KR100516419B1 - 면역억제제로서 피롤로[2,3-d]피리미딘 화합물 - Google Patents
면역억제제로서 피롤로[2,3-d]피리미딘 화합물 Download PDFInfo
- Publication number
- KR100516419B1 KR100516419B1 KR10-2002-7017610A KR20027017610A KR100516419B1 KR 100516419 B1 KR100516419 B1 KR 100516419B1 KR 20027017610 A KR20027017610 A KR 20027017610A KR 100516419 B1 KR100516419 B1 KR 100516419B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- amino
- pyrrolo
- pyrimidin
- alkyl
- Prior art date
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- 229940125721 immunosuppressive agent Drugs 0.000 title 1
- 239000003018 immunosuppressive agent Substances 0.000 title 1
- 150000004943 pyrrolo[2,3-d]pyrimidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- -1 NC (= O) Chemical group 0.000 claims description 126
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 78
- 238000000034 method Methods 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 13
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 9
- 125000004442 acylamino group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052805 deuterium Inorganic materials 0.000 claims description 9
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- RDGVREXPTVNIOZ-UHFFFAOYSA-N (3-hydroxypyrrolidin-1-yl)-[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]methanone Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)N1CCC(O)C1 RDGVREXPTVNIOZ-UHFFFAOYSA-N 0.000 claims description 5
- JHQOCEWOJAFCTJ-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid Chemical compound CC1CCN(C(O)=O)CC1N(C)C1=NC=NC2=C1C=CN2 JHQOCEWOJAFCTJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YXPJSLNLGWWFQK-UHFFFAOYSA-N 4-[[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]methyl]benzenesulfonamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1CC1=CC=C(S(N)(=O)=O)C=C1 YXPJSLNLGWWFQK-UHFFFAOYSA-N 0.000 claims description 4
- BXLOTZYFEBJGFO-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-(1,2-oxazol-3-yl)piperidine-1-carboxamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC=1C=CON=1 BXLOTZYFEBJGFO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- HJWUCTNLSFICSW-UHFFFAOYSA-N 2-[2-[[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=NC(CC(O)=O)=CS1 HJWUCTNLSFICSW-UHFFFAOYSA-N 0.000 claims description 3
- JTRGLKTYLIFFTR-UHFFFAOYSA-N 2-[4-[[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carbonyl]amino]phenyl]acetic acid Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CC=C(CC(O)=O)C=C1 JTRGLKTYLIFFTR-UHFFFAOYSA-N 0.000 claims description 3
- XLWYJSMYNALODL-UHFFFAOYSA-N 3-[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carbonyl]cyclopentan-1-one Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)C1CCC(=O)C1 XLWYJSMYNALODL-UHFFFAOYSA-N 0.000 claims description 3
- TXZVMZALSHPMNV-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-(1,3-thiazol-2-yl)piperidine-1-carboxamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=NC=CS1 TXZVMZALSHPMNV-UHFFFAOYSA-N 0.000 claims description 3
- WQXRYEVRJRVDSK-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-(4-methyl-1,3-thiazol-2-yl)piperidine-1-carboxamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=NC(C)=CS1 WQXRYEVRJRVDSK-UHFFFAOYSA-N 0.000 claims description 3
- JNDULUJHHAKHFI-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-(4-methylsulfonylphenyl)piperidine-1-carboxamide Chemical class C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 JNDULUJHHAKHFI-UHFFFAOYSA-N 0.000 claims description 3
- BAMSJXFWGUSAPN-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-(4-nitrophenyl)piperidine-1-carboxamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CC=C([N+]([O-])=O)C=C1 BAMSJXFWGUSAPN-UHFFFAOYSA-N 0.000 claims description 3
- MNZUYWZVJCMTLM-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-(4-sulfamoylphenyl)piperidine-1-carboxamide Chemical class C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CC=C(S(N)(=O)=O)C=C1 MNZUYWZVJCMTLM-UHFFFAOYSA-N 0.000 claims description 3
- KSZRXZRZFBENAS-UHFFFAOYSA-N 4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-n-[4-(methylsulfamoyl)phenyl]piperidine-1-carboxamide Chemical class C1=CC(S(=O)(=O)NC)=CC=C1NC(=O)N1CC(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CC1 KSZRXZRZFBENAS-UHFFFAOYSA-N 0.000 claims description 3
- HIOUMGNWXIKDEL-UHFFFAOYSA-N 4-methyl-n-(3-methyl-1,2-oxazol-4-yl)-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carboxamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CON=C1C HIOUMGNWXIKDEL-UHFFFAOYSA-N 0.000 claims description 3
- NHFAFANWNRBBTO-UHFFFAOYSA-N 5-[2-[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-2-oxoethyl]-1,3-thiazolidine-2,4-dione Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)CC1SC(=O)NC1=O NHFAFANWNRBBTO-UHFFFAOYSA-N 0.000 claims description 3
- IKJVHXOXTUJMHW-UHFFFAOYSA-N cyclopentyl-[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]methanone Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)C1CCCC1 IKJVHXOXTUJMHW-UHFFFAOYSA-N 0.000 claims description 3
- STPGXNKIIWAKOY-UHFFFAOYSA-N ethyl 2-[2-[[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carbonyl]amino]-1,3-thiazol-4-yl]acetate Chemical compound CCOC(=O)CC1=CSC(NC(=O)N2CC(C(C)CC2)N(C)C=2C=3C=CNC=3N=CN=2)=N1 STPGXNKIIWAKOY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- VEMGCXQTHHJHSV-UHFFFAOYSA-N n-(4-cyanophenyl)-4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carboxamide Chemical class C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CC=C(C#N)C=C1 VEMGCXQTHHJHSV-UHFFFAOYSA-N 0.000 claims description 3
- PJIDNSQIATYRAD-UHFFFAOYSA-N n-(6-cyanopyridin-3-yl)-4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-carboxamide Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)NC1=CC=C(C#N)N=C1 PJIDNSQIATYRAD-UHFFFAOYSA-N 0.000 claims description 3
- KNRLJPBXCVZFKC-UHFFFAOYSA-N 1-[4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-2-(tetrazol-1-yl)ethanone Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)CN1C=NN=N1 KNRLJPBXCVZFKC-UHFFFAOYSA-N 0.000 claims description 2
- IGNOXKOLEZVMMV-UHFFFAOYSA-N [4-methyl-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-(oxolan-3-yl)methanone Chemical compound C1C(N(C)C=2C=3C=CNC=3N=CN=2)C(C)CCN1C(=O)C1CCOC1 IGNOXKOLEZVMMV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims 6
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 125000005256 alkoxyacyl group Chemical group 0.000 claims 2
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- 210000000078 claw Anatomy 0.000 claims 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
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- 239000003112 inhibitor Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
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- 239000000203 mixture Substances 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
본 발명은 단백질 키나제, 예컨대 효소 야누스 키나제 3의 억제제로서 유용한 화학식 I의 화합물에 관한 것이다.
<화학식 I>
상기 식에서, R1, R2 및 R3은 상기 정의된 바와 같다.
Description
본 발명은 단백질 키나제, 예컨대 효소 야누스 (Janus) 키나제 3 (이후, JAK3로도 지칭함)의 억제제인 피롤로[2,3-d]피리미딘 화합물에 관한 것으로서, 이는 면역억제제로서 기관 이식, 이종 이식, 루푸스, 다발성 경화증, 류마티스양 관절염, 건선, 제I형 당뇨병 및 당뇨병으로 인한 합병증, 암, 천식, 아토피성 피부염, 자가면역 갑상선 질환, 궤양성 대장염, 크론병, 알쯔하이머병, 백혈병, 및 면역억제가 요구되는 다른 증상에 유용한 치료법에 이용된다.
본 발명은 또한 포유동물, 특히 인간에서 상기 증상의 치료에 상기 화합물을 사용하는 방법, 및 그에 유용한 제약 조성물에 관한 것이다.
JAK3은 단백질 키나제의 야누스족의 일원이다. 야누스족의 다른 일원은 거의 모든 조직에서 발현되는 반면, JAK3은 조혈 세포에서만 발현된다. 이는 IL-2, IL-4, IL-7, IL-9 및 IL-15에 대한 수용체와 같은 다쇄 수용체에서 공통되는 감마쇄와 JAK3의 비공유 회합에 의해 상기 수용체를 통해 신호전달하는 JAK3의 필수적인 역할에 부합된다. XSCID 환자군은 JAK3 단백질 수치의 심각한 감소 또는 공통된 감마쇄의 유전적 결함이 있는 것으로 확인되었으며, JAK3 경로를 통해 신호전달을 차단하여 면역을 억제해야함을 제시한다. 동물 연구를 통해, JAK3는 B 및 T 림프구 성숙에 중요한 역할을 할 뿐만 아니라, T 세포 기능 유지를 위해 구성적으로 필요하다는 것이 제시되었다. 이와 같은 신규 메카니즘을 통한 면역 활성의 조절은 T 세포 증식성 질환, 예컨대 이식 거부 및 자가면역 질환의 치료에 유용함이 입증될 수 있다.
<발명의 개요>
본 발명은 화학식 I의 화합물 또는 그의 제약상 허용가능한 염에 관한 것이다.
