C3-8シクロアルキル-C1-4アルキル、置換または非置換5〜8員環ヘテロシクロアルキル-C1-4アルキル、置換または非置換C6-10アリール-C1-4アルキル、置換または非置換5〜6員環ヘテロアリール-C1-4アルキル、-L1-R8、-L1-OR8、-L1-N(R8)2、-L1-C(O)OR8、-L1-OC(O)R8、-L1-C(O)N(R8)2、-L1-N(R8)C(O)R8、-L1-N(R8)C(O)N(R8)2、-L1-S(O)0-2R8、-L1-N(R8)S(O)2N(R8)2、-L1-S(O)2N(R8)2、-L1-N(R8)S(O)2R8、および-L1-OP(O)(O-R8)2から選択され;
さらにここで、R8bにおいて、置換C1-4アルキル、置換C1-4アルコキシ、置換C3-8シクロアルキル、置換5〜8員環ヘテロシクロアルキル、置換C6-10アリール、置換5〜6員環ヘテロアリール、置換C3-8シクロアルキル-C1-4アルキル、置換5〜8員環ヘテロシクロアルキル-C1-4アルキル、置換C6-10アリール-C1-4アルキル、または置換5〜6員環ヘテロアリール-C1-4アルキルは、F、Cl、Br、-OH、-SH、-CN、-NO2、-NH2、C1-4アルキルチオール、C3-8シクロアルキル、-C(O)NR6R6a、-OC(O)R6、-OC(O)OR6、-OC(O)NR6R6a、-C(O)OR6、-C(O)R6、-C(O)NR6R6a、-NR6R6a、-NR6C(O)R6a、-NR6C(O)R6a、-NR6C(O)OR6a、-NR6C(O)NR6R6a、-NR6C(O)NR6R6a、-NR6S(O)2R6a、-NR6S(O)2NR6R6a、-S(O)0-2R6、-S(O)2NR6R6a、置換または非置換C1-4アルキル、置換または非置換C1-4アルコキシ、C2-6アルケニル、C2-6アルキニル、置換または非置換フェニル、5〜6員環ヘテロアリール、C3-8シクロアルキル、及び5〜8員環ヘテロシクロアルキルから独立して選択される1〜3のR14基によって任意の位置で置換され、ここでR14基において、置換C1-4アルキル、置換C1-4アルコキシ、または置換フェニル、置換ヘテロアリール、置換シクロアルキル、または置換ヘテロシクロアルキルは、C1-3アルキル、ハロゲン、C1-3アルコキシ、ハロ-C1-3アルコキシ、ヒドロキシル、およびアミノから独立して選択される1〜3の置換基(単数または複数)によって任意の位置で置換され;
R6およびR6aは、独立して水素、C1-4アルキル、ハロ-C1-4アルキル、C3-8シクロアルキル、5〜8員環ヘテロシクロアルキル、C6-10アリール、5〜6員環ヘテロアリール、5〜8員環ヘテロシクロアルキル-C1-4アルキル、C3-8シクロアルキル-C1-4アルキル、C6-10アリール-C1-4アルキル、または5〜6員環ヘテロアリール-C1-4アルキルであり、またはR6およびR6aが、それらが結合している窒素原子と一緒になって3〜8員のモノヘテロシクロアルキル環を形成し;
rは、1〜8までの整数であり; および
mは、0、1、2、3である。)
である立体異性体、またはその薬学的に許容される塩。 - Uが、CHであり、
または、R1が、-OH、-SH、-CN、水素、ハロゲン、アミノ、C1-3アルコキシ、C1-3アルキルチオール、C1-3アルキル、ハロ-C1-3アルキルまたはハロ-C1-3アルコキシである、請求項1に記載の式(I)の化合物、その立体異性体、またはその薬学的に許容される塩。 - R3が、置換または非置換アザビシクロ[2.2.1]ヘプチル、置換または非置換2-オキサビシクロ[2.2.1]ヘプチル、置換または非置換2,5-ジアザビシクロ[2.2.1]ヘプチル、置換または非置換(1S, 5S)-9-オキサビシクロ[3.3.1]ノニル、置換または非置換(1R, 5S)-8-オキサビシクロ[3.2.1]オクチル、置換または非置換(1R, 5S)-3-オキサビシクロ[3.2.1]オクチル、置換または非置換(1R, 5S)-3-アザビシクロ[3.2.1]オクチル、置換または非置換(1R, 5S)-8-アザビシクロ[3.2.1]オクチル、置換または非置換キヌクリジニル、置換または非置換2-アザ-ビシクロ[2.2.2]オクチル、または置換または非置換2-アザアダマンタニルであり、ここで、置換2-アザビシクロ[2.2.1]ヘプチル、置換2-オキサビシクロ[2.2.1]ヘプチル、置換2,5-ジアザビシクロ[2.2.1]ヘプチル、置換(1S, 5S)-9-オキサビシクロ[3.3.1]ノニル、置換(1R, 5S)-8-オキサビシクロ[3.2.1]オクチル、置換(1R, 5S)-3-オキサビシクロ[3.2.1]オクチル、置換(1R, 5S)-3-アザビシクロ[3.2.1]オクチル、置換(1R, 5S)-8-アザビシクロ[3.2.1]オクチル、置換キヌクリジニル、置換2-アザ-ビシクロ[2.2.2]オクチル、または置換2-アザアダマンタニルが、一つまたはそれ以上のR10によって置換され;
または、R3が、置換または非置換アダマンタニルであり、ここで、置換アダマンタニルが、一つまたはそれ以上のR10によって置換され;
