JP4796487B2 - 新生物疾患、炎症および免疫系障害の処置に有用な2,4−ジ(フェニルアミノ)ピリミジン - Google Patents
新生物疾患、炎症および免疫系障害の処置に有用な2,4−ジ(フェニルアミノ)ピリミジン Download PDFInfo
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- JP4796487B2 JP4796487B2 JP2006504673A JP2006504673A JP4796487B2 JP 4796487 B2 JP4796487 B2 JP 4796487B2 JP 2006504673 A JP2006504673 A JP 2006504673A JP 2006504673 A JP2006504673 A JP 2006504673A JP 4796487 B2 JP4796487 B2 JP 4796487B2
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- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—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
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/02—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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
R0、R1、R2、およびR3の各々は独立して水素、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、C3−C8シクロアルキルC1−C8アルキル、C5−C10アリールC1−C8アルキル、ヒドロキシC1−C8アルキル、C1−C8アルコキシC1−C8アルキル、アミノC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個、2個または3個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、ヒドロキシ、C1−C8アルコキシ、ヒドロキシC1−C8アルコキシ、C1−C8アルコキシC1−C8アルコキシ、ハロC1−C8アルコキシ、非置換または置換C5−C10アリールC1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、または非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルチオ、C1−C8アルキルスルフィニル、C1−C8アルキルスルホニル、C5−C10アリールスルホニル、ハロゲン、カルボキシ、C1−C8アルコキシカルボニル、非置換または置換カルバモイル、非置換または置換スルファモイル、シアノまたはニトロであるか;
またはR0およびR1、R1およびR2、および/またはR2およびR3は、それらが結合している炭素原子と一体になって、N、OおよびSからなる群から選択される0個、1個、2個または3個のヘテロ原子を含む5または6員炭素環式またはヘテロ環式環を形成し;
R4は水素またはC1−C8アルキルであり;
R5およびR6の各々は独立して水素、C1−C8アルキル、C1−C8アルコキシC1−C8アルキル、ハロC1−C8アルキル、C1−C8アルコキシ、ハロゲン、カルボキシ、C1−C8アルコキシカルボニル、非置換または置換カルバモイル、シアノ、またはニトロであり;
R7、R8、R9、およびR10の各々は独立してC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、C3−C8シクロアルキルC1−C8アルキル、C5−C10アリールC1−C8アルキル、ヒドロキシC1−C8アルキル、C1−C8アルコキシC1−C8アルキル、アミノC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個、2個または3個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、ヒドロキシ、C1−C8アルコキシ、ヒドロキシC1−C8アルコキシ、C1−C8アルコキシC1−C8アルコキシ、ハロC1−C8アルコキシ、非置換または置換C5−C10アリールC1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、または非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルチオ、C1−C8アルキルスルフィニル、C1−C8アルキルスルホニル、C5−C10アリールスルホニル、ハロゲン、カルボキシ、C1−C8アルコキシカルボニル、非置換または置換カルバモイル、非置換または置換スルファモイル、シアノまたはニトロであり;ここで、R7、R8およびR9は、互いに独立して水素であってもよく;
または、R7およびR8、R8およびR9、および/またはR9およびR10は、それらが結合している炭素原子と一体になって、N、OおよびSからなる群から選択される0個、1個、2個または3個のヘテロ原子を含む5または6員炭素環式またはヘテロ環式環を形成し;
AはCまたはN、最も好ましくはCである。〕
の化合物およびその塩を提供する。
化合物、塩などに関して複数形を使用するとき、これらは一つの化合物、塩なども意味すると取るべきである。
本発明はまた式Iの化合物の可能性のある互換体にも関する。
ヒドロキシC1−C8アルキルはとりわけヒドロキシメチル、2−ヒドロキシエチルまたは2−ヒドロキシ−2−プロピルである。
ヒドロキシC1−C8アルコキシはとりわけ2−ヒドロキシエトキシまたは3−ヒドロキシプロポキシである。
C1−C8アルコキシC1−C8アルキルはとりわけメトキシメチル、2−メトキシエチルまたは2−エトキシエチルである。
ハロC1−C8アルキルは好ましくはクロロC1−C8アルキルまたはフルオロC1−C8アルキル、とりわけトリフルオロメチルまたはペンタフルオロエチルである。
C1−C8アルコキシカルボニルはとりわけtert−ブトキシカルボニル、イソ−プロポキシカルボニル、メトキシカルボニルまたはエトキシカルボニルである。
C5−C10アリールC1−C8アルキルはとりわけベンジルまたは2−フェニルエチルである。
C5−C10アリールC1−C8アルコキシはとりわけベンジルオキシまたは2−フェニルエトキシである。
このような塩は、例えば、好ましくは有機または無機酸との、酸付加塩として、塩基性窒素原子を有する式Iの化合物から形成され、とりわけ薬学的に許容される塩である。適当な無機酸は、例えば、ハロゲン酸、例えば塩酸、硫酸、またはリン酸である。適当な有機酸は、例えば、カルボン酸、リン酸、スルホン酸またはスルファミン酸、例えば酢酸、プロピオン酸、オクタン酸、デカン酸、ドデカン酸、グリコール酸、乳酸、フマル酸、コハク酸、アジピン酸、ピメリン酸、スベリン酸、アゼライン酸、リンゴ酸、酒石酸、クエン酸、アミノ酸、例えばグルタミン酸またはアスパラギン酸、マレイン酸、ヒドロキシマレイン酸、メチルマレイン酸、シクロヘキサンカルボン酸、アダマンタンカルボン酸、安息香酸、サリチル酸、4−アミノサリチル酸、フタル酸、フェニル酢酸、マンデル酸、ケイ皮酸、メタン−またはエタン−スルホン酸、2−ヒドロキシエタンスルホン酸、エタン−1,2−ジスルホン酸、ベンゼンスルホン酸、2−ナフタレンスルホン酸、1,5−ナフタレン−ジスルホン酸、2−、3−または4−メチルベンゼンスルホン酸、メチル硫酸、エチル硫酸、ドデシル硫酸、N−シクロヘキシルスルファミン酸、N−メチル−、N−エチル−またはN−プロピル−スルファミン酸、または他の有機プロトン酸、例えばアスコルビン酸である。
(a)R0またはR2の各々は、独立して水素、C1−C8アルキル、例えばメチル、エチルまたはイソプロピル、ヒドロキシC1−C8アルキル、例えばヒドロキシエチルまたはヒドロキシブチル、ハロC1−C8アルキル、例えばトリフルオロメチル、非置換または置換C5−C10アリール、例えばフェニルまたはメトキシフェニル、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、例えばモルホリノ、ピペリジノ、ピペラジノまたはN−メチルピペラジノ、C1−C8アルコキシ、例えばメトキシ、エトキシまたはイソプロポキシ、ハロC1−C8アルコキシ、例えばトリフルオロメトキシ、C5−C10アリールオキシ、例えばフェノキシ、非置換または置換ヘテロシクリルオキシ、例えば1−メチル−4−ピペリジルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、例えば2−(1−イミダゾリル)エトキシ、3−モルホリノプロポキシまたは2−モルホリノエトキシ、非置換または置換アミノ、例えばメチルアミノ、ジメチルアミノまたはアセチルアミノ、C1−C8アルキルスルホニル、例えばメチルスルホニル、ハロゲン、例えばフルオロまたはクロロ、非置換または置換カルバモイル、例えばシクロヘキシルカルバモイル、ピペリジノカルボニル、ピペラジノカルボニル、N−メチルピペラジノカルボニルまたはモルホリノカルボニル、非置換または置換スルファモイル、例えばスルファモイル、メチルスルファモイルまたはジメチルスルファモイル;好ましくは水素、ピペラジノ、N−メチルピペラジノまたは1−メチル−4−ピペリジルオキシ、特に水素であり;
(f)R5は水素;C1−C8アルキル、例えばメチルまたはエチル、ハロゲン、例えばクロロまたはブロモ、ハロC1−C8アルキル、例えばトリフルオロメチル、シアノまたはニトロ;好ましくは水素、メチル、エチル、クロロ、ブロモ、トリフルオロメチルまたはニトロ;特にクロロまたはブロモであり;
(g)R6は水素であり;
(a')R0またはR2の各々は独立して水素、C1−C8アルキル、例えばメチル、エチルまたはイソプロピル、ハロC1−C8アルキル、例えばトリフルオロメチル、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、例えばモルホリノ、ピペリジノ、ピペラジノまたはN−メチルピペラジノ、C1−C8アルコキシ、例えばメトキシ、エトキシまたはイソプロポキシ、非置換または置換ヘテロシクリルオキシ、例えば1−メチル−4−ピペリジルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、例えば2−(1−イミダゾリル)エトキシ、3−モルホリノプロポキシまたは2−モルホリノエトキシ、非置換または置換アミノ、例えばメチルアミノ、ジメチルアミノまたはアセチルアミノ、ハロゲン、例えばフルオロまたはクロロ;好ましくは水素、ピペラジノ、N−メチルピペラジノまたは1−メチル−4−ピペリジルオキシ、特に水素であり;
(f')R5は水素、ハロゲン、例えばクロロまたはブロモ、ハロC1−C8アルキル、例えばトリフルオロメチル、またはニトロ;好ましくは水素、クロロ、ブロモ、トリフルオロメチルまたはニトロ;特にクロロまたはブロモであり;
(g')R6は水素であり;
の化合物を、式III
の化合物を反応させ、
そして、所望により、置換基が上記の意味を有する式Iの化合物を、他の定義した式Iの化合物に変換し;
そして得られた遊離形または塩としての式Iの化合物を回収し、そして、必要であれば、遊離形で得られた式Iの化合物を所望の塩に、または得られた塩を遊離形に変換することを含む、方法を提供する。
IC50=[(ABS試験−ABS開始)/(ABSコントロール−ABS開始)]×100。(ABS=吸収)
これらの実験におけるIC50値は、当該試験化合物が、阻害剤なしのコントロールを使用して得られたものより50%低い細胞計数をもたらす試験化合物の濃度として記載する。式Iの化合物は、約0.01から1μMの範囲のIC50で阻害活性を示す。
(1)医薬として使用する、本発明の化合物;
(2)FAK阻害剤、ALK阻害剤および/またはZAP−70阻害剤として使用するための、例えば前記に明示の特定の適応症のいずれかに使用するための、本発明の化合物;
(3)例えば前記に明示の適応症のいずれかに使用するための、活性成分としての本発明の化合物を、1個またはそれ以上の薬学的に許容される希釈剤または担体と共に含む、医薬組成物;
(4)必要とする対象における前記に明示の特定の適応症のいずれかの処置法であり、有効量の本発明の化合物またはそれを含む医薬組成物を投与することを含む方法;
(5)FAK、ALKおよび/またはZAP−70活性化が役割を演じるまたは関連する疾患または状態の処置または予防のための医薬の製造のための、本発明の化合物の使用;
(6)治療的有効量の本発明の化合物と1個またはそれ以上のさらなる医薬物質(該さらなる医薬物質は、前記に明示の特定の適応症のいずれかに有用である)を、例えば、同時にまたは連続して、併用投与することを含む、(4)で定義の方法;
(8)未分化リンパ腫キナーゼの阻害に応答する疾患の処置または予防のための医薬の製造のための本発明の化合物の使用;
(9)該疾患が未分化大細胞リンパ腫、非ホジキンリンパ腫、炎症性筋線維芽細胞腫瘍および神経芽腫からなる群から選択される、(8)に記載の使用;
(10)化合物が2−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンズアミドまたはその薬学的に許容される塩、または下記実施例に記載の化合物のいずれか、またはこれらのいずれか一つの薬学的に許容される塩である、(8)または(9)に記載の使用;
(11)未分化リンパ腫キナーゼの阻害に応答する疾患、とりわけ未分化大細胞リンパ腫、非ホジキンリンパ腫、炎症性筋線維芽細胞腫瘍および神経芽腫からなる群から選択される疾患の処置法であり、有効量の本発明の化合物、とりわけ2−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンズアミド、またはその薬学的に許容される塩を投与することを含む、方法。
2−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンズアミド、
N2−(4−[1,4']ビピペリジニル−1'−イル−2−メトキシ−フェニル)−5−クロロ−N4−[2−(プロパン−1−スルホニル)−フェニル]−ピリミジン−2,4−ジアミン、
2−{5−クロロ−2−[2−メトキシ−4−(4−メチル−ピペラジン−1−イル)−フェニルアミノ]−ピリミジン−4−イルアミノ}−N−イソプロピル−ベンゼンスルホンアミド、
2−[5−ブロモ−2−(2−メトキシ−5−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンゼンスルホンアミド
2−{2−[5−(1−アセチル−ピペリジン−4−イルオキシ)−2−メトキシ−フェニルアミノ]−5−ブロモ−ピリミジン−4−イルアミノ}−N−メチル−ベンゼンスルホンアミド、
N−[5−ブロモ−2−(2,5−ジメトキシ−フェニルアミノ)−ピリミジン−4−イル]−N−(4−モルホリン−4−イル−フェニル)−メタンスルホンアミド、
5−ブロモ−N−4−(4−フルオロ−フェニル)−N*2*−(2−メトキシ−4−モルホリン−4−イル−フェニル)−ピリミジン−2,4−ジアミン、
2−[5−クロロ−2−(2−メトキシ−4−ピペラジン−1−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンゼンスルホンアミド、
2−[5−ブロモ−2−(5−フルオロ−2−メトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンゼンスルホンアミド、
2−[5−クロロ−2−(5−フルオロ−2−メトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−イソブチル−ベンゼンスルホンアミド、および
2−{5−クロロ−2−[2−メトキシ−5−(4−メチル−ピペラジン−1−イルメチル)−フェニルアミノ]−ピリミジン−4−イルアミノ}−N−メチル−ベンゼンスルホンアミド。
略語
AcOH=酢酸、ALK=未分化リンパ腫キナーゼ、ATP=アデノシン5'−三リン酸、塩水=飽和塩化ナトリウム溶液、BSA=ウシ血清アルブミン、DIAD=ジイソプロピルアゾジカルボン酸、DIPCDI=N,N'−ジイソプロピルカルボジイミド、DMAP=4−ジメチルアミノピリジン、DMF=N,N−ジメチルホルムアミド、DTT=1,4−ジチオ−D,L−スレイトール、EDTA=エチレンジアミンテトラ酢酸、Et=エチル、EtOAc=酢酸エチル、EtOH=エタノール、Eu−PT66=LANCETMユーロピウム−W1024−標識抗−ホスホチロシン抗体(Perkin Elmer)、FAK=接着斑キナーゼ、FRET=蛍光共鳴エネルギー移動、HEPES=N−2−ヒドロキシエチルピペラジン−N'−2−エタンスルホン酸、HOAt=1−ヒドロキシ−7−アザベンゾトリアゾール、Me=メチル、RT−PCR=逆転写ポリメラーゼ連鎖反応、SA−(SL)APC=SuperLightTMアロフィコシアニン(Perkin Elmer)に結合したストレプトアビジン、subst.=置換、TBTU=O−(ベンゾトリアゾール−1−イル)−N,N,N',N'−テトラメチルアンモニウムテトラフルオロボレート、THF=テトラヒドロフラン。
Rf=0.47(n-ヘキサン:酢酸エチル=1:1). 1H-NMR(400 MHz, CDCl3), δ(ppm):2.36(d, 3H), 3.57(s, 3H), 3.73(s, 3H), 6.72(d, 1H), 6.99(d, 1H), 7.17(s, 1H), 7.35(t, 1H), 7.4-7.6(m, 1H), 7.63(d, 1H), 7.81(d, 1H), 8.0-8.2(m, 1H), 9.13(s, 1H), 9.41(br.s, 1H), 11.0(s, 1H).