상기 식에서,
R1은 화학식 의 기이고,
식 중, y는 0, 1 또는 2이고;
R4는 수소, (C1-C6)알킬, (C1-C6)알킬술포닐, (C
2-C6)알케닐, (C2-C6)알키닐로 구성된 군으로부터 선택되고, 이 때, 알킬, 알케닐 및 알키닐기는 중수소, 히드록시, 아미노, 트리플루오로메틸, (C1-C4)알콕시, (C1-C6)아실옥시, (C1-C6)알킬아미노, ((C1-C6)알킬)2아미노, 시아노, 니트로, (C2-C6)알케닐, (C2-C6)알키닐 또는 (C1-C6)아실아미노에 의해 임의로 치환되거나; 또는 R4는 (C3-C10)시클로알킬이고, 이 때, 시클로알킬기는 중수소, 히드록시, 아미노, 트리플루오로메틸, (C1-C6)아실옥시, (C1
-C6)아실아미노, (C1-C6)알킬아미노, ((C1-C6)알킬)
2아미노, 시아노, 시아노(C1-C6)알킬, 트리플루오로메틸(C1-C6)알킬, 니트로, 니트로(C1-C6)알킬 또는 (C1-C6)아실아미노에 의해 임의로 치환되고;
R5는 (C2-C9)헤테로시클로알킬이고, 이 때, 헤테로시클로알킬기는 카르복시, 시아노, 아미노, 중수소, 히드록시, (C1-C6)알킬, (C1-C6)알콕시, 할로, (C1-C6)아실, (C1-C6)알킬아미노, 아미노(C1-C6)알킬, (C1-C6
)알콕시-CO-NH, (C1-C6)알킬아미노-CO-, (C2-C6)알케닐, (C2-C6)알키닐, (C1-C6)알킬아미노, 아미노(C1-C6)알킬, 히드록시 (C1-C6)알킬, (C1-C6)알콕시(C1-C6)알킬, (C1-C6)아실옥시(C1-C6)알킬, 니트로, 시아노(C1-C6)알킬, 할로(C1-C6)알킬, 니트로(C1-C
6)알킬, 트리플루오로메틸, 트리플루오로메틸(C1-C6)알킬, (C1-C6)아실아미노, (C1-C
6)아실아미노(C1-C6)알킬, (C1-C6)알콕시(C1-C6)아실아미노, 아미노(C1-C6)아실, 아미노(C1
-C6)아실(C1-C6)알킬, (C1-C6)알킬아미노(C1-C6)아실, ((C1-C6)알킬)2아미노(C1
-C6)아실, R15R16N-CO-O-, R15R16N-CO-(C1-C6)알킬, (C1-C6)알킬-S(O)m, R15R
16NS(O)m, R15R16NS(O)m(C1-C6
)알킬, R15S(O)mR16N, R15S(O)mR16N(C1-C6)알킬 (이 때, m은 0, 1 또는 2이고, R15 및 R16은 각각 독립적으로 수소 또는 (C1-C6)알킬로부터 선택됨) 및 화학식 II의 기로 구성된 군 중 1 내지 5개로 치환되어야 하고;
식 중, a는 0, 1, 2, 3 또는 4이고;
b, c, e, f 및 g는 각각 독립적으로 0 또는 1이고;
d는 0, 1, 2 또는 3이고;
X는 S(O)n (이 때, n은 0, 1 또는 2임), 산소, 카르보닐 또는 -C(=N-시아노)-이고;
Y는 S(O)n (이 때, n은 0, 1 또는 2임) 또는 카르보닐이고;
Z는 카르보닐, C(O)O-, C(O)NR- (이 때, R은 수소 또는 (C1-C6)알킬임) 또는 S(O)n (이 때, n은 0, 1 또는 2임)이고;
R6, R7, R8, R9, R10 및 R11은 각각 독립적으로 수소, 또는 중수소, 히드록시, 아미노, 트리플루오로메틸, (C1-C6)아실옥시, (C1-C6)아실아미노, (C1-C6)알킬아미노, ((C1-C6)알킬)2아미노, 시아노, 시아노(C1-C6)알킬, 트리플루오로메틸(C1-C6)알킬, 니트로, 니트로(C1-C6)알킬 또는 (C1-C6)아실아미노에 의해 임의로 치환된 (C1-C6)알킬로 구성된 군으로부터 선택되고;
R12는 (C6-C10)아릴, (C2-C9)헤테로아릴, (C3
-C10)시클로알킬 또는 (C2-C9)헤테로시클로알킬이고, 이 때, 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬기는 수소, 중수소, 아미노, 할로, 옥소, 히드록시, 니트로, 카르복시, (C2-C6)알케닐, (C2-C6)알키닐, 트리플루오로메틸, 트리플루오로메톡시, (C1-C6)알킬, (C1-C6)알콕시, (C3-C10)시클로알킬, (C1-C6)알킬-CO-NH-, (C1-C
6)알콕시-CO-NH-, (C1-C6)알킬-CO-NH-(C1-C6)알킬, (C1-C6)알콕시-CO-NH-(C1-C6
)알킬, (C1-C6)알콕시-CO-NH-(C1-C6)알콕시, 카르복시, 카르복시(C1-C6)알킬, 카르복시(C1-C6)알콕시, 벤질옥시카르보닐(C
1-C6)알콕시, (C1-C6)알콕시카르보닐(C1-C6)알콕시, (C6-C
10)아릴, 아미노, 아미노(C1-C6)알킬, (C1-C6)알콕시카르보닐아미노, (C6-C10)아릴(C1-C
6)알콕시카르보닐아미노, (C1-C6)알킬아미노, ((C1-C6)알킬)2아미노, (C1-C6)알킬아미노(C
1-C6)알킬, ((C1-C6)알킬)2아미노(C1-C6)알킬, 히드록시, (C1-C6)알콕시, 카르복시, 카르복시(C
1-C6)알킬, (C1-C6)알콕시카르보닐, (C1-C6)알콕시카르보닐(C1-C6)알킬, (C1
-C6)알콕시-CO-NH-, (C1-C6)알킬-CO-NH-, 시아노, (C5-C9)헤테로시클로알킬, 아미노-CO-NH-, (C1-C
6)알킬아미노-CO-NH-, ((C1-C6)알킬)2아미노-CO-NH-, (C6-C10)아릴아미노-CO-NH-, (C5-C9)헤테로아릴아미노-CO-NH-, (C1-C6)알킬아미노-CO-NH-(C1-C6)알킬, ((C
1-C6)알킬)2아미노-CO-NH-(C1-C6)알킬, (C6-C10)아릴아미노-CO-NH-(C1-C
6)알킬, (C5-C9)헤테로아릴아미노-CO-NH-(C1-C6)알킬, (C1-C6)-알킬시아노, (C1-C6
)알킬카르복시(C1-C6)알콕시, (C1-C6)알킬카르복시, 술포닐아미노, 아미노술포닐, 술포닐아미노(C1-C6)알킬, 술포닐아미노카르복시(C1-C6)알킬, (C1-C6)알킬술포닐, (C1-C6
)알킬술포닐아미노, (C1-C6)알킬술포닐아미노(C1-C6)알킬, (C6-C10)아릴술포닐, (C6-C
10)아릴술포닐아미노, (C6-C10)아릴술포닐아미노(C1-C6)알킬, (C1-C6)알킬술포닐아미노, (C1-C
6)알킬술포닐아미노(C1-C6)알킬, (C3-C10)시클로알킬, (C3-C10)시클로알콕시, (C1-C
6)알킬아미노, ((C1-C6)알킬)2아미노, (C6-C10)아릴아미노, (C1-C6)알킬티오, (C6-C
10)아릴티오, (C1-C6)알킬술피닐, (C6-C10)아릴술피닐, (C1-C6)알킬술포닐, (C6-C
10)아릴술포닐, (C1-C6)아실, (C1-C6)알콕시-CO-NH-, (C1-C6)알킬아미노-CO-, (C5-C9)헤테로아릴, (C
2-C9)헤테로시클로알킬 또는 (C6-C10)아릴 (이 때, R12상에 임의로 치환된 헤테로아릴, 헤테로시클로알킬 및 아릴기는 할로, (C1-C6)알킬, (C1-C6)알킬-CO-NH-, (C1
-C6)알콕시-CO-NH-, (C1-C6)알킬-CO-NH-(C1-C6)알킬, (C1-C6)알콕시-CO-NH-(C1-C
6)알킬, (C1-C6)알콕시-CO-NH-(C1-C6)알콕시, 카르복시, 카르복시(C1-C6)알킬, 카르복시(C1-C
6)알콕시, 벤질옥시카르보닐(C1-C6)알콕시, (C1-C6)알콕시카르보닐(C1-C6
)알콕시, (C6-C10)아릴, 아미노, 아미노(C1-C6)알킬, (C1-C6)알콕시카르보닐아미노, (C6
-C10)아릴(C1-C6)알콕시카르보닐아미노, (C1-C6)알킬아미노, ((C1-C6)알킬)2아미노, (C1-C6)알킬아미노(C1-C6)알킬, ((C1-C6)알킬)2아미노(C1-C6)알킬, 히드록시, (C
1-C6)알콕시, 카르복시, 카르복시(C1-C6)알킬, (C1-C6)알콕시카르보닐, (C1-C6)알콕시카르보닐(C
1-C6)알킬, (C1-C6)알콕시-CO-NH-, (C1-C6)알킬-CO-NH-, 시아노, (C5-C9)헤테로시클로알킬, 아미노-CO-NH-, (C1-C6)알킬아미노-CO-NH-, ((C1-C6)알킬)2아미노-CO-NH-, (C6-C10)아릴아미노-CO-NH-, (C5-C9)헤테로아릴아미노-CO-NH-, (C1-C6)알킬아미노-CO-NH-(C
1-C6)알킬, ((C1-C6)알킬)2아미노-CO-NH-(C1-C6)알킬, (C6-C10)아릴아미노-CO-NH-(C
1-C6)알킬, (C5-C9)헤테로아릴아미노-CO-NH-(C1-C6)알킬, (C1-C6)알킬술포닐, (C1
-C6)알킬술포닐아미노, (C1-C6)알킬술포닐아미노(C1-C6)알킬, (C6-C10)아릴술포닐, (C6-C10)아릴술포닐아미노, (C6-C10)아릴술포닐아미노(C1-C6)알킬, (C1-C6
)알킬술포닐아미노, (C1-C6)알킬술포닐아미노(C1-C6)알킬, (C5-C9)헤테로아릴 및 (C2-C9
)헤테로시클로알킬로 구성된 군 중 1 내지 3개에 의해 추가로 치환될 수 있음)로 구성된 군 중 1 내지 4개에 의해 임의로 치환되고;
R2 및 R3은 각각 독립적으로 수소, 중수소, 아미노, 할로, 히드록시, 니트로, 카르복시, (C2-C6)알케닐, (C2-C6)알키닐, 트리플루오로메틸, 트리플루오로메톡시, (C1-C6)알킬, (C1-C6)알콕시, (C3-C10
)시클로알킬로 구성된 군으로부터 선택되고, 이 때, 알킬, 알콕시 또는 시클로알킬기는 할로, 히드록시, 카르복시, 아미노(C1-C6)알킬티오, (C1-C6)알킬아미노, ((C1-C6)알킬)
2아미노, (C5-C9)헤테로아릴, (C2-C9)헤테로시클로알킬, (C3-C9)시클로알킬 또는 (C6-C10)아릴로부터 선택된 1 내지 3개의 기에 의해 임의로 치환되거나; 또는 R2 및 R3은 각각 독립적으로 (C3-C
10)시클로알킬, (C3-C10)시클로알콕시, (C1-C6)알킬아미노, ((C1-C
6)알킬)2아미노, (C6-C10)아릴아미노, (C1-C6)알킬티오, (C6-C10)아릴티오, (C1-C
6)알킬술피닐, (C6-C10)아릴술피닐, (C1-C6)알킬술포닐, (C6-C10)아릴술포닐, (C1-C
6)아실, (C1-C6)알콕시-CO-NH-, (C1-C6)알킬아미노-CO-, (C5-C9)헤테로아릴, (C2-C9)헤테로시클로알킬 또는 (C6-C10)아릴이고, 이 때, 헤테로아릴, 헤테로시클로알킬 및 아릴기는 할로, (C1-C6)알킬, (C1
-C6)알킬-CO-NH-, (C1-C6)알콕시-CO-NH-, (C1-C6)알킬-CO-NH-(C
1-C6)알킬, (C1-C6)알콕시-CO-NH-(C1-C6)알킬, (C1-C6)알콕시-CO-NH-(C1-C
6)알콕시, 카르복시, 카르복시(C1-C6)알킬, 카르복시(C1-C6)알콕시, 벤질옥시카르보닐(C1-C6)알콕시, (C1-C6)알콕시카르보닐(C1-C6)알콕시, (C6-C10)아릴, 아미노, 아미노(C1-C
6)알킬, (C1-C6)알콕시카르보닐아미노, (C6-C10)아릴(C1-C6)알콕시카르보닐아미노, (C1
-C6)알킬아미노, ((C1-C6)알킬)2아미노, (C1-C6)알킬아미노(C1-C6)알킬, ((C1-C
6)알킬)2아미노(C1-C6)알킬, 히드록시, (C1-C6)알콕시, 카르복시, 카르복시(C1-C6)알킬, (C1-C
6)알콕시카르보닐, (C1-C6)알콕시카르보닐(C1-C6)알킬, (C1-C6)알콕시-CO-NH-, (C1-C
6)알킬-CO-NH-, 시아노, (C5-C9)헤테로시클로알킬, 아미노-CO-NH-, (C1-C6)알킬아미노-CO-NH-, ((C1-C6)알킬)2아미노-CO-NH-, (C6-C10)아릴아미노-CO-NH-, (C5-C9)헤테로아릴아미노-CO-NH-, (C1-C6)알킬아미노-CO-NH-(C1-C6)알킬, ((C1-C
6)알킬)2아미노-CO-NH-(C1-C6)알킬, (C6-C10)아릴아미노-CO-NH-(C1-C6)알킬, (C5-C
9)헤테로아릴아미노-CO-NH-(C1-C6)알킬, (C1-C6)알킬술포닐, (C1-C6)알킬술포닐아미노, (C1
-C6)알킬술포닐아미노(C1-C6)알킬, (C6-C10)아릴술포닐, (C6-C10)아릴술포닐아미노, (C6
-C10)아릴술포닐아미노(C1-C6)알킬, (C1-C6)알킬술포닐아미노, (C1-C6)알킬술포닐아미노(C
1-C6)알킬, (C5-C9)헤테로아릴 또는 (C2-C9)헤테로시클로알킬 중 1 내지 3개에 의해 임의로 치환되고;
단, R5는 화학식 II의 기에 의해 치환되어야 한다.
본 발명은 또한 화학식 I의 화합물의 제약상 허용가능한 산부가염에 관한 것이다. 상기 언급한 본 발명의 염기 화합물의 제약상 허용가능한 산부가염의 제조에 사용되는 산은 무독성 산부가염, 즉 약리학상 허용가능한 음이온, 예컨대 히드로클로라이드, 히드로브로마이드, 히드로요오다이드, 니트레이트, 술페이트, 비술페이트, 포스페이트, 산 포스페이트, 아세테이트, 락테이트, 시트레이트, 산 시트레이트, 타르트레이트, 비타르트레이트, 숙시네이트, 말레에이트, 푸마레이트, 글루코네이트, 사카레이트, 벤조에이트, 메탄술포네이트, 에탄술포네이트, 벤젠술포네이트, p-톨루엔술포네이트 및 파모에이트 [즉, 1,1'-메틸렌-비스-(2-히드록시-3-나프토에이트)]를 함유하는 염을 형성하는 것이다.
본 발명은 또한 화학식 I의 염기부가염에 관한 것이다. 본래 산성인 화학식 I의 화합물의 제약상 허용가능한 염기염을 제조하기 위한 시약으로 사용될 수 있는 화학적 염기는 상기 화합물과 무독성 염기염을 형성하는 것이다. 상기 무독성 염기염으로는 약리학상 허용되는 양이온, 예컨대 알칼리 금속 양이온 (예, 칼륨 및 나트륨) 및 알칼리 토금속 양이온 (예, 칼슘 및 마그네슘)으로부터 유래된 염, 암모늄 또는 수용성 아민부가염, 예컨대 N-메틸글루카민-(메글루민), 및 저급 알칸올암모늄 및 제약상 허용가능한 유기 아민의 다른 염기염이 포함되나, 이로 한정되는 것은 아니다.
용어 "옥손(Oxone:등록상표)"은 2KHSO5ㆍKHSO4ㆍK2SO4의 화학식을 갖는 본 발명에 사용된 모노퍼술페이트의 명칭이며, 알드리치 케미컬 캄파니 (Aldrich Chemical Company, 미국 53201 윌밍톤 밀워키 피.오.박스 2060)에서 시판하고 있다.
본원에 사용된 용어 "알킬"에는, 달리 언급하지 않는 한, 직쇄형 또는 분지형 잔기 또는 이들을 함께 갖는 포화 1가 탄화수소 라디칼이 포함된다.
본원에 사용된 용어 "알콕시"에는 0-알킬기가 포함되고, 이 때, "알킬"은 상기 정의된 바와 같다.
본원에 사용된 용어 "할로"에는, 달리 언급하지 않는 한, 플루오로, 클로로, 브로모 또는 요오도가 포함된다.
본 발명의 화합물은 이중 결합을 함유할 수 있다. 이중 결합이 존재하는 경우, 본 발명의 화합물은 시스 및 트랜스 형태, 및 이들의 혼합물로서 존재한다.
달리 언급하지 않는 한, 본원에 언급된 알킬 및 알케닐기뿐 아니라 본원에 언급된 다른 기 (예, 알콕시)의 알킬 잔기는 선형 또는 분지형일 수 있으며, 환형 (예, 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실 또는 시클로헵틸)일 수도 있고, 또는 선형 또는 분지형이며 환형 잔기를 함유할 수 있다. 달리 언급하지 않는 한, 할로겐에는 불소, 염소, 브롬 및 요오드가 포함된다.
본원에 사용된 (C2-C9)헤테로시클로알킬은 피롤리디닐, 테트라히드로푸라닐, 디히드로푸라닐, 테트라히드로피라닐, 피라닐, 티오피라닐, 아지리디닐, 옥시라닐, 메틸렌디옥실, 크로메닐, 이속사졸리디닐, 1,3-옥사졸리딘-3-일, 이소티아졸리디닐, 1,3-티아졸리딘-3-일, 1,2-피라졸리딘-2-일, 1,3-피라졸리딘-1-일, 피페리디닐, 티오모르폴리닐, 1,2-테트라히드로티아진-2-일, 1,3-테트라히드로티아진-3-일, 테트라히드로티아디아지닐, 모르폴리닐, 1,2-테트라히드로디아진-2-일, 1,3-테트라히드로디아진-1-일, 테트라히드로아제피닐, 피페라지닐, 크로마닐 등을 나타낸다. 당업자라면 상기 (C2-C9)헤테로시클로알킬 고리가 탄소 또는 sp3 혼성화 질소 헤테로원자를 통해 연결된다는 것을 이해할 것이다.
