TW202128682A - 含氮雜環類自分泌運動因子抑制劑及其組合物和用途 - Google Patents
含氮雜環類自分泌運動因子抑制劑及其組合物和用途 Download PDFInfo
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- TW202128682A TW202128682A TW109143732A TW109143732A TW202128682A TW 202128682 A TW202128682 A TW 202128682A TW 109143732 A TW109143732 A TW 109143732A TW 109143732 A TW109143732 A TW 109143732A TW 202128682 A TW202128682 A TW 202128682A
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- alkyl
- halogen
- compound
- cycloalkyl
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- 239000000203 mixture Substances 0.000 title claims description 96
- 229940122849 Autotaxin inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 244
- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 claims abstract description 177
- 150000003839 salts Chemical class 0.000 claims abstract description 72
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- 229910052717 sulfur Inorganic materials 0.000 claims description 103
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 89
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- 125000005842 heteroatom Chemical group 0.000 claims description 83
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- 239000013078 crystal Substances 0.000 claims description 67
- 125000000623 heterocyclic group Chemical group 0.000 claims description 61
- 125000004432 carbon atom Chemical group C* 0.000 claims description 57
- 125000003545 alkoxy group Chemical group 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 150000001721 carbon Chemical group 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
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- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 10
- 125000004419 alkynylene group Chemical group 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
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- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
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- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 230000004899 motility Effects 0.000 claims description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
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- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
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- 208000003251 Pruritus Diseases 0.000 claims description 2
- 206010052779 Transplant rejections Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 230000007870 cholestasis Effects 0.000 claims description 2
- 231100000359 cholestasis Toxicity 0.000 claims description 2
- 230000006806 disease prevention Effects 0.000 claims description 2
- 208000030533 eye disease Diseases 0.000 claims description 2
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- 208000030159 metabolic disease Diseases 0.000 claims description 2
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 claims 1
- 201000006370 kidney failure Diseases 0.000 claims 1
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 abstract description 17
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- 230000005496 eutectics Effects 0.000 abstract description 5
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 abstract 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 257
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- 239000000243 solution Substances 0.000 description 191
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 157
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 103
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
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- 229960000583 acetic acid Drugs 0.000 description 26
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- HZSLJFGMNPIAOY-UHFFFAOYSA-N 4,5,6,7-tetrahydro-2H-triazolo[4,5-c]pyridine hydrochloride Chemical compound Cl.C1Cc2n[nH]nc2CN1 HZSLJFGMNPIAOY-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
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Abstract
本發明公開一種式(I)所示的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽、共晶或它們的醫藥組合物,及其在製備治療/預防自分泌運動因子介導的疾病的藥物中的用途,式(I)中各基團如說明書之定義。
Description
本發明涉及一種含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽、共晶或它們的醫藥組合物,及其在製備治療/預防自分泌運動因子介導的疾病的藥物中的用途。
自分泌運動因子(ATX)是一種酶,其負責腹水和血漿中溶血磷脂酸的增加,並且其是將溶血磷脂醯膽鹼(LPC)轉化為作為生物活性信號傳導分子的溶血磷脂酸(LPA)的重要分泌酶。自分泌運動因子(ATX)是一種也稱作外核苷酸焦磷酸酶/磷酸二酯酶2或溶血磷脂酶D的分泌型酶,其對於將溶血磷脂醯膽鹼(LPC)轉化為生物活性的信號分子溶血磷脂酸(LPA)而言是重要的。ATX在引起包括纖維化、關節炎、神經變性、神經性疼痛和癌症的病理狀況中起作用。
LPA是一種生理活性脂質,其對各種類型細胞的遷移、增生和存活具有影響。由於血漿中的LPA水準與ATX的活性高度相關,因此認為ATX是細胞外LPA的重要供應來源。已經表明,在病理條件下,ATX的抑制降低了LPA水準。早期用原型ATX抑制劑的實驗已經證實了,這樣的化合物能夠抑制在小鼠血漿中的LPA合成活性。在早期進行的工作已經證明,LPA可以引起各種各樣的細胞反應:包括平滑肌細胞收縮、血小板活化、細胞增生、趨化性等等。LPA經由向若干G蛋白偶聯受體(GPCR)發出信號來介導它的效果;第一批成員最初
被表示為Edg(內皮細胞分化基因)受體或心室區基因-1,但現在稱為LPA受體。現在原型群由LPA1/Edg-2、VZG-1、LPA2/Edg-4和LPA3/Edg-7組成。最近,已經描述了三種附加的LPA受體LPA4/p2y9/GPR23、LPA5/GPR92和LPA6/p2y5,它們與原型LPA1-3受體相聯繫相比,更加緊密地與核苷酸選擇性嘌呤能受體相聯繫。ATX-LPA信號軸涉及多種多樣的生理和病理功能,包括例如:神經系統功能、血管發育、心血管生理學、繁殖、免疫系統功能、慢性炎症、腫瘤轉移和進展、器官纖維化及肥胖症和/或其他代謝疾病如糖尿病。
因此,提高的ATX活性或提高的LPA水準,改變的LPA受體表現和改變的對LPA的反應可以有助於與ATX/LPA軸相關的大量不同的病理生理病症的引發、進展和結果。
作為本發明的第一技術方案,本發明首先提供了一種具有ATX抑制活性的式(I)的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
L1為鍵、-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-、或-C(O)-(CR3R4)c-C=CR7-;
W為-C(=X)-、或含有1-3個選自N、O或S雜原子的3-6員伸雜環基;
X為O、S或NRx,Rx為H或氰基;
每個R1至R6獨立地選自H、鹵素、C1-4烷基或C3-6環烷基;
每個R7和R8獨立地選自H、C1-4烷基或C3-6環烷基;
作為選擇,同碳原子上的R1和R2、R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;
a、c和e獨立地選自0-5的整數,b和d獨立地為0或1;
Ra'和Ra"獨立地為H或C1-4烷基;
n為1-2的整數;
X1和X2獨立地為N或CRA1,且不同時為CRA1,X3為S、O或NRA1;X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;
每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA或-ORA;
RA為C1-4烷基、C3-6環烷基、C3-6環烷基氧基、C1-4烷氧基、C1-4鹵