または、R10が、独立して-NO2、-CN、-OH、-NH2、-SH、ハロゲン、置換または非置換C1-4アルキル、置換または非置換C1-4アルコキシ、置換または非置換C6-10アリール、置換または非置換5〜10員環ヘテロアリール、-N(R8)-L-R8b、-L-R8、-O-L-R8、-L-C(O)R8b、-L-C(=R7)NR8R8b、-L-S(O)2R8b、-L-NR8R8b、-L-N(R8)C(=R7)R8b、-L-N(R8)C(=R7)NR8R8bおよび-L-N(R8)S(O)2R8bであり、ここで、置換C1-4アルキル、置換C1-4アルコキシ、置換C6-10アリール、置換5〜10員環ヘテロアリールが、1〜3のR13によって置換される、請求項1に記載の式(I)の化合物、その立体異性体、またはその薬学的に許容される塩。 - L1が、-CH2-、-CH2CH2-、-CH2CH2CH2-または-C(CH3)2-であり;
または、R10が、水素、F、Cl、Br、メチル、エチル、メトキシ、エトキシ、イソプロポキシ、シクロヘキシルオキシ、フェノキシ、ベンジルオキシ、フェニル、ピリジニル、ピリミジニル、テトラゾール、カルボキシル、-OH、-NO2、-NH2、-NHC(O)CH3、-C(O)NH2、-CN、-OCF3、-CF3、-CH2OH、-CH2NH2、-OP(O)(OH)2、
または、R3が、
- 式(I)の化合物、その立体異性体、またはその薬学的に許容される塩が、
1)式(IA)の化合物、その立体異性体、またはその薬学的に許容される塩、
2)式(IB)の化合物、その立体異性体、またはその薬学的に許容される塩、
3)式(IC)の化合物、その立体異性体、またはその薬学的に許容される塩、
4)式(ID)の化合物、その立体異性体、またはその薬学的に許容される塩、
5)式(IA-1)の化合物、その立体異性体、またはその薬学的に許容される塩、
6)式(IB-1)の化合物、その立体異性体、またはその薬学的に許容される塩、
7)式(IE)の化合物、その立体異性体、またはその薬学的に許容される塩、
8)式(IF)の化合物、その立体異性体、またはその薬学的に許容される塩、
9)式(IF-1)の化合物、その立体異性体、またはその薬学的に許容される塩、
10)式(IG)の化合物、その立体異性体、またはその薬学的に許容される塩、
11)式(IH)の化合物、その立体異性体、またはその薬学的に許容される塩、
12)式(IJ)の化合物、その立体異性体、またはその薬学的に許容される塩、または、
13)式(IK)の化合物、その立体異性体、またはその薬学的に許容される塩、
式(IA)、(IB)、(IC)および(ID)において、Y、Y1、XおよびX1は、独立してCまたはNであり; pは、1または2であり;
Z、Z1、Z2、Z3、Z4、R1、R2、U、結合α、A1、A2、R10、nおよびtは、請求項1での定義と同様であり、
式(IA-1)、(IB-1)において、XおよびX1は、独立してCまたはNであり; pは1または2であり; R1、R2、R4、R10、A1、A2およびnは、請求項1での定義と同じであり、
式(IE)、(IF)において、XおよびX1は、独立してCまたはNであり; R1、R2、R4、R10、n、A1およびA2は、請求項1での定義と同じであり、
式(IF-1)において、R1が、水素またはハロゲンであり;R10が、独立して水素、置換または非置換アルキル、置換または非置換アリール、置換または非置換ヘテロアリール、または-L-R8であり、ここで、置換アルキル、アリール、およびヘテロアリールは、1、2または3のR13によって置換され、さらにR8およびR13は、請求項1での定義と同じであり;A1およびA2は、請求項1での定義と同じであり;
式(IG)、(IH)において、X、X1、YおよびY1が、独立してCまたはNであり; R1、R4、R10、n、A1、およびA2が、請求項1での定義と同じであり、
式(IJ)、(IK)において、Y、Y1、XおよびX1は、独立してCまたはNであり; Z、Z1、Z2、Z3、Z4、R1、R2、R3、R5、t、およびnは請求項1での定義と同じであり; *でラベルされた炭素分子の立体異性体配置は、それぞれ(S, S)、(S, R)、(R, S)、(R, R)である)
である、請求項1に記載の式(I)の化合物、その立体異性体、またはその薬学的に許容される塩。 - 結合αが、単結合であり、式(IA)、(IB)、(IC)および(ID)において、UがCR4であり、
または、式(IA-1)、(IB-1)、(IE)、(IF)、(IG)および(IH)において、R4が、水素、ヒドロキシル、フッ素、またはメチルであり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IE)および(IF)において、XおよびX1が、Cであり、または式(IC)および(ID)において、YおよびY1が、Cであり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IE)および(IF)において、XおよびX1の一つが、Nであり、他がCであり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IC)、(ID)、(IE)、(IF)、(IG)、(IH)、(IJ)および(IK)において、R1が、-OH、-SH、-CN、水素、ハロゲン、アミノ、C1-3アルコキシ、C1-