2,4−ジクロロ−5−ニトロ−ピリミジン(1.94g、10mmol)および2−アミノ−N−メチル−ベンゼンスルホンアミド(1.86g、10mmol)をCHCl3(30mL)に溶解する。反応混合物を61℃で2時間加熱する。溶媒を蒸発し、残渣をエーテルで洗浄して表題生成物を得る。
Rf=0.5(n-ヘキサン:酢酸エチル=1:1). 1H-NMR(400MHz, CDCl3), δ(ppm):2.67(d, 3H), 4.6-4.7(m, 2H), 7.41(dd, 1H), 7.7(dd, 1H), 8.04(d, 1H), 8.15(d, 1H), 9.21(s, 1H), 11.2(s, 1H).
1H-NMR(CDCl3), δ(ppm):8.95(s, 1H), 8.44(d, 1H), 8.20(s, 1H), 7.98(dd, 1H), 7.58(ddd, 1H), 7.22-7.32(m, 1H), 6.51(d, 1H), 6.40(d, 1H), 4.56-4.48(m, 1H), 3.86(s, 3H), 3.81(s, 3H), 2.64(d, 3H). Rf(n-ヘキサン:酢酸エチル=1:1):0.31.
5−ブロモ−2,4−ジクロロピリミジン(684mg、3.0mmol)および2−アミノ−N−メチル−ベンゼンスルホンアミド(559mg、3.0mmol)の、炭酸カリウム(830mg、6.0mmol)含有N,N−ジメチルホルムアミド(10mL)溶液を、室温で23時間攪拌する。飽和水性塩化アンモニウムを添加し、混合物を水に注ぎ、酢酸エチルで2回抽出する。有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、真空で蒸発させる。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン−酢酸エチル勾配)で精製し、表題化合物をわずかに黄色の固体として得る。
1H-NMR(CDCl3), δ(ppm):2.67(d, 3H), 4.79(q, 1H), 7.26(s, 1H), 7.29(ddd, 1H), 7.66(ddd, 1H), 7.95(dd, 1H), 8.37(s, 1H), 8.48(d, 1H), 9.52(s, 1H). Rf(n-ヘキサン:酢酸エチル=10:3):0.33.
下記2−[5−ブロモ−2−(置換フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンゼンスルホンアミドを、2−(5−ブロモ−2−クロロ−ピリミジン−4−イルアミノ)−N−メチル−ベンゼンスルホンアミドおよび対応するアニリンから、実施例2の方法に従い製造する:
これらの化合物を、2−(5−ブロモ−2−クロロ−ピリミジン−4−イルアミノ)−N−プロピル−ベンゼンスルホンアミドおよび対応するアニリンを使用して、実施例2に準じて製造し、実施例3で化合物番号3−1から3−31に関して列記した通りの置換基Rxを有する化合物番号4−1から4−31を得る。
5−ブロモ−2,4−ジクロロピリミジン(90μL、0.70mmol)および2−アミノ−N−プロピル−ベンゼンスルホンアミド(100mg、0.47mmol)の溶液に、水素化ナトリウム(54.2mg、0.56mmol)のDMSO(1.0mL)溶液を添加し、得られた溶液を80℃で3.0時間攪拌する。混合物を水に注ぎ、酢酸エチルで3回抽出する。有機層を水、次いで塩水で洗浄し、硫酸ナトリウムで乾燥させ、真空で蒸発させる。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=5:1)で精製し、表題化合物をわずかに黄色の固体として得る。
1H-NMR(δ, ppm):0.89(t, 3H), 1.41(q, 2H), 3.56(t, 2H), 4.92(br.s, 2H), 6.71(dd, 1H), 6.77(dd, 1H), 7.33(dd, 1H), 7.54(dd, 1H), 8.79(s, 1H)
Rf(ヘキサン:酢酸エチル=1:1):0.64.
これらの化合物を、2−(2−クロロ−5−トリフルオロメチル−ピリミジン−4−イルアミノ)−N−メチル−ベンゼンスルホンアミドおよび対応するアニリンを使用して、実施例2に準じて製造し、実施例3で化合物番号3−1から3−31に関して列記した通りの置換基Rxを有する化合物番号5−1から5−31を得る。
2,4−ジクロロ−5−トリフルオロメチル−ピリミジン(386mg、1.79mmol)のアセトニトリル(10mL)溶液に、2−アミノ−N−メチル−ベンゼンスルホンアミド(333mg、1.79mmol)および1,8−ジアザ[5.4.0]ビシクロ−7−ウンデセン(280μL、1.88mmol)を連続して環境温度で添加する。15時間室温で攪拌後、ジクロロメタン(30mL)を混合物に添加し、溶液を飽和水性炭酸水素ナトリウムおよび飽和水性塩化ナトリウムで洗浄し、硫酸マグネシウムで乾燥させ、真空で蒸発させる。得られた固体をフラッシュクロマトグラフィーで精製する。
1H NMR(CDCl3)δ: 3.73(s, 3H), 6.67-6.69(m, 1H), 6.72-6.73(m, 1H), 7.27-7.31(m, 1H), 7.78(dd, 1H), 8.60(s, 1H). Rf(ヘキサン:酢酸エチル=1:1):0.28.
Rf(n-ヘキサン:酢酸エチル=1:1):0.46. 1H-NMR:(CDCl3)4.83(bs, 2H), 6.77(dd, 1H), 6.86(s, 1H), 6.97(dd, 1H), 7.31-7.24(m, 1H), 7.57(dd, 1H), 7.81(d, 1H), 8.02(dd, 1H), 8.28(d, 1H), 8.29(s, 1H), 8.88(s, 1H).
5−ブロモ−2,4−ジクロロピリミジン(300mg、1.32mmol)および2−アミノ−ベンゼンスルホンアミド(340mg、1.97mmol)の2−プロパノール(3mL)溶液に、濃塩酸(0.06mL)を添加し、混合物を90℃で4.5時間攪拌する。混合物を水性炭酸水素ナトリウムに注ぎ、酢酸エチルで3回抽出する。有機層を水で洗浄し、硫酸ナトリウムで乾燥させ、真空で蒸発させる。残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)で精製し、表題化合物を得る。
Rf(ヘキサン:酢酸エチル=1:1):0.55. 1H-NMR(400MHz, CDCl3)δ:4.78(br.s, 2H), 7.22(dd, 1H), 7.61(ddd, 1H), 7.95(dd, 1H), 8.35(s, 1H), 8.35(d, 1H), 9.18(s, 1H).
1H-NMR(400MHz, DMSO-d6, δ):2.80(d, 3H, J=4.52 Hz), 3.10-3.20(m, 4H), 3.78(s, 3H), 3.70-3.80(m, 4H), 6.49(dd, 1H, J=8.56, 2.52 Hz), 6.66(d, 1H, J=2.52 Hz), 7.08(dd, 1H, J=8.04, 8.04 Hz), 7.44(d, 1H, J=8.56 Hz), 7.71(dd, 1H, J=8.04, 1.48 Hz), 8.10(s, 1H), 8.13(s, 1H), 8.59(d, 1H, J=8.04 Hz)8.68-8.75(m, 1H), 11.59(S, 1H). MS m/z 469, 471(M+1)+.
7−(2,5−ジクロロ−ピリミジン−4−イルアミノ)−2−メチル−2,3−ジヒドロ−イソインドール−1−オンの合成法
N−メチル−7−ニトロ−2,3−ジヒドロイソインドール−1−オン。室温で、メチル2−ブロモメチル−6−ニトロベンゾエート(1.26g、4.63mmol)のTHF(13mL)溶液を、メチルアミンのTHF(14mL)中2M溶液で処理し、5時間攪拌し、EtOAc(100mL)で希釈し、飽和水性NaHCO3(15mL)および塩水(15mL)で洗浄し、乾燥し(MgSO4)、蒸発した。フラッシュクロマトグラフィー(30gのシリカゲル;CH2Cl2/EtOAc 1:1)により、N−メチル−7−ニトロ−2,3−ジヒドロイソインドール−1−オン(0.561g、2.92mmol)を63%で得た。黄色固体。Rf(CH2Cl2/EtOAc 1:1)0.46. 1H-NMR(400 MHz, CDCl3)3.21(s), 4.44(s), 7.63 -7.69(m, 2 H), 7.70 -7.75(m, 1 H).
2−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−安息香酸(5.5g、12.1mmol)の100mLのTHF中の懸濁液に、Et3N(2.06mL、14.8mmol)およびイソブチルクロロホルメート(1.7mL、12.8mmol)を−5℃で添加する。その温度で30分攪拌後、反応混合物をさらに室温で1時間攪拌し、次いでH2Oを反応混合物に添加する。得られた沈殿を濾過により回収し、H2Oで洗浄し、減圧下で乾燥させて、中間体(4.80g)(10.96mmol、91%)を黄色固体として得る。
NMR(400MHz, DMSO-d6, δ):3.10-3.20(m, 4H), 3.70-3.80(m, 4H), 3.93(s, 3H), 6.53(dd, 1H, J=9.08, 2.0 Hz), 6.70(d, 1H, J=2.0 Hz), 7.49-7.54(m, 1H), 7.67(d, 1H, J=8.56 Hz), 7.89(s, 1H), 7.85-7.95(m, 1H), 8.23(d, 1H, J=9.08 Hz), 8.26(d, 1H, J=8.56Hz), 12.60(s, 1H).
カラム:YMC CombiScreen ODS-A(5μm, 12nm)、50×4.6mm I.D.
流速:2.0ml/分
溶離剤:A)TFA/水(0.1/100)、B)TFA/アセトニトリル(0.1/100)
勾配:5−100%B(0−5分)
検出:215nmでUV
36−1 2−アミノ−N−メチル−ベンズアミドの製造
NMR(400MHz, CDCl3, δ):2.97(d, 3H, J=4.52 Hz), 5.49(bs, 1H), 6.07(bs, 1H), 6.64(ddd, 1H, J=8.04, 7.56, 1.0 Hz), 6.68(dd, 1H, J=8.32, 1.0 Hz), 7.20(ddd, 1H, J=8.32, 7.56, 1.52 Hz), 7.29(dd, 1H, J=8.04, 1.52 Hz).
2−(2,5−ジクロロ−ピリミジン−4−イルアミノ)−N−メチル−ベンズアミド
NMR(400MHz, DMSO-d6, δ):2.81(d, 3H, J=4.52 Hz), 7.22(dd, 1H, J=8.56, 8.04 Hz), 7.60(ddd, 1H, J=8.56, 8.56, 1.0 Hz), 7.81(dd, 1H, J=8.04, 1.0 Hz), 8.48(s, 1H), 8.52(d, 1H, J=8.56 Hz)8.80-8.90(m, 1H), 12.18(s, 1H).
36−3
2−(5−ブロモ−2−クロロ−ピリミジン−4−イルアミノ)−N−メチル−ベンズアミド
2−(2,5−ジクロロ−ピリミジン−4−イルアミノ)−N−エチル−ベンズアミド
2−(5−ブロモ−2−クロロ−ピリミジン−4−イルアミノ)−N−メチル−ベンゼンスルホンアミドの製造
1H-NMR(CDCl3), δ(ppm):2.67(d, 3H), 4.79(q, 1H), 7.26(s, 1H), 7.29(ddd, 1H), 7.66(ddd, 1H), 7.95(dd, 1H), 8.37(s, 1H), 8.48(d, 1H), 9.52(s, 1H). Rf(n-ヘキサン:酢酸エチル=10:3):0.33.
36−6
2−(2,5−ジクロロ−ピリミジン−4−イルアミノ)−N−メチル−ベンゼンスルホンアミド
2−(2,5−ジクロロ−ピリミジン−4−イルアミノ)−N−イソプロピル−ベンゼンスルホンアミド
1H-NMR(400MHz, CDCl3, δ);1.06(d, 6H), 3.43-3.53(m, 1H), 4.38(d,1H), 7.29(dd, 1H), 7.66(dd, 1H), 7.98(d, 1H), 8.29(s, 1H), 8.51(d, 1H), 9.51(brs, 1H). Rf:0.45(n-ヘキサン:AcOEt=4:1).
2−(2−クロロ−5−ニトロ−ピリミジン−4−イルアミノ)−N−メチル−ベンゼンスルホンアミドの製造:
Rf=0.5(n-ヘキサン:酢酸エチル=1:1). 1H-NMR(400MHz, CDCl3), δ(ppm):2.67(d, 3H), 4.6-4.7(m, 2H), 7.41(t, 1H), 7.7(t, 1H), 8.04(d, 1H), 8.15(d, 1H), 9.21(s, 1H), 11.2(s, 1H).
(2,5−ジクロロ−ピリミジン−4−イル)−[2−(プロパン−1−スルホニル)−フェニル]−アミンの製造
1H-NMR(CDCl3), δ(ppm):0.99(t, 3H), 1.77(d, 2H), 3.07-3.11(m, 2H), 7.26(s, 1H), 7.32(ddd, 1H), 7.73(ddd, 1H), 7.95(dd, 1H), 8.31(s, 1H), 8.61(dd, 1H), 9.94(bs, 1H). Rf(n-ヘキサン:酢酸エチル=3:1):0.63.
市販されていない置換アミンの合成:
3−アミノ−4'−メトキシ−4−メチルビフェニルの製造
4−メトキシフェニル−ボロン酸(500mg、3.29mmol)のトルエン(5.2mL)およびエタノール(1.3mL)の溶液に、炭酸カリウム(910mg、6.58mmol)、テトラキス(トリフェニルホスフィン)パラジウム(228.1mg、0.099mmol)および4−ブロモ−1−メチル−2−ニトロベンゼン(711mg、3.29mmol)を添加し、100℃で7時間攪拌する。混合物を水に注ぎ、酢酸エチルで2回抽出する。有機層を水、次いで塩水で洗浄し、硫酸マグネシウムで乾燥させ、真空で蒸発させる。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=5:1)で精製し、該4'−メトキシ−4−メチル−3−ニトロビフェニルを黄色固体として得る。
1H-NMR(δ, ppm):2.62(s, 3H), 3.86(s, 3H), 7.02-6.98(m, 2H), 7.37(d, 1H), 7.54(dd, 2H), 7.68(dd, 1H), 8.18(d, 1H). Rf(ヘキサン:酢酸エチル=3:1):0.40.