代烷基、C1-4鹵代烷氧基、或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、環烷基氧基、烷氧基、鹵代烷基、鹵代烷氧基、雜環基視情況進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;
Y1為O、S或NRB3;
Cy具有結構:,其中,表示單鍵或雙鍵,Z1為C或N,環E為含有1-3個選自N、O或S雜原子的5員雜環,環D為含有0-3個選自N、O或S雜原子的6員環;所述5員雜環和6員環獨立視情況被1-3個RB2取代;
每個RB1和RB2獨立地選自H、側氧基(oxo)、OH、鹵素、氰基、C1-4烷基、鹵代C1-4烷基、C1-4烷基氧基或C3-6環烷基;RB3選自H、C1-4烷基或C3-6環烷基;
作為選擇,A上的基團RA1和B上的基團RB1與其連接的原子一起形成含有1-3個選自N、S、O雜原子的6-10員雜環;
f為0-3的整數;
L2為-O-、-NR9-、-C(O)NR9-、-NR9C(O)NR9-、-(CR10R11)g-、-NR9-(CR10R11)g-或鍵,g為1-3的整數;
R9為H或C1-4烷基;
每個R10和R11獨立地為H、鹵素、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R10和R11與其連接的碳原子形成3-6員碳環;
Z2、Z3為CRM或N,Z4為O、S或NRM1;
每個RM獨立地為H、C1-4烷基、C1-4烷氧基烷基、氰基、C3-6環烷基、C3-6環烷基氧基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6烯基、C2-6炔基、-NRM1,含有1-3個選自N、O或S雜原子的3-6員雜環基、或鹵素;所述烷基、烯基、炔基、環烷基視情況被1-3個選自鹵素、氰基、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-4烷基的基團取代;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
Rm為H、C1-4烷基、鹵代C1-4烷基;
Rm'為C1-4烷基、鹵代C1-4烷基;
RM1為H、C1-4烷基、C3-6環烷基、C1-4鹵代烷基或C1-4烷氧基烷基;
RM2為鹵代C1-4烷氧基;
每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;
h為0-3的整數;
i為0、1或2;
當M1為,L1為-C(O)-CH2-,A為,B為或,L2為-NH-,M2為時,A至少有一個取代基RA1選自氰基、鹵素、C3-4環烷基氧基、環丙基甲基氧基、C1-4鹵代烷氧基、環丙基甲基、-C1-4烷基-O-C1-4烷基、-NHC(O)RA、-C(O)NHRA、-C(O)-C3-6環烷基、、、、、、或;
在一些實施例中,式(I)所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
L1為-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-、或-C(O)-(CR3R4)c-C=CR7-;
W為-C(=X)-、或含有1-3個選自N、O或S雜原子的3-6員伸雜環基;
X為O、S或NRx,Rx為H或氰基;
每個R1至R6獨立地選自H、鹵素、C1-4烷基或C3-6環烷基;
每個R7和R8獨立地選自H、C1-4烷基或C3-6環烷基;
作為選擇,同碳原子上的R1和R2、R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;
a、c和e獨立地選自0-5的整數,b和d獨立地為0或1;
n為1-2的整數;
X1和X2獨立地為N或CRA1,且不同時為CRA1,X3為S、O或NRA1;
每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA、或-ORA;
RA為C1-4烷基、C3-6環烷基、或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、雜環基視情況進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;
Y1為O、S或NRB3;
Cy具有結構:,其中,表示單鍵或雙鍵,Z1為C或N,環E為含有1-3個選自N、O或S雜原子的5員雜環,環D為含有0-3個選自N、O或S雜原子的6員環;所述5員雜環和6員環獨立視情況被1-3個RB2取代;
每個RB1和RB2獨立地選自H、側氧基、OH、鹵素、氰基、C1-4烷基、鹵代C1-4烷基、C1-4烷基氧基或C3-6環烷基;RB3選自H、C1-4烷基或C3-6環烷基;
作為選擇,A上的基團RA1和B上的基團RB1與其連接的原子一起形成含有1-3個選自N、S、O雜原子的6-10員雜環;
f為0-3的整數;
L2為-O-,-NR9-,-(CR10R11)g-或鍵,g為1-3的整數;
R9為H或C1-4烷基;
每個R10和R11獨立地為H、鹵素、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R10和R11與其連接的碳原子形成3-6員碳環;
Z2、Z3為CRM或N,Z4為O、S或NRM1;
每個RM獨立地為H、C1-4烷基、氰基、C3-6環烷基或鹵素;所述烷
基、環烷基視情況被1-3個選自鹵素、氰基的基團取代;
RM1為H、C1-4烷基或C3-6環烷基;
h為0-3的整數;
當M1為,L1為-C(O)-CH2-,A為,B為或,L2為-NH-,M2為時,A至少有一個取代基RA1選自氰基、鹵素、C3-4環烷基氧基、環丙基甲氧基、C1-4鹵代烷氧基、環丙基甲基、-C1-4烷基-O-C1-4烷基、-NHC(O)RA、-C(O)NHRA、-C(O)-
C3-6環烷基、、、、、、或;
作為本發明的第二技術方案,式(I)所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,
a、c和e獨立地選自0-3的整數,b和d獨立地為0或1;
W為-C(=X)-、或含有1-2個選自N、O雜原子的5員伸雜環基,X為O、S或NRx,Rx為氰基;
每個R1至R6獨立地選自H、鹵素、C1-4烷基,R7和R8獨立地選自H或C1-4烷基;
作為選擇,同碳原子上的R3和R4、或R5和R6與其連接的碳原子一起形成3-4員碳環,所述碳環視情況被1-2個選自鹵素、C1-2烷基的取代基取代;
RA為C1-4烷基、C3-4環烷基、含有1-2個選自N、O雜原子的4-6員雜
環基,所述烷基、雜環基視情況進一步地被1-5個選自C3-4環烷基、C1-4烷基、鹵素、-S(O)2C1-2烷基、-OC1-2烷基或氰基的基團取代,
其餘基團如前述第一技術方案之定義。
作為本發明的第三技術方案,式(I)所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,
L1為-C(=O)-(NH)d-CR3R4-,d為0或1,R3、R4至少有一個為鹵素,或R3和R4及其連接的碳原子一起形成3-4員碳環;或者
L1為-C(=S)-CR3R4-,其中R3和R4獨立地選自H、鹵素或C1-4烷基;或者
L1為-C(=N-CN)-CR3R4-,其中R3和R4獨立地選自H、鹵素或C1-4烷基;或者
L1為-C(O)-CR3R4-C=CR7-,其中R3和R4獨立地選自H、鹵素或C1-4烷基,R7為H或C1-4烷基;或者
L1為-W-(CR3R4)c-,其中W為含有1-2個選自N或O雜原子的5員伸雜環基,c為0-3的整數,
其餘基團如前述第一或第二技術方案之定義。
作為本發明的第四技術方案,式(I)所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物具有更具體的式(II)的結構:
其餘基團如前述第三技術方案之定義。
作為本發明的第五技術方案,式(I)所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,L1為-W-(CR3R4)c-,W為含有1-2個選自N、O雜原子的5員伸雜環基,c為0-3的整數時,所述5員伸雜環基為,
其餘基團如前述第三技術方案之定義。
作為本發明的第六技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:
作為本發明的第七技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,M1為,A為,B為,L2為-NH-,M2為;或者M1為,A為,B為,L2為-NH-,M2為,
其餘基團如前述第六技術方案之定義。
作為本發明的第八技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,L2為-C(O)NR9-、-NR9C(O)NR9-、-O-、或-CR10R11-,R10和R11中至少一個為鹵素或C1-4烷基,或R10和R11與其連接的碳原子形成3-4員碳環,其餘基團如前述第一或第二技術方案之定義。
作為本發明的第九技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物具有更具體的式(III)的結構
其餘基團如前述第八技術方案之定義。
作為本發明的第十技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:
A為C3-6伸環烷基、C2-4伸炔基、、、、-RaC(O)NRa'-或,X1為N或CRA1,X3為S、O或NRA1,每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA或-ORA,Ra為,Ra'為H或C1-4烷基,其餘基團如前述第一或第二技術方案之定義;
或者
A為,n不為0,且至少有一個RA1選自氰基、鹵素、C3-4環烷基氧基、環丙基甲氧基、鹵代C1-4烷氧基、環丙基甲基、-C1-4烷基-O-C1-4烷基、-NHC(O)RA、-C(O)NHRA、-C(O)-C3-6環烷基、、、、、、或,其餘基團如前述第一或第二技術方案之定義。
作為本發明的第十一技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物具有更具體的式(IV)的結構
L1為-C(O)-(CR5R6)e-,其餘基團定義如前述第十技術方案之定義。
作為本發明的第十二技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:
B為,其中RB1和RB2中至少有一個選自OH、鹵素、氰基、鹵代C1-4烷基、C1-4烷基氧基、C3-6環烷基,或者A上的基團RA1和B上的基團RB1與其連接的原子一起形成含有1個O原子的6-8員雜環,某餘基團如前述第一或第二技術方案之定義;或者
作為本發明的第十三技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物具有更具體的式(V)的結構
作為本發明的第十四技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物具有更具體的式(VI)的結構
其中,L1為-C(=O)-(CR3R4)c-(NR8)d-、c為0-3的整數,d為0或1,R3、R4和R8獨立地選自H或C1-3烷基,鹵素,R3和R4與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;A為或鍵;
Cy具有結構:,其中,表示單鍵或雙鍵,Z1為C或N,環E為含有1-3個選自N、O或S雜原子的5員雜環,環D為飽和或不飽和的含有0-3個選自N、O或S雜原子的6員環;所述5員雜環和6員環獨立視情況被1-3個RB2取
代;
每個RB2獨立地選自H、鹵素、氰基、C1-4烷基、鹵代C1-4烷基;
L2為-NH-或鍵,
其餘基團如前述第一或第二技術方案之定義。
作為本發明的第十六技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:
當M2為時,h不為0,且至少有一個RM為鹵代C1-4烷基、氰基、C3-6環烷基、C2-6炔基或含有1-3個選自N、O或S雜原子的3-6員雜環基;所述烷基視情況被1-3個選自鹵素或氰基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基或C1-4烷基的基團取代;或者,作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的3-6員碳環或3-6員雜環基;其餘基團如前述第一或第二技術方案之定義;較佳地,M2為,其中RM為三氟甲基、二氟甲基、環丙基、乙炔基、呋喃-3-基、甲基胺基羰基、氮雜環丁-1-基、氧雜環丁-3-基、3,3-二氟-氮雜環丁-1-基、乙醯胺基、1-甲基-1H-吡唑-4-基、四氫呋喃-3-基、甲硫基、4-甲基-5-側氧基-1,2,4-三唑-1-基、2-側氧基-吡咯啶-1-基、甲磺醯基、甲氧基甲基、二氟甲氧基甲基或三氟甲基乙炔基;更佳地,M2為、、、