본원에 사용된 (C2-C9)헤테로아릴은 푸릴, 티에닐, 티아졸릴, 피라졸릴, 이소티아졸릴, 옥사졸릴, 이속사졸릴, 피롤릴, 트리아졸릴, 테트라졸릴, 이미다졸릴, 1,3,5-옥사디아졸릴, 1,2,4-옥사디아졸릴, 1,2,3-옥사디아졸릴, 1,3,5-티아디아졸릴, 1,2,3-티아디아졸릴, 1,2,4-티아디아졸릴, 피리딜, 피리미딜, 피라지닐, 피리다지닐, 1,2,4-트리아지닐, 1,2,3-트리아지닐, 1,3,5-트리아지닐, 피라졸로[3,4-b]피리디닐, 신놀리닐, 프테리디닐, 푸리닐, 6,7-디히드로-5H-[1]피리디닐, 벤조[b]티오페닐, 5,6,7,8-테트라히드로-퀴놀린-3-일, 벤즈옥사졸릴, 벤조티아졸릴, 벤즈이소티아졸릴, 벤즈이속사졸릴, 벤즈이미다졸릴, 티아나프테닐, 이소티아나프테닐, 벤조푸라닐, 이소벤조푸라닐, 이소인돌릴, 인돌릴, 인돌리지닐, 인다졸릴, 이소퀴놀릴, 퀴놀릴, 프탈라지닐, 퀴녹살리닐, 퀴나졸리닐, 벤즈옥사지닐 등을 나타낸다. 당업자라면 상기 (C2-C9)헤테로아릴 고리가 탄소 또는 sp3 혼성화 질소 헤테로원자를 통해 연결된다는 것을 이해할 것이다.
본원에 사용된 (C6-C6)아릴은 페닐 또는 나프틸을 나타낸다.
화학식 I의 화합물은 포유동물 면역계를 조절하는 1종 이상의 추가 제제 또는 항염증제와 함께 또는 단독으로 제약상 허용가능한 형태로 투여될 수 있다. 이들 제제로는 시클로스포린 A (예, 샌드이뮨(Sandimmune:등록상표) 또는 네오랄(Neoral:등록상표)), 라파마이신, FK-506 (타크롤리무스 (tacrolimus)), 레플루노미드 (leflunomide), 데옥시스페르구알린 (deoxyspergualin), 미코페놀레이트 (예, 셀셉트(Cellcept:등록상표), 아자티오프린 (예, 이뮤란(Imuran:등록상표)), 다클리주맙 (daclizumab) (예, 제나팍스(Zenapax:등록상표)), OKT3 (예, 오르토클론(Orthoclone:등록상표)), 아트감 (AtGam), 아스피린, 아세트아미노펜, 이부프로펜, 나프록센, 피록시캄, 및 항염증성 스테로이드 (예, 프레드니솔론 (prednisolone) 또는 덱사메타손 (dexamethasone))이 포함되나, 이로 한정되는 것은 아니다. 이들 제제는 표준 제약 실무에 따라 동일한 투여 형태의 일부로서 또는 별도의 투여 형태로, 동일 또는 상이한 투여 경로를 통해 동일 또는 상이한 투여 스케쥴로 투여될 수 있다.
본 발명의 화합물은 모든 형태 이성질체 (예, 시스 및 트랜스 이성질체)를 포함한다. 본 발명의 화합물은 비대칭 중심을 가지며, 따라서 상이한 거울상 이성질체 및 부분입체 이성질체 형태로 존재한다. 본 발명은 본 발명의 화합물의 모든 광학 이성질체 및 입체 이성질체, 및 이들의 혼합물의 용도, 및 이를 이용하거나 함유할 수 있는 제약 조성물 및 치료 방법에 관한 것이다. 이와 관련하여, 본 발명은 E 및 Z 구조 모두를 포함한다. 화학식 I의 화합물은 호변 이성질체 형태로 존재할 수도 있다. 본 발명은 상기 모든 호변 이성질체 및 이들의 혼합물의 용도에 관한 것이다.
본 발명은 또한 화학식 I의 화합물의 프로드러그를 함유하는 제약 조성물을 포함한다. 본 발명은 또한 화학식 I의 화합물의 프로드러그를 투여하는 것을 포함하는, 단백질 키나제, 예컨대 효소 야누스 카니제 3의 억제에 의해 치료 또는 예방될 수 있는 질병의 치료 또는 예방 방법을 포함한다. 유리 아미노, 아미도, 히드록시 또는 카르복실기를 갖는 화학식 I의 화합물은 프로드러그로 전환시킬 수 있다. 프로드러그로는 아미노산 잔기, 또는 2개 이상 (예, 2, 3 또는 4개)의 아미노산 잔기의 폴리펩티드쇄가 펩티드 결합을 통해 화학식 I의 화합물의 유리 아미노, 히드록시 또는 카르복실산기에 공유 결합된 화합물이 포함된다. 아미노산 잔기에는 보통 3문자 기호로 지칭되는 20종의 천연 아미노산이 포함되며, 4-히드록시프롤린, 히드록시리신, 데모신, 이소데모신, 3-메틸히스티딘, 노르블린, 베타-알라닌, 감마-아미노부티르산, 시트룰린, 호모시스테인, 호모세린, 오르니틴 및 메티오닌 술폰 또한 포함된다. 프로드러그에는 또한 카르보네이트, 카르바메이트, 아미드 및 알킬 에스테르가 카르보닐 탄소 프로드러그 측쇄를 통해 화학식 I의 화합물의 상기 치환기에 공유 결합된 화합물이 포함된다.
바람직한 화학식 I의 화합물로는 R5가 중수소, 히드록시, (C1-C6)알킬, 할로, (C1-C6)알콕시 및 화학식 II의 기로부터 선택된 1 내지 3개의 기에 의해 임의로 치환된 (C2-C9)헤테로시클로알킬인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 카르보닐이고, c가 0이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 카르보닐이고, c가 0이고, d가 1이고, e가 0이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 -C(=N=시아노)-이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 0이고, c가 0이고, d가 0이고, e가 0이고, f가 0이고, g가 1이고, Z가 -(CO)-O-인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 S(O)n이고, n이 2이고, c가 0이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 S(O)n이고, n이 2이고, c가 0이고, d가 2이고, e가 0이고, f가 1이고, g가 1이고, Z가 카르보닐인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 S(O)n이고, n이 2이고, c가 0이고, d가 2이고, e가 0이고, f가 1이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 0이고, e가 1이고, Y가 S(O)n이고, n이 2이고, f가 0이고 g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 S(O)n이고, n이 2이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고 g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 1이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 S(O)n이고, c가 0이고, d가 1이고, e가 1이고, Y가 S(O)n이고, n이 2이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 S(O)n이고, c가 0이고, d가 1이고, e가 1이고, Y가 S(O)n이고, n이 2이고, f가 1이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 산소이고, c가 0이고, d가 1이고, e가 1이고, Y가 S(O)n이고, n이 2이고, f가 1이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 산소이고, c가 0이고, d가 1이고, e가 1이고, Y가 S(O)n이고, n이 2이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 1이고, e가 1이고, Y가 S(O)n이고, f가 0이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 1이고, e가 1이고, Y가 S(O)n이고, n이 2이고, f가 1이고, g가 0인 화합물이 포함된다.
다른 바람직한 화학식 I의 화합물로는 R12가 (C6-C10)아릴 또는 (C2
-C9)헤테로아릴이고, 이 때, 아릴 또는 헤테로아릴기가 수소, 할로, 히드록시, 카르복시, 트리플루오로메틸, (C1-C6)알킬, (C1-C6)알콕시, (C1-C
6)알킬-CO-NH-, 아미노, 아미노(C1-C6)알킬, (C1-C6)알킬아미노, ((C1-C
6)알킬)2아미노, 시아노, 아미노-CO-NH-, (C1-C6)알킬아미노-CO-NH-, ((C1-C6)알킬)2아미노-CO-NH-, (C5-C9)헤테로아릴아미노-CO-NH-, (C1-C6)알킬술포닐, (C1-C6)알킬술포닐아미노, (C6-C10)아릴술포닐아미노, (C1-C6)알킬술포닐아미노 및 (C1-C6)알콕시-CO-NH-로 구성된 군 중 1 내지 4개에 의해 임의로 치환된 화합물이 포함된다.
구체적인 바람직한 화학식 I의 화합물로는
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤젠술폰아미드;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-술파모일-페닐)-아미드;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-니트로-페닐)-아미드;
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-테트라졸-1-일-에타논;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸술파모일-페닐)-아미드;
(3-히드록시-피롤리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논;
[2-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-티아졸-4-일]-아세트산;
메틸-(4-메틸-5'-니트로-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민;
5-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-옥소-에틸)-티아졸리딘-2,4-디온;
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-티아졸리딘-3-일-메타논;
메틸-[4-메틸-1-(5-니트로-티아졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민;
[2-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-티아졸-4-일]-아세트산 에틸 에스테르;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메탄술포닐-페닐)-아미드;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 티아졸-2-일아미드;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-시아노-페닐)-아미드;
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피롤리딘-1-일-메타논;
푸란-2-카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드;
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(테트라히드로-푸란-3-일)-메타논;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 이속사졸-3-일아미드;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-시아노-피리딘-3-일)-아미드;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-카르보니트릴;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸-티아졸-2-일)-아미드;
2-시클로프로필-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논;
시클로펜틸-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이속사졸-4-일)-아미드;
[4-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-페닐]-아세트산;
[1-(5-아미노-티아졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)아민;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이소티아졸-5-일)-아미드;
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-시클로펜타논;
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 벤질-메틸-아미드; 및
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 디메틸아미드
로 구성된 군으로부터 선택된 화합물이 포함된다.
본 발명은 또한 유효량의 화학식 I의 화합물 또는 그의 제약상 허용가능한 염, 및 제약상 허용가능한 담체를 포함하는, 인간을 비롯한 포유동물에서 (a) 기관 이식 거부, 이종 이식, 루푸스, 다발성 경화증, 류마티스양 관절염, 건선, 제I형 당뇨병 및 당뇨병으로 인한 합병증, 암, 천식, 아토피성 피부염, 자가면역 갑상선 질환, 궤양성 대장염, 크론병, 알쯔하이머병, 백혈병 및 다른 자가면역 질환으로부터 선택된 질병 또는 증상의 치료 또는 예방용, 또는 (b) 단백질 키나제 또는 야누스 키나제 3 (JAK3) 억제용 제약 조성물에 관한 것이다.
본 발명은 또한 유효량의 화학식 I의 화합물 또는 그의 제약상 허용가능한 염을 인간을 비롯한 포유동물에게 투여하는 것을 포함하는, 인간을 비롯한 포유동물에서 단백질 티로신 키나제 또는 야누스 키나제 3 (JAK3)의 억제 방법에 관한 것이다.
본 발명은 또한 치료 유효량의 화학식 I의 화합물 또는 그의 제약상 허용가능한 염을 인간을 비롯한 포유동물에게 투여하는 것을 포함하는, 인간을 비롯한 포유동물에서 기관 이식 거부, 이종 이식, 루푸스, 다발성 경화증, 류마티스양 관절염, 건선, 제I형 당뇨병 및 당뇨병으로 인한 합병증, 암, 천식, 아토피성 피부염, 자가면역 갑상선 질환, 궤양성 대장염, 크론병, 알쯔하이머병, 백혈병 및 다른 자가면역 질환으로부터 선택된 질병 또는 증상의 치료 또는 예방 방법에 관한 것이다.
하기 반응식은 본 발명의 화합물의 제조 방법을 설명한다. 달리 언급하지 않는 한, 하기 반응식 및 설명에서 R2, R3, R4 및 R5는 상기 정의된 바와 같다.
반응식 A의 반응 1에서, R이 수소 또는 보호기, 예컨대 벤젠술포닐 또는 벤질인 화학식 XXI의 4-클로로피롤로[2,3-d]피리미딘 화합물을 N-클로로숙신이미드, N-브로모숙신이미드 또는 N-요오도숙신이미드와 반응시켜, Y가 클로로, 브로모 또는 요오도인 화학식 XX의 4-클로로-5-할로피롤로[2,3-d]피리미딘 화합물로 전환시킨다. 반응 혼합물을 클로로포름중에서 약 1 내지 약 3시간, 바람직하게는 약 1시간 동안 환류 가열한다. 별법으로, 반응식 A의 반응 1에서, R이 수소인 화학식 XXI의 4-클로로피롤로[2,3-d]피리미딘을 약 -10 내지 약 10℃, 바람직하게는 약 0℃에서 약 5분 내지 약 15분, 바람직하게는 약 10분 동안 황산중에서 질산과 반응시킴으로써 Y가 니트로인 상응하는 화학식 XX의 4-클로로-5-니트로피롤로[2,3-d]피리미딘으로 전환시킨다. Y가 니트로인 화학식 XXI의 화합물을 당업자에게 공지된 다양한 조건하에, 예컨대 팔라듐 가수소분해 또는 염화주석(IV) 및 염산을 이용하여 반응시켜 Y가 아미노인 상응하는 화학식 XX의 4-클로로-5-아미노피롤로[2,3-d]피리미딘으로 전환시킨다.
반응식 A의 반응 2에서, R이 수소인 화학식 XX의 4-클로로-5-할로피롤로[2,3-d]피리미딘 화합물을 약 -78℃에서 N-부틸리튬으로 처리하고, 형성된 2음이온 중간체를 약 -78℃ 내지 실온, 바람직하게는 실온에서 알킬할라이드 또는 벤질할라이드와 반응시켜, R2가 (C1-C6)알킬 또는 벤질인 상응하는 화학식 XIX의 화합물로 전환시킨다. 별법으로, 형성된 2음이온을 분자 산소와 반응시켜 R2가 히드록시인 상응하는 화학식 XIX의 4-클로로-5-히드록시피롤로[2,3-d]피리미딘 화합물을 형성한다. Y가 브롬 또는 요오드이고 R이 벤젠술포네이트인 화학식 XX의 화합물을 약 -78℃에서 N-부틸리튬으로 처리한 후, 약 -78℃에서 염화아연을 첨가함으로써, R2가 (C6-C12)아릴 또는 비닐인 화학식 XIX의 화합물로 전환시킨다. 다음, 형성된 상응하는 유기 아연 중간체를 촉매량의 팔라듐의 존재하에 아릴 요오다이드 또는 비닐 요오다이드와 반응시킨다. 반응 혼합물을 약 50℃ 내지 약 80℃, 바람직하게는 약 70℃에서 약 1시간 내지 약 3시간, 바람직하게는 약 1시간 동안 교반시킨다.