1H-NMR(δ, ppm):2.20(s, 3H), 3.84(s, 3H), 6.87(d, 1H), 6.89(dd, 1H), 6.95(d, 2H), 7.09(d, 1H), 7.48(d, 2H). Rf(n-ヘキサン:酢酸エチル=1:1):0.50.
4−メチル−3−ニトロ−安息香酸(300mg、2.76mmol)、N−ブトキシカルボニル−ピペラジン(340mg、1.83mmol)のDMF(3.0mL)溶液に、トリエチルアミン(300μL、3.59mmol)、TBTU(800mg、2.49mmol)およびHOAt(270.5mg、1.99mmol)を添加し、室温で24時間攪拌する。混合物を水に注ぎ、酢酸エチルで2回抽出する。有機層を水、次いで塩水で洗浄し、硫酸マグネシウムで乾燥させ、真空で蒸発させる。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=5:1)で精製し、4−(4−メチル−3−ニトロベンゾイル)−ピペラジン−1−カルボン酸tert−ブチルエステルを無色固体として得る。
1H-NMR(δ, ppm):1.47(s, 9H), 2.64(s, 3H), 3.28-3.88(m, 8H), 7.42(d, 1H), 7.56(dd, 1H), 8.03(d, 1H). Rf(ヘキサン:酢酸エチル=10:1):0.13.
表題化合物を、10%パラジウム/炭素のメタノール溶液上の水素での還元により得る。
4−ブロモ−1−メチル−2−ニトロベンゼン(225mg、1.04mmol)、モルホリン(125μL、1.25mmol)、および炭酸セシウム(474.4mg、1.46mmol)のトルエン溶液に、パラジウムジアセテート(31.2mg、0.139mmol)および2−(ジ−t−ブチルホスフィノ)ビフェニル(125mg、0.403mmol)を添加し、100℃で5時間攪拌する。冷却後、混合物を濾過して不溶性物質を除去する。濾液を水に注ぎ、酢酸エチルで2回抽出する。有機層を水、次いで塩水で洗浄し、硫酸マグネシウムで乾燥させ、真空で蒸発させる。残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=5:1)で精製し、4−(4−メチル−3−ニトロフェニル)−モルホリンを黄色固体として得る。
1H-NMR(δ, ppm):2.50(s, 3H), 3.17-3.19(m, 4H), 3.86-3.88(m, 4H), 7.04(dd, 1H), 7.21(d, 1H), 7.47(d, 1H). Rf(ヘキサン:酢酸エチル=5:1):0.20.
表題化合物を、10%パラジウム/炭素のメタノール溶液上の水素での還元により得る。
37−1
1−(3−メトキシ−4−ニトロ−フェニル)−ピペリジン−4−オールの製造
1H-NMR(400MHz, CDCl3, δ, ppm):1.54(d, 1H), 1.62-1.71(m, 2H), 1.98-2.04(m, 2H), 3.22(ddd, 4H), 3.73-3.80(m, 2H), 3.95(s, 3H), 3.98-4.02(m, 1H), 6.33(d, 1H), 6.43(dd, 1H), 8.00(d, 1H).
1−[4−(4−メトキシ−3−ニトロ−フェニル)−ピペラジン−1−イル]−エタノンの製造
1H-NMR(400MHz, CDCl3, δ, ppm):2.14(s, 3H), 3.63(ddd, 4H), 3.63(t, 2H), 3.78(t, 2H), 3.92(s, 3H), 7.03(d, 1H), 7.12(d, 1H), 7.41(d, 1H). Rf(酢酸エチル):0.18
1−(3−メトキシ−4−ニトロ−フェニル)−ピペリジン−4−オンの製造
1−[1−(3−メトキシ−4−ニトロ−フェニル)−ピペリジン−4−イル]−4−メチル−ピペラジンの製造
1H-NMR(400 MHz, CDCl3, δ):1.70-1.57(2H, m), 2.03-1.93(2H, m), 2.29(3H, s), 2.55-2.38(5H, m), 2.70-2.56(4H, m), 2.97(2H, ddd), 3.97-3.92(2H, m), 3.95(3H, s), 6.31(1H, d,), 6.42(1H, dd), 8.00(1H, d).
4'−メトキシ−4−メチル−3−ニトロ−ビフェニルの製造
1H-NMR(400MHz, CDCl3, δ, ppm):2.62(s, 3H), 3.86(s, 3H), 7.02-6.98(m,2H), 7.37(d, 1H), 7.54(dd, 2H), 7.68(dd, 1H), 8.18(d, 1H). Rf(ヘキサン:酢酸エチル=3:1):0.40.
4−(2−エトキシ−エトキシ)−1−(3−メトキシ−4−ニトロ−フェニル)−ピペリジンの製造
1H-NMR(400MHz, CDCl3, δ, ppm):1.52(t, 3H), 1.95-2.00(m, 2H), 1.70-1.79(m, 2H), 3.23(ddd, 2H), 3.58-3.64(m, 2H), 3.65-3.68(m, 2H), 3.64-3.72(m, 2H), 3.95(s, 3H), 6.31(d, 1H), 6.42(dd, 1H), 8.00(d, 1H). Rf 0.53(n-ヘキサン:AcOEt=1:1).
2−メトキシ−4−(1−メチル−ピペリジン−4−イルオキシ)−フェニルアミン4−(3−メトキシ−4−ニトロ−フェノキシ)−1−メチル−ピペリジン
Rf=0.22(メタノール:ジクロロメタン=1:4). 1H-NMR(400 MHz, CDCl3, δ, ppm):1.84-1.92(m, 2H), 2.0-2.1(m, 2H), 2.3-2.4(m, 2H), 2.33(s, 3H), 2.65-2.75(m, 2H), 3.94(s, 3H), 4.39-4.46(m, 1H), 6.49(dd, 1H), 6.99(d, 1H), 6.54(d, 1H), 7.99(d, 1H).
2−メトキシ−4−(2−モルホリン−4−イル−エトキシ)−フェニルアミン
3−メトキシ−4−ニトロ−フェノール
Rf=0.11(AcOEtのみ). 1H-NMR(400 MHz, CDCl3), δ(ppm):2.56-2.61(m, 4H), 2.83(t、反応混合物室温に冷却し、ゆっくり1N HCl水溶液で0℃でクエンチする。得られた混合物を酢酸エチルで2回抽出し、次いで有機層を連続して塩水で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空で蒸発させて、粗化合物を94%収率で得る(15.9g)。
Rf=0.22(メタノール:ジクロロメタン=1:4). 1H-NMR(400 MHz, CDCl3), δ(ppm):3.95(s, 3H), 5.49(s, 1H), 6.44(dd, 1H, J=8.8, 2.52Hz), 6.54(d, 1H, J=2.52Hz), 7.96(d, 1H J=8.6Hz).
3.72-3.76(m, 4H), 3.94(s, 3H), 4.18(t, 2H), 6.51(dd, 1H, J=9.08, 2.52Hz), 6.56(d, 1H, J=2.48Hz), 8.00(d, 1H J=9.08Hz).
2H),
2−メトキシ−4−(2−モルホリン−4−イル−エトキシ)−フェニルアミン
酢酸4−メトキシ−3−ニトロ−フェニルエステル
Rf=0.59(AcOEt:n-ヘキサン=3:7). 1H-NMR(400 MHz, CDCl3), δ(ppm):2.31(s, 3H), 3.96(s, 3H), 7.08(d, 1H, J=9.04Hz), 7.31(dd, 1H, J=9.04, 3.04Hz), 7.96(d, 1H J=3.04 Hz).
Rf=0.59(AcOEt:n-ヘキサン=3:7). 1H-NMR(400 MHz, CDCl3), δ(ppm):3.91(s, 3H), 6.99(d, 1H, J=9.04Hz), 7.17(dd, 1H, J=9.04, 3.00Hz), 7.38(d, 1H J=3.04 Hz).
Rf=0.41(メタノール:ジクロロメタン=1:1). 1H-NMR(400 MHz, CDCl3), δ(ppm):1.75-1.86(m, 2H), 1.92-2.05(m, 2H), 2.2-2.32(m, 2H), 2.30(s, 3H), 3.4-3.7(brs, 2H), 3.82(s, 3H), 4.1-4.2(m, 1H), 6.37(dd, 1H), 6.46(d, 1H), 6.61(d, 1H).
4−(3−アミノ−4−メチルベンゾイル)−ピペラジン−1−カルボン酸tert−ブチルエステルの製造
1H-NMR(δ, ppm):1.47(s,9H), 2.64(s, 3H), 3.88-3.28(m, 8H), 7.42(d, 1H), 7.56(dd, 1H), 8.03(d, 1H). Rf(ヘキサン:酢酸エチル=10:1):0.13.
表題化合物を、10%パラジウム/炭素のメタノール溶液上の水素での還元により得る。
4−(3−アミノ−4−メチルフェニル)−モルホリンの製造
1H-NMR(δ, ppm):2.50(s, 3H), 3.19-3.17(m, 4H), 3.88-3.86(m, 4H), 7.04(dd, 1H), 7.21(d, 1H), 7.47(d, 1H). Rf(ヘキサン:酢酸エチル=5:1):0.20.
表題化合物を、10%パラジウム/炭素のメタノール溶液上の水素での還元により得る。
2−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−安息香酸の製造
NMR(400MHz, DMSO-d6, δ):3.10-3.20(m, 4H), 3.78(s, 3H), 3.70-3.80(m, 4H), 6.52(dd, 1H, J=8.56, 2.52 Hz), 6.67(d, 1H, J=2.52 Hz), 7.08(dd, 1H, J=8.04, 8.04 Hz), 7.39(d, 1H, J=8.56 Hz), 7.35-7.45(m, 1H), 7.99(dd, 1H, J=8.04, 1.52Hz), 8.14(s, 1H), 8.28(s, 1H)8.70-8.80(m, 1H).
2−アミノ−4−クロロ−5−メチル−ベンゼンスルホニルクロライドの製造
2−アミノ−5−クロロ−4−メチル−ベンゼンスルホン酸(3.0g、1.35mmol)のジクロロエタン(10mL)溶液に、塩化スルフリル(4.4mL、3.83mmol)を添加し、60℃で攪拌する。1時間後、塩化チオニル(1.3mL)を添加し、混合物をさらに100℃で7.0時間攪拌する。混合物を氷水に注ぎ、エーテルで3回抽出する。有機層を水、次いで塩水で洗浄し、硫酸ナトリウムで乾燥させ、真空で蒸発させる。1H-NMR(δ, ppm):2.35(s, 3H), 6.68(s, 1H), 7.75(s, 1H).
この置換スルホニルクロライドを適当なアミンと反応させる。例えばメチルアミンとの反応により、2−アミノ−5−クロロ−4,N−ジメチルベンゼンスルホンアミドが形成する。
2−[5−ブロモ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N、N−ジメチル−ベンゼンスルホンアミドの製造
NMR(400MHz, CDCl3, δ):2.74((s, 6H), 3.05-3.18(m, 4H), 3.84-3.93(m, 4H), 3.88(s, 3H), 6.43(dd, 1H), 6.53(d, 1H), 7.24(m, 1H), 7.31(s, 1H), 7.56(m, 1H), 7.87(dd, 1H), 8.05(d, 1H), 8.21(s, 1H), 8.49(d, 1H), 8.49(d, 1H), 9.27(s, 1H). Rf:0.23(AcOEt:ヘキサン=1:1).
2−[5−ブロモ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−5−フルオロ−N−メチル−ベンゼンスルホンアミドの製造
クロロスルホニルイソシアネート(1.2mL、13.5mmol)のニトロエタン(10mL)溶液に、4−フルオロアニリン(1.0g、8.97mmol)を0℃で滴下し、反応混合物を30分攪拌する。この溶液に、塩化アルミニウム(1.3g、9.87mmol)を0℃で添加し、混合物を100℃で1時間攪拌する。冷却後から室温、水を添加し、混合物を酢酸エチルで2回抽出する。有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下濃縮する。得られた固体を濾過により回収し、エーテルで洗浄してわずかに灰色の固体を得る(803.9mg、41%)。
NMR(400MHz, DMSO-d6, δ):7.22-7.28(m, 1H), 7.45-7.57(m, 1H), 7.60(m, 1H), 11.15-11.30(m, 1H). Rf:0.43(MeOH:AcOEt=1:5).
7−フルオロ−1,1−ジオキソ−1,4−ジヒドロ−2H−1−λ6−ベンゾ[1,2,4]チアジアジン−3−オン(5.19g、24.0mmol)のDMF(50mL)溶液に、水素化ナトリウム(1.04g、26.0mmol)およびヨードメタン(1.5mL、24.0mmol)を連続的に添加し、混合物を1時間、70℃で攪拌する。冷却後から室温、混合物を水に注ぎ、沈殿を濾過により回収し、水およびヘキサンで連続的に洗浄して、わずかに灰色の固体を得る(5.38g、94%)。
NMR(400MHz, DMSO-d6, δ):3.32(s, 3H), 7.44(dd, 1H), 7.75(ddd, 1H), 7.94(dd, 1H).
Rf(MeOH:AcOEt=1:5):0.21. Rf:0.39(ヘキサン:AcOEt=1:1).
6.79gの7−フルオロ−2−メチル−1,1−ジオキソ−1,4−ジヒドロ−2H−1λ6−ベンゾ[1,2,4]チアジアジン−3−オン(29.5mmol)を20%水性水酸化ナトリウムに溶解し、得られた溶液を100℃で13.5時間攪拌する。混合物を室温に冷却し、水に注ぐ。78mLの5M HCl水溶液を添加し、沈殿を濾過により回収し、水で洗浄して、わずかに紫色の固体を得る(3.96g、65%)。
NMR(400MHz, CDCl3, δ):2.60(d, 3H), 4.55-4.82(m, 3H), 6.74(dd, 1H), 7.05-7.12(m, 1H), 7.45(dd, 1H). Rf:0.41(ヘキサン:AcOEt=1:1).
ピリミジンと2−アミノ−5−フルオロ−N−メチル−ベンゼンスルホンアミドの反応を、実施例Bに記載の方法に準じて行う。
NMR(400MHz, CDCl3, δ):2.67(d, 3H), 4.56(m, 1H), 7.36-7.45(m, 1H), 7.68(dd, 1H), 8.39(s, 1H), 8.42(dd, 1H), 9.26(s, 1H). Rf 0.59(ヘキサン:AcOEt=1:1).