;較佳地,M2為,其中RM為C1-4烷基,所述烷基
被1-3個鹵素(較佳為F)取代;較佳為三氟甲基或二氟甲基;
作為本發明的第十七技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物的具有更具體的式(VII)的結構
M2如前述第十六技術方案之定義。
作為本發明的第十八技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
L1為-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-;
W為-C(=X)-,X為O或S;
a、b為0,c為1或2,d、e為0;
每個R3、R4獨立地選自H、鹵素、C1-4烷基,且不同時為H;
L2為-NR9-,R9為H;
每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;
h為0、1或2;
每個RM獨立地為H或C1-4烷基,所述烷基視情況被1-3個鹵素取代;
其餘基團如前述第一或第二技術方案之定義。
作為本發明的第十九技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
L1為鍵或-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-;
W為-C(=X)-;
X為O、S或NRx,Rx為H或氰基;
每個R1至R6獨立地選自H、鹵素、C1-4烷基或C3-6環烷基;
每個R7和R8獨立地選自H、C1-4烷基或C3-6環烷基;
作為選擇,同碳原子上的R1和R2、R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代
基取代;
a、c和e獨立地選自0、1、2和3,b和d獨立地為0或1;
Ra'和Ra"為H或C1-4烷基;
n為1或2;
X1和X2獨立地為N、NRA1或CRA1,且不同時為CRA1;
X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;
每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA、-ORA的取代基取代;
RA為C1-4烷基、C3-6環烷基、或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、雜環基視情況進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;
每個RB1和RB2獨立地選自H、OH、鹵素、氰基、C1-4烷基、鹵代C1-4烷基、C1-4烷基氧基或C3-6環烷基;
L2為-O-,-NR9-,-(CR10R11)g-,-NR9-(CR10R11)g-或鍵,g為1-3的整數;
R9為H或C1-4烷基;
每個R10和R11獨立地為H、鹵素、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R10和R11與其連接的碳原子形成3-6員碳環;
Z2、Z3為CRM或N,Z4為O、S或NRM1;
每個RM獨立地為H、C1-4烷基、氰基、C3-6環烷基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6炔基、或含有1-3個選自N、O或S雜原子的3-6員雜環基、或鹵素;所述烷基、炔基、環烷基視情況被1-3個選自鹵素、氰基、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-4烷基的基團取代;
Rm為H、C1-4烷基、鹵代C1-4烷基,Rm'為C1-4烷基、鹵代C1-4烷基;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-2選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
RM1為H、C1-4烷基或C3-6環烷基;
RM2為鹵代C1-4烷氧基;
每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;
h為0-3的整數;
i為0、1或2;
作為本發明的第二十技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
其中,L1為鍵或-W-(CR3R4)c-;
W為-C(=X)-;
X為O或S;
每個R3和R4獨立地選自H、鹵素或C1-4烷基;
作為選擇,同碳原子上的R3和R4與其連接的碳原子一起形成3-6員碳環;
c選自0、1和2;
Ra'和Ra"為H或C1-4烷基;
n為1或2;
X1和X2獨立地為N、NRA1或CRA1,且不同時為CRA1;
X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;
每個RA1獨立地為H;
RB1和RB2均為H;
L2為-NR9-或-NR9-(CR10R11)g-,g為1-3的整數;
R9為H;
每個R10和R11獨立地為H;
Z2、Z3為CRM,Z4為O或S;
每個RM獨立地為H、C1-4烷基、C3-6環烷基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6炔基、含有1-3個選自N、O或S雜原子的3-6員雜環基或鹵素;所述烷基、炔基、環烷基視情況被1-3個選自鹵素、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-4烷基的基團取代;
Rm為H或C1-4烷基,Rm'為C1-4烷基;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-2選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
RM2為鹵代C1-4烷氧基;
h為0、1或2;
i為0、1或2;
其餘基團如前述第十九技術方案之定義。
作為本發明的第二十技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
h為1或2,
RM為C1-4烷基、C3-6環烷基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6炔基、或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基視情況被1-3個選自鹵素、C1-4烷氧基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-2烷基的基團取代;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-2選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
其餘基團如前述第二十技術方案之定義。
作為本發明的第二十二技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
作為本發明的第二十三技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,c為1或2,同碳原子上的R3和R4與其連接的碳原子一起形成3-6員碳環,其餘基團如前述第二十技術方案之定義。
作為本發明的第二十四技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,
L1為-W-(CR3R4)c-或-W-(NR8)d-(CR5R6)e-;
W為-C(=X)-;
X為O或S;
每個R3、R4、R5和R6獨立地選自H、鹵素或C1-4烷基;
每個R8獨立地選自H、C1-4烷基或C3-6環烷基;
作為選擇,同碳原子上的R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環;
c和e獨立選自0或1,d為1;
X1和X2獨立地為N或CRA1,且不同時為CRA1;
RA1為氰基、C1-4烷基、-RA或鹵素;
RA為C3-6環烷基、C3-6環烷基氧基、C1-4烷氧基、C1-4鹵代烷基、C1-4鹵代烷氧基,所述環烷基、環烷基氧基、烷氧基、鹵代烷基、鹵代烷氧基視情況進一步地被1-3個選自C1-4烷基、鹵素、氰基的基團取代;
RB1和RB2均為H;
L2為-NR9-;
R9為H或C1-4烷基;
Z2、Z3為CRM或N,Z4為O或S;
每個RM獨立地為H、C1-4烷基、C1-4烷氧基烷基、氰基、C3-6環烷基、C3-6環烷基氧基、C2-6烯基、C2-6炔基、-NRM1、或含有1-3個選自N、O或S雜原子的3-6員雜環基;所述烷基、烯基、炔基、環烷基視情況被1-3個選自鹵素、氰基的基團取代,所述雜環基視情況被1-3個選自鹵素或C1-4烷基的基團取代;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3個選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
RM1為H、C1-4烷基、C3-6環烷基、C1-4鹵代烷基或C1-4烷氧基烷基;
每個R12獨立地為H、鹵素或C1-4烷基;
h為0-3的整數;
i為0、1或2。
作為本發明的第二十五技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,
Z2為CRM;
每個RM獨立地為H、C1-4烷基、C1-4烷氧基烷基、C3-6環烷基氧基、C2-6烯基、C2-4的炔基、-NRM1、或含有1-3個選自N、O或S雜原子的3-6員雜環基;所述烷基、烯基、炔基視情況被1-3個鹵素、氰基取代;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3個選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
RM1為H、C1-4烷基或C3-6環烷基;
h為1或2;
其餘基團如前述第十七或二十四技術方案之定義。
作為本發明的第二十六技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,L1為-C(O)CR3R4-;
R3、R4獨立地選自H、鹵素和C1-4烷基;
L2為NH;
h為1或2;
每個RM獨立地為H、C1-4烷基或C2-4的炔基;所述烷基或炔基視情況被1-3個選自鹵素和氰基的基團取代;
且R3、R4和RM不同時為H。
作為本發明的第二十七技術方案,式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,所述化合物選自以下結構之一:
其次,本發明還提供了一種醫藥組合物,其含有醫藥有效量的前述任一實施例所述的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,以及醫藥上可接受的輔料和/或載劑。
進一步地,本發明還提供了前述任一實施例所述的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,或者它們的組合物在製備治療/預防自分泌運動因子介導的疾病的藥物中的用途;以及
前述任一實施例所述的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,或者它們的組合物在治療或預防自分泌運動因子介導的疾病中的用途。
上述兩項所述的用途,其中,自分泌運動因子介導的疾病選自心血管病症、癌症、代謝紊亂、腎臟病症、肝臟病症、炎症性病症、神經系統病症、呼吸系統病症、纖維化疾病、眼部病症、膽汁淤積和其他形式的慢性瘙癢症以及急性或慢性器官移植排斥。
較佳地,所述炎症性病症包括但不限於關節炎、特應性皮炎、關節炎和哮喘。
具有ATX抑制劑活性的式(I)所示的含氮雜環化合物,其立體異
構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,
在一些實施例中,L1為鍵、-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-、或-C(O)-(CR3R4)c-C=CR7-;在一些實施例中,L1為-C(=O)-(NH)d-CR3R4-;在一些實施例中,L1為-C(=S)-CR3R4-,在一些實施例中,L1為C(=N-CN)-CR3R4-,在一些實施例中,L1為-C(O)-CR3R4-C=CR7-,在一些實施例中,L1為-W-(CR3R4)c-;在一些實施例中,L1為-W-(CR3R4)c-或-W-(NR8)d-(CR5R6)e-;在一些實施例中,L1為-C(O)-CF2-;在一些實施例中,L1為-C(O)-CHF-;在一些實施例中,L1為-C(O)-C(CH3)(F)-;在一些實施例中,L1為-C(O)-(CR3R4)-,其中R3和R4一起形成3-4員碳環,例如環丙基;在一些實施例中,L1為-C(O)-NH-(CR5R6)-,R5和R6一起形成3-4員碳環;