반응식 A의 반응 3에서, 화학식 XIX의 화합물을 약 -78℃에서 극성 비양성자성 용매, 예컨대 테트라히드로푸란의 존재하에 N-부틸리튬, 리튬 디이소프로필아민 또는 수소화나트륨으로 처리하여 상응하는 화학식 XVI의 화합물로 전환시킨다. 형성된 음이온성 중간체를 (a) R3이 알킬 또는 벤질인 경우, 약 -78℃ 내지 실온, 바람직하게는 -78℃에서 알킬할라이드 또는 벤질할라이드와 반응시키고, (b) R3이 알콕시인 경우, 약 -78℃ 내지 실온, 바람직하게는 -78℃에서 알데히드 또는 케톤과 반응시키고, (c) 약 -78℃ 내지 실온, 바람직하게는 -78℃에서 염화아연과 반응시킨 다음, 형성된 상응하는 유기 아연 중간체를 촉매량의 팔라듐의 존재하에 아릴 요오다이드 또는 비닐 요오다이드와 반응시킨다. 생성된 반응 혼합물을 약 50℃ 내지 약 80℃, 바람직하게는 약 70℃에서 약 1시간 내지 약 3시간, 바람직하게는 약 1시간 동안 교반시킨다. 별법으로, 형성된 음이온을 분자 산소와 반응시켜, R3이 히드록시인 상응하는 화학식 XVI의 4-클로로-6-히드록시피롤로[2,3-d]피리미딘 화합물을 형성한다.
반응식 B의 반응 1에서, 화학식 XXI의 4-클로로피롤로[2,3-d]피리미딘 화합물을 반응식 A의 반응 3에 기재된 것과 유시한 절차에 따라 상응하는 화학식 XXII의 화합물로 전환시킨다.
반응식 B의 반응 2에서, 화학식 XXII의 화합물을 반응식 A의 반응 1 및 2에 기재된 것과 유시한 절차에 따라 상응하는 화학식 XVI의 화합물로 전환시킨다.
반응식 C의 반응 1에서, 화학식 XXXI의 4-메틸피리딘 화합물을 먼저 극성 비양성자성 용매, 예컨대 아세톤의 존재하에 벤질클로라이드를 이용하여 알킬화시켜 상응하는 화학식 XXX의 화합물로 전환시킨다. 반응 혼합물을 약 40℃ 내지 약 80℃에서 약 4시간 내지 약 24시간 동안 교반하였다. 다음, 형성된 피리디늄 중간체를 극성 양성자성 용매, 예컨대 메탄올, 에탄올, 물, 또는 이들의 혼합물의 존재하에 환원제, 예컨대 붕수소화나트륨을 이용하여 환원시킨다. 반응 혼합물을 약 0℃ 내지 약 실온에서 약 18시간 내지 24시간 동안 교반시킨다.
반응식 C의 반응 2에서, 화학식 XXX의 화합물을 환원제 및 비양성자성 용매, 예컨대 테트라히드로푸란의 존재하에 보로트리플루오라이드 에테레이트로 처리하여 상응하는 화학식 XXIX의 화합물로 전환시킨다. 반응 혼합물을 약 0℃ 내지 실온에서 약 1시간 내지 약 3시간 동안 교반시킨다. 다음, 형성된 중간체 착물을 수성 수산화나트륨으로 염기성화시킨 후, 약 0℃ 내지 실온에서 약 12시간 내지 약 24시간 동안 산화제, 예컨대 과산화수소 또는 옥손(등록상표)으로 처리한다.
반응식 C의 3에서, 화학식 XXIX의 화합물을 약 1시간 내지 3 시간 동안 주위 온도에서 산화제, 예컨대 산화크롬 또는 디메틸술폭시드, 옥살릴클로라이드 또는 SO3-피리딘 착물로 처리한다. 다음, 형성된 케톤 중간체를 산, 예컨대 아세트산의 존재하에 약 실온에서 약 2 내지 약 24시간 동안 유기 용매, 예컨대 메탄올, 에탄올 또는 테트라히드로푸란 중에서 아민 (R4-NH2)으로 처리한다. 다음, 형성된 상응하는 이민 중간체를 주위 온도에서 약 2 내지 약 24시간 동안 환원제, 예컨대 붕수소화나트륨 또는 시아노붕수소화나트륨 또는 트리아세톡시붕수소화나트륨으로 처리한다.
반응식 1의 반응 1에서, 화학식 XVII의 4-클로로피롤로[2,3-d]피리미딘 화합물을 염기, 예컨대 수소화나트륨 또는 탄산칼륨, 및 극성 비양성자성 용매, 예컨대 디메틸포름아미드 또는 테트라히드로푸란의 존재하에 벤젠술포닐 클로라이드, 벤질클로라이드 또는 벤질브로마이드로 처리하여 R이 벤젠술포닐 또는 벤질인 상응하는 화학식 XVI의 화합물로 전환시킨다. 반응 혼합물을 약 0℃ 내지 약 70℃, 바람직하게는 약 30℃에서 약 1시간 내지 약 3시간, 바람직하게는 약 2시간 동안 교반시킨다.
반응식 1의 반응 2에서, 화학식 XVI의 4-클로로피롤로[2,3-d]피리미딘 화합물을 화학식 HNR4R5의 아민과 커플링시켜 상응하는 화학식 XV의 4-아미노피롤로[2,3-d]피리미딘 화합물로 전환시킨다. 반응은 알콜 용매, 예컨대 tert-부탄올, 메탄올 또는 에탄올, 또는 다른 고비점 유기 용매, 예컨대 디메틸포름아미드, 트리에틸아민, 1,4-디옥산 또는 1,2-디클로로에탄 중에서 약 60℃ 내지 약 120℃, 바람직하게는 약 80℃에서 수행한다. 전형적인 반응 시간은 약 2시간 내지 약 48시간, 바람직하게는 약 16시간이다. R5가 질소 함유 헤테로시클로알킬기인 경우, 각각의 질소는 보호기, 예컨대 벤질로 보호되어야 한다. R5 보호기의 제거는 피롤로[2,3-d]피리미딘 고리상의 R 보호기에 영향을 미지치 않는 특정 보호기에 대한 적절한 조건하에 수행한다. 벤질의 경우에는, R5 보호기의 제거를 알콜 용매, 예컨대 에탄올 중에서 수소 및 촉매, 예컨대 탄소상 수산화팔라듐의 존재하에 수행한다. 형성된 R5 질소 함유 헤테로시클로알킬기를 다양한 상이한 화학식 II의 친전자체와 추가로 반응시킬 수 있다. 우레아 형성의 경우, 화학식 II의 친전자체, 예컨대 이소시아네이트, 카르바메이트 및 카르바모일 클로라이드를 용매, 예컨대 아세토니트릴 또는 디메틸포름아미드 중에서 염기, 예컨대 탄산나트륨 또는 탄산칼륨의 존재하에 약 20℃ 내지 약 100℃에서 약 24시간 내지 약 72시간 동안 헤테로알킬기의 R5 질소와 반응시킨다. 아미드 및 술폰아미드 형성의 경우, 화학식 II의 친전자체, 예컨대 아실클로라이드 및 술포닐 클로라이드를 용매, 예컨대 메틸렌 클로라이드 중에서 염기, 예컨대 피리딘의 존재하에 주위 온도에서 약 12시간 내지 약 24시간 동안 헤테로알킬기의 R5 질소와 반응시킨다. 아미드 형성은 또한 카르보디이미드, 예컨대 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드의 존재하에 용매, 예컨대 메틸렌 클로라이드 중에서 주위 온도에서 12 내지 24시간 동안 카르복실산과 헤테로알킬기를 반응시킴으로써 수행할 수 있다. 알킬 형성의 경우, 화학식 II의 친전자체, 예컨대 α,β-불포화 아미드, 산, 니트릴, 에스테르 및 α-할로 아미드를 용매, 예컨대 메탄올 중에서 주위 온도에서 약 12시간 내지 약 18시간 동안 헤테로알킬기의 R5 질소와 반응시킨다. 알킬 형성은 또한 환원제, 예컨대 시아노붕수소화나트륨의 존재하에 용매, 예컨대 메탄올 중에서 주위 온도에서 약 12시간 내지 약 18시간 동안 알데히드와 헤테로알킬기를 반응시킴으로써 수행할 수 있다.
반응식 1의 반응 3에서, R이 벤젠술포닐인 화학식 XV의 화합물로부터 보호기를 제거하여 상응하는 화학식 I의 화합물을 수득하는 것은 화학식 XV의 화합물을 알콜 용매, 예컨대 메탄올 또는 에탄올, 또는 혼합 용매, 예컨대 알콜/테트라히드로푸란 또는 알콜/물 중에서 알칼리 염기, 예컨대 수산화나트륨 또는 수산화칼륨으로 처리함으로써 수행한다. 반응은 실온에서 약 15분 내지 약 1시간, 바람직하게는 30분 동안 수행한다. R이 벤질인 화학식 XV의 화합물로부터 보호기의 제거는 화학식 XV의 화합물을 약 -78℃에서 약 15분 내지 약 1시간 동안 암모니아 중에서 나트륨으로 처리함으로써 수행한다.
반응식 2의 반응 1에서, 화학식 XX의 4-클로로피롤로[2,3-d]피리미딘 화합물을 반응식 1의 반응 2에 상기 기재된 것과 유사한 절차에 따라 상응하는 화학식 XXIV의 4-아미노피롤로[2,3-d]피리미딘 화합물로 전환시킨다.
반응식 2의 반응 2에서, R이 벤젠술포네이트이고 Z가 브롬 또는 요오드인 화학식 XXIV의 4-아미노-5-할로피롤로[2,3-d]피리미딘 화합물을 (a) R2가 아릴인 경우, 비양성자성 용매, 예컨대 테트라히드로푸란 또는 디옥산 중에서 촉매량의 팔라듐(0)의 존재하에 약 50℃ 내지 약 100℃, 바람직하게는 약 70℃에서 약 2시간 내지 약 48시간, 바람직하게는 약 12시간 동안 아릴보론산과 반응시키고, (b) R2가 알키닐인 경우, 촉매량의 요오드화구리(I) 및 팔라듐(0)의 존재하에 극성 용매, 예컨대 디메틸포름아미드 중에서 실온에서 약 1시간 내지 약 5시간, 바람직하게는 약 3시간 동안 알킨과 반응시키고, (c) R2가 비닐 또는 스티레닐인 경우, 촉매량의 팔라듐의 존재하에 디메틸포름아미드, 디옥산 또는 테트라히드로푸란 중에서 약 80℃ 내지 약 100℃, 바람직하게는 약 100℃에서 약 2시간 내지 약 48시간, 바람직하게는 약 48시간 동안 알켄 또는 스티렌과 반응시켜, 상응하는 화학식 XXIII의 화합물로 전환시킨다.
반응식 2의 반응 3에서, 화학식 XXIII의 화합물을 반응식 A의 반응 3에 상기 기재된 것과 유사한 절차에 따라 상응하는 화학식 XV의 화합물로 전환시킨다.
반응식 3의 반응 1에서, 화학식 XVII의 화합물을 반응식 1의 반응 2에 상기 기재된 것과 유사한 절차에 따라 상응하는 화학식 I의 화합물로 전환시킨다.
본래 염기성인 본 발명의 화합물은 다양한 무기산 및 유기산과 매우 다양한 상이한 염을 형성할 수 있다. 이러한 염은 동물에게 투여하는 데 있어서 제약상 허용가능하여야 하나, 실제로는 반응 혼합물로부터 제약상 허용불가능한 염으로서 본 발명의 화합물을 먼저 단리한 다음, 이를 알칼리 시약으로 처리하여 유리 염기 화합물로 간단히 다시 전환시킨 후, 이 유리 염기를 제약상 허용가능한 산부가염으로 전환시키는 것이 바람직한 경우가 있다. 본 발명의 염기 화합물의 산부가염은 염기 화합물을 수성 용매 매질중에서 또는 적합한 유기 용매, 예컨대 메탄올 또는 에탄올 중에서 거의 동량의 선택된 광물산 또는 유기산으로 처리함으로써 용이하게 제조한다. 용매를 조심해서 증발시킨 후, 목적하는 고체염을 용이하게 수득한다. 목적하는 산염은 또한 용액에 적절한 광물산 또는 유기산을 첨가함으로써 유기 용매중에서 유리 염기 용액으로부터 침전시킬 수 있다.
본래 산성인 본 발명의 화합물은 다양한 약리학상 허용가능한 양이온과 함께 염기염을 형성할 수 있다. 이러한 염의 예로는 알칼리 금속염 또는 알칼리 토금속염, 특히 나트륨염 및 칼륨염이 포함된다. 이들 염은 모두 통상적인 기술에 의해 제조된다. 본 발명의 제약상 허용가능한 염기염을 제조하기 위한 시약으로 사용되는 화학적 염기는 본 발명의 산성 화합물과 무독성 염기염을 형성하는 것이다. 이러한 무독성 염기염으로는 약리학상 허용가능한 양이온, 예컨대 나트륨, 칼륨, 칼슘 및 마그네슘 등으로부터 유래된 것이 포함된다. 이들 염은 상응하는 산성 화합물을 목적하는 약리학상 허용가능한 양이온 함유 수용액으로 처리한 다음, 생성된 용액을 바람직하게는 감압하에 증발 건조시킴으로써 용이하게 제조할 수 있다. 별법으로, 이는 산성 화합물의 저급 알칸올 용액 및 목적하는 알칼리 금속 알콕시화물을 함께 혼합한 다음, 생성된 용액을 상기와 동일한 방식으로 증발 건조시킴으로써 제조할 수도 있다. 어떤 경우에든, 반응의 완료 및 목적하는 최종 생성물의 최대 수율을 보장하기 위해서는 화학량론적 양의 시약을 사용하는 것이 바람직하다.
본 발명의 조성물은 1종 이상의 제약상 허용가능한 담체를 이용하여 통상적인 방식으로 제제화시킬 수 있다. 즉, 본 발명의 활성 화합물은 경구, 협측, 비강내, 비경구 (예, 정맥내, 근육내 또는 피하) 또는 직장 투여용으로, 또는 흡입 또는 취입 투여에 적합한 형태로 제제화될 수 있다. 본 발명의 활성 성분은 또한 서방성 전달용으로 제제화될 수 있다.