置換アニリンの挿入を、実施例Aに記載の方法に準じて行う。
NMR(400MHz, CDCl3, δ):2.65(d, 3H), 3.09-3.16(m, 4H), 3.87(s, 3H), 4.50(q, 1H), 6.41(dd, 1H), 6.52(d, 1H), 7.25-7.33(m, 2H), 7.69(dd, 1H), 7.95(d, 1H), 8.20(s, 1H), 8.37(dd, 1H), 8.70(s, 1H). Rf 0.30(ヘキサン:AcOEt=1:1)
実施例53:FAKアッセイ
すべての工程を96ウェル黒色マイクロタイタープレートで行う。精製した組み換えヘキサヒスチジン標識ヒトFAKキナーゼドメインを希釈緩衝液(50mM HEPES、pH7.5、0.01%BSA、0.05%Tween−20、水中)で、94ng/mL(2.5nM)の濃度まで希釈する。反応混合物を、10μL 5×キナーゼ緩衝液(250mM HEPES、pH7.5、50μM Na3VO4、5mM DTT、10mM MgCl2、50mM MnCl2、0.05%BSA、0.25%Tween−20、水中)、20μL 水、5μLの4μM ビオチニル化ペプチド基質(Biot−Y397)の水性溶液、5μLの試験化合物のDMSO溶液、および5μLの組み換え酵素溶液の混合により調製し、30分、室温でインキュベートする。酵素反応を5μLの5μM ATPの水溶液の添加により開始し、混合物を3時間、37℃でインキュベートする。反応を200μLの検出混合物(1nM Eu−PT66、2.5μg/mL SA−(SL)APC、6.25mM EDTA、希釈緩衝液中)の添加により停止し、30分の室温でのインキュベーション後に、ユーロピウムからアロフィコシアニンへのFRETシグナルをARVOsx+L(Perkin Elmer)により測定する。665nmに対する615nmの強度比を、試験化合物による消色作用を相殺するために、データ分析用FRETシグナルとして使用する。結果を酵素活性のパーセントとして示す。DMSOおよび0.5M EDTAを各々0%および100%阻害のコントロールとして使用する。IC50値を、OriginPro 6.1プログラム(OriginLab)を使用した非直線状曲線適合分析(non-linear curve fit analysis)により測定する。
ZAP−70キナーゼアッセイは、時間分解蛍光共鳴エネルギー移動(FRET)に基づく。80nM ZAP−70を80nM Lck(リンパ様T細胞タンパク質チロシンキナーゼ)および4μM ATPのZAP−70キナーゼ緩衝液(20mM Tris、pH7.5、10μM Na3VO4、1mM DTT、1mM MnCl2、0.01%BSA、0.05%Tween−20)溶液と、1時間、室温でシリコン処理したポリプロピレン・チューブ中でインキュベートする。次いで、選択的Lck阻害剤PP2(1−tert−ブチル−3−(4−クロロ−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イルアミン;Alexis Biochemicals)を添加し(最終濃度1.2μM)、さらに10分インキュベートする。10μLのこの溶液を基質としての10μL ビオチニル化ペプチドLAT−11(1μM)および20μLの阻害剤の連続希釈と混合し、4時間、室温でインキュベートする。キナーゼ反応を検出緩衝液(20mM Tris、pH7.5、0.01%BSA、0.05%Tween−20)中の10μLの10mM EDTA溶液で停止させる。検出緩衝液中の50μL ユーロピウム−標識した抗ホスホチロシン抗体(Eu−PT66;最終濃度0.125nM);および50μLストレプトアビジン−アロフィコシアニン(SA−APC;最終濃度40nM)を添加する。1時間、室温でインキュベーション後、蛍光をVictor2 Multilabel Counter(Wallac)で665nmで測定する。背景値(低コントロール)を試験サンプルおよびATPの非存在下に得て、全値から引く。試験サンプルの非存在下に得たサンプルを100%(高コントロール)として取る。試験化合物の存在下に得た阻害を、高コントロールの阻害パーセントとしてケイ酸する。50%阻害をもたらす試験化合物の濃度(IC50)を、用量応答曲線から得る。このアッセイにおいて、本発明の薬剤は、10nMから2μM、好ましくは10nMから100nMの範囲のIC50値を有する。
FAKのTyr397でのリン酸化レベルをサンドイッチELISAにより定量する。マウス乳癌4T1細胞(1×105)を、96ウェル培養プレートのウェルに入れ、種々の濃度の阻害剤ありまたはなしで、1時間、0.5%BSA含有ダルベッコ改変イーグル培地でインキュベートする。培地を取り、細胞を1%NP−40、0.25%ナトリウムデオキシコレート、150mM NaCl、1mM EDTA、1mM PMSF、1mM Na3VO4、1mM NaF、1μg/mL アプロチニン、1μg/mL ロイペプチンおよび1μg/mL ペプスタチン含有200μL 50mM Tris−HCl、pH7.4中で融解する。遠心分離後、上清をサンドイッチELISAに付し、リン酸化FAKおよび全FAKを定量する。細胞融解物を、150mM NaCl含有50mM Tris−HCl、pH9.5中、100μL/ウェルの4μg/mL マウスモノクローナル抗−FAK抗体(クローン77、Becton Dickinson Transduction Laboratories)で予めコートした96ウェル平底ELISAプレートに18時間、4℃で入れ、H2Oで1:4希釈した300μLのBlockAce(Dainippon Pharmaceuticals Co.)で室温で2時間遮断する。TBSN(20mM Tris−HCl、pH8.3、300mM NaCl、0.1%SDSおよび0.05%NP−40含有)で洗浄した後、全FAKを100μLの1μg/ml 抗−FAKポリクローナル抗体(#65-6140, Upstate Biology Inc.)で検出し、リン酸化FAKを100μLの0.25μg/μL抗リン酸化FAK(Y397)抗体(Affinity BioReagents, #OPA1-03071)で、H2Oで1:10に希釈したBlockAceで検出する。1時間、室温でインキュベーション後、プレートをTBSNで洗浄し、H2Oで1:10に希釈したBlockAceで1:2000に希釈した100μLのビオチニル化抗−ウサギIgG(#65-6140, Zymed Laboratolies Inc.)と、室温で1時間インキュベートする。TBSNで洗浄後、ABTS溶液基質キット(#00-2011, Zymed Lobolatories Inc.)を発色用に使用する。405nmでの吸光度を、20分、室温でインキュベーション後に測定する。FAKのリン酸化レベルの50%減少をもたらす化合物の濃度を決定する。
マウス乳癌4T1細胞(5×103)を、96ウェルUltra low Attachmentプレート(#3474, Corning Inc.)に、10%FBS含有100μLのダルベッコ改変イーグル培地中、播く。細胞を2時間培養し、阻害剤を最終濃度0.1%DMSO中、種々の濃度で添加する。48時間後、細胞増殖を、水溶性テトラゾリウム塩WST8を使用する細胞計数キット−8(Wako Pure Chemical)でアッセイする。20μLの試薬を各ウェルに添加し、細胞をさらに2時間培養する。光学密度を450nmで測定する。増殖の50%阻害をもたらす化合物の濃度を決定する。
FAK阻害剤の免疫細胞の移動性における阻害活性を下記のインビトロ試験で確認する。すなわち、Jurkat Tヒト白血病細胞系を、1×105細胞で、8μm孔を有するFluoroblok(Beckton Dickinson, UK)の上室に入れ、4時間、37℃で、95%空気−5%CO2中ウシ胎児血清(10%FBS)の濃度勾配に依存して遊走させる。細胞移動性を、カルセイン−AM(Molecular Probes, Netherlands)の8μg/mlのHBSS溶液で1時間標識することにより、下室に遊走した細胞の数を介して見積もる。FAK阻害剤の評価のために、上室および下室の両方に種々の濃度(0.03−1μM)のFAK阻害剤を添加する。IC50値を、Ascent(励起:485nm、放出:538nm)で測定した媒体処置群と比較した蛍光強度の減少により計算する。
アッセイは下記のように行う:
アッセイのために、Kato et al., J. Biol. Chem. 268, 2655-61, 1993に記載のように調製したヒトIGF−IR cDNA(完全ヒトIGF−IR cDNA:GenBank Acc. No. NM_000875)でトランスフェクトしたNIH−3T3マウス繊維芽細胞を使用する。ヒトIGF−IRを過剰発現する細胞を、10%ウシ胎児血清(FCS)添加ダルベッコの最小必須培地(DMEM)で培養する。アッセイのために、5,000細胞/ウェルを1日目に96ウェルプレート(Costar #3595)で通常の増殖培地中に播き、2日間、37℃で標準CO2細胞インキュベーター中、インキュベートする。細胞密度は、3日目に70−80%を超えない。3日目に、培地を捨て、細胞を24時間、最小培地(DMEM、0.5%FCS含有)でインキュベートする。式Iの化合物[10mM ジメチルスルホキシド(DMSO)貯蔵溶液から開始]を添加し、最終濃度0.01、0.03、0.1、0.3、1、3および10μMとし、IC50値を得る。細胞を90分、式Iの化合物の存在下にインキュベートする。その後、細胞を50μl IGF−I(ウェル中のIGF−I最終濃度=10ng/ml;IGF−IはSigmaから得る;Product Code:I 3769)で刺激し、10分、37℃でインキュベートする。
抗体抽出物と二次抗体を2時間、4℃でインキュベーション後、抽出物を廃棄し、プレートを2回0.05%(v/v)Tween−20のPBS溶液で、および1回ナノピュア水で洗浄する。
雌または雄BALB/cヌードマウス(5−8週齢、日本チャールズ・リバー、横浜、日本)を、水と餌は自由に摂取できる無菌条件下に置く。腫瘍細胞(ヒト上皮細胞系MIA PaCa−2;European Collection of Cell Cultures(ECACC), Salisbury, Wiltshire, UK, Catalogue Number 85062806;65歳白色人種男性由来の細胞系;非分化ヒト膵臓癌細胞系)を、フォーレン(登録商標)麻酔(アボット ジャパン株式会社、東京、日本)下にマウスの左または右脇腹に皮下注射することにより、腫瘍を誘発する。試験化合物での処置は、平均腫瘍体積が約100mm3に達したときに開始する。腫瘍増殖を1週間に2回および最後の処置の1日後に、2軸の長さを測定することにより測定する。腫瘍体積を公開法にしたがい計算する(Evans et al., Brit. J. Cancer 45, 466-8, 1982参照)。抗効果を、処置動物の腫瘍体積の平均増加を非処置動物(コントロール)の腫瘍体積の平均増加で割り、100倍したものとして決定し、δT/C[%]として示す。腫瘍退行は、処置動物の腫瘍体積の平均変化を、処置開始時の平均腫瘍体積で割り、100倍したものとして記載し、退行[%]として示す。試験化合物を、経口で毎日休薬日ありまたはなしで投与する。
−4T1乳癌細胞系(ATCC Number CRL-2539;Cancer. 88(12 Supple), 2979-2988, 2000も参照)で、雌BALB/cマウスで(乳房脂肪に注射)。
塑性の塊を約3mmメッシュサイズの篩から押し出し、乾燥させ、得られた顆粒を再び篩を通す。次いで小麦デンプンの残り、タルクおよびステアリン酸マグネシウムを混ぜ入れ、混合物を圧縮して、145mgの重量および割線を有する錠剤に圧縮する。
Claims (20)
- 遊離形または薬学的に許容される塩形態の、式I
R0、R1 およびR 2 の各々は独立して水素、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、C3−C8シクロアルキルC1−C8アルキル、C5−C10アリールC1−C8アルキル、ヒドロキシC1−C8アルキル、C1−C8アルコキシC1−C8アルキル、アミノC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個、2個または3個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、ヒドロキシ、C1−C8アルコキシ、ヒドロキシC1−C8アルコキシ、C1−C8アルコキシC1−C8アルコキシ、ハロC1−C8アルコキシ、非置換または置換C5−C10アリールC1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルチオ、C1−C8アルキルスルフィニル、C1−C8アルキルスルホニル、C5−C10アリールスルホニル、ハロゲン、カルボキシ、C1−C8アルコキシカルボニル、非置換または置換カルバモイル、非置換または置換スルファモイル、シアノまたはニトロであり;
R 3 はC 1−C8アルキルスルフィニル、C 1 −C 8 アルキルスルホニル、C 5 −C 10 アリールスルホニル、非置換または置換カルバモイル、または非置換または置換スルファモイルであるか;または
隣接している置換基R2 とR3 のペアは、−CH 2 −NH−CO−または−CH 2 −CH 2 −CO−を形成し、ここで、NHは非置換であるかC 1 −C 8 アルキルで置換されており;
R4は水素またはC1−C8アルキルであり;
R5 はクロロまたはブロモであり;
R 6 は水素であり;そして
R7、R8、R9、およびR10の各々は独立してC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、C3−C8シクロアルキルC1−C8アルキル、C5−C10アリールC1−C8アルキル、ヒドロキシC1−C8アルキル、C1−C8アルコキシC1−C8アルキル、アミノC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個、2個または3個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、ヒドロキシ、C1−C8アルコキシ、ヒドロキシC1−C8アルコキシ、C1−C8アルコキシC1−C8アルコキシ、ハロC1−C8アルコキシ、非置換または置換C5−C10アリールC1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルチオ、C1−C8アルキルスルフィニル、C1−C8アルキルスルホニル、C5−C10アリールスルホニル、ハロゲン、カルボキシ、C1−C8アルコキシカルボニル、非置換または置換カルバモイル、非置換または置換スルファモイル、シアノまたはニトロであり;ここで、R7、R8およびR9は、互いに独立して水素であってもよく;
またはR7 とR8、R8 とR9、および/またはR9 とR10は、それらが結合している炭素原子と一体になって、5または6員炭素環式環またはN、OおよびSからなる群から選択される1個、2個または3個のヘテロ原子を含む5または6員ヘテロ環式環を形成し、それら環は非置換であるか、またはC 1 −C 8 アルキル、C 1 −C 8 アルコキシ、ハロ−C 1 −C 8 アルキル、ヒドロキシ、アミノ、置換アミノ、ハロゲン、カルボキシ、C 1 −C 8 アルコキシカルボニル、カルバモイル、シアノまたはオキソにより置換されている。〕
の化合物。 - R0 およびR2の各々が独立して水素、C1−C8アルキル、ヒドロキシC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、ハロC1−C8アルコキシ、C5−C10アリールオキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルスルホニル、ハロゲン、非置換または置換カルバモイル、または非置換または置換スルファモイルであり;
R1が水素、C1−C8アルキル、ヒドロキシC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、ハロC1−C8アルコキシ、C5−C10アリールオキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルスルホニル、ハロゲン、非置換または置換カルバモイル、または非置換または置換スルファモイルであり;
R3 がC 1−C8アルキルスルフィニル、C 1−C8アルキルスルホニル、C5−C10アリールスルホニル、置換または非置換カルバモイル、または非置換または置換スルファモイルであるか;または
隣接している置換基R 2とR 3 のペアが−CH2−NH−CO−または−CH 2 −CH 2 −CO−を形成し、ここで、NHは非置換であるかC 1 −C 8 アルキルで置換されており;
R4が水素またはC1−C8アルキルであり;
R5がクロロまたはブロモであり;
R6が水素であり;
R7およびR9の各々が独立して水素、C1−C8アルキル、ヒドロキシC1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、ハロC1−C8アルコキシ、C5−C10アリールオキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルスルホニル、ハロゲン、非置換または置換カルバモイル、または非置換または置換スルファモイルであり;
R8が水素、C1−C8アルキル、ヒドロキシC1−C8アルキル、ハロC1−C8アルキル、C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、ハロC1−C8アルコキシ、C5−C10アリールオキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、C1−C8アルキルスルホニル、ハロゲン、非置換または置換カルバモイル、非置換または置換スルファモイル、シアノ、またはニトロであり;そして
R10がC1−C8アルキル、ヒドロキシC1−C8アルキル、ハロC1−C8アルキル、C1−C8アルコキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、ハロゲン、カルボキシ、カルバモイル、または非置換または置換スルファモイルであるか;または
隣接している置換基R7とR8、またはR8とR9またはR9とR10の各ペアが−NH−CH=CH−、−CH=CH−NH−、−NH−N=CH−、−CH=N−NH−、−CH2−CH2−CH2−、−CH2−CH2−CH2−CH2−、−CH2−CH2−O−、−CH=CH−O−、−O−CH2−O−、または−O−CF2−O−である、
請求項1記載の式Iの化合物。 - R0 およびR2の各々が独立して水素、C1−C8アルキル、ハロC1−C8アルキル、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、またはハロゲンであり;
R1が水素、C1−C8アルキル、ハロC1−C8アルキル、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、またはハロゲンであり;
R 3 がC 1−C8アルキルスルフィニル、C 1−C8アルキルスルホニル、C5−C10アリールスルホニル、置換または非置換カルバモイル、または非置換または置換スルファモイルであるか;または
隣接している置換基R 2とR3 のペアが−CH2−NH−CO−または−CH 2 −CH 2 −CO−を形成し、ここで、NHは非置換であるかC 1 −C 8 アルキルで置換されており;
R4が水素であり;
R5がクロロまたはブロモであり;
R6が水素であり;
R7およびR9の各々が独立して水素、C1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、ハロゲン、非置換または置換カルバモイル、または非置換または置換スルファモイルであり;
R8が水素、C1−C8アルキル、ハロC1−C8アルキル、C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、ハロC1−C8アルコキシ、C5−C10アリールオキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、ハロゲン、非置換または置換スルファモイル、またはニトロであり;そして
R10がC1−C8アルキル、ハロC1−C8アルキル、C1−C8アルコキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、またはハロゲンであるか;または
隣接している置換基R7とR8、またはR8とR9またはR9とR10の各ペアが−NH−CH=CH−、−CH=CH−NH−、−NH−N=CH−、−CH=N−NH−、−CH2−CH2−CH2−、−CH2−CH2−CH2−CH2−、−O−CH2−O−、または−O−CF2−O−である、
請求項1記載の式Iの化合物。 - R0 およびR2の各々が独立して水素、ピペラジノ、N−メチルピペラジノまたは1−メチル−4−ピペリジルオキシであり;
R1が水素、ピペラジノ、N−メチルピペラジノ、モルホリノ、1−メチル−4−ピペリジニルオキシ、3−モルホリノプロポキシまたは2−モルホリノエトキシであり;
R 3がスルファモイル、メチルスルファモイルまたはプロピルスルファモイルであるか;または
隣接する置換基R 2とR3のペアが−CH2−NH−CO−または−または−CH 2 −CH 2 −CO−を形成し、ここで、NHは非置換であるかC 1 −C 8 アルキルで置換されており;
R4が水素であり;
R5 がクロロまたはブロモであり;
R6が水素であり;
R7およびR9の各々が独立して水素、C1−C8アルキル、ハロC1−C8アルキル、非置換または置換C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、ハロゲン、非置換または置換カルバモイル、または非置換または置換スルファモイルであり;
R8が水素、C1−C8アルキル、ハロC1−C8アルキル、C5−C10アリール、N、OおよびSからなる群から選択される1個または2個のヘテロ原子を含む非置換または置換5または6員ヘテロシクリル、C1−C8アルコキシ、ハロC1−C8アルコキシ、C5−C10アリールオキシ、非置換または置換ヘテロシクリルオキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、ハロゲン、非置換または置換スルファモイル、またはニトロであり;そして
R10がC1−C8アルキル、ハロC1−C8アルキル、C1−C8アルコキシ、非置換または置換ヘテロシクリルC1−C8アルコキシ、非置換または置換アミノ、またはハロゲンであるか;または
隣接している置換基R7とR8、またはR8とR9またはR9とR10の各ペアが−NH−CH=CH−、−CH=CH−NH−、−NH−N=CH−、−CH=N−NH−、−CH2−CH2−CH2−、−CH2−CH2−CH2−CH2−、−O−CH2−O−、または−O−CF2−O−である、