在一些實施例中,W為-C(=X)-、或含有1-3個選自N、O或S雜原子的3-6員伸雜環基,在一些實施例中,W為-C(=X)-、或含有1-2個選自N、O雜原子的5員伸雜環基,在一些實施例中,5員伸雜環基為;
在一些實施例中,X為O、S或NRx,Rx為H或氰基;在一些實施例中,X為O、S或NRx,Rx為氰基;在一些實施例中,X為O或S;
在一些實施例中,每個R1至R6獨立地選自H、鹵素、C1-4烷基或C3-6環烷基;在一些實施例中,每個R1至R6獨立地選自H、鹵素或C1-4烷基;
在一些實施例中,同碳原子上的R1和R2、R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;在一些實施例中,同碳原子上的R3和R4、或R5和R6與其連接的碳原子一起形成3-4員碳環,所述碳環視情況被1-2個選自鹵素或C1-2烷基的取代基取代;
在一些實施例中,每個R7和R8獨立地選自H、C1-4烷基或C3-6環烷基;
在一些實施例中,a、c和e獨立地選自0-5的整數,在一些實施例中,a、c和e獨立地選自0-3的整數,在一些實施例中,a、c和e獨立地為0或1;
在一些實施例中,b和d獨立地為0或1;
在一些實施例中,A為C3-6伸環烷基、、、、、C2-4伸炔基、-RaC(O)NRa'-、-RaNRa'C(O)-、-RaNRa'-、
-RaC(O)-、-Ra(CRa' Ra")n-或鍵;在一些實施例中,A為C3-6伸環烷基、C2-4伸炔基、、、或;在一些實施例中,A為;Ra為;在一些實施例中,Ra為、、或;在一些實施例中,A為;在一些實施例中,A為;
Ra'和Ra"獨立地為H或C1-4烷基;
在一些實施例中,n為1-2的整數;
在一些實施例中,X1和X2獨立地為N或CRA1,在一些實施例中,X1和X2不同時為CRA1,在一些實施例中,X3為S、O或NRA1;
在一些實施例中,X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;
在一些實施例中,每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA、或-ORA;
在一些實施例中,RA為C1-4烷基、C3-6環烷基、C3-6環烷基氧基、C1-4烷氧基、C1-4鹵代烷基、C1-4鹵代烷氧基或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、環烷基氧基、烷氧基、鹵代烷基、鹵代烷氧基、雜環基視情況進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;在一些實施例中,RA為C1-4烷基、C3-6環烷基或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、雜環基視情況
進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;在一些實施例中,RA為C1-4烷基、C3-4環烷基、含有1-2個選自N、O雜原子的4-6員雜環基,所述烷基、雜環基視情況進一步地被1-5個選自C3-4環烷基、C1-4烷基、鹵素、-S(O)2C1-2烷基、-OC1-2烷基或氰基的基團取代;在一些實施例中,RA為C3-6環烷基、C3-6環烷基氧基、C1-4烷氧基、C1-4鹵代烷基、C1-4鹵代烷氧基,所述環烷基、環烷基氧基、烷氧基、鹵代烷基、鹵代烷氧基視情況進一步地被1-3個選自C1-4烷基、鹵素、氰基的基團取代;
在一些實施例中,B為、、、
、、、、、或;
在一些實施例中,B為,RB1和RB2至少有一個選自OH、鹵素、氰基、鹵代C1-4烷基、C1-4烷基氧基、C3-6環烷基,或者A上的基團RA1和B上的基團RB1與其連接的原子一起形成含有1個O原子的6-8員雜環;在一些實施例中,B為,RB2為鹵素或氰基,f不為0;在一些實施例中,B為、、、、、、或;在一些實施例中,B為,其中RB1和RB2均為H;
在一些實施例中,Y1為O、S或NRB3;
在一些實施例中,Cy具有結構:,其中,表示單鍵或雙鍵,Z1為C或N,環E為含有1-3個選自N、O或S雜原子的5員雜環,環D為含有0-3個選自N、O或S雜原子的6員環;所述5員雜環和6員環獨立視情況被1-3個RB2取代;在一些實施例中,Cy選自以下結構之一:
在一些實施例中,每個RB1和RB2獨立地選自H、側氧基、OH、鹵素、氰基、C1-4烷基、鹵代C1-4烷基、C1-4烷基氧基、C3-6環烷基,RB3選自H、C1-4烷基、C3-6環烷基,在一些實施例中,A上的基團RA1和B上的基團RB1與其連接的原子一起形成含有1-3個選自N、S、O雜原子的6-10員雜環;
在一些實施例中,f為0-3的整數;
在一些實施例中,L2為-O-、-C(O)NR9-、-NR9C(O)NR9-、-NR9-、-(CR10R11)g-、-NR9-(CR10R11)g-或鍵,g為1-3的整數;
在一些實施例中,L2為-O-、或-CR10R11-,其中R10和R11中至少一個為鹵素或C1-4烷基,或R10和R11與其連接的碳原子形成3-4員碳環,例如環丙基;
在一些實施例中,L2為-NR9-,R9為H或C1-4烷基;
在一些實施例中,每個R10和R11獨立地為H、鹵素、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R10和R11與其連接的碳原子形成3-6員碳環;
在一些實施例中,M2為、、
、、、或
;在一些實施例中,M2為、或;在一些實施例中,M2為;在一些實施例中,
、、或。在一些實施例中,Z2、Z3為CRM或N,Z4為O、S或NRM1;在一些實施例中,Z2為CRM;
在一些實施例中,每個RM獨立地為H、C1-4烷基、C1-4烷氧基烷基、氰基、C3-6環烷基、C3-6環烷基氧基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6烯基、C2-6炔基、-NRM1,含有1-3個選自N、O或S雜原子的3-6員雜環基、或鹵素;所述烷基、烯基、炔基、環烷基視情況被1-3個選自鹵素、氰基、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-4烷基的基團取代;在一些實施例中,每個RM獨立地為H、C1-4烷基、C2-6炔基或含有1-3個選自N、O或S雜原子的3-6員雜環基;所述烷基視情況被1-3個選自鹵素的基團取代;在一些實施例中,每個RM獨立地為氰基、二氟代烷基、三氟代烷基、C2-4的炔基、C3-4環烷基、含有1-3個選自N、O或S雜原子的5-6員雜環基,所述雜環基視情況被1-3個選自C1-4烷基的基團取代;
作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的3-6員碳環或3-6員雜環基;進一步的,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的3-5員碳環或3-5員雜環基;更進一步的,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的4-5員碳環或4-5員雜環基;更進一步的,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成環丁烷或含有1-2選自N、O或S雜原子的5員雜環基;
Rm為H、C1-4烷基或鹵代C1-4烷基;
Rm'為C1-4烷基或鹵代C1-4烷基;在一些實施例中,M2為,其中RM為三氟甲基、二氟甲基、環丙基、乙炔基、呋喃-3-基、甲基胺基羰基、氮雜環丁-1-基、氧雜環丁-3-基、3,3-二氟-氮雜環丁-1-基、乙醯胺基、1-甲基-1H-吡唑-4-基、四氫呋喃-3-基、甲硫基、4-甲基-5-側氧基-1,2,4-三唑-1-基、2-側氧基-吡咯啶-1-基、甲磺醯基、甲氧基甲基、二氟甲氧基甲基或三氟甲基乙炔基;
在一些實施例中,H、C1-4烷基、C3-6環烷基、C1-4鹵代烷基或C1-4
烷氧基烷基;在一些實施例中,RM1為H、C1-4烷基或C3-6環烷基;
在一些實施例中,每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;在一些實施例中,每個R12獨立地為H;
在一些實施例中,h為0-3的整數;在一些實施例中,h為1或2;
i為0、1或2;
當M1為,L1為-C(O)-CH2-,A為,B為或,L2為-NH-,M2為時,A至少有一個取代基RA1選自氰基、鹵素、C3-4環烷基氧基、環丙基甲氧基、C1-4鹵代烷氧基、環丙基甲基、-C1-4烷基-O-C1-4烷基、-NHC(O)RA、-C(O)NHRA、-C(O)-C3-6環烷基、、
、、、、或;
合成路線
專利文獻CN109476664A中介紹了一類ATX抑制劑的製備方法,熟習此項技術者可以結合該文獻以及已知的有機合成技術製備本發明的化合物,其起始物質為市售化學品和(或)化學文獻中所述的化合物。「市售化學品」是從正規商業來源獲得的,供應商包括:泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、南京藥石、藥明康德和百靈威科技等公司。
本領域的參考書和專著,詳細介紹了可用于製備本文所述化合物的反應物的合成,或提供了描述該製備方法的文章以供參考。這些參考書和專著包括:「Synthetic Organic Chemistry」,John Wiley & Sons,Inc.,New York;S.R.Sandler et al.,「Organic Functional Group Preparations,」2nd Ed.,Academic Press,New York,1983;H.O.House,「Modern Synthetic Reactions」,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,「Heterocyclic Chemistry」,2nd Ed.,John Wiley & Sons,New York,1992;J.March,「Advanced Organic Chemistry:Reactions,Mechanisms and Structure」,4th Ed.,Wiley-Interscience,New York,1992;Fuhrhop,J.and Penzlin G.「Organic Synthesis:Concepts,Methods,
Starting Materials」,Second,Revised and Enlarged Edition(1994)John Wiley & Sons ISBN:3-527-29074-5;Hoffman,R.V.「Organic Chemistry,An Intermediate Text」(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C.「Comprehensive Organic Transformations:A Guide to Functional Group Preparations」2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J.「Advanced Organic Chemistry:Reactions,Mechanisms,and Structure」4th Edition(1992)John Wiley & Sons,ISBN:0-471-60180-2;Otera,J.(editor)「Modern Carbonyl Chemistry」(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.「Patai’s 1992 Guide to the Chemistry of Functional Groups」(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.「Organic Chemistry」7th Edition(2000)John Wiley & Sons,ISBN:0-471-19095-0;Stowell,J.C.,「Intermediate Organic Chemistry」2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;「Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia」(1999)John Wiley & Sons,ISBN:3-527-29645-X,in 8 volumes;「Organic Reactions」(1942-2000)John Wiley & Sons,in over 55 volumes;and「Chemistry of Functional Groups」John Wiley & Sons,in 73 volumes.