3アルキルチオール、C1-3アルキル、ハロ-C1-3アルキル、またはハロ-C1-3アルコキシであり、および、式(IG)、(IH)、(IJ)および(IK)において、nが2であり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IC)、(ID)、(IE)、(IF)、(IG)、(IH)、(IJ)および(IK)において、R2が、-OH、-SH、-NH2、水素、ハロゲン、C1-3アルコキシ、C1-3アルキルチオール、C1-3アルキル、またはハロ-C1-3アルキルであり、および、式(IG)、(IH)、(IJ)および(IK)において、tは2であり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IC)、(ID)、(IE)、(IF)、(IF-1)、(IG)および(IH)において、A1が、-CH2-であり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IC)、(ID)、(IE)、(IF)、(IF-1)、(IG)および(IH)において、A2が、
または、式(IG)、(IH)、(IJ)および(IK)において、Y、Y1、XおよびX1が、Cであり、
または、式(IJ)および(IK)において、R5が、独立してH、OH、-OR6および-OP(O)(O-R6)2であり、ここで、R6が、HまたはC1-4アルキルであり、
または、式(IJ)および(IK)において、R3が、非置換アダマンタニルまたは1または2個のR10で置換されたアダマンタニルであり、
または、式(IJ)および(IK)において、R3が、非置換2-アザアダマンタニルまたは1または2個のR10で置換された2-アザアダマンタニルであり、
または、式(IA)、(IA-1)、(IB)、(IB-1)、(IC)、(ID)、(IE)、(IF)、(IF-1)、(IG)および(IH)において、R10が、独立して-NO2、-CN、-OH、-NH2、-SH、ハロゲン、置換または非置換アルキル、置換または非置換アルコキシ、置換または非置換アリール、置換または非置換ヘテロアリール、-N(R8)-L-R8b、-L-R8、-O-L-R8、-L-C(O)R8b、-L-C(=R7)NR8R8b、-L-S(O)2R8b、-L-NR8R8b、-L-N(R8)C(=R7)R8b、-L-N(R8)C(=R7)NR8R8bおよび-L-N(R8)S(O)2R8bであり、ここで、置換アルキル、置換アルコキシ、置換アリールおよび置換ヘテロアリールが、1、2または3のR13によって置換される、
請求項5に記載の式(I)の化合物、その立体異性体、またはその薬学的に許容される塩。 - 化合物が、
請求項1〜6のいずれか1項に記載の式(I)の化合物、その立体異性体、またはその薬学的に許容される塩。 - 1)請求項1〜7のいずれか1項に記載の式(I)の化合物、その立体異性体、および/またはその薬学的に許容される塩、および2)薬学的に許容される賦形剤、を含む医薬組成物。
- 1)請求項1〜7のいずれか1項に請求項1に記載の式(I)の化合物、その立体異性体、および/またはその薬学的に許容される塩、および2)追加の薬剤が、抗微小管剤、アルキル化剤、トポイソメラーゼI/II阻害剤、白金配位錯体(platinum coordination complexes)、代謝拮抗物質、免疫療法剤、シグナル伝達経路阻害剤、血管新生阻害剤から選択される、追加の薬剤を含む、医薬組成物。
- (1)請求項1〜7のいずれか1項に記載の式(I)の化合物、その立体異性体、および/またはその薬学的に許容される塩、または(2)請求項8または9に記載の医薬組成物、の治療有効量を含む、哺乳動物におけるIDO1および/またはTDO2の阻害によって治療可能な疾患を治療する医薬組成物。
- IDO1および/またはTDO2の阻害によって治療可能な疾患が、癌、ウイルス感染、または自己免疫疾患である、または、哺乳動物がヒトである、請求項10に記載の医薬組成物。
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CN114236024B (zh) * | 2021-12-07 | 2023-12-29 | 江苏宝众宝达药业股份有限公司 | 一种同时测定4-氟-3-硝基苯腈及其异构体含量的方法 |
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EP3259272A4 (en) | 2018-03-21 |
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CN107438611B (zh) | 2019-10-29 |
CA2976670A1 (en) | 2016-08-25 |
CN105884780B (zh) | 2019-11-08 |
US10202388B2 (en) | 2019-02-12 |
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CN107438611A (zh) | 2017-12-05 |
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