請求項1記載の式Iの化合物。 - R0 およびR2の各々が独立して水素、ピペラジノ、N−メチルピペラジノまたは1−メチル−4−ピペリジルオキシであり;
R1が水素、ピペラジノ、N−メチルピペラジノ、モルホリノ、1−メチル−4−ピペリジニルオキシ、3−モルホリノプロポキシまたは2−モルホリノエトキシであり;
R 3がスルファモイル、メチルスルファモイルまたはプロピルスルファモイルであるか;または
隣接する置換基R 2とR3のペアが−CH2−NH−CO−または−CH 2 −CH 2 −CO−を形成し、ここで、NHは非置換であるかC 1 −C 8 アルキルで置換されており;
R4が水素であり;
R5 がクロロまたはブロモであり;
R6が水素であり;
R7およびR9の各々が独立して水素、メチル、イソプロピル、トリフルオロメチル、フェニル、o−、m−またはp−メトキシフェニル、ピペリジノ、ピペラジノ、N−メチルピペラジノ、モルホリノ、メトキシ、エトキシ、イソプロポキシ、フェノキシ、3−モルホリノプロポキシ、2−モルホリノエトキシ、2−(1−イミダゾリル)エトキシ、ジメチルアミノ、フルオロ、モルホリノカルボニル、ピペリジノカルボニル、ピペラジノカルボニルまたはシクロヘキシルカルバモイルであり;
R8が水素、メチル、ピペリジノ、ピペラジノ、N−メチルピペラジノ、モルホリノ、メトキシ、エトキシ、トリフルオロメトキシ、フェノキシ、1−メチル−4−ピペリジルオキシ、3−モルホリノプロポキシ、2−モルホリノエトキシ、3−(N−メチルピペラジノ)−プロポキシ、メチルアミノ、フルオロ、クロロ、スルファモイルまたはニトロであり;そして
R10がメチル、ブチル、メトキシ、エトキシ、2−(1−イミダゾリル)エトキシ、メチルアミノ、ジメチルアミノまたはフルオロであるか;または
隣接する置換基R7とR8またはR8とR9のペアが−O−CH2−O−であるか、または隣接する置換基R9とR10のペアが−NH−CH=CH−、−CH=N−NH−、−CH2−CH2−CH2−、−CH2−CH2−CH2−CH2−または−O−CF2−O−である、
請求項1記載の式Iの化合物。 - R0、R1 およびR2の各々が水素であり;
R3がスルファモイル、メチルスルファモイルまたはプロピルスルファモイルであり;
R4が水素であり;
R5がクロロまたはブロモであり;
R6が水素であり;
R7およびR9の各々が独立して水素、メチル、イソプロピル、トリフルオロメチル、フェニル、o−、m−またはp−メトキシフェニル、ピペリジノ、ピペラジノ、N−メチルピペラジノ、モルホリノ、メトキシ、エトキシ、イソプロポキシ、フェノキシ、3−モルホリノプロポキシ、2−モルホリノエトキシ、2−(1−イミダゾリル)エトキシ、ジメチルアミノ、フルオロ、モルホリノカルボニル、ピペリジノカルボニル、ピペラジノカルボニルまたはシクロヘキシルカルバモイルであり;
R8が水素、メチル、ピペリジノ、ピペラジノ、N−メチルピペラジノ、モルホリノ、メトキシ、エトキシ、トリフルオロメトキシ、フェノキシ、1−メチル−4−ピペリジルオキシ、3−モルホリノプロポキシ、2−モルホリノエトキシ、3−(N−メチルピペラジノ)−プロポキシ、メチルアミノ、フルオロ、クロロ、スルファモイルまたはニトロであり;そして
R10がメチル、ブチル、メトキシ、エトキシ、2−(1−イミダゾリル)エトキシ、メチルアミノ、ジメチルアミノまたはフルオロであるか;または
隣接する置換基R7とR8またはR8とR9のペアが−O−CH2−O−であるか、または隣接する置換基R9とR10のペアが−NH−CH=CH−、−CH=N−NH−、−CH2−CH2−CH2−、−CH2−CH2−CH2−CH2−または−O−CF2−O−である、
請求項1記載の式Iの化合物。 - R0、R1 およびR2の各々が水素であり、R3がメチルスルファモイルであり、R4が水素であり、R5がブロモであり、R6が水素であり、R7およびR8の各々がメトキシであり、R9が水素であり、そしてR10がメチルである、請求項1記載の式Iの化合物。
- R0、R1 およびR2の各々が水素であり、R3がメチルスルファモイルであり、R4が水素であり、R5がブロモであり、R6が水素であり、R7およびR8の各々が水素であり、そして隣接する置換基R9とR10のペアが−CH2−CH2−CH2−である、請求項1記載の式Iの化合物。
- 次の群から選択される、請求項1記載の式Iの化合物:
2−[5−ブロモ−2−(2,4−ジメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンゼンスルホンアミド;
式
化合物;
2−[5−ブロモ−2−(2,3−[ジフルオロメチレンジオキシ]フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミド;
2−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N−メチル−ベンズアミド;
式
化合物;式
化合物;
式
化合物;
式
化合物;
式
化合物;
7−[5−クロロ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−2−メチル−2,3−ジヒドロ−イソインドール−1−オン;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
式
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
式
化合物;
下記表:
式
化合物;
2−[5−ブロモ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−N、N−ジメチル−ベンゼンスルホンアミド;および
2−[5−ブロモ−2−(2−メトキシ−4−モルホリン−4−イル−フェニルアミノ)−ピリミジン−4−イルアミノ]−5−フルオロ−N−メチル−ベンゼンスルホンアミド。 - 活性成分として請求項1から10のいずれかに記載の化合物を、1個またはそれ以上の薬学的に許容される希釈剤または担体と共に含む、医薬組成物。
- 新生物疾患および免疫系障害の処置または予防に有用な医薬の製造のための、請求項1から10のいずれかに記載の化合物の使用。
- 治療的有効量の請求項1から10のいずれかに記載の化合物と、新生物疾患または免疫系障害の処置に有用である1個またはそれ以上のさらなる医薬物質を含む、組み合わせ剤。
- 未分化リンパ腫キナーゼ(ALK)および/またはIGF−1レセプターの阻害に応答する疾患の処置または予防に有用な医薬の製造のための、請求項1から10のいずれかに記載の化合物、またはその薬学的に許容される塩の使用。
- 処置すべき疾患が増殖性疾患から選択される、請求項15記載の使用。
- 処置すべき増殖性疾患が、乳房、腎臓、前立腺、結腸直腸、甲状腺、卵巣、膵臓、神経細胞、肺、子宮および胃腸の腫瘍ならびに骨肉腫および黒色腫から選択される、請求項16記載の使用。
- 処置すべき疾患が免疫疾患である、請求項15記載の使用。
- 炎症性および/または免疫障害の処置または予防に有用な医薬の製造のための、請求項1から10のいずれかに記載の化合物、またはその薬学的に許容される塩の使用。
- 炎症性および/または免疫障害が、Tリンパ球、Bリンパ球、マクロファージ、樹状細胞、肥満細胞および好酸球を含む免疫細胞により介在される、移植拒絶反応、アレルギーおよび自己免疫障害から選択される、請求項19記載の使用。
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Families Citing this family (323)
Publication number | Priority date | Publication date | Assignee | Title |
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TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
CN103169708B (zh) | 2002-07-29 | 2018-02-02 | 里格尔药品股份有限公司 | 用2,4‑嘧啶二胺化合物治疗或者预防自体免疫性疾病的方法 |
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RS53109B (en) | 2003-07-30 | 2014-06-30 | Rigel Pharmaceuticals Inc. | 2,4 PIRIMIDINDIAMINE COMPOUNDS FOR USE IN TREATMENT OR PREVENTION OF AUTOIMMUNE DISEASES |
DK1663242T3 (da) * | 2003-08-07 | 2011-08-01 | Rigel Pharmaceuticals Inc | 2,4-Pyrimidindiamin-forbindelser og anvendelse som antiproliferative midler |
DK1660458T3 (da) * | 2003-08-15 | 2012-05-07 | Irm Llc | 2, 4-pyrimidindiaminer egnede i behandling af neoplastiske sygdomme, in-flammatoriske lidelser og lidelser i immunsystemet. |
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WO2005118543A1 (ja) * | 2004-06-03 | 2005-12-15 | Ono Pharmaceutical Co., Ltd. | キナーゼ阻害薬およびその用途 |
US7521457B2 (en) * | 2004-08-20 | 2009-04-21 | Boehringer Ingelheim International Gmbh | Pyrimidines as PLK inhibitors |
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ATE540035T1 (de) | 2004-11-24 | 2012-01-15 | Rigel Pharmaceuticals Inc | Spiro-2,4-pyrimidindiamin-verbindungen und ihre verwendungen |
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SG10201809390QA (en) | 2005-05-10 | 2018-11-29 | Incyte Holdings Corp | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
NZ563454A (en) | 2005-06-08 | 2011-03-31 | Rigel Pharmaceuticals Inc | 2,4-diaminopyrimidine derivatives for inhibition of the JAK pathway |
US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
WO2007028445A1 (en) * | 2005-07-15 | 2007-03-15 | Glaxo Group Limited | 6-indolyl-4-yl-amino-5-halogeno-2-pyrimidinyl-amino derivatives |
WO2007009681A1 (en) * | 2005-07-15 | 2007-01-25 | Glaxo Group Limited | 1 , 1-DIOXID0-2 , 3-DIHYDRO-l , 2-BENZISOTHIAZ0L-6-YL-1H-INDAZOL-4-YL-2 , 4-PYRIMIDINEDI AMINE DERIVATIVES |
CA2621261C (en) | 2005-09-22 | 2014-05-20 | Incyte Corporation | Azepine inhibitors of janus kinases |
US8133900B2 (en) | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
US8604042B2 (en) | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
NZ592990A (en) | 2005-11-01 | 2013-01-25 | Targegen Inc | Bi-aryl meta-pyrimidine inhibitors of kinases |
CN103214483B (zh) | 2005-12-13 | 2014-12-17 | 因塞特公司 | 作为两面神激酶抑制剂的杂芳基取代的吡咯并[2,3-b]吡啶和吡咯并[2,3-b]嘧啶 |
US20080318989A1 (en) * | 2005-12-19 | 2008-12-25 | Burdick Daniel J | Pyrimidine Kinase Inhibitors |
WO2007085540A1 (en) * | 2006-01-27 | 2007-08-02 | Glaxo Group Limited | 1h-indaz0l-4-yl-2 , 4-pyrimidinediamine derivatives |
CA2642211C (en) | 2006-02-17 | 2012-01-24 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds for treating or preventing autoimmune diseases |
TW200804364A (en) * | 2006-02-22 | 2008-01-16 | Boehringer Ingelheim Int | New compounds |
EP1991532B1 (en) | 2006-02-24 | 2017-01-11 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
EP2004632B1 (en) | 2006-03-30 | 2014-03-12 | Janssen R&D Ireland | Hiv inhibiting 5-amido substituted pyrimidines |
ES2637592T3 (es) | 2006-04-14 | 2017-10-13 | Cell Signaling Technology, Inc. | Defectos de genes y quinasa ALK mutante en tumores sólidos humanos |
US8168383B2 (en) | 2006-04-14 | 2012-05-01 | Cell Signaling Technology, Inc. | Gene defects and mutant ALK kinase in human solid tumors |
US8623887B2 (en) | 2006-05-15 | 2014-01-07 | Boehringer Ingelheim International Gmbh | Compounds |
JP2009544592A (ja) * | 2006-07-21 | 2009-12-17 | ノバルティス アクチエンゲゼルシャフト | Jakキナーゼ阻害剤としての2,4−ジ(アリールアミノ)−ピリミジン−5−カルボキサミド化合物 |
CA2598893C (en) | 2006-10-11 | 2012-04-10 | Astellas Pharma Inc. | Eml4-alk fusion gene |
EP1914240B1 (en) | 2006-10-11 | 2009-12-02 | Astellas Pharma Inc. | EML4-ALK fusion gene |
ES2633318T3 (es) | 2006-10-23 | 2017-09-20 | Cephalon, Inc. | Derivados bicíclicos fusionados de 2,4-diaminopirimidina como inhibidores de ALK y c-Met |
AU2007333394C1 (en) * | 2006-12-08 | 2011-08-18 | Novartis Ag | Compounds and compositions as protein kinase inhibitors |
MY148427A (en) * | 2006-12-08 | 2013-04-30 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
US20100144732A1 (en) * | 2006-12-19 | 2010-06-10 | Krueger Elaine B | Pyrimidine kinase inhibitors |
SI2125822T1 (sl) * | 2006-12-21 | 2015-01-30 | Nerviano Medical Sciences S.R.L. | Substituirani pirazolo-kinazolinski derivati, postopek za njihovo pripravo in njihova uporaba kot inhibitorji kinaze |
ES2415863T3 (es) | 2006-12-22 | 2013-07-29 | Incyte Corporation | Heterociclos sustituidos como inhibidores de Janus Quinasas |
TW200902010A (en) | 2007-01-26 | 2009-01-16 | Smithkline Beecham Corp | Anthranilamide inhibitors of aurora kinase |
WO2008118823A2 (en) * | 2007-03-26 | 2008-10-02 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
UA97834C2 (ru) | 2007-04-18 | 2012-03-26 | Пфайзер Продактс Инк. | Производные сульфониламида для лечения анормального роста клеток |
EP2740731B1 (en) | 2007-06-13 | 2016-03-23 | Incyte Holdings Corporation | Crystalline salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
CL2008001709A1 (es) | 2007-06-13 | 2008-11-03 | Incyte Corp | Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras. |
TWI389893B (zh) | 2007-07-06 | 2013-03-21 | Astellas Pharma Inc | 二(芳胺基)芳基化合物 |
CN101796046A (zh) | 2007-07-16 | 2010-08-04 | 阿斯利康(瑞典)有限公司 | 嘧啶衍生物934 |
CN101827848B (zh) * | 2007-08-08 | 2012-11-07 | 葛兰素史密丝克莱恩有限责任公司 | 作为IGF-1R抑制剂用于治疗癌症的2-[(2-{苯基氨基}-1H-吡咯并[2,3-d]嘧啶-4-基)氨基]苯甲酰胺衍生物 |
JP2010538004A (ja) * | 2007-08-28 | 2010-12-09 | アイアールエム・リミテッド・ライアビリティ・カンパニー | キナーゼ阻害剤としての2−ビフェニルアミノ−4−アミノピリミジン誘導体 |
MX2010005300A (es) | 2007-11-16 | 2010-06-25 | Incyte Corp | 4-pirazolil-n-arilpirimidin-2-aminas y 4-pirazolil-n-heteroarilpir imidin-2-aminas como inhibidores de cinasas janus. |
JP5400791B2 (ja) * | 2007-12-04 | 2014-01-29 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | 置換ジヒドロプテリジン−6−オン誘導体、その製造方法及びキナーゼ阻害剤としてのその使用 |
DK2288610T3 (en) | 2008-03-11 | 2016-11-28 | Incyte Holdings Corp | Azetidinesulfonic AND CYCLOBUTANDERIVATER AS JAK INHIBITORS |
CA2720946C (en) * | 2008-04-07 | 2013-05-28 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
WO2009127642A2 (en) * | 2008-04-15 | 2009-10-22 | Cellzome Limited | Use of lrrk2 inhibitors for neurodegenerative diseases |
US8138339B2 (en) | 2008-04-16 | 2012-03-20 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
ES2546502T3 (es) | 2008-04-16 | 2015-09-24 | Portola Pharmaceuticals, Inc. | 2,6-Diamino-pirimidin-5-il-carboxamidas como inhibidores de syk o JAK quinasas |
CA2722326A1 (en) | 2008-04-24 | 2009-10-29 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
SI2300013T1 (en) * | 2008-05-21 | 2018-03-30 | Adriad Pharmacaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
MX2010014057A (es) | 2008-06-17 | 2011-03-21 | Astrazeneca Ab | Compuestos de piridina. |
UY31929A (es) | 2008-06-25 | 2010-01-05 | Irm Llc | Compuestos y composiciones como inhibidores de cinasa |