通過美國化學會化學文摘社製備的已知化學物質的索引,可以選擇性地識別特定和類似的反應物,這些索引可在大多數公共圖書館和大學圖書館以及線上獲得。已知但在目錄中不可商購的化學品可選地由定制化學合成工廠製備,其中許多標準化學供應工廠(例如,上面列出的那些)提供定制合成服務。製備和選擇本文所述化合物的藥用鹽的參考文獻是P.H.Stahl & C.G.Wermuth「Handbook of Pharmaceutical Salts」,Verlag Helvetica Chimica Acta,Zurich,2002.
術語
「鹵素」在本文中是指F、Cl、Br、I、或者它們的同位素。
「鹵代」或「鹵素取代」是指被一個以上選自F、Cl、Br、I、或者它們的同位素取代,鹵素取代基數量的上限等於被取代基團可被取代的氫數之和,在未作特殊限定下,鹵素取代基數量為1至該上限之間的任意整數,當鹵素取代基數量大於1時,可以是相同或不同的鹵素進行取代。
「烷基」是指一價的直鏈或支鏈飽和脂肪族烴基,無特殊說明時,為1至20個碳原子的烷基,較佳為1至8個碳原子的烷基,更佳為1至6個碳原子的烷基,進一步較佳為1至4個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構物。
「伸烷基」是指二價的直鏈和支鏈飽和烷基。伸烷基實例包括但不限於伸甲基、伸乙基等。
「環」的定義包括碳環和雜環。無特殊說明時,通常為含有0至3個選自N、O或S的雜原子的3-12員單環,較佳為4-7員環,更佳為五員環或六員環。
「環烷基」是指一價飽和的、取代或未取代的碳環烴基,無特殊說明時,通常有3至10個碳原子,較佳有3-6個碳原子,進一步較佳有3-4個碳原子,非限制性實例包括環丙基、環丁基、環戊基、環己基或環庚基等。
「碳環」或「碳環基」是指取代或未取代、飽和或不飽和的碳環基團,包括單環碳環、雙環橋環、雙環並環和雙環螺環等,通常有3至12個碳原子,較佳有3-10個碳原子,進一步較佳有3-6個碳原子。非限制性實例中,單環碳環包括環丙基、環丁基、環戊基、環己基、環庚基或苯基等,雙環橋環包括、、等,雙環並環包括、、、和等,雙環螺環包括、、、、和等。
「雜環」或「雜環基」是指取代或未取代、飽和或不飽和的芳香環或者非芳香環,未特殊限定時,包含1至3個選自N、O或S的雜原子,包括單環雜環、雙環橋雜環、雙環並雜環和雙環螺雜環等,較佳3至12員雜環,更佳為4-12員雜環,更佳為4-10員雜環。雜環基的環中選擇性取代的N、S可被氧化成各種氧化態。雜環基可以連接在雜原子或者碳原子上,非限制性實例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、哌嗪基、氮雜環庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑基、嗒嗪基、咪唑基、哌啶基、哌叮基、嗎啉基、硫代嗎啉基、1,3-二噻基、二氫呋喃基、二氫吡喃基、二噻戊環基、四氫呋喃基、四氫吡咯基、四氫咪唑基、噁唑基、二氫噁唑基、四氫噁唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.31庚烷基、、、、、
、、、、等。
「炔基」是指直鏈或支鏈的、含有碳碳三鍵的一價不飽和烴基,除非特殊說明,炔基含有2-6個碳原子,較佳含有2-4個碳原子,非限制性實例包括乙炔基。「伸炔基」是指直鏈或支鏈的、含有碳碳三鍵的二價不飽和烴基。
「烷氧基」或「烷基氧基」是指-O-烷基。非限制性實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基等。
「視情況」或「視情況地」是指隨後所描述的事件或環境可以但不必須發生,該說明包括該事件或環境發生或不發生的場合。如:「視情況被F取代的烷基」指烷基可以但不必須被F取代,說明包括烷基被F取代的情形和烷基不被F取代的情形。
「醫藥上可接受的鹽」是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性,且所述的游離酸通過與無毒的無機鹼或者有機鹼,所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。
「氘代物」是指化合物中一個或多個氫原子被相應數目的氘原子取代。
「醫藥組合物」表示一種或多種本文所述化合物或其立體異構
物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,與其他組成成分的混合物,其中其他組分包含生理學/醫藥上可接受的載劑和/賦形劑。
「載劑」指的是:不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性,並能改變藥物進入人體的方式和在體內的分佈、控制藥物的釋放速度並將藥物輸送到靶向器官的體系,非限制性的實例包括微囊與微球、奈米粒、脂質體等。
「賦形劑」指的是:其本身並非治療劑,用作稀釋劑、輔料、粘合劑和/或媒介物,用於添加至醫藥組合物中以改善其處置或儲存性質或允許或促進化合物或醫藥組合物形成用於給藥的單位劑型。如熟習此項技術者所已知的,藥用賦形劑可提供各種功能且可描述為潤濕劑、緩衝劑、助懸劑、潤滑劑、乳化劑、崩解劑、吸收劑、防腐劑、表面活性劑、著色劑、矯味劑及甜味劑。藥用賦形劑的實例包括但不限於:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)澱粉,例如玉米澱粉及馬鈴薯澱粉;(3)纖維素及其衍生物,例如羧甲基纖維素鈉、乙基纖維素、乙酸纖維素、羥丙基甲基纖維素、羥丙基纖維素、微晶纖維素及交聯羧甲基纖維素(例如交聯羧甲基纖維素鈉);(4)黃蓍膠粉;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,例如可哥脂及栓劑蠟;(9)油,例如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,例如氫氧化鎂及氫氧化鋁;(15)海藻酸;(16)無熱原水;(17)等滲鹽水;(18)林格溶液(Ringer’s solution);(19)乙醇;(20)pH緩衝溶液;(21)聚酯、聚碳酸酯和/或聚酐;及(22)其他用於藥物製劑中的無毒相容物質。
「立體異構物」是指由分子中原子在空間上排列方式不同所產生
的異構物,包括順反異構物、對映異構物和構形異構物。
本發明的化合物還包括其互變異構物,例如當本發明闡述嘧啶環被OH取代的左側化合物時,也同時包括右側的互變異構物化合物。
「溶劑合物」指本發明化合物或其鹽與分子間非共價力結合的化學計量或非化學計量的溶劑形成的物質。當溶劑為水時,則為水合物。
「共晶」是指活性藥物成分(API)和共晶形成物(CCF)在氫鍵或其他非共價鍵的作用下結合而成的晶體,其中API和CCF的純態在室溫下均為固體,並且各組分間存在固定的化學計量比。共晶是一種多組分晶體,既包含兩種中性固體之間形成的二元共晶,也包含中性固體與鹽或溶劑合物形成的多元共晶。
以下將通過實例對本發明的內容進行詳細描述。實例中未注明具體條件的,按照常規條件的實驗方法進行。所舉實例是為了更好地對本發明的內容進行說明,但並不能理解為本發明的內容僅限於所舉實例。一般熟習此項技術者根據上述發明內容對實施例進行非本質的改進和調整,仍屬於本發明的保護範圍。
在本發明中使用以下縮寫:
檢測方法
化合物結構通過核磁共振(NMR)和/或質譜(MS)確定。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定用(Bruker Avance III 400和Bruker Avance 300)核磁儀進行,其中測定溶劑為氘代二甲基亞碸(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),內標為四甲基矽烷(TMS);MS的測定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));HPLC的測定使用Agilent 1260DAD高壓液相層析儀(Zorbax SB-C18 100×4.6mm,3.5μM);薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板,薄層層析法(TLC)使用的矽膠板採用0.15mm-0.20mm規格,薄層層析分離純化產品採用0.4mm-0.5mm規格;柱層析一般使
用煙臺黃海矽膠200-300目矽膠為載體。
化合物的製備
中間物1:N-(2,3-二氫-1H-茚-2-基)嘧啶-2,5-二胺(中間物1)
N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2,5-diamine(intermediate 1)
第一步:N-(2,3-二氫-1H-茚2-基)-5-硝基嘧啶-2-胺(1C)
N-(2,3-dihydro-1H-inden-2-yl)-5-nitropyrimidin-2-amine(1C)
將2-氯-5-硝基嘧啶(1A)(4.8g,30mmol)、2-胺基茚滿(1B)(4.01g,30mmol)和N,N-二異丙基乙胺(5.2g,40mmol)溶解在乙醇(50mL)中並在90℃下攪拌2小時。反應完成後,將混合物冷卻至室溫,過濾所得固體,用乙醇(20mL)洗滌,乾燥,得到標題化合物1C,呈米色固體(5.6g,73%)。LC-MS(ESI):m/z=257.1[M+H]+