경구 투여의 경우, 제약 조성물은 예를 들어 제약상 허용가능한 부형제, 예컨대 결합제 (예, 예비 젤라틴화 옥수수 전분, 폴리비닐피롤리돈 또는 히드록시프로필 메틸셀룰로즈), 충전제 (예, 락토즈, 미결정질 셀룰로즈 또는 칼슘 포스페이트), 윤활제 (예, 마그네슘 스테아레이트, 활석 또는 실리카), 붕괴제 (예, 감자 전분 또는 나트륨 전분 글리콜레이트) 또는 습윤제 (예, 소듐 라우릴 술페이트)를 이용하여 통상적인 방식으로 제조된 정제 또는 캡슐제 형태일 수 있다. 정제는 당업자에게 널리 공지된 방식으로 코팅시킬 수 있다. 경구 투여용 액상 제제는 예를 들어 용액제, 시럽제 또는 현탁제 형태일 수 있거나, 또는 사용전에 물 또는 다른 적합한 비히클로 재구성하는 건조 생성물 형태일 수 있다. 이러한 액상 제제는 제약상 허용가능한 첨가제, 예커대 현탁화제 (예, 소르비톨 시럽, 메틸 셀룰로즈 또는 경화 식용 지방), 유화제 (예, 레시틴 또는 아카시아), 비수성 비히클 (예, 아몬드유, 유성 에스테르 또는 에틸 알콜) 및 보존제 (예, 메틸 또는 프로필 p-히드록시벤조에이트 또는 소르브산)을 이용하여 통상적인 방식으로 제조할 수 있다.
협측 투여의 경우, 조성물은 통상적인 방식으로 제제화된 정제 또는 로젠지제 형태일 수 있다.
본 발명의 활성 화합물은 통상적인 카테터화 기술 또는 삽입법을 이용하는 것을 비롯한 주입법에 의한 비경구 투여용으로 제제화될 수 있다. 주입용 제제는 단위 투여 형태, 예를 들어 보존제가 첨가된 앰플제 또는 다투여 용기 형태일 수 있다. 조성물은 유성 또는 수성 비히클 중 현탁제, 용액제 또는 에멀젼제 형태일 수 있으며, 현탁화제, 안정화제 및(또는) 분산화제와 같은 제제화제를 함유할 수 있다. 별법으로, 활성 성분은 사용전에 적합한 비히클, 예를 들어 발열원 무함유 멸균수로 재구성하는 분말 형태일 수 있다.
본 발명의 활성 화합물은 또한 예를 들어 통상적인 좌약용 기재, 예컨대 코코아 버터 또는 다른 글리세리드를 함유하는 좌약제 또는 정체 관장제와 같은 직장용 조성물로 제제화될 수 있다.
비강내 투여 또는 흡입 투여의 경우, 본 발명의 활성 화합물은 환자에 의해 압착 또는 펌핑되는 펌프 스프레이 용기로부터의 용액제 또는 현탁제 형태로, 또는 적합한 추진제, 예를 들어 디클로로디플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적합한 가스를 사용하는 가압 용기 또는 분무기로부터의 에어로졸 스프레이 제제로서 편리하게 전달된다. 가압 에어로졸의 경우, 투여 단위는 계량된 양으로 전달하기 위해 밸브를 제공함으로써 측정할 수 있다. 가압 용기 또는 분무기는 활성 화합물의 용액제 또는 현탁제를 함유할 수 있다. 흡입제 또는 취입제로 사용되는 캡슐제 또는 카트리지 (예를 들어 젤라틴으로부터 제조)는 본 발명의 화합물 및 적합한 분말 기재, 예컨대 락토즈 또는 전분의 분말 혼합물을 함유하는 것으로 제제화될 수 있다.
상기 언급된 증상 (예, 류마티스성 관절염)의 치료를 위해 평균적인 성인에게 경구, 비경구 또는 협측 투여하기 위한 본 발명의 활성 화합물의 제안된 투여량은 투여할 수 있는 단위 투여 (예, 1일 1 내지 4회) 당 활성 성분 0.1 내지 1000 mg이다.
평균적인 성인에서 상기 언급한 증상 (예, 천식)의 치료를 위한 에어로졸 제제의 경우, 바람직하게는 에어로졸의 계량된 각 투여량 또는 "퍼프(puff)"가 본 발명의 화합물 20 내지 1000 ㎍을 함유하도록 제조된다. 에어로졸을 이용한 1일 총 투여량은 0.1 내지 1000 mg 범위일 것이다. 투여는 1일 수회, 예를 들어 2, 3, 4 또는 8회, 예를 들어 각 회마다 1, 2 또는 3번 투여할 수 있다.
포유동물 면역계를 조절하는 1종 이상의 추가 제제 또는 항염증제와 함께 또는 단독으로 화학식 I의 화합물이 제약상 허용가능한 형태로 투여되는 데, 상기 제제에는 시클로스포린 A (예, 샌드이뮨(등록상표) 또는 네오랄(등록상표)), 라파마이신, FK-506 (타크롤리무스), 레플루노미드, 데옥시스페르구알린, 미코페놀레이트 (예, 셀셉트(등록상표), 아자티오프린 (예, 이뮤란(등록상표)), 다클리주맙 (예, 제나팍스(등록상표)), OKT3 (예, 오르토클론(등록상표)), 아트감, 아스피린, 아세트아미노펜, 이부프로펜, 나프록센, 피록시캄, 및 항염증성 스테로이드 (예, 프레드니솔론 또는 덱사메타손)이 포함될 수 있으나, 이로 한정되는 것은 아니며, 이들 제제는 표준 제약 실무에 따라 동일한 투여 형태의 일부로서 또는 별도의 투여 형태로, 동일 또는 상이한 투여 경로를 통해 동일 또는 상이한 투여 스케쥴로 투여될 수 있다.
FK-506 (타크롤리무스)은 수술후 48시간부터 매 12시간 마다 0.10 내지 0.15 mg/kg 체중으로 경구 투여한다. 투여량은 혈청 타크롤리무스 최저치로 모니터한다.
시클로스포린 A (샌드이뮨, 경구 또는 정맥내 제제, 또는 네오랄(등록상표), 경구 용액제 또는 캡슐제)는 수술후 48시간부터 매 12시간 마다 5 mg/kg 체중으로 경구 투여한다. 투여량은 혈중 시클로스포린 A 최저치로 모니터한다.
활성 제제는 당업자에게 공지된 방법에 따라 서방성 전달용으로 제제화될 수 있다. 이러한 제제의 예는 미국 특허 제3,538,214호, 제4,060,598호, 제4,173,626호, 제3,119,742호 및 제3,492,397호에서 확일할 수 있다.
화학식 I의 화합물 또는 그의 제약상 허용가능한 염이 야누스 키나제 3을 억제하는 능력, 및 그에 따른 야누스 키나제 3을 특징으로 하는 질병 또는 증상의 치료 효과에 대한 입증을 시험관내 분석 시험으로 하기에 나타내었다.
<생물학적 분석>
<JAK3 (JH1:GST) 효소 분석>
JAK3 키나제 분석에는 글루타티온-세파로즈상에서 친화성 크로마토그래피에 의해 정제한 바쿨로바이러스 감염된 SF9 세포에서 발현된 단백질 (GST와 인간 JAK3 촉매 도메인의 융합 단백질)을 이용하였다. 반응을 위한 기질은 37℃에서 밤새 100 ㎍/ml로 눈크 맥시 솔프 (Nunc Maxi Sorp) 플레이트상에 코팅된 폴리-글루탐산-티로신 (PGT (4:1), 시그마 (Sigma) 목록 번호 P0275)이었다. 코팅한 다음 날 아침에, 플레이트를 3회 세척하고, JAK3를 키나제 완충액 (50 mM HEPES (pH 7.3, 125 mM NaCl, 24 mM MgCl2) + 0.2 μM ATP + 1 mM Na 오르토바나데이트) 100 ㎕를 함유하는 웰에 첨가하였다. 실온에서 30분 동안 반응을 진행시키고, 플레이트를 3회 더 세척하였다. 주어진 웰에서 포스포릴화 티로신의 수치를 항-포스포티로신 항체 (ICN PY20, 목록 번호 69-151-1)를 이용한 표준 ELISA 분석으로 정량화하였다.
<인간 IL-2 의존성 T-모세포 증식의 억제>
이 스크린에서는 시험관내에서 IL-2 의존성 T-모세포 증식에 대한 화합물의 억제 효과를 측정한다. IL-2 수용체를 통한 신호전달은 JAK-3을 필요로 하기 때문에, JAK-3의 세포 활성 억제제는 IL-2 의존성 T-모세포 증식을 억제할 것이다.
이 분석을 위한 세포는 새로운 인간 혈액으로부터 단리하였다. 아쿠스핀 시스템-히스토파크-1077 (Accuspin System-Histopaque-1077, 시그마 목록 번호 A7054)를 이용하여 단핵 세포를 분리한 후, 일차 인간 T-세포를 림포-퀵 티 (Lympho-Kwik T, 원 람다, 인크. (One Lambda, Inc.), 목록 번호 LK-50T)를 이용하여 네가티브 선택에 의해 단리하였다. T-세포를 배지 (RPMI + 10% 열불활성화된 우태아 혈청 (하이클론 (Hyclone) 목록 번호 A-1111-L) + 1% 페니실린/스트렙토마이신 (깁코 (Gibco))중에서 1-2 x 106/ml으로 배양하고, PHA (뮤렉스 다이아그노스틱스 (Murex Diagnostics), 목록 번호 HA 16) 10 ㎍/ml를 첨가하여 증식을 유도하였다. 5% CO2하에 37℃에서 3일 후에, 세포를 배지로 3회 세척하고, 배지 + 100 유닛/ml의 인간 재조합 IL-2 (알앤디 시스템즈 (R&D Systems), 목록 번호 202-IL)에 1-2 x 106 세포/ml의 밀도로 재현탁시켰다. 1주일 후, 세포는 IL-2 의존성이었고, 동부피의 배지 + 100 유닛/ml의 IL-2를 주 2회 공급하여 3주까지 유지시킬 수 있었다.
IL-2 의존성 T-세포 증식을 억제하는 시험 화합물의 능력을 분석하기 위해, IL-2 의존성 세포를 3회 세척하고, 배지에 재현탁시킨 다음, 평탄 바닥 96-웰 마이크로타이터 플레이트 (팔콘 (Falcon) 목록 번호 353075)에 50,000 세포/웰/0.1 ml로 플레이팅하였다. DMSO 중 10 mM의 시험 화합물 원액으로부터 2배씩 희석한 일련의 화합물을 10 μM에서 시작하여 3벌로 웰에 첨가하였다. 1시간 후, 10 유닛/ml의 IL-2를 각 시험 웰에 첨가하였다. 다음, 플레이트를 5% CO2하에 37℃에서 72시간 동안 인큐베이션하였다. 다음, 플레이트를 3H-티미딘 (0.5 μCi/웰) (NEN 목록 번호 NET-027A)로 펄싱하고, 18시간 더 인큐베이션하였다. 다음, 배양 플레이트를 96-웰 플레이트 수확기로 수확하고, 증식 세포에 삽입된 3H-티미딘의 양을 팩카드 탑 카운트 (Packard Top Count) 섬광 계수기로 계수하여 측정하였다. 증식 억제율%과 시험 화합물 농도를 플롯팅하여 데이타를 분석하였다. 상기 플롯으로부터 IC50 값 (μM)을 측정하였다.
하기 실시예는 본 발명의 화합물의 제조 방법을 설명하나, 본 발명이 하기 설명으로 제한되는 것은 아니다. 시판되는 시약은 추가 정제하지 않고 사용하였다. THF는 테트라히드로푸란을 나타낸다. DMF는 N,N-디메틸포름아미드를 나타낸다. 저해상도 질량 스펙트럼 (LRMS)은, 화학 이온화 (암모늄)를 이용하는 휴렛 팩커드 5989 (Hewlett Packard 5989:등록상표), 또는 이온화제로서 0.1% 포름산 함유 아세토니트릴/물의 50/50 혼합물을 이용하는 피손스 (Fisons) (또는 마이크로 매스 (Micro Mass)) 대기압 화학 이온화 (APCI) 플랫폼을 이용하여 기록하였다. 실온 또는 주위 온도는 20 내지 25℃를 나타낸다.
실시예 1
푸란-2-일-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논
방법 A
1-벤질-4-메틸-피리디늄 클로라이드
아세톤 70 mL 중 4-메틸피리딘 (26 mL/0.268 mol)의 교반된 용액에 벤질클로라이드 31 mL (0.268 mol)을 첨가하였다. 생성된 혼합물을 50℃에서 18시간 동안 교반하였다. 실온으로 냉각시킨 후, 반응물을 여과하고, 아세톤으로 세척하고, 감압하에 건조시켜, 표제 화합물 38 g을 수득하였다. 여액을 감압하에 농축시켜 추가의 표제 화합물 5.6 g을 수득하였다 (합한 수율 74%). LRMS: 184.
방법 B
1-벤질-4-메틸-1,2,3,6-테트라히드로-피리딘
10:1 에탄올/물 140 mL에 용해된 방법 A로부터의 생성물 (38 g/0.171 mol)의 교반된 용액에 0℃에서 붕수소화나트륨 16 g (0.427 mol)을 25분에 걸쳐 적가하였다. 생성된 혼합물을 실온에서 18시간 동안 교반하고, 이 때, 물 100 mL을 첨가하여 반응을 켄칭시켰다. 반응 혼합물을 여과하고, 여과 케이크를 물 및 에틸아세테이트로 세척하고, 합한 여액을 감압하에 농축시켜 유기물을 제거하였다. 잔류물을 물 (100 mL)로 희석하고, 에틸아세테이트 150 mL로 3회 추출하였다. 합한 에틸아세테이트 추출물을 Na2SO4 상에서 건조시키고, 진공하에 농축 건조시켜, 표제 화합물 32 g (100%)을 황색 오일로서 수득하였다. LRMS: 188 (M+1).
방법 C
1-벤질-4-메틸-피페리딘-3-올
THF 240 mL에 용해된 방법 B로부터의 생성물 (72.45 g/0.387 mol)의 용액에 NaBH4 21.4 g을 첨가하고, 혼합물을 0℃로 냉각시켰다. 다음, 보론트리플루오라이드 에테레이트 용액 (THF 200 mL에 용해된 109.4 mL)을 1.5시간에 걸쳐 적가하였다. 첨가한 후, 반응 혼합물을 실온으로 가온시키고, 2시간 동안 교반하였다. 반응물을 다시 0℃로 냉각시키고, 물 29.3 mL을 15분에 걸쳐 적가한 후, 2N 수산화나트륨 (97.5 mL)을 20분에 걸쳐 적가하였다. 생성된 혼합물을 0℃에서 40분 동안 교반한 다음, 실온으로 가온시켰다. 과산화수소 (30%) (97.5 mL)를 반응 혼합물이 50℃를 초과하지 않도록 하는 속도로 (대략 30분) 적가하였다. 첨가를 완료한 후, 반응 혼합물을 10분 동안 교반한 다음, 0℃로 냉각시켰다. 진한 염산 (97.5 mL)을 5분에 걸쳐 첨가하고, 반응 혼합물을 진공하에 원래 부피의 1/3으로 감소시키고, 6N 수산화나트륨 (수성)을 이용하여 pH를 9 내지 10으로 조정하였다. 생성된 혼합물을 에테르로 3회 추출하고, 합한 에테르층을 MgSO4 상에서 건조시키고, 진공하에 증발 건조시켜, 표제 화합물 65.32 g (79%)을 황색 오일로서 수득하였다. LRMS: 206.1 (M+1).