US8445505B2 (en) | 2008-06-25 | 2013-05-21 | Irm Llc | Pyrimidine derivatives as kinase inhibitors |
US11351168B1 (en) | 2008-06-27 | 2022-06-07 | Celgene Car Llc | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
CA2986640C (en) | 2008-06-27 | 2019-03-26 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
US8338439B2 (en) * | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
CN102164902B (zh) | 2008-07-08 | 2014-07-23 | 因塞特公司 | 作为吲哚胺2,3-双加氧酶的抑制剂的1,2,5-噁二唑 |
CL2009001884A1 (es) | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco. |
TW201024281A (en) | 2008-11-24 | 2010-07-01 | Boehringer Ingelheim Int | New compounds |
TWI491605B (zh) | 2008-11-24 | 2015-07-11 | Boehringer Ingelheim Int | 新穎化合物 |
US8765727B2 (en) | 2009-01-23 | 2014-07-01 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
WO2010129053A2 (en) * | 2009-05-05 | 2010-11-11 | Dana Farber Cancer Institute | Egfr inhibitors and methods of treating disorders |
MX2011011875A (es) | 2009-05-08 | 2011-12-08 | Astellas Pharma Inc | Compuesto de carboxamida heterociclica diamino. |
BRPI1012159B1 (pt) | 2009-05-22 | 2022-01-25 | Incyte Holdings Corporation | Compostos derivados de n-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d] pirimidinas e pirrol-3-il-pirrolo[2,3-d] pirimidinas como inibidores de janus cinase, composições farmacêuticas compreendendo os referidos compostos e usos dos mesmos |
DK2432472T3 (da) | 2009-05-22 | 2019-11-18 | Incyte Holdings Corp | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octan- eller heptan-nitril som jak-inhibitorer |
TW201100441A (en) * | 2009-06-01 | 2011-01-01 | Osi Pharm Inc | Amino pyrimidine anticancer compounds |
HUE039167T2 (hu) | 2009-06-10 | 2018-12-28 | Chugai Pharmaceutical Co Ltd | Tetraciklikus vegyületek |
PL2448938T3 (pl) | 2009-06-29 | 2014-11-28 | Incyte Holdings Corp | Pirymidynony jako inhibitory PI3K |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
PT2486041E (pt) | 2009-10-09 | 2013-11-14 | Incyte Corp | Derivados hidroxilo, ceto e glucuronido de 3-(4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)-3-ciclopentil-propanonitrilo |
US8759359B2 (en) | 2009-12-18 | 2014-06-24 | Incyte Corporation | Substituted heteroaryl fused derivatives as PI3K inhibitors |
WO2011075630A1 (en) | 2009-12-18 | 2011-06-23 | Incyte Corporation | Substituted fused aryl and heteroaryl derivatives as pi3k inhibitors |
MX2012009541A (es) | 2010-02-18 | 2012-10-01 | Incyte Corp | Derivados de ciclobutano y metilciclobutano como inhibidores de janus cinasa. |
KR102283091B1 (ko) | 2010-03-10 | 2021-07-30 | 인사이트 홀딩스 코포레이션 | Jak1 저해제로서의 피페리딘4일 아제티딘 유도체 |
US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
WO2011130342A1 (en) | 2010-04-14 | 2011-10-20 | Incyte Corporation | FUSED DERIVATIVES AS ΡI3Κδ INHIBITORS |
US9301962B2 (en) | 2010-05-14 | 2016-04-05 | Baylor College Of Medicine | Male contraceptive compositions and methods of use |
HUE031073T2 (en) | 2010-05-14 | 2017-06-28 | Dana Farber Cancer Inst Inc | Thieno triazolo-diazepine compounds for the treatment of neoplasia |
EP2569434B1 (en) | 2010-05-14 | 2019-09-04 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating leukemia and related disorders |
AU2011254550B2 (en) | 2010-05-21 | 2013-11-07 | Noviga Research Ab | Novel pyrimidine derivatives |
EP2574168B9 (en) | 2010-05-21 | 2016-10-05 | Incyte Holdings Corporation | Topical formulation for a jak inhibitor |
US9062055B2 (en) | 2010-06-21 | 2015-06-23 | Incyte Corporation | Fused pyrrole derivatives as PI3K inhibitors |
WO2012019132A2 (en) | 2010-08-06 | 2012-02-09 | Cell Signaling Technology, Inc. | Anaplastic lymphoma kinase in kidney cancer |
BR112013003388A2 (pt) | 2010-08-10 | 2016-07-12 | Celgene Avilomics Res Inc | sal de besilato de um inibidor de btk |
EP3698788A1 (en) | 2010-08-20 | 2020-08-26 | Chugai Seiyaku Kabushiki Kaisha | Composition comprising tetracyclic compound |
US9238629B2 (en) | 2010-11-01 | 2016-01-19 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
MX2013004894A (es) | 2010-11-01 | 2013-10-17 | Celgene Avilomics Res Inc | Compuestos heterociclicos y usos de los mismos. |
WO2012060847A1 (en) | 2010-11-07 | 2012-05-10 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
EP2637502B1 (en) | 2010-11-10 | 2018-01-10 | Celgene CAR LLC | Mutant-selective egfr inhibitors and uses thereof |
JP5917544B2 (ja) | 2010-11-19 | 2016-05-18 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Jak阻害剤としての複素環置換ピロロピリジンおよびピロロピリミジン |
AR083933A1 (es) | 2010-11-19 | 2013-04-10 | Incyte Corp | Derivados de pirrolopiridina y pirrolopirimidina sustituidos con ciclobutilo como inhibidores de jak |
EP2646448B1 (en) | 2010-11-29 | 2017-08-30 | OSI Pharmaceuticals, LLC | Macrocyclic kinase inhibitors |
JP5961187B2 (ja) | 2010-12-20 | 2016-08-02 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Pi3k阻害剤としてのn−(1−(置換フェニル)エチル)−9h−プリン−6−アミン |
US8546443B2 (en) | 2010-12-21 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Benzylic oxindole pyrimidines |
ME02200B (me) * | 2011-02-02 | 2016-02-20 | Novartis Ag | Postupci za korisćenje alk inhibitora |
CA2827172C (en) | 2011-02-17 | 2019-02-26 | Cancer Therapeutics Crc Pty Limited | Selective fak inhibitors |
CA2827171C (en) * | 2011-02-17 | 2019-04-09 | Cancer Therapeutics Crc Pty Limited | Fak inhibitors |
PT2675451E (pt) | 2011-02-18 | 2015-10-16 | Incyte Corp | Terapia de combinação com inibidores mtor/jak |
US9108984B2 (en) | 2011-03-14 | 2015-08-18 | Incyte Corporation | Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors |
EP2688883B1 (en) | 2011-03-24 | 2016-05-18 | Noviga Research AB | Pyrimidine derivatives |
US9126948B2 (en) | 2011-03-25 | 2015-09-08 | Incyte Holdings Corporation | Pyrimidine-4,6-diamine derivatives as PI3K inhibitors |
EP3628665B1 (en) * | 2011-04-01 | 2022-11-02 | University of Utah Research Foundation | Substituted n-phenylpyrimidin-2-amine analogs as inhibitors of the axl kinase |
EP2704572B1 (en) | 2011-05-04 | 2015-12-30 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
CN103797010B (zh) | 2011-06-20 | 2016-02-24 | 因塞特控股公司 | 作为jak抑制剂的氮杂环丁烷基苯基、吡啶基或吡嗪基甲酰胺衍生物 |
CA2844507A1 (en) | 2011-08-10 | 2013-02-14 | Novartis Pharma Ag | Jak pi3k/mtor combination therapy |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
HUE030869T2 (en) | 2011-09-02 | 2017-06-28 | Incyte Holdings Corp | Heterocyclic amines as inhibitors of PI3K |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
EP2770830A4 (en) | 2011-10-28 | 2015-05-27 | Celgene Avilomics Res Inc | METHODS OF TREATING A DISEASE OR DISEASE ASSOCIATED WITH TYROSINE KINASE BTK (BRUTON'S TYROSINE KINASE) |
US9359308B2 (en) | 2011-11-23 | 2016-06-07 | Portola Pharmaceuticals, Inc. | Pyrazine kinase inhibitors |
PT2785711T (pt) * | 2011-11-29 | 2016-09-30 | Hoffmann La Roche | Derivados de 2-(fenil ou pirid-3- il)aminopiridinacomo moduladores de lrrk2 quinase, para o tratamento da doença de parkinson |
US9108927B2 (en) | 2012-03-15 | 2015-08-18 | Celgene Avilomics Research, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
CA2866852C (en) | 2012-03-15 | 2020-12-29 | Celgene Avilomics Research, Inc. | Solid forms of an epidermal growth factor receptor kinase inhibitor |
AR090548A1 (es) | 2012-04-02 | 2014-11-19 | Incyte Corp | Azaheterociclobencilaminas biciclicas como inhibidores de pi3k |
US20150166591A1 (en) | 2012-05-05 | 2015-06-18 | Ariad Pharmaceuticals, Inc. | Methods and compositions for raf kinase mediated diseases |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
SG11201408238WA (en) | 2012-06-13 | 2015-01-29 | Incyte Corp | Substituted tricyclic compounds as fgfr inhibitors |
KR101446742B1 (ko) * | 2012-08-10 | 2014-10-01 | 한국화학연구원 | N2,n4-비스(4-(피페라진-1-일)페닐)피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
DK2902029T3 (en) | 2012-09-25 | 2018-10-29 | Chugai Pharmaceutical Co Ltd | RET INHIBITOR |
CN103788066A (zh) * | 2012-10-31 | 2014-05-14 | 韩冰 | 一类保护移植器官的化合物及其用途 |
SG10201703533VA (en) | 2012-11-01 | 2017-06-29 | Incyte Corp | Tricyclic fused thiophene derivatives as jak inhibitors |
AU2013344049B2 (en) * | 2012-11-06 | 2017-12-21 | Fochon Pharmaceuticals, Ltd. | ALK kinase inhibitors |
CR20190073A (es) | 2012-11-15 | 2019-04-25 | Incyte Holdings Corp | FORMAS DE DOSIFICACIÓN DE RUXOLITINIB DE LIBERACIÓN SOTENIDA (Divisional 2015-265) |
WO2014100748A1 (en) | 2012-12-21 | 2014-06-26 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
MX2015009952A (es) | 2013-02-08 | 2015-10-05 | Celgene Avilomics Res Inc | Inhibidores de cinasas reguladas por señales extracelulares (erk) y sus usos. |
BR112015018418A2 (pt) | 2013-02-22 | 2017-07-18 | Hoffmann La Roche | métodos para tratar câncer, para aumentar a eficácia de um tratamento, para adiar e/ou prevenir o desenvolvimento de câncer, para aumentar a sensibilidade a um terapêutico direcionado, para estender o período de sensibilidade, para estender a duração de resposta a um terapêutico direcionado e produto farmacêutico |
TWI736135B (zh) | 2013-03-01 | 2021-08-11 | 美商英塞特控股公司 | 吡唑并嘧啶衍生物治療PI3Kδ相關病症之用途 |
RS62867B1 (sr) | 2013-03-06 | 2022-02-28 | Incyte Holdings Corp | Postupci i intermedijeri za dobijanje inhibitora jak |
US9714946B2 (en) | 2013-03-14 | 2017-07-25 | Dana-Farber Cancer Institute, Inc. | Bromodomain binding reagents and uses thereof |
KR102334260B1 (ko) | 2013-03-14 | 2021-12-02 | 스미토모 다이니폰 파마 온콜로지, 인크. | Jak2 및 alk2 억제제 및 이들의 사용 방법 |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
EA035095B1 (ru) | 2013-04-19 | 2020-04-27 | Инсайт Холдингс Корпорейшн | Бициклические гетероциклы в качестве ингибиторов fgfr |
HUE043573T2 (hu) | 2013-05-17 | 2019-08-28 | Incyte Corp | Bipirazol só, amely JAK-gátlóként alkalmazható |
RU2656591C2 (ru) | 2013-07-11 | 2018-06-06 | Бетта Фармасьютикалз Ко., Лтд | Модуляторы протеин-тирозинкиназы и способы их применения |
KR20160034379A (ko) | 2013-07-25 | 2016-03-29 | 다나-파버 캔서 인스티튜트 인크. | 전사 인자의 억제제 및 그의 용도 |
EP3030227B1 (en) | 2013-08-07 | 2020-04-08 | Incyte Corporation | Sustained release dosage forms for a jak1 inhibitor |
US20150065447A1 (en) | 2013-08-20 | 2015-03-05 | Incyte Corporation | Survival benefit in patients with solid tumors with elevated c-reactive protein levels |
US9492471B2 (en) | 2013-08-27 | 2016-11-15 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase |
WO2015070020A2 (en) | 2013-11-08 | 2015-05-14 | Dana-Farber Cancer Institute, Inc. | Combination therapy for cancer using bromodomain and extra-terminal (bet) protein inhibitors |
US9415049B2 (en) | 2013-12-20 | 2016-08-16 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
EP3099693A4 (en) | 2014-01-31 | 2017-08-16 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
CA2936865A1 (en) | 2014-01-31 | 2015-08-06 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
WO2015117083A1 (en) | 2014-01-31 | 2015-08-06 | Dana-Farber Cancer Institute, Inc. | Diazepane derivatives and uses thereof |
US10231965B2 (en) | 2014-02-20 | 2019-03-19 | Ignyta, Inc. | Molecules for administration to ROS1 mutant cancer cells |
HUE041456T2 (hu) | 2014-02-28 | 2019-05-28 | Incyte Corp | JAK1 inhibitorok myelodysplasiás szindrómák kezelésére |
KR101656382B1 (ko) | 2014-02-28 | 2016-09-09 | 한국화학연구원 | 피리미딘-2,4-디아민 유도체 및 이를 유효성분으로 함유하는 항암용 약학적 조성물 |
AU2015222805B2 (en) | 2014-02-28 | 2020-05-21 | Tensha Therapeutics, Inc. | Treatment of conditions associated with hyperinsulinaemia |
UA119767C2 (uk) | 2014-04-08 | 2019-08-12 | Інсайт Корпорейшн | Лікування b-клітинних злоякісних новоутворень із застосуванням комбінації інгібіторів jak та pi3k |
KR20220042486A (ko) | 2014-04-25 | 2022-04-05 | 추가이 세이야쿠 가부시키가이샤 | 4환성 화합물의 신규 결정 |
KR102478887B1 (ko) | 2014-04-25 | 2022-12-16 | 추가이 세이야쿠 가부시키가이샤 | 4환성 화합물을 고용량 함유하는 제제 |
CA2947418A1 (en) | 2014-04-30 | 2015-11-05 | Incyte Corporation | Processes of preparing a jak1 inhibitor and new forms thereto |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
WO2015191677A1 (en) | 2014-06-11 | 2015-12-17 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as pi3k inhibitors |
CN105330698B (zh) * | 2014-07-04 | 2019-05-28 | 齐鲁制药有限公司 | 螺环芳基磷氧化物和硫化物 |
JP6487527B2 (ja) | 2014-07-04 | 2019-03-20 | チル ファーマシューティカル カンパニー リミテッド | スピロ環アリールリン酸化物及びアリールリン硫化物(spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide) |
WO2016022460A1 (en) * | 2014-08-03 | 2016-02-11 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Potent dual brd4-kinase inhibitors as cancer therapeutics |
TWI718102B (zh) | 2014-08-08 | 2021-02-11 | 日商中外製藥股份有限公司 | 4環性化合物的非晶質體 |
CA2955077A1 (en) | 2014-08-08 | 2016-02-11 | Dana-Farber Cancer Institute, Inc. | Dihydropteridinone derivatives and uses thereof |
CN106715437A (zh) | 2014-08-08 | 2017-05-24 | 达纳-法伯癌症研究所股份有限公司 | 二氮杂环庚烷衍生物及其用途 |
US10005760B2 (en) | 2014-08-13 | 2018-06-26 | Celgene Car Llc | Forms and compositions of an ERK inhibitor |
WO2016029002A2 (en) * | 2014-08-22 | 2016-02-25 | Clovis Oncology, Inc. | Growth factor receptor inhibitors |
JP6684780B2 (ja) | 2014-08-25 | 2020-04-22 | ソーク インスティテュート フォー バイオロジカル スタディーズ | 新規ulk1阻害剤およびそれを使用する方法 |
WO2016050171A1 (zh) * | 2014-09-29 | 2016-04-07 | 山东轩竹医药科技有限公司 | 多环类间变性淋巴瘤激酶抑制剂 |
KR101633722B1 (ko) | 2014-10-08 | 2016-06-28 | 한국화학연구원 | 4-(1-퍼롤-3,4-디카르복시아미드)피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
BR112017008714A2 (pt) | 2014-10-27 | 2017-12-19 | Tensha Therapeutics Inc | inibidores de bromodomínio |
JP6744309B2 (ja) | 2014-12-02 | 2020-08-19 | イグニタ,インコーポレイテッド | 神経芽細胞腫の治療のための併用 |
WO2016114375A1 (ja) | 2015-01-16 | 2016-07-21 | 中外製薬株式会社 | 併用医薬 |
JP6479490B2 (ja) * | 2015-01-27 | 2019-03-06 | 東ソー・ファインケム株式会社 | 5−(トリフルオロメチル)ピリミジン誘導体及びその製造方法 |
WO2016130501A1 (en) | 2015-02-09 | 2016-08-18 | Incyte Corporation | Aza-heteroaryl compounds as pi3k-gamma inhibitors |
CN105985317B (zh) * | 2015-02-12 | 2018-09-18 | 正大天晴药业集团股份有限公司 | 一种色瑞替尼的制备方法及其中间体 |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
CR20170390A (es) | 2015-02-20 | 2017-10-23 | Incyte Holdings Corp | Heterociclos biciclicos como inhibidores de fgfr |
AU2016222556B2 (en) | 2015-02-27 | 2020-08-27 | Incyte Holdings Corporation | Salts of Pl3K inhibitor and processes for their preparation |
KR101772134B1 (ko) | 2015-04-14 | 2017-08-29 | 한국화학연구원 | N2-(2-메톡시페닐)피리미딘 유도체, 이의 제조 방법 및 이를 유효 성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
CN106146468B (zh) * | 2015-04-17 | 2020-12-01 | 杭州雷索药业有限公司 | 吡啶酮类蛋白激酶抑制剂 |
KR101653571B1 (ko) | 2015-04-22 | 2016-09-05 | 한국화학연구원 | 4-(2-아미노-테트라하이드로나프탈렌닐)피리미딘 유도체, 이의 제조 방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
WO2016183063A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Crystalline forms of a pi3k inhibitor |
WO2016183060A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
WO2016183062A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Salts of (s)-7-(1-(9h-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5h-thiazolo[3,2-a]pyrimidin-5-one |
AU2016276963C1 (en) | 2015-06-12 | 2021-08-05 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
CN104892526A (zh) * | 2015-06-17 | 2015-09-09 | 药源药物化学(上海)有限公司 | 一种2,5-二氯-n-(2-(异丙基磺酰基)苯基)嘧啶-4-胺的制备方法 |
PE20181086A1 (es) | 2015-09-11 | 2018-07-05 | Dana Farber Cancer Inst Inc | Acetamida tienotrizolodiazepinas y usos de las mismas |
WO2017044849A1 (en) | 2015-09-11 | 2017-03-16 | Dana-Farber Cancer Institute, Inc. | Cyano thienotriazolodiazepines and uses thereof |
WO2017066428A1 (en) | 2015-10-13 | 2017-04-20 | H. Lee Moffitt Cancer Center & Research Institute, Inc. | Brd4-kinase inhibitors as cancer therapeutics |
CN106699743B (zh) * | 2015-11-05 | 2020-06-12 | 湖北生物医药产业技术研究院有限公司 | 嘧啶类衍生物及其用途 |
AR106595A1 (es) | 2015-11-06 | 2018-01-31 | Incyte Corp | COMPUESTOS HETEROCÍCLICOS COMO INHIBIDORES DE PI3K-g |
SG10201913450PA (en) | 2015-11-25 | 2020-03-30 | Dana Farber Cancer Inst Inc | Bivalent bromodomain inhibitors and uses thereof |
WO2017106492A1 (en) | 2015-12-18 | 2017-06-22 | Ignyta, Inc. | Combinations for the treatment of cancer |
CN106928275B (zh) * | 2015-12-29 | 2020-10-02 | 齐鲁制药有限公司 | 螺环胺类芳基磷氧化合物的制备方法及其中间体和晶型 |
US20170190689A1 (en) | 2016-01-05 | 2017-07-06 | Incyte Corporation | Pyridine and pyridimine compounds as pi3k-gamma inhibitors |
CN107216319B (zh) * | 2016-03-21 | 2021-10-08 | 中国科学院上海药物研究所 | 一种2,4-二氨基嘧啶类衍生物、其制备方法及用途 |
TW201803871A (zh) | 2016-06-24 | 2018-02-01 | 英塞特公司 | 作為PI3K-γ抑制劑之雜環化合物 |
CN106220608B (zh) | 2016-07-25 | 2018-11-27 | 安润医药科技(苏州)有限公司 | 二苯氨基嘧啶及三嗪化合物、其药用组合物及用途 |
KR101937529B1 (ko) * | 2016-07-26 | 2019-01-14 | 한국화학연구원 | 신규한 피리미딘-2,4-디아민 유도체 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
AU2017319135B2 (en) * | 2016-08-29 | 2021-03-18 | The Regents Of The University Of Michigan | Aminopyrimidines as ALK inhibitors |
EP3586848B1 (en) | 2017-02-24 | 2021-09-01 | Daegu-Gyeongbuk Medical Innovation Foundation | Pharmaceutical composition comprising compound capable of penetrating blood-brain barrier as effective ingredient for preventing or treating brain cancer |
CN106905303A (zh) * | 2017-03-16 | 2017-06-30 | 北京师范大学 | 一类靶向fak的化合物和其标记物、及它们的制备方法和应用 |
IT201700047189A1 (it) * | 2017-05-02 | 2018-11-02 | Fondazione St Italiano Tecnologia | Composti e composizioni per il trattamento di cancro, disordini della retina e cardiomiopatie |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
WO2019007293A1 (zh) * | 2017-07-01 | 2019-01-10 | 浙江同源康医药股份有限公司 | 用作alk激酶抑制剂的化合物及其应用 |
BR112020000793A2 (pt) | 2017-07-19 | 2020-07-14 | Ignyta, Inc. | composições farmacêuticas e formas de dosagem |
MD3658552T2 (ro) | 2017-07-28 | 2024-02-29 | Yuhan Corp | Procedeu de obținere a N-(5-((4-(4-((dimetilamino)metil)-3-fenil-1H-pirazol-1-il)pirimidin-2-il)amino)-4-metoxi-2-morfolinofenil)acrilamidei prin prin reacţia aminei corespunzătoare cu clorură de 3-halo-propionil |
JP7311498B2 (ja) | 2017-10-17 | 2023-07-19 | イグナイタ インコーポレイテッド | 薬学的組成物および剤形 |
JP7244504B2 (ja) | 2017-10-18 | 2023-03-22 | インサイト・コーポレイション | PI3K-γ阻害剤としての三級ヒドロキシ基で置換された縮合イミダゾール誘導体 |
CN109836415B (zh) * | 2017-11-29 | 2020-11-06 | 北京博远精准医疗科技有限公司 | 作为alk抑制剂的脲类化合物 |
AR113922A1 (es) | 2017-12-08 | 2020-07-01 | Incyte Corp | Terapia de combinación de dosis baja para el tratamiento de neoplasias mieloproliferativas |
WO2019120094A1 (zh) * | 2017-12-21 | 2019-06-27 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制激酶活性的芳基磷氧化物 |
US11306079B2 (en) | 2017-12-21 | 2022-04-19 | Incyte Corporation | 3-(5-amino-pyrazin-2-yl)-benzenesulfonamide derivatives and related compounds as PI3K-gamma kinase inhibitors |
CN108047204A (zh) * | 2018-01-08 | 2018-05-18 | 沈阳药科大学 | 2,4-二芳氨基嘧啶衍生物及其制备方法和应用 |
PE20211310A1 (es) | 2018-01-30 | 2021-07-22 | Incyte Corp | Procedimiento para la elaboracion de un recipiente de vidrio de sosa-cal a partir de materiales formadores de vidrio 100% reciclados y un recipiente de vidrio elaborado a partir de dicho procedimiento |
CN110092759A (zh) * | 2018-01-31 | 2019-08-06 | 陆柯潮 | 作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物 |
WO2019161098A1 (en) | 2018-02-16 | 2019-08-22 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of cytokine-related disorders |
US20190292188A1 (en) | 2018-02-27 | 2019-09-26 | Incyte Corporation | Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors |
PT3762368T (pt) | 2018-03-08 | 2022-05-06 | Incyte Corp | Compostos de aminopirazina diol como inibidores de pi3k-y |
JP2021519775A (ja) | 2018-03-30 | 2021-08-12 | インサイト・コーポレイションIncyte Corporation | Jak阻害剤を用いる化膿性汗腺炎の治療 |
US11220510B2 (en) | 2018-04-09 | 2022-01-11 | Incyte Corporation | Pyrrole tricyclic compounds as A2A / A2B inhibitors |
WO2019213506A1 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Salts of an fgfr inhibitor |
SG11202010636VA (en) | 2018-05-04 | 2020-11-27 | Incyte Corp | Solid forms of an fgfr inhibitor and processes for preparing the same |
CA3100731A1 (en) | 2018-05-18 | 2019-11-21 | Incyte Corporation | Fused pyrimidine derivatives as a2a / a2b inhibitors |
CA3101368A1 (en) | 2018-05-25 | 2019-11-28 | Incyte Corporation | Tricyclic heterocyclic compounds as sting activators |
WO2020010003A1 (en) | 2018-07-02 | 2020-01-09 | Incyte Corporation | AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS |
CA3105721A1 (en) | 2018-07-05 | 2020-01-09 | Incyte Corporation | Fused pyrazine derivatives as a2a / a2b inhibitors |
EP3826684A4 (en) | 2018-07-26 | 2022-04-06 | Sumitomo Dainippon Pharma Oncology, Inc. | METHODS FOR TREATING DISEASES ASSOCIATED WITH ABNORMAL ACVR1 EXPRESSION AND ACVR1 INHIBITORS FOR USE THEREOF |
US10875872B2 (en) | 2018-07-31 | 2020-12-29 | Incyte Corporation | Heteroaryl amide compounds as sting activators |
US11008344B2 (en) | 2018-07-31 | 2021-05-18 | Incyte Corporation | Tricyclic heteroaryl compounds as STING activators |