第二步:N-(2,3-二氫-1H-茚-2-基)嘧啶-2,5-二胺(中間物1)
N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2,5-diamine(intermediate 1)
將1C(5.6g,22mmol)、鐵粉(5.6g,100mmol)和氯化銨(0.54g,10mmol)溶解在乙醇(50mL)和水(15mL)中並在80℃下攪拌2小時。反應完成後,將混合物冷卻至室溫,過濾,濾液減壓濃縮後矽膠柱層析分離,得到標題化合物中間物1,呈黃色固體(3.6g,72%)。LC-MS(ESI):m/z=227.2[M+H]+。
中間物2:2-(5-(2-氯嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(中間 物2)
ethyl 2-(5-(2-chloropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(intermediate 2)
第一步:2-氯嘧啶-5-碳醯氯(2B)
2-chloropyrimidine-5-carbonyl chloride(2B)
將化合物2A(2.5g,15.8mmol)溶於DCM(40ml),加入DMF(0.1ml),冰浴冷卻至0℃,滴加草醯氯(3.0g,23.7mmol),加畢,緩慢恢復至室溫攪拌隔夜;將反應混合物減壓蒸幹,得到化合物2B(2.8g,99%)。
第二步:3-(2-氯嘧啶-5-羰基)肼基)-3-側氧基丙酸乙酯(2C)
ethyl 3-(2-(2-chloropyrimidine-5-carbonyl)hydrazinyl)-3-oxopropanoate(2C)
將3-側氧基-3-肼基丙酸乙酯(3.5g,23.7mmol)和三乙胺(4.8g,47.4mmol)溶於DCM(60ml)中,冰浴冷卻至0℃,緩慢滴加化合物2B(2.8g,15.8mmol)的DCM溶液15ml,加畢,緩慢恢復至室溫,攪拌隔夜,將反應混合物減壓蒸幹,剩餘物直接經矽膠柱層析(PE/EA=2/1)純化,得到2C(2.7g,60.0%)。
第三步:2-(5-(2-氯嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(中間物2)
ethyl 2-(5-(2-chloropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate
(intermediate 2)
將2C(2.7g,9.4mmol)置於100ml單口瓶中,加入無水THF(50ml),室溫加入伯吉斯試劑(3.4g,14.1mmol),加畢,升溫至70℃,攪拌2小時,反應混合物直接經矽膠柱層(PE/EA=2/1)析純化,得到中間物2(1.6g,59.3%)。
實例1:2-(3-環丙氧基-4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1H-吡唑-1-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物1)
2-(3-cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 1)
第一步:1-(3-環丙氧基-1H-吡唑-1-基)乙酮(1b)
1-(3-cyclopropoxy-1H-pyrazol-1-yl)ethenone(1b)
將化合物1a(5.04g,40mmol)溶於甲苯(50mL)中,在0℃下依次添加環丙醇(2.9g,50mmol)、三苯基膦(15.8g,60mmol),攪拌均勻後向體系分批加入DBAD(13.8g,60mmol),氮氣保護下110℃反應5小時。反應完成後,
體系減壓濃縮後,直接矽膠柱層析分離,得到目標化合物(1b)(1.2g,18%)。LC-MS(ESI):m/z=167.2[M+H]+。1H NMR(400MHz,CDCl3)δ 8.08(d,1H),6.04(d,1H),4.12-4.05(m,1H),2.61(s,3H),0.87-0.68(m,4H).
第二步:3-環丙氧基-4-碘-1H-吡唑(1c)
3-cyclopropoxy-4-iodo-1H-pyrazole(1c)
向化合物1b(1.2g,7.2mmol)在水(10mL)和乙醇(6mL)的混合溶劑中的溶液中依次添加碘化鈉(1.08g,7.2mmol)、碘(2.79g,11mmol)和碳酸鉀(3.86g,28mmol),將混合物在室溫下攪拌1.5小時。反應完成後,混合物用飽和碳酸氫鈉(30mL)溶液稀釋,乙酸乙酯(50mL)萃取,有機相用無水硫酸鈉乾燥,過濾,濾液減壓濃縮後直接進行下一步反應。LC-MS(ESI):m/z=251.1[M+H]+
第三步:2-(3-環丙氧基-4-碘-1H-吡唑-1-基)乙酸第三丁酯(1e)
tert-butyl 2-(3-cyclopropoxy-4-iodo-1H-pyrazol-1-yl)acetate(1e)
向化合物1c(0.85g,3.4mmol)的N,N-二甲基甲醯胺(10mL)溶液中依次添加碳酸銫(2.28g,7mmol)和溴乙酸第三丁酯(0.99g,5.1mmol),將混合物在室溫下攪拌1小時。反應完成後,將混合物用飽和鹽水(30mL)稀釋,並用乙酸乙酯(30mLx2)萃取。有機相用無水硫酸鈉乾燥,過濾,濃縮。殘餘物通過矽膠柱層析純化,得到白色固體1e(1.1g,89%)。LC-MS(ESI):m/z=365.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 7.69(s,1H),4.77(s,2H),4.06-4.00(m,1H),1.42(s,9H),0.68-0.64(m,4H).
第四步:2-(3-環丙氧基-4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1H-吡唑-1-基)乙酸第三丁酯(1g)
tert-butyl 2-(3-cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)acetate(1g)
向化合物1e(1.1g,3mmol)和化合物1f(1.0g,3mmol)在1,4-二噁烷(9mL)和蒸餾水(3mL)的混合溶劑中的混合物中,加入四(三苯基膦)鈀(0)(0.35g,0.6mmol)和碳酸鈉(0.64g,6mmol),並將混合物在80℃和氮氣保護下攪拌90分鐘。反應完成後,將混合物冷卻至室溫,用飽和鹽水(50mL)稀釋,並用乙酸乙酯(80mL)萃取。有機層用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析分離純化殘餘物,得到標題化合物1g,呈黃色固體(0.84g,63%)。LC-MS(ESI):m/z=448.3[M+H]+
第五步:2-(3-環丙氧基-4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1H-吡唑-1-基)乙酸(1h)
2-(3-cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)acetic acid(1h)
向化合物1g(0.45g,1mmol)的二氯甲烷(3mL)溶液中添加4N氯化氫的二噁烷溶液(3mL),將混合物在室溫下攪拌隔夜。反應完成後,去除溶劑,過濾得到固體,用乙醚打漿,過濾,乾燥,得到標題化合物1h,呈淺棕色固體(0.22g,56%)。LC-MS(ESI):m/z=392.3[M+H]+
第六步:2-(3-環丙氧基-4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1H-吡唑-1-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物1)
2-(3-cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 1)
在0℃下,向化合物1i(0.11g,0.68mmol)的N,N-二甲基甲醯胺(10mL)溶液中依次地緩慢添加化合物1h(0.22g,0.58mmol)、N,N-二異丙基乙胺(1mL)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(0.45g,0.87mmol),並
將混合物在室溫下在氮氣保護下攪拌隔夜。反應完成後,將反應混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取(50mLx2)。用蒸餾水和飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。矽膠柱層析分離純化,得到標題化合物1(12mg)。LC-MS(ESI):m/z=498.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.45(s,2H),7.87(d,1H),7.37(d,1H),7.24-7.19(m,2H),7.16-7.11(m,2H),5.18-5.09(m,2H),4.82-4.54(m,4H),4.12-4.06(m,2H),3.86-3.78(m,3H),2.93-2.85(m,4H),0.73-0.65(m,4H).