별법:
THF (150mL) 중 방법 B로부터의 생성물 (18.7 g/0.1 mol)의 용액에 NaBH4 (6.5 g/0.170 mol)를 실온에서 N2하에 첨가하였다. 슬러리를 0℃로 냉각시키고, THF (25mL) 중 BF3OEt2 (15 mL, 16.8 g/0.118 mol)를 첨가 깔때기를 통해 천천히 첨가하였다. 반응 혼합물의 온도를 0℃ 미만으로 유지시키기 위채 충분히 천천히 첨가하였다. 첨가 후, 반응 혼합물을 0℃에서 1시간 동안 및 실온에서 1.5시간 동안 교반하였다. 반응물을 0℃로 재냉각시키고, 물 (50 mL)을 천천히 첨가하여 과량의 보란을 파괴하였다. 반응물을 실온에서 2시간 동안 교반한 후, 0℃에서 물 (500 mL) 중 옥손 (110 g/0.343 mol)을 첨가하였다. 반응 혼합물을 실온으로 가온시키고 밤새 교반하였다. 고체 NaHSO3를 과량의 모든 산화제가 파괴될 때까지 첨가하여 반응을 켄칭시켰다 (KI/전분 시험지). 반응 혼합물의 pH는 1 내지 2였다. 다음, 반응 혼합물을 에틸 아세테이트 50 mL로 3회 추출하고, 6N 수산화나트륨을 이용하여 수성층을 pH 12로 조정하고, 에틸 아세테이트 (100 mL로 4회)로 추출하였다. 유기층을 염수로 세척하고, Na2SO4 상에서 건조시키고, 진공하에 농축시켜, 표제 화합물 19.0 g (92%)을 오일로서 수득하였다. LRMS: 206.1 (M+1).
방법 D
1-벤질-4-메틸-피페리딘-3-올-톨루엔-4-술폰산염
0℃로 냉각되고 아세톤 175 mL에 용해된 방법 C로부터의 생성물 (65.32 g/0.318 mol)의 교반된 용액에 아세톤 350 mL 중 파라-톨루엔술폰산 일수화물의 용액을 2시간에 걸쳐 적가하고, 생성된 혼합물을 0℃에서 1.5시간 동안 교반하였다. 침전물을 여과하고, 여과 케이크를 디이소프로필 에테르 90 mL로 세척하였다. 다음, 고체 생성물을 진공하에 건조시켜, 표제 화합물 58.55 g (100%)을 백색 고체로서 수득하였다. LRMS: 378.5 (M+1).
방법 E
1-벤질-4-메틸-피페리딘-3-온
0℃로 냉각되고 디클로로메탄 250 mL에 용해된 방법 D로부터의 생성물 (9.8 g/0.026 mol) 및 디이소프로필에틸아민 31.7 mL의 용액에 디메틸술폭시드 153 mL에 용해된 S03ㆍ피리딘 착물 12.4 g을 40분에 걸쳐 적가하였다. 첨가한 후, 반응물을 실온에서 1.5시간 동안 교반한 다음, 포화 NaHCO3 (수성) 200 mL을 첨가하여 켄칭시켰다. 디클로로메탄을 진공하에 제거하고, 나머지 수성 잔류물을 디이소프로필 에테르 (150 mL)로 4회 추출하였다. 합한 에테르층을 물 (100 mL)로 4회 세척하고, Na2SO4 상에서 건조시키고, 진공하에 농축 건조시켜, 표제 화합물 3.81 g (72.97%)을 황색 오일로서 수득하였다. LRMS: 204 (M+1).
방법 F
(1-벤질-4-메틸-피페리딘-3-일)-메틸-아민
THF 중 방법 E로부터의 생성물 (3.81 g/0.019 mol) 및 2.0M 메틸아민 38 mL의 교반된 용액에 아세트산 2.2 mL을 첨가하고, 생성된 혼합물을 실온에서 1.5시간 동안 교반하였다. 트리아세톡시 붕수소화나트륨 (NaB(OAc)3H) (7.94 g/0.038 mol)을 고체로서 첨가하고, 생성된 혼합물을 실온에서 18시간 동안 교반하였다. 2N 염산을 첨가하여 반응을 켄칭시키고, pH를 1로 조정하였다. 반응 혼합물을 에테르로 2회 세척한 다음, 6N 수산화나트륨 (수성)을 이용하여 수성층을 pH 12로 조정하고, 디클로로메탄으로 3회 추출하였다. 합한 디클로로메탄층을 Na2SO4 상에서 건조시키고, 여과하고 진공하에 증발 건조시켜, 표제 화합물 3.51 g (87.75%)을 진한 황색 오일로서 수득하였다. LRMS: 219.1 (M+1).
방법 G
(1-벤질-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민
문헌 [Davoll, J. Am. Chem. Soc., (1960), 82, 131]의 방법에 의해 제조된 4-클로로피롤로[2,3-d]피리미딘 (2.4 g, 15.9 mmol), 방법 F로부터의 생성물 (1.7 g, 7.95 mmol) 및 트리에틸아민 10 mL의 혼합물을 100℃에서 4일 동안 밀봉관에서 가열하였다. 실온으로 냉각시키고, 감압하에 농축시킨 후, 잔류물을 플래쉬 크로마토그래피 (실리카; 디클로로메탄 중 3% 메탄올)에 의해 정제하여, 표제 화합물 1.0 g (38%)을 무색 오일로서 수득하였다. LRMS: 336.1 (M+1).
방법 H
메틸-(4-메틸-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민
에탄올 15 mL에 용해된 방법 G로부터의 생성물 (0.7 g, 2.19 mmol)에 20% 탄소상 수산화팔라듐 (50% 물) (알드리치) 0.5 g을 첨가하고, 생성된 혼합물을 수소 (50 psi) 대기하에 실온에서 2일 동안 진탕 (파르(Parr) 진탕기)시켰다. 셀라이트 여과 반응 혼합물을 진공하에 농축 건조시키고, 잔류물을 플래쉬 크로마토그래피 (실리카; 디클로로메탄 중 5% 메탄올)에 의해 정제하여, 표제 화합물 0.48 g (90%)을 수득하였다. LRMS: 246.1 (M+1).
방법 I
[1-(4-메톡시-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민
피리딘 1 mL 및 디클로로메탄 9 ml의 교반된 용액에 방법 H로부터의 생성물 40 mg (0.163 mmol) 및 4-메톡시-벤젠술포닐 클로라이드 20 L를 첨가하고, 생성된 혼합물을 실온에서 18시간 동안 교반하였다. 다음, 포화 NaHCO3 (수성)를 첨가하여 반응을 켄칭시키고, 유기층을 제거하고, 수성층을 디클로로메탄으로 세척하였다. 디클로로메탄층을 Na2SO4 상에서 건조시키고, 진공하에 농축 건조시켰다. 잔류물을 PTLC (실리카; 10:1 디클로로메탄/메탄올)에 의해 정제하여, 표제 화합물 22 mg (32%)을 밝은 황색 고체로서 수득하였다. LRMS: 416.5 (M+1).
실시예 2 내지 297의 표제 화합물은 실시예 1에 기재된 것과 유사한 방법으로 제조하였다.
실시예 2
[1-(4-메톡시-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 416.
실시예 3
(1-벤젠술포닐-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 386.
실시예 4
2-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-이소인돌-1,3-디온. LRMS: 483.
실시예 5
시클로헥산카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. RMS: 463.
실시예 6
2-클로로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 492.
실시예 7
4-클로로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 492.
실시예 8
푸란-2-카르복실산 (2-{4-메틸-3-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 447.
실시예 9
3-메톡시-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 487.
실시예 10
이속사졸-5-카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 448.
실시예 11
2,4-디플루오로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 493.
실시예 12
3-클로로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 492.
실시예 13
3-플루오로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 475.
실시예 14
2-플루오로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 475.
실시예 15
4-플루오로-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)벤즈아미드. LRMS: 475.
실시예 16
N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-벤즈아미드. LRMS: 457.
실시예 17
시클로프로판카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 421.
실시예 18
시클로펜탄카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 449.
실시예 19
시클로펜틸-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 342.
실시예 20
테트라히드로-푸란-2-카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)]아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 451.
실시예 21
테트라히드로-푸란-3-카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 451.
실시예 22
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(테트라히드로-푸란-2-일)-메타논. LRMS: 344.
실시예 23
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(테트라히드로-푸란-3-일)-메타논. LRMS: 344.
실시예 24
시클로헥산카르복실산 (3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-3-옥소-프로필)-아미드. LRMS: 427.
실시예 25
2-시클로프로필-1-{4-메틸-3-[메틸-(7H-피롤로-[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 328.
실시예 26
2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피롤리딘-1-카르복실산 tert-부틸 에스테르. LRMS: 443.
실시예 27
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피롤리딘-2-일-메타논. LRMS: 343.
실시예 28
1-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피롤리딘-1-일)-에타논 히드로클로라이드. LRMS: 385.
실시예 29
푸란-3-일-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)]-아미노]-피페리딘-1-일}-메타논. LRMS: 340.
실시예 30
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피리딘-2-일-메타논. LRMS : 351.
실시예 31
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-페닐-메타논. LRMS: 350.
실시예 32
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-페닐-에타논. LRMS: 364.
실시예 33
2-시클로프로필-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논 히드로클로라이드. LRMS: 364.
실시예 34
2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피롤리딘-1-카르복실산 tert-부틸 에스테르. LRMS: 443.
실시예 35
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 벤질아미드. LRMS: 379.
실시예 36
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 페닐아미드. LRMS: 365.
실시예 37
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 테트라히드로-푸란-3-일 에스테르. LRMS: 360.
실시예 38
1-(4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피페리딘-1-일)-에타논. LRMS: 399.
실시예 39
2-시클로펜틸-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 356.
실시예 40
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 시클로헥실아미드. LRMS: 371.
실시예 41
아제티딘-3-일-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일)-메타논 트리플루오로아세테이트. LRMS: 443.
실시예 42
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피롤리딘-1-일-메타논. LRMS: 343.
실시예 43
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 메틸-페닐-아미드. LRMS: 379.
실시예 44
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-모르폴린-4-일-메타논. LRMS: 359.
실시예 45
메틸-(4-메틸-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 323.
실시예 46
메틸-(4-메틸-1-티아졸-2-일-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-l)-아민. LRMS: 329.
실시예 47
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 피리딘-3-일아미드. LRMS: 366.
실시예 48
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-플루오로-페닐)-아미드. LRMS: 383.
실시예 49
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-니트로-페닐)-아미드. LRMS: 410.
실시예 50
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메톡시-페닐)-아미드. LRMS: 395.
실시예 51
4-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-벤조산 에틸 에스테르. LRMS: 437.
실시예 52
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피페리딘-1-일-메타논. LRMS: 357.
실시예 53
메틸-(4-메틸-5'-니트로-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 368.
실시예 54
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-플루오로-페닐)-아미드. LRMS: 383.
실시예 55
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (2,4-디플루오로-페닐)-아미드. LRMS: 401.
실시예 56
메틸-[4-메틸-1-(피롤리딘-1-술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 379.
실시예 57
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]--피페리딘-1-카르복실산 (3-메톡시-페닐)-아미드. LRMS: 395.
실시예 58
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-니트로-페닐)-아미드. LRMS: 410.
실시예 59
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피롤리딘-2-카르복실산 메틸 에스테르. LRMS: 401.
실시예 60
메틸-[4-메틸-1-(5-니트로-티아졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 374.
실시예 61
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-카르복실산 메틸 에스테르. LRMS: 381.
실시예 62
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-일}-메탄올. LRMS: 353.
실시예 63
메틸-[4-메틸-1-(피페리딘-1-술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노. LRMS: 393.
실시예 64
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-시아노-페닐)-아미드. LRMS: 390.
실시예 65
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3,4-디플루오로-페닐)-아미드. LRMS: 401.
실시예 66
메틸-[4-메틸-1-(모르폴린-4-술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 395.
실시예 67
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-클로로-페닐)-아미드. LRMS: 399.
실시예 68
메틸-[4-메틸-1-(6-메틸-피리다진-3-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 338.
실시예 69
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-시아노-페닐)-아미드. LRMS: 390.
실시예 70
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 비페닐-4-일아미드. LRMS: 441.
실시예 71
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-트리플루오로메틸-페닐)-아미드. LRMS: 433.
실시예 72
메틸-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸) 카르밤산 벤질 에스테르. LRMS: 501.
실시예 73
시클로프로필-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 314.
실시예 74
시클로부틸-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 328.
실시예 75
테트라히드로-푸란-3-카르복실산 메틸-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸}-아미드. LRMS: 465.
실시예 76
시클로헥산카르복실산 메틸-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드. LRMS: 477.
실시예 77
(5,7-디클로로-1H-인돌-2-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 458.
실시예 78
4-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-벤조산. LRMS: 409.
실시예 79
(1-벤조옥사졸-2-일-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 363.
실시예 80
(1H-인돌-2-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 389.
실시예 81
(5-플루오로-1H-인돌-2-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 407.
실시예 82
(5-메톡시-3-메틸-벤조푸란-2-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 434.
실시예 83
(5-클로로-벤조푸란-2-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 424.
실시예 84
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(5-니트로-벤조푸란-2-일)-메타논. LRMS: 435.
실시예 85
(5-클로로-2,3-디히드로-벤조푸란-2-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 426.
실시예 86
(4-히드록시-피페리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 373.
실시예 87
1-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-벤조푸란-5-일)-에타논. LRMS: 432.
실시예 88
1-(3-메틸-2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-1H-인돌-5-일)-에타논. LRMS: 445.
실시예 89
[1-(5-클로로-벤조티아졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 413.
실시예 90
(3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-3-아자-비시클로[3.1.0]헥스-6-일)-카르밤산 tert-부틸 에스테르. LRMS: 470.