CN110835320A (zh) * | 2018-08-15 | 2020-02-25 | 江苏奥赛康药业有限公司 | 二氨基嘧啶类化合物及其应用 |
EP3848361A4 (en) | 2018-09-04 | 2022-06-15 | Chugai Seiyaku Kabushiki Kaisha | TETRACYCLIC COMPOUND PRODUCTION PROCESS |
PT3847175T (pt) | 2018-09-05 | 2024-04-16 | Incyte Corp | Formas cristalinas de um inibidor da fosfoinositídeo 3-quinase (pi3k) |
AU2019348011A1 (en) * | 2018-09-27 | 2021-02-11 | Dana-Farber Cancer Institute, Inc. | Degradation of FAK or FAK and ALK by conjugation of FAK and ALK inhibitors with E3 ligase ligands and methods of use |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
CN111171017B (zh) * | 2018-11-09 | 2021-12-24 | 天津大学 | 基于嘧啶的衍生物及其制备方法和应用 |
US11161838B2 (en) | 2018-11-13 | 2021-11-02 | Incyte Corporation | Heterocyclic derivatives as PI3K inhibitors |
WO2020102198A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Heterocyclic derivatives as pi3k inhibitors |
WO2020102216A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Substituted heterocyclic derivatives as pi3k inhibitors |
US11596692B1 (en) | 2018-11-21 | 2023-03-07 | Incyte Corporation | PD-L1/STING conjugates and methods of use |
WO2020146237A1 (en) | 2019-01-07 | 2020-07-16 | Incyte Corporation | Heteroaryl amide compounds as sting activators |
TWI829857B (zh) | 2019-01-29 | 2024-01-21 | 美商英塞特公司 | 作為a2a / a2b抑制劑之吡唑并吡啶及三唑并吡啶 |
MX2021009682A (es) | 2019-02-15 | 2021-11-12 | Incyte Corp | Biomarcadores de cinasa 2 dependientes de ciclinas y sus usos. |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
WO2020223558A1 (en) | 2019-05-01 | 2020-11-05 | Incyte Corporation | Tricyclic amine compounds as cdk2 inhibitors |
CA3150975A1 (en) | 2019-06-10 | 2020-12-17 | Incyte Corporation | Topical treatment of vitiligo by a jak inhibitor |
EP3994132A1 (en) | 2019-07-03 | 2022-05-11 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
AU2020319875A1 (en) | 2019-08-01 | 2022-02-17 | Incyte Corporation | A dosing regimen for an IDO inhibitor |
KR20220064369A (ko) | 2019-08-14 | 2022-05-18 | 인사이트 코포레이션 | Cdk2 저해제로서의 이미다졸릴 피리디미딘일아민 화합물 |
EP4021907A1 (en) | 2019-08-26 | 2022-07-06 | Incyte Corporation | Triazolopyrimidines as a2a / a2b inhibitors |
WO2021072232A1 (en) | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
CR20220169A (es) | 2019-10-14 | 2022-10-27 | Incyte Corp | Heterociclos bicíclicos como inhibidores de fgfr |
WO2021076124A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Use of jak1 inhibitors for the treatment of cutaneous lupus erythematosus and lichen planus (lp) |
US11992490B2 (en) | 2019-10-16 | 2024-05-28 | Incyte Corporation | Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and Lichen planus (LP) |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
KR102168179B1 (ko) * | 2019-10-31 | 2020-10-20 | 주식회사 온코빅스 | 암세포 성장 억제 효과를 나타내는 신규한 헤테로 고리 치환 피리미딘 유도체 및 그를 포함하는 약제학적 조성물 |
CN114761006A (zh) | 2019-11-08 | 2022-07-15 | Inserm(法国国家健康医学研究院) | 对激酶抑制剂产生耐药性的癌症的治疗方法 |
CN114929675B (zh) * | 2019-12-03 | 2024-02-13 | 三进制药株式会社 | 作为粘着斑激酶抑制剂的新型金刚烷衍生物 |
CA3162010A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Derivatives of an fgfr inhibitor |
JP2023505258A (ja) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
EP4079726A4 (en) * | 2019-12-16 | 2024-01-24 | Korea Research Institute of Chemical Technology | NEW PYRIMIDINE DERIVATIVE AND CORRESPONDING USE |
AU2020406824A1 (en) * | 2019-12-16 | 2022-08-11 | Korea Research Institute Of Chemical Technology | Novel pyrimidine derivative and use thereof |
US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2021178779A1 (en) | 2020-03-06 | 2021-09-10 | Incyte Corporation | Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors |
CN111233834B (zh) * | 2020-03-09 | 2021-08-31 | 北京师范大学 | 一类靶向fak的化合物和其标记物、及它们的制备方法和应用 |
PE20230825A1 (es) | 2020-04-16 | 2023-05-19 | Incyte Corp | Inhibidores de kras triciclicos fusionados |
WO2021231526A1 (en) | 2020-05-13 | 2021-11-18 | Incyte Corporation | Fused pyrimidine compounds as kras inhibitors |
EP4157831A1 (en) | 2020-06-02 | 2023-04-05 | Incyte Corporation | Processes of preparing a jak1 inhibitor |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
CN111560013B (zh) * | 2020-06-08 | 2023-04-07 | 中山大学 | 一种自噬抑制剂及其应用 |
US11999752B2 (en) | 2020-08-28 | 2024-06-04 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of KRAS |
CA3195357A1 (en) | 2020-09-16 | 2022-03-24 | Incyte Corporation | Topical treatment of vitiligo |
US11767320B2 (en) | 2020-10-02 | 2023-09-26 | Incyte Corporation | Bicyclic dione compounds as inhibitors of KRAS |
CN112390760B (zh) * | 2020-10-15 | 2022-07-29 | 北京师范大学 | 靶向fak的化合物及其制备方法和应用 |
AU2021396231A1 (en) | 2020-12-08 | 2023-06-22 | Incyte Corporation | Jak1 pathway inhibitors for the treatment of vitiligo |
WO2022155941A1 (en) | 2021-01-25 | 2022-07-28 | Qilu Regor Therapeutics Inc. | Cdk2 inhibitors |
CN113024454B (zh) * | 2021-03-25 | 2022-09-09 | 浙江工业大学 | 一种布格替尼中间体的合成方法 |
CN113061117B (zh) * | 2021-03-30 | 2023-02-10 | 长治学院 | 一种2-((5-氯-2-(4-吗啉甲基苯胺基)嘧啶-4-基)氨基)苯甲酰胺衍生物 |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997019065A1 (en) * | 1995-11-20 | 1997-05-29 | Celltech Therapeutics Limited | Substituted 2-anilinopyrimidines useful as protein kinase inhibitors |
WO1999031073A1 (fr) * | 1997-12-15 | 1999-06-24 | Yamanouchi Pharmaceutical Co., Ltd. | Nouveaux derives de pyrimidine-5-carboxamide |
WO2001060816A1 (en) * | 2000-02-17 | 2001-08-23 | Amgen Inc. | Kinase inhibitors |
JP2002533446A (ja) * | 1998-12-24 | 2002-10-08 | アストラゼネカ アクチボラグ | ピリミジン化合物 |
WO2003018021A1 (en) * | 2001-08-22 | 2003-03-06 | Amgen Inc. | 2,4-disubstituted pyrimidinyl derivatives for use as anticancer agents |
WO2003063794A2 (en) * | 2002-02-01 | 2003-08-07 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds and their uses |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL129020C (ja) | 1964-12-15 | |||
US3432493A (en) | 1966-06-27 | 1969-03-11 | Abbott Lab | Substituted sulfanilamides |
US3367149A (en) * | 1966-12-15 | 1968-02-06 | Minnesota Mining & Mfg | Radiant white light source |
GB9619284D0 (en) | 1996-09-16 | 1996-10-30 | Celltech Therapeutics Ltd | Chemical compounds |
GB9622363D0 (en) | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
GB9705361D0 (en) | 1997-03-14 | 1997-04-30 | Celltech Therapeutics Ltd | Chemical compounds |
AU751573C (en) | 1998-03-27 | 2003-10-09 | Janssen Pharmaceutica N.V. | HIV inhibiting pyrimidine derivatives |
JP2002523497A (ja) | 1998-08-29 | 2002-07-30 | アストラゼネカ・アクチエボラーグ | ピリミジン化合物 |
PT1184376E (pt) | 1999-06-09 | 2005-04-29 | Yamanouchi Pharma Co Ltd | Novos derivados heterociclicos de carboxamida |
WO2001025220A1 (en) | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
US6376770B1 (en) * | 2000-02-28 | 2002-04-23 | Douglas Hyde | Quick connecting universal electrical box and wiring system |
GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0004887D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0004888D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
US20040100251A1 (en) * | 2000-08-02 | 2004-05-27 | Peter Lohberg | Active magnetic field sensor, use thereof, method and device |
US20020132823A1 (en) | 2001-01-17 | 2002-09-19 | Jiahuai Han | Assay method |
WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
CA2476281A1 (en) | 2002-02-08 | 2003-08-14 | Smithkline Beecham Corporation | Pyrimidine compounds |
GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
AU2003231231A1 (en) | 2002-05-06 | 2003-11-11 | Bayer Pharmaceuticals Corporation | Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders |
AU2003244098A1 (en) | 2002-06-28 | 2004-01-19 | Yamanouchi Pharmaceutical Co., Ltd. | Diaminopyrimidinecarboxa mide derivative |
UA80767C2 (en) | 2002-12-20 | 2007-10-25 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
DE602004021472D1 (en) | 2003-02-20 | 2009-07-23 | Smithkline Beecham Corp | Pyrimiidinverbindungen |
GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
DK1660458T3 (da) | 2003-08-15 | 2012-05-07 | Irm Llc | 2, 4-pyrimidindiaminer egnede i behandling af neoplastiske sygdomme, in-flammatoriske lidelser og lidelser i immunsystemet. |
GB0321710D0 (en) | 2003-09-16 | 2003-10-15 | Novartis Ag | Organic compounds |
EP1663992A1 (en) | 2003-09-18 | 2006-06-07 | Novartis AG | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
US7521457B2 (en) * | 2004-08-20 | 2009-04-21 | Boehringer Ingelheim International Gmbh | Pyrimidines as PLK inhibitors |
GB0419160D0 (en) * | 2004-08-27 | 2004-09-29 | Novartis Ag | Organic compounds |
ATE540035T1 (de) | 2004-11-24 | 2012-01-15 | Rigel Pharmaceuticals Inc | Spiro-2,4-pyrimidindiamin-verbindungen und ihre verwendungen |
-
2003
- 2003-03-14 GB GBGB0305929.2A patent/GB0305929D0/en not_active Ceased
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2004
- 2004-03-12 CN CN2004800130419A patent/CN1788001B/zh not_active Expired - Lifetime
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- 2005-10-13 NO NO20054726A patent/NO331977B1/no unknown
-
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-
2013
- 2013-05-27 CY CY20131100414T patent/CY1114238T1/el unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997019065A1 (en) * | 1995-11-20 | 1997-05-29 | Celltech Therapeutics Limited | Substituted 2-anilinopyrimidines useful as protein kinase inhibitors |
WO1999031073A1 (fr) * | 1997-12-15 | 1999-06-24 | Yamanouchi Pharmaceutical Co., Ltd. | Nouveaux derives de pyrimidine-5-carboxamide |
JP2002533446A (ja) * | 1998-12-24 | 2002-10-08 | アストラゼネカ アクチボラグ | ピリミジン化合物 |
WO2001060816A1 (en) * | 2000-02-17 | 2001-08-23 | Amgen Inc. | Kinase inhibitors |
WO2003018021A1 (en) * | 2001-08-22 | 2003-03-06 | Amgen Inc. | 2,4-disubstituted pyrimidinyl derivatives for use as anticancer agents |
WO2003063794A2 (en) * | 2002-02-01 | 2003-08-07 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds and their uses |
JP2005516046A (ja) * | 2002-02-01 | 2005-06-02 | ライジェル ファーマシューティカルズ, インコーポレイテッド | 2,4−ピリミジンジアミン化合物とその用途 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11013741B1 (en) | 2018-04-05 | 2021-05-25 | Sumitomo Dainippon Pharma Oncology, Inc. | AXL kinase inhibitors and use of the same |
US11400091B2 (en) | 2018-04-05 | 2022-08-02 | Sumitomo Pharma Oncology, Inc. | AXL kinase inhibitors and use of the same |
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