實例2:4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)-1H-吡唑-3-甲腈(化合物2)
4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carbonitrile(compound 2)
第一步:2-(4-溴-3-氰基-1H-吡唑-1-基)乙酸第三丁酯(2b)
tert-butyl 2-(4-bromo-3-cyano-1H-pyrazol-1-yl)acetate(2b)
將化合物2a(3.3g,19mmol)溶於乙腈(30mL)中,添加1d(4.1g,21mmol)、碳酸鉀(8.1g,58mmol),室溫反應5小時。反應完成後,加水,用乙
酸乙酯萃取,用飽和鹽水洗,用無水硫酸鈉乾燥,濃縮物經矽膠柱層析分離純化,得到目標化合物(2b)(4.3g,78%)。1H NMR(400MHz,CDCl3)δ 7.61(s,1H),4.83(s,2H),1.49(s,9H)。
第二步:2-(3-氰基-4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1H-吡唑-1-基)乙酸第三丁酯(2c)
tert-butyl-2-(3-cyano-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)acetate(2c)
將化合物2b(0.31g,1.08mmol)溶於1,4-二氧六環/水(4:1)混合溶劑中,依次添加1f(0.4g,1.18mmol)、四三苯基磷鈀(0.12g,1.08mmol)和碳酸鉀(0.35g,3.23mmol),在氮氣保護下於80℃反應5h。反應完成後,濃縮物經矽膠柱層析分離純化,得目標化合物(2c)(0.15g,33%)。LC-MS(ESI):m/z=417.3[M+H]+
第三步:2-(3-氰基-4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1H-吡唑-1-基)乙酸(2d)
2-(3-cyano-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)acetic acid(2d)
將化合物2c(0.13g,0.31mmol)溶於THF/H2O=4:1混合溶劑溶解後加入LiOH(0.02g,0.62mmol),室溫反應2h。加水,DCM萃取,收集水相,稀酸至pH=4,用DCM萃取,用飽和鹽水洗,用無水硫酸鈉乾燥,濃縮。得到白色固體2d(0.12g,90%)。LC-MS(ESI):m/z=361.2[M+H]+
第四步:4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)-1H-吡唑-3-甲腈(化合物2)
4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carbonitrile(compound 2)
將化合物2d(67mg,0.19mmol)、化合物1i(46mg,0.37mmol),DPEA(72mg,0.56mmol)和HATU(106mg,0.28mmol)溶於DMF中,室溫反應隔夜。反應完成後加水,用乙酸乙酯萃取,用飽和鹽水洗,用無水硫酸鈉乾燥,濃縮,矽膠柱層析分離純化,得到化合物27mg,8%)。LC-MS(ESI):m/z=467.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.57(s,2H),8.26(d,1H),7.80(d,1H),7.23-7.13(m,4H),5.52-5.48(m,2H),4.77-4.63(m,3H),3.84-3.82(m,2H),3.26-3.24(m,2H),2.95-2.89(m,4H),2.77-2.74(m,1H).
實例3:4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-N-甲基-1-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)-1H-吡唑-3-羧醯胺(化合物3)
4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-N-methyl-1-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carboxamide(compound 3)
第一步:4-碘-1H-吡唑-3-羧酸(3b)
4-iodo-1H-pyrazole-3-carboxylic acid(3b)
將化合物3a(0.5g,1.88mmol)溶於2-甲基四氫呋喃(10mL)和蒸餾水(2ml)中,再加入KOH(0.2g,3.76mmol);然後,在60℃反應2小時。反應完成後,冷卻,加水20mL,用乙酸乙酯20mLx3萃取。水相加酸調pH=3,再加乙酸乙酯50mLx3萃取,有機相用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到目標化合物(3b)(0.43g,95%)。LC-MS(ESI):m/z=239.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ 13.66(s,2H),7.88(s,1H).
第二步:4-碘-N-甲基-1H-吡唑-3-羧醯胺(3c)
4-iodo-N-methyl-1H-pyrazole-3-carboxamide(3c)
向化合物3b(0.3g,1.26mmol)在N,N-二甲基甲醯胺(10mL)的溶液中依次添加N,N-二異丙基乙胺(0.65g,5.04mmol)、甲胺鹽酸鹽(0.08g,2.52mmol)和2-(7-氮雜苯並三唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.528g,1.39
mmol),將混合物在室溫下攪拌隔夜。反應完成後加水淬滅,乙酸乙酯(50mLx3)萃取,有機相用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到類白色固體3c(0.150g,47%)。LC-MS(ESI):m/z=252.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 13.60(s,1H),8.07(s,1H),7.97(s,1H),2.71(s,3H)。
第三步:2-(4-碘-3-(甲基胺基甲醯基)-1H-吡唑-1-基)乙酸第三丁酯(3e)
tert-butyl 2-(4-iodo-3-(methylcarbamoyl)-1H-pyrazol-1-yl)acetate(3e)
向化合物3c(0.15g,0.60mmol)的乙腈(10mL)溶液中依次添加碳酸銫(0.25g,1.79mmol)和溴乙酸第三丁酯(0.13g,0.66mmol),將混合物在室溫下攪拌2小時。反應完成後,將混合物用飽和鹽水(30mL)稀釋,並用乙酸乙酯(30mLx2)萃取。有機相用無水硫酸鈉乾燥,過濾,濃縮。殘餘物用矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到白色固體3e(0.170g,78%)。LC-MS(ESI):m/z=366.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.04(s,1H),7.98(s,1H),4.99(s,2H),2.70(s,3H),1.43(s,9H).
第四步:2-(4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-3-(甲基胺基甲醯基)-1H-吡唑-1-基)乙酸第三丁酯(3g)
tert-butyl2-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-3-(methylcarbamoyl)-1H-pyrazol-1-yl)acetate(3g)
向化合物3e(0.18g,0.49mmol)和化合物1f(0.2g,0.59mmol)在1,4-二氧六烷(18mL)和蒸餾水(4mL)的混合溶劑中的混合物中加入四(三苯基膦)鈀(0)(0.057g,0.05mmol)和碳酸鈉(0.16g,1.48mmol),並將混合物在80℃和
氮氣保護下攪拌2小時。反應完成後,將混合物冷卻至室溫,用飽和鹽水(50mL)稀釋,並用乙酸乙酯(80mL)萃取。有機相用無水硫酸鈉乾燥,濃縮。矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物3g,呈淡黃色固體(0.115g,52%)。LC-MS(ESI):m/z=449.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.46(s,2H),(d,1H),8.01(s,1H),7.48(d,1H),7.23-7.21(m,2H),7.16-7.13(m,2H),5.01(s,2H),4.67-4.61(m,1H),3.25(t,2H),2.91(q,2H),2.71(d,3H),1.45(s,9H).
第五步:2-(4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-3-(甲基胺基甲醯基)-1H-吡唑-1-基)乙酸(3h)
2-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-3-(methylcarbamoyl)-1H-pyrazol-1-yl)acetic acid(3h)
向化合物3g(0.115g,0.26mmol)的二氯甲烷(4mL)溶液中添加4N氯化氫二氧六烷溶液(6mL),將混合物在室溫下攪拌隔夜。反應完成後,去除溶劑,過濾得到的固體,用乙醚打漿,過濾,乾燥,得到標題化合物3h,呈淺棕色固體(0.08g,80%)。LC-MS(ESI):m/z=393.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.46(s,2H),8.05(d,1H),8.01(s,1H),7.48(d,1H),7.23-7.21(m,2H),7.16-7.13(m,2H),5.01(s,2H),4.67-4.61(m,1H),3.25(t,2H),2.91(q,2H),2.71(d,3H).
第六步:4-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-N-甲基-1-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)-1H-吡唑-3-羧醯胺(化合物3)
4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-N-methyl-1-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carboxamide(compound 3)
在0℃下,向化合物1i(0.05g,0.41mmol)的N,N-二甲基甲醯胺(6mL)溶液中依次地緩慢添加化合物3h(0.080g,0.20mmol)、N,N-二異丙基乙胺(0.09g,0.71mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(0.16g,
0.31mmol),並將混合物在室溫下在氮氣保護下攪拌隔夜。反應完成後,將反應混合物用蒸餾水(20mL)稀釋,並用乙酸乙酯萃取(30mLx3)。用蒸餾水和飽和鹽水(50mL)洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:二氯甲烷:乙酸乙酯:甲醇=1:0:0~:2:10:1)分離純化,得到化合物3(14mg)。LC-MS(ESI):m/z=499.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.47(s,2H),7.94(d,2H),7.46(d,1H),7.23-7.21(m,2H),7.15-7.13(m,2H),5.34(d,2H),4.79(s,1H),4.68-4.62(m,2H),3.83(d,2H),3.25(t,2H),2.91(q,2H),2.71(d,3H).
實例4:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)甲酮(化合物4)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone(compound4)
第一步:2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-碳醯肼(4b)
2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide(4b)
將化合物4a(500mg,1.96mmol)溶於10mL DMF中,加入
HATU(1.11g,2.94mmol),DIPEA(758mg,5.88mmol),室溫攪拌,再加入水合肼(0.25mL),室溫反應隔夜。反應完全後,直接用於下一步。
第二步:1-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼-1-羰基)環丙烷-1-羧酸乙酯(4c)
Ethyl 1-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazine-1-carbonyl)cyclopropane-1-carboxylate(4c)
往第一步的反應液中加入HATU(1.11g,2.94mmol),DIEA(758mg,5.88mmol),再加入1,1-環丙烷二甲酸單乙酯(620mg,3.92mmol),室溫攪拌3小時。反應完全後,加入水、乙酸乙酯萃取,合併乾燥有機相,得到化合物4c(675mg,84%)。
LC-MS(ESI):m/z=410.2[M+H]+.
第三步:1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙烷-1-羧酸乙酯(4d)
Ethyl-1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxylate(4d)
將化合物4c(500mg,1.22mmol)溶于無水四氫呋喃中,加入(甲氧基羰基胺磺醯基)三乙基氫氧化銨(582mg,2.44mmol)加熱至75℃攪拌1小時。反應完全後,加入乙酸乙酯、水萃取2次,乾燥濃縮有機相,矽膠柱層析(DCM:MeOH=40:1)分離純化,得到化合物4d(465mg,97%)。LC-MS(ESI):m/z=392.2[M+H]+。
第四步:1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙烷-1-羧酸(4e)
1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-
oxadiazol-2-yl)cyclopropane-1-carboxylic acid(4e)
將化合物4d(465mg,1.19mmol)溶於10mL無水乙醇中,加入2mL水溶解的氫氧化鋰(143mg,5.95mmol),室溫攪拌,反應2小時。TLC監測反應完全後,濃縮反應液,加水稀釋,再加2N鹽酸水溶液調pH至3,有大量固體析出,抽濾,濾餅烘乾,得到化合物4e(205mg,48%)。LC-MS(ESI):m/z=364.2[M+H]+.