실시예 91
3-(4-클로로-페녹시)-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-프로판-1-온. LRMS: 428.
실시예 92
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 피리딘-2-일아미드. LRMS: 366.
실시예 93
1-{4-메틸-3-(메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피페리딘-4-카르복실산 아미드 히드로클로라이드. LRMS: 436.
실시예 94
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-클로로-피리딘-2-일)-아미드. LRMS: 400.
실시예 95
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-시클로펜타논. LRMS: 356.
실시예 96
(3-히드록시-시클로펜틸)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 358.
실시예 97
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-시클로헥사논. LRMS: 370.
실시예 98
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-시클로헥사논. LRMS: 370.
실시예 99
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-니트로-피리딘-2-일)-아미드. LRMS: 413.
실시예 100
[4-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-페닐]-아세트산. LRMS: 423.
실시예 101
(4-아미노-피페리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논 히드로클로라이드. LRMS: 408.
실시예 102
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-메틸-피리딘-2-일)-아미드. LRMS: 380.
실시예 103
1-메틸-4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피롤리딘-2-온. LRMS: 371.
실시예 104
1-벤질-3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-피롤리딘-2-온. LRMS: 447.
실시예 105
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-트리플루오로메틸-피리딘-2-일)-아미드. LRMS: 434.
실시예 106
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-시클로헥산카르복실산 (4-시아노-페닐)-아미드. LRMS: 389.
실시예 107
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-카르바모일-페닐)-아미드. LRMS: 408.
실시예 108
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-술파모일-페닐)-아미드. LRMS: 444.
실시예 109
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-메틸-티아졸-2-일)-아미드. LRMS: 386.
실시예 110
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5,6-디클로로-벤조티아졸-2-일)-아미드. LRMS: 491.
실시예 111
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸-티아졸-2-일)-아미드. LRMS: 386.
실시예 112
아제티딘-1-일-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논 히드로클로라이드. LRMS: 365.
실시예 113
[2-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-티아졸-4-일]-아세트산 에틸 에스테르. LRMS: 458.
실시예 114
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4,5-디메틸-티아졸-2-일)-아미드. LRMS: 400.
실시예 115
[2-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-티아졸-4-일]-아세트산. LRMS: 430.
실시예 116
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 벤조티아졸-2-일아미드. LRMS: 422.
실시예 117
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 티아졸-2-일아미드. LRMS: 372.
실시예 118
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [6-(2-디메틸아미노-에틸아미노)-피리딘-3-일)-아미드. LRMS: 452.
실시예 119
N-(4-클로로-페닐)-2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-아세트아미드. LRMS: 413.
실시예 120
N,N-디메틸-2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-아세트아미드. LRMS: 331.
실시예 121
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [6-(2-피롤리딘-1-일-에틸아미노)-피리딘-3-일]-아미드. LRMS: 478.
실시예 122
{2-[5-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-피리딘-2-일옥시]-에틸}-카르밤산 tert-부틸 에스테르. LRMS: 525.
실시예 123
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [6-(2-아미노-에톡시)-피리딘-3-일]-아미드. LRMS: 425.
실시예 124
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸술파모일-페닐)-아미드. LRMS: 458.
실시예 125
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메탄술포닐-페닐)-아미드. LRMS: 443.
실시예 126
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-메틸-[1,3,4]티아디아졸-2-일)-아미드. LRMS: 387.
실시예 127
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸술파모일-페닐)-아미드 히드로클로라이드. LRMS: 495.
실시예 128
메틸-[4-메틸-1-(1-페닐-에틸)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 350.
실시예 129
(3-히드록시-피롤리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 359.
실시예 130
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 tert-부틸 에스테르. LRMS: 346.
실시예 131
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [4-(2-디메틸아미노-에틸)-티아졸-2-일]-아미드. LRMS: 443.
실시예 132
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 4-메탄술포닐-벤질아미드. LRMS: 457.
실시예 133
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-아세틸술파모일-페닐)-아미드. LRMS: 486.
실시예 134
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-페닐-에탄-1,2-디온. LRMS: 378.
실시예 135
메틸-[4-메틸-1-(6-메틸아미노-피리미딘-4-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 353.
실시예 136
메틸-[4-메틸-1-(6-피롤리딘-1-일-피리미딘-4-일)-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 393.
실시예 137
[1-(6-벤질아미노-피리미딘-4-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 429.
실시예 138
N,N-디메틸-N'-(6-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피리미딘-4-일)-에탄-1,2-디아민. LRMS: 410.
실시예 139
[1-(6-클로로-피리미딘-4-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 358.
실시예 140
[1-(2-플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 354
실시예 141
[1-(2-클로로-피리미딘-4-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 359.
실시예 142
[1-(4-클로로-피리미딘-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 359.
실시예 143
메틸-[4-메틸-1-(2-메틸아미노-피리미딘-4-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 353.
실시예 144
메틸-[4-메틸-1-(4-피롤리딘-1-일-피리미딘-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 353.
실시예 145
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이속사졸-5-일)-아미드. LRMS: 370.
실시예 146
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이속사졸-4-일)-아미드. LRMS: 370.
실시예 147
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-메틸-이속사졸-3-일)-아미드. LRMS: 370.
실시예 148
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-tert-부틸-이속사졸-3-일)-아미드. LRMS: 412.
실시예 149
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 이속사졸-3-일아미드. LRMS: 356.
실시예 150
N-메틸-3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-프로피온아미드. LRMS: 331.
실시예 151
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-프로판-2-온. LRMS: 302.
실시예 152
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-옥소-아세트산 메틸 에스테르. LRMS: 332.
실시예 153
(1-시클로헥실메틸-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 342.
실시예 154
[1-(5-아미노-티아졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 344.
실시예 155
메틸-(4-메틸-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 246.
실시예 156
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-3-옥소-프로피온산 메틸 에스테르. LRMS: 346.
실시예 157
(1-벤젠술포닐메틸-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 400.
실시예 158
(3-히드록시-피롤리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 359.
실시예 159
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-프로판-1,2-디온. LRMS: 316.
실시예 160
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-술파모일-피리딘-3-일)-아미드. LRMS: 445.
실시예 161
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-아세틸아미노-피리딘-3-일)-아미드. LRMS: 423.
실시예 162
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [4-(2-디메틸아미노-에틸술파모일)-페닐]-아미드. LRMS: 515.
실시예 163
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-시아노-피리딘-3-일)-아미드. LRMS: 391.
실시예 164
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-술폰산 피리딘-2-일아미드. LRMS: 479.
실시예 165
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [6-(피롤리딘-1-카르보닐)-피리딘-3-일]-아미드. LRMS : 463.
실시예 166
2-이미다졸-1-일-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 354.
실시예 167
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-카르복실산 메틸아미드. LRMS: 380.
실시예 168
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-일}-모르폴린-4-일-메타논. LRMS: 436.
실시예 169
5-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-피리딘-2-카르복실산 프로필아미드. LRMS: 451.
실시예 170
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-카르복실산 아미드. LRMS: 366.
실시예 171
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-카르보니트릴. LRMS: 348.
실시예 172
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-~피페리딘-1-카르복실산 [4-(피롤리딘-1-술포닐)-페닐]-아미드. LRMS: 498.
실시예 173
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [4-(모르폴린-4-술포닐)-페닐]-아미드. LRMS: 514.
실시예 174
(3-히드록시-피롤리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 359.
실시예 175
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [6-(모르폴린-4-카르보닐)-피리딘-3-일]-아미드. LRMS: 479.
실시예 176
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 [6-(모르폴린-4-카르보닐)-피리딘-3-일]-아미드. LRMS: 479.
실시예 177
2-이미다졸-1-일-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS : 354.
실시예 178
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 이속사졸-3-일아미드. LRMS: 356.
실시예 179
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (2,5-디메틸-2H-피라졸-3-일)-아미드. LRMS: 383.
실시예 180
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (5-시클로프로필-2-메틸-2H-피라졸-3-일)-아미드. LRMS: 409.
실시예 181
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이소티아졸-5-일)-아미드. LRMS: 386.
실시예 182
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤조산. LRMS : 380.
실시예 183
메틸-[4-메틸-5'-(피롤리딘-1-술포닐)-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 456.
실시예 184
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-술폰산 메틸아미드. LRMS: 416.
실시예 185
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤젠술폰아미드. LRMS: 415.
실시예 186
N-tert-부틸-4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤젠술폰아미드. LRMS: 472.
실시예 187
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-피라졸-1-일-에타논. LRMS: 354.
실시예 188
메틸-[4-메틸-1-(5-니트로-벤조옥사졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 408.
실시예 189
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-술폰산 (2-히드록시-에틸)-아미드. LRMS: 446.
실시예 190
N-tert-부틸-4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤젠술폰아미드. LRMS: 471.
실시예 191
N-메틸-2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-옥소-아세트아미드. LRMS : 331.
실시예 192
[1-(5-에탄술포닐-벤조옥사졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 455.
실시예 193
메틸-{4-메틸-1-(5-메틸-벤조옥사졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 377.
실시예 194
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-클로로-피리딘-3-일)-아미드. LRMS: 400.
실시예 195
메틸-(4-메틸-1-퀴놀린-2-일-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 373.
실시예 196
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-3,4,5,6-테트라히드로-2H-[1,2']비피리디닐-5'-술폰산 아미드. LRMS: 402.
실시예 197
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-피롤리딘-1-일-에탄-1,2-디온. LRMS: 371.
실시예 198
메틸-[4-메틸-1-(4-메틸-벤조옥사졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 377.
실시예 199
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-모르폴린-4-일-에탄-1,2-디온. LRMS: 387.
실시예 200
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-메탄술포닐-피리딘-3-일)-아미드. LRMS: 444.
실시예 201
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-메탄술포닐-피리딘-3-일)-아미드. LRMS: 444.
실시예 202
메틸-[4-메틸-1-(6-니트로-벤조옥사졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 408.
실시예 203
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-메탄술포닐-피리딘-3-일)-아미드. LRMS: 444.
실시예 204
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-메탄술포닐-피리딘-3-일)-아미드. LRMS: 444.
실시예 205
메틸-[4-메틸-1-(6-니트로-벤조옥사졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 408.
실시예 206
메틸-[4-메틸-1-(톨루엔-3-술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 400.
실시예 207
메틸-[4-메틸-1-(4-트리플루오로메틸-벤젠술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 454.
실시예 208
(1-벤조티아졸-2-일-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 379.
실시예 209
[1-(5,7-디메틸-벤조옥사졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 391.
실시예 210
2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-벤조옥사졸-6-카르복실산 메틸 에스테르. LRMS: 421.
실시예 211
메틸-[4-메틸-1-(6-메틸-벤조옥사졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 377.
실시예 212
[1-(6-메톡시-벤조옥사졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 393.
실시예 213
메틸-[4-메틸-1-(5-트리플루오로메틸-벤조티아졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 447.
실시예 214
[1-(5,7-디클로로-벤조옥사졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 432.
실시예 215
[1-(6-클로로-피리딘-3-술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 422.
실시예 216
[1-(4-클로로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 421.
실시예 217
[1-(4-플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 404.
실시예 218
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤조니트릴. LRMS: 411.
실시예 219
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤젠술포닐 플루오라이드. LRMS: 468.
실시예 220
2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤조니트릴. LRMS: 411.
실시예 221
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-테트라졸-1-일-에타논. LRMS: 356.
실시예 222
메틸-[4-메틸-1-(2,2,2-트리플루오로-에탄술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 392.
실시예 223
[1-(2,6-디플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 422.
실시예 224
[1-(4-tert-부틸-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 442.
실시예 225
[1-(2,4-디플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 422.
실시예 226
메틸-[4-메틸-1-(2-트리플루오로메틸-벤젠술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 454.
실시예 227
[1-(3,5-비스-트리플루오로메틸-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 522.
실시예 228
[1-(3,5-디클로로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 455.
실시예 229
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤조산. LRMS: 431.
실시예 230
[1-(6-클로로-피리딘-3-술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 422.
실시예 231
[1-(4-클로로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 421.
실시예 232
[1-(4-플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 404.
실시예 233
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤조니트릴. LRMS: 411.
실시예 234
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤젠술포닐 플루오라이드. LRMS: 468.
실시예 235
2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤조니트릴. LRMS: 411.
실시예 236
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-테트라졸-1-일-에타논. LRMS: 356.
실시예 237
메틸-[4-메틸-1-(2,2,2-트리플루오로-에탄술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 392.
실시예 238
[1-(2,6-디플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 422.
실시예 239
[1-(4-tert-부틸-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 442.
실시예 240
[1-(2,4-디플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 422.
실시예 241
메틸-[4-메틸-1-(2-트리플루오로메틸-벤젠술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 454.
실시예 242
[1-(3,5-비스-트리플루오로메틸-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸 (7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 522.
실시예 243
[1-(3,5-디클로로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 455.
실시예 244
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤조산. LRMS: 431.
실시예 245
(3-플루오로-페닐)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 368.
실시예 246
이소티아졸-4-일-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 357.
실시예 247
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-티오펜-3-일-메타논. LRMS: 356.
실시예 248
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(5-메틸-1H-피라졸-3-일)-메타논. LRMS: 354.
실시예 249
(5-메틸-이속사졸-3-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 355.
실시예 250
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(5-메틸-티오펜-2-일)-메타논. LRMS: 371.
실시예 251
(4-플루오로-페닐)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 368.
실시예 252
메틸-[4-메틸-1-(3-니트로-벤젠술포닐)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 431.
실시예 253
[1-(3-플루오로-벤젠술포닐)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 404.
실시예 254
(2-플루오로-페닐)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 368.
실시예 255
(1,5-디메틸-1H-피라졸-3-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 368.
실시예 256
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(2-메틸-티아졸-4-일)-메타논. LRMS: 371.
실시예 257
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-티아졸-4-일-메타논. LRMS: 357.
실시예 258
(4-메틸-이소티아졸-5-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 371.
실시예 259
2,2-디메틸-5-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-옥소-에틸)-[1,3]디옥솔란-4-온. LRMS: 403.
실시예 260
2-시클로프로필-N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아세트아미드. LRMS: 436.
실시예 261
N-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-메탄술폰아미드. LRMS: 432.
실시예 262
(3-히드록시-피롤리딘-1-일)-{4-메틸-3-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 359.
실시예 263
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤조니트릴. LRMS: 362.
실시예 264
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-벤젠술포닐 플루오라이드. LRMS: 469.
실시예 265
2,2-디메틸-5-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-옥소-에틸)-[1,3]디옥솔란-4-온. LRMS: 402.
실시예 266
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 벤질 에스테르. LRMS: 381.
실시예 267
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤젠술폰아미드. LRMS: 416.
실시예 268
[1-(1H-이미다졸-2-일메틸)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 326.
실시예 269
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 2-클로로-벤질 에스테르. LRMS: 415.
실시예 270
메틸-[4-메틸-1-(1-메틸-1H-이미다졸-2-일메틸)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 340.
실시예 271
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-페녹시-에타논. LRMS: 380.
실시예 272
2-(4-플루오로-페녹시)-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 381.
실시예 273
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일]-아미노]-피페리딘-1-카르복실산 2,2,2-트리클로로-에틸 에스테르. LRMS: 420.
실시예 274
2-(2-클로로-페녹시)-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 415.
실시예 275
2-(3-클로로-페녹시)-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 415.
실시예 276
2-메탄술포닐-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 367.
실시예 277
2-(1,1-디옥소-테트라히드로-1$1%6&-티오펜-3-일)-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 407.
실시예 278
메틸-[4-메틸-1-(1-페닐-에틸)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 351.
실시예 279
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-(톨루엔-4-술포닐)-에타논. LRMS: 443.
실시예 280
2-히드록시-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논. LRMS: 304.
실시예 281
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-3-니트로-프로판-1-온. LRMS: 347.
실시예 282
5-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-옥소-에틸)-티아졸리딘-2,4-디온. LRMS: 404.
실시예 283
3-히드록시-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-프로판-1-온. LRMS: 318.
실시예 284
N-(4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-4-옥소-부틸)-메탄술폰아미드. LRMS: 410.
실시예 285
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 2,2-디메틸-프로필 에스테르. LRMS: 360.
실시예 286
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-(티아졸리딘-3-술포닐)-에타논. LRMS: 440.
실시예 287
(3,4-디히드록시-피롤리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논. LRMS: 376.
실시예 288
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-티아졸리딘-2-온. LRMS: 376
실시예 289
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 프로프-2-이닐 에스테르. LRMS: 328.
실시예 290
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (2-시아노-에틸)-아미드. LRMS: 342.
실시예 291
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (2-시아노-에틸)아미드. LRMS : 342.
실시예 292
1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-시클로헥실}-에타논 옥심. LRMS: 302.
실시예 293
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 시아노메틸-메틸-아미드. LRMS: 342.
실시예 294
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 이소프로필 에스테르. LRMS: 332.
실시예 295
4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (2-시아노-에틸)-메틸-아미드. LRMS: 356.
실시예 296
4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-피리딘-1-올. LRMS: 355.
실시예 297
{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-아세토니트릴. LRMS: 285.
실시예 298
[1-(2-플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민.
방법 J
메탄올 5 mL에 용해된 방법 H로부터의 생성물 (50 mg, mmol ?)의 용액에 2-플루오로-벤즈알데히드 154 ㎕ (mmol ?)를 첨가하였다. 생성된 혼합물을 실온에서 4시간 동안 교반하고, 이 때, 시아노붕수소화나트륨 x mg (y mmol)을 첨가하고, 생성된 혼합물을 실온에서 18시간 동안 교반하였다. 1N NaOH (수성) 2 액적을 첨가하여 반응을 켄칭시키고, 혼합물을 감압하에 농축시켜 메탄올을 제거하였다. 잔류물을 클로로포름에 용해시키고, 물로 세척하였다. 수성층을 다시 클로로포름으로 3회 세척하고, 합한 클로로포름 추출물을 MgSO4 상에서 건조시키고, 진공하에 농축 건조시켰다. 다음, 조생성물을 플래쉬 크로마토그래피 (실리카; 클로로포름 중 2.5% 메탄올)에 의해 정제하여, 표제 화합물 36 mg (47.5%)을 백색 고체로서 수득하였다. LRMS: 372.4 (M+1).
실시예 299 내지 324의 표제 화합물을 실시예 298에 기재된 것과 유사한 방법으로 제조하였다.
실시예 299
(1-벤질-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 336.
실시예 300
(1-푸란-2-일메틸-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 326.
실시예 301
[1-(4-메톡시-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 366.
실시예 302
[1-(4-플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 354.
실시예 303
메틸-(4-메틸-1-피리딘-3-일메틸-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 337.
실시예 304
메틸-(4-메틸-1-티아졸-2-일메틸-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 343.
실시예 305
메틸-(4-메틸-1-피리딘-2-일메틸-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 337.
실시예 306
메틸-[4-메틸-1-(1-페닐-에틸)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 350.
실시예 307
(1-벤질-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 336.
실시예 308
(1-벤질-4-메틸-피페리딘-3-일)-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 336.
실시예 309
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤조니트릴. LRMS: 361.
실시예 310
[1-(3-플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 354.
실시예 311
[1-(3-메톡시-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 366.
실시예 312
3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤조산. LRMS: 380.
실시예 313
[1-(2-플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 354.
실시예 314
[1-(2,6-디플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 372.
실시예 315
메틸-(4-메틸-1-펜에틸-피페리딘-3-일)-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 350.
실시예 316
[1-(2,3-디플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 372.
실시예 317
[1-(3,4-디플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 372.
실시예 318
[1-(4-메탄술포닐-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 414.
실시예 319
메틸-{4-메틸-1-[4-(피페리딘-1-술포닐)-벤질]-피페리딘-3-일}-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 483.
실시예 320
[1-(3,5-디플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 372.
실시예 321
[1-(3-클로로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 371.
실시예 322
[1-(3,5-디플루오로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 372.
실시예 323
[1-(3-클로로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 371.
실시예 324
[1-(3,5-디클로로-벤질)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아민. LRMS: 405.
Claims (29)
- 화학식 I의 화합물 또는 그의 제약상 허용가능한 염.<화학식 I>상기 식에서,R1은 화학식 의 기이고,식 중, y는 0이고;R4는 (C1-C6)알킬이고;R5는 피페리디닐이고, 이는 (C1-C6)알킬, 시아노(C1-C6)알킬, [(시아노(C1-C6)알킬)((C1-C6)알킬)아미노]아실, 히드록시(C1-C6)알킬아실, 니트로(C1-C6)알킬아실, (C1-C6)알킬SO2HN(C1-C6)알킬아실, (C1-C6)알콕시아실, 시아노(C1-C6)알킬-O-C(=O), (C1-C6)알킬-O-C(=O), 시아노(C1-C6)알킬-HN-C(=O), 시아노(C1-C6)알킬-(C1-C6)알킬N-C(=O), (C1-C6)알킬술포닐(C1-C6)알킬아실, 트리플루오로메틸(C1-C6)알킬술포닐, (C3-C10)시클로알킬(C1-C6)알킬-C(=O)NH(C1-C6)알킬술포닐, (C3-C10)시클로알킬(C1-C6)알킬, (C1-C6)알킬아실(C1-C6)알킬, (C1-C6)알킬-(C(=O))2, (C1-C6)알콕시-(C(=O))2, [((C1-C6)알킬)2아미노]아실(C1-C6)알킬 및 화학식 II의 기로 구성된 군 중 1 내지 5개로 치환되어야 하고;<화학식 II>식 중, a는 0, 1, 2, 3 또는 4이고;b, c, e, f 및 g는 각각 독립적으로 0 또는 1이고;d는 0, 1, 2 또는 3이고;X는 S(O)2, 산소 또는 카르보닐이고;Y는 S(O)2 또는 카르보닐이고;Z는 카르보닐, C(O)O-, C(O)NR- (이 때, R은 수소 또는 (C1-C6)알킬임)이거나; 또는 Z는 S(O)2이고;R6, R7, R8, R9, R10 및 R11은 각각 독립적으로 수소, 또는 중수소, 히드록시, 아미노, 트리플루오로메틸, (C1-C6)아실옥시, (C1-C6)아실아미노, (C1-C6)알킬아미노, ((C1-C6)알킬)2아미노, 시아노, 시아노(C1-C6)알킬, 트리플루오로메틸(C1-C6)알킬, 니트로, 니트로(C1-C6)알킬 또는 (C1-C6)아실아미노에 의해 치환될 수 있는 (C1-C6)알킬로 구성된 군으로부터 선택되고;R12는 (C6-C10)아릴, (C2-C9)헤테로아릴, (C3-C10)시클로알킬 또는 (C2-C9)헤테로시클로알킬이고, 이 때, 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬기는 수소, (C1-C6)알콕시, 할로, 옥소, (C1-C6)알콕시아실, (C1-C6)알킬아실, 니트로, 시아노, (C1-C6)알킬, 히드록시(C1-C6)알킬, 트리플루오로메틸, 카르복시, 히드록시, (C1-C6)알콕시아실HN-, 아미노아실, (C1-C6)알킬HN아실, ((C1-C6)알킬)2N아실, 카르복시(C1-C6)알킬, 아미노, (C1-C6)알킬HN, ((C1-C6)알킬)2N, 아미노(C1-C6)알킬HN, ((C1-C6)알킬)2N(C1-C6)알킬HN, 아미노술포닐, (C1-C6)알콕시아실(C1-C6)알킬, (C2-C9)헤테로시클로알킬(C1-C6)알킬HN, 아미노(C1-C6)알콕시, (C1-C6)알콕시아실HN(C1-C6)알콕시, (C1-C6)알킬술포닐, ((C1-C6)알킬)2N(C1-C6)알킬, (C2-C9)헤테로시클로알킬, (C6-C10)아릴(C1-C6)알킬아미노, ((C1-C6)알킬)2N(C1-C6)알킬, ((C1-C6)알킬아실아미노, ((C1-C6)알킬)2N((C1-C6)알킬)HN술포닐, (C2-C9)헤테로아릴아미노술포닐, (C2-C9)헤테로시클로알킬아실, (C2-C9)헤테로아릴(C1-C6)알킬아실, (C1-C6)알킬아미노아실, (C2-C9)헤테로시클로알킬술포닐, (C1-C6)알킬아미노술포닐, 히드록시(C1-C6)알킬아미노술포닐 및 할로술포닐로 구성된 군 중 1 내지 4개에 의해 치환될 수 있고;R2 및 R3은 각각 수소이고;단, R5는 화학식 II의 기에 의해 치환되어야 한다.
- 제1항에 있어서, R5가 중수소, 히드록시, (C1-C6)알킬, 할로, (C1-C6)알콕시 및 화학식 II의 기로부터 선택된 1 내지 3개의 기에 의해 치환된 피페리디닐인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 카르보닐이고, c가 0이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 카르보닐이고, c가 0이고, d가 1이고, e가 0이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물.
- 삭제
- 제1항에 있어서, a가 0이고, b가 0이고, c가 0이고, d가 0이고, e가 0이고, f가 0이고, g가 1이고, Z가 C(O)O-인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 S(O)2이고, c가 0이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 S(O)2이고, c가 0이고, d가 2이고, e가 0이고, f가 1이고, g가 1이고, Z가 카르보닐인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 S(O)2이고, c가 0이고, d가 2이고, e가 0이고, f가 1이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 0이고, e가 1이고, Y가 S(O)2이고, f가 0이고 g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 S(O)2이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고 g가 0인 화합물.
- 제1항에 있어서, a가 1이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 0이고, e가 0이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 S(O)2이고, c가 0이고, d가 1이고, e가 1이고, Y가 S(O)2이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 S(O)2이고, c가 0이고, d가 2 또는 3이고, e가 1이고, Y가 S(O)2이고, f가 1이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 산소이고, c가 0이고, d가 2 또는 3이고, e가 1이고, Y가 S(O)2이고, f가 1이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 산소이고, c가 0이고, d가 2 또는 3이고, e가 1이고, Y가 S(O)2이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 2 또는 3이고, e가 1이고, Y가 S(O)2이고, f가 0이고, g가 0인 화합물.
- 제1항에 있어서, a가 0이고, b가 1이고, X가 카르보닐이고, c가 1이고, d가 2 또는 3이고, e가 1이고, Y가 S(O)2이고, f가 1이고, g가 0인 화합물.
- 제1항에 있어서, R12가 (C6-C10)아릴 또는 (C2-C9)헤테로아릴이고, 이 때, 아릴 또는 헤테로아릴기가 수소, 할로, 히드록시, 카르복시, 트리플루오로메틸, (C1-C6)알킬, (C1-C6)알콕시, (C1-C6)알킬-CO-NH-, 아미노, (C1-C6)알킬아미노, ((C1-C6)알킬)2아미노, 시아노, (C1-C6)알킬술포닐 및 (C1-C6)알콕시-CO-NH로 구성된 군 중 1 내지 4개에 의해 치환될 수 있는 화합물.
- 제1항에 있어서,4-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일메틸}-벤젠술폰아미드;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-술파모일-페닐)-아미드;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-니트로-페닐)-아미드;1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-테트라졸-1-일-에타논;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸술파모일-페닐)-아미드;(3-히드록시-피롤리딘-1-일)-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논;[2-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-티아졸-4-일]-아세트산;5-(2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-2-옥소-에틸)-티아졸리딘-2,4-디온;메틸-[4-메틸-1-(5-니트로-티아졸-2-일)-피페리딘-3-일]-(7H-피롤로[2,3-d]피리미딘-4-일)-아민;[2-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-티아졸-4-일]-아세트산 에틸 에스테르;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메탄술포닐-페닐)-아미드;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 티아졸-2-일아미드;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-시아노-페닐)-아미드;{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-피롤리딘-1-일-메타논;푸란-2-카르복실산 (2-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-술포닐}-에틸)-아미드;{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-(테트라히드로-푸란-3-일)-메타논;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 이속사졸-3-일아미드;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (6-시아노-피리딘-3-일)-아미드;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (4-메틸-티아졸-2-일)-아미드;2-시클로프로필-1-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-에타논;시클로펜틸-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-일}-메타논;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이속사졸-4-일)-아미드;[4-({4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-아미노)-페닐]-아세트산;[1-(5-아미노-티아졸-2-일)-4-메틸-피페리딘-3-일]-메틸-(7H-피롤로[2,3-d]피리미딘-4-일)아민;4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르복실산 (3-메틸-이소티아졸-5-일)-아미드; 및3-{4-메틸-3-[메틸-(7H-피롤로[2,3-d]피리미딘-4-일)-아미노]-피페리딘-1-카르보닐}-시클로펜타논;으로 구성된 군으로부터 선택된 화합물.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 하기 화학식의 화합물.상기 식에서,R4는 (C1-C6)알킬이다.
- 하기 화학식의 화합물.
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