第五步:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)甲酮(化合物4)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone(compound 4)
將化合物4e(205mg,0.56mmol)溶於10mL N,N-二甲基甲醯胺中,加入HATU(322mg,0.85mmol)、N,N-二異丙基乙胺(0.3mL,1.68mmol)、化合物1i(139mg,1.12mmol),室溫反應2小時。TLC監測反應完全後,加乙酸乙酯、水萃取,飽和鹽水洗2次,乾燥濃縮有機相,得到粗品,矽膠柱層析(DCM:MeOH=20:1)分離純化,得到化合物4(25mg,9%)。
LC-MS(ESI):m/z=470.2[M+H]+.
1H NMR(400MHz,DMSO-d 6 ):8.79-8.85(m,2H),8.38-8.40(d,1H),7.14-7.24(m,4H),4.81-4.68(m,3H),4.44(d,2H),3.28(m,2H),2.91-3.00(m,3H),2.73-2.76(m,1H),1.88-1.91(m,4H).
化合物5:2-(5-(6-((2,3-二氫-1H-茚-2-基)胺基)嗒嗪-3-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物5)
2-(5-(6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-
one(compound 5)
第一步:6-((2,3-二氫-1H-茚-2-基)胺基)嗒嗪-3-羧酸甲酯(5b)
methyl 6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazine-3-carboxylate(5b)
在250mL的單口瓶中加入化合物5a(6.95g,32mmol)溶於100mL的DMF中的溶液,加入2,3-二氫-1H-茚-2-胺鹽酸鹽(5.71g,33.6mmol)和碳酸銫(22.95g,70.4mmol),在80℃反應2h,冷卻至室溫,過濾,再倒入300毫升水中,用乙酸乙酯100mL×3萃取,合併有機相,飽和氯化鈉洗滌(100mL),用無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析分離純化,得到化合物5b(4.0g,產率46%)。LC-MS(ESI):m/z=270.2[M+H]+。
第二步:6-((2,3-二氫-1H-茚-2-基(胺基)嗒嗪-3-羧酸(5c)
6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazine-3-carboxylic acid(5c)
將化合物5b(4.0g,14.9mmol)溶於30毫升THF和10毫升水中,加入一水氫氧化鋰(1.87g,44.6mmol),室溫攪拌,反應1小時。TLC監測反應完全後,再加硫酸氫鉀水溶液調pH至4-5,再加入二甲基四氫呋喃,有機層用飽和鹽
水洗滌,用無水硫酸鈉乾燥,減壓濃縮,得到化合物5c(3.2g,84%)。LC-MS(ESI):m/z=256.2[M+H]+.
第三步:3-(2-(6-((2,3-二氫-1H-茚-2-基)胺基)嗒嗪-3-羰基)肼基)-3-側氧基丙酸乙酯(5d)
Ethyl 3-(2-(6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazine-3-carbonyl)hydrazineyl)-3-oxopropanoate(5d)
將化合物5c(2.84g,11.1mmol)溶於DMF(50mL)中,再加入HATU(5.1g,13.4mmol)和DIPEA(4.3g,33.5mmol),攪拌反應10分鐘,然後再加入3-側氧基-3-肼基丙酸乙酯(2.0g,13.4mmol),室溫攪拌隔夜。將反應液倒入水中(200mL),乙酸乙酯(50mL×3)萃取,飽和鹽水洗滌,無水硫酸鈉乾燥,減壓濃縮得到化合物5d(3.0g,71%)。LC-MS(ESI):m/z=384.2[M+H]+.
第四步:2-(5-(6-((2,3-二氫-1H-茚-2-基)胺基)嗒嗪-3-基)-1,3,4-噁二唑-2-基)乙酸乙酯(5e)
ethyl 2-(5-(6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)acetate(5e)
將化合物5d(1.0g,2.6mmol)溶于無水四氫呋喃(15mL)中,加入伯吉斯試劑(1.24g,5.2mmol)加熱至90℃,在氮氣保護下微波反應30分鐘。反應完全後,加水和乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,矽膠柱層析(PE/EA=1/1)分離純化,得到化合5e(480mg,51%)。LC-MS(ESI):m/z=366.2[M+H]+.
第五步:2-(5-(6-((2,3-二氫-1H-茚-2-基)胺基)嗒嗪-3-基)-1,3,4-噁二唑-2-基)乙酸(5f)
2-(5-(6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)acetic acid(5f)
將化合物5e(480mg,1.32mmol)溶於10毫升THF和5毫升水中,加入一水氫氧化鋰(166mg,3.95mmol),室溫攪拌,反應1小時。TLC監測反應完全後,濃縮反應液,加水稀釋,再加硫酸氫鉀水溶液調pH至4-5,有大量固體析出,抽濾,濾餅烘乾,得到化合物5f(420mg,94%)。LC-MS(ESI):m/z=338.2[M+H]+.
第六步:2-(5-(6-((2,3-二氫-1H-茚-2-基)胺基)嗒嗪-3-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物5)
2-(5-(6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 5)
將化合物5f(100mg,0.3mmol)溶於3毫升DMF中,加入CDI(58mg,0.36mmol),室溫攪拌30分鐘,另外將4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(192mg,1.2mmol)溶於2毫升DMF,往裡加入DIEA(155mg,1.2mmol)再將該溶液加入到5f的反應液中,反應1h,濃縮,先用HPLC(乙腈和水)進行分離,再用矽膠製備板分離(MeOH/DCM=1/8),得到化合物5(6mg,5%)。
LC-MS(ESI):m/z=444.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 7.91-7.88(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.99(d,1H),4.82-4.75(m,2H),4.69(s,1H),4.48(d,2H),3.88-3.82(m,2H),3.40-3.34(m,2H),2.94-2.89(m,3H),2.76-2.74(m,1H).
化合物6:2-(5-(2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物6)
2-(5-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-
one(compound 6)
第一步:(1-苯基吡咯啶-3-基)胺基甲酸第三丁酯(6b)
tert-butyl(1-phenylpyrrolidin-3-yl)carbamate(6b)
將化合物6a(8.0g,43.0mmol)溶於DMF(100mL)中,再依次加入化合物溴苯(13.5g,85.9mmol)、1,1'-聯萘-2,2'-雙二苯膦(4.0g,6.44mmol)、碳酸銫(22.5g,68.9mmol)和醋酸鈀(965mg,4.3mmol)。在氮氣的保護下100℃反應4小時。冷卻至室溫,過濾,將反應液倒入(200mL)水中,用乙酸乙酯(60mL×3)萃取,有機相用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,通過矽膠柱層析(PE/EA=4/1)分離純化,得到化合物6b(5.6g,50%)。LC-MS(ESI):m/z=263.2[M+H]+.
第二步:1-苯基吡咯啶-3-胺(6c)
1-phenylpyrrolidin-3-amine(6c)
室溫下,向化合物6b(5.6g,21.4mmol)中加入4N的鹽酸1,4-二氧六環溶液(60mL)。攪拌反應1小時。反應完後濃縮得到6c(5.5g粗品)直接用於下
一步。LC-MS(ESI):m/z=163.2[M+H]+.
第三步:5-溴-N-(1-苯基吡咯啶-3-基)嘧啶-2-胺(6d)
5-bromo-N-(1-phenylpyrrolidin-3-yl)pyrimidin-2-amine(6d)
將化合物6c(5.5g粗品)溶於NMP(80mL)中,加入DIEA(8.27g,64.1mmol)和5-溴-2-氯吡啶(4.13g,21.4mmol),100℃攪拌反應2小時。將反應液倒入(300mL)水中,有大量固體析出,過濾,濾餅烘乾,得到化合物6d(4.0g,兩步收率58%)。LC-MS(ESI):m/z=319.2和321.2[M+H]+.
第四步:2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-甲腈(6e)
2-((1-phenylpyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile(6e)
將化合物6d(1.0g,3.1mmol)溶於N,N-二甲基乙醯胺(15mL)中,依次加入氰化亞銅(563mg,6.29mmol)、三乙胺(951mg,9.42mmol)和1,1'-雙(二苯基膦)二茂鐵二氯化鈀(234mg,0.32mmol),在氮氣的保護下,加熱至130℃,微波反應1小時。反應完全後,倒入水和乙酸乙酯體系,過濾,再用乙酸乙酯萃取兩遍,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮得到化合物6e(600mg,73%)。LC-MS(ESI):m/z=266.2[M+H]+.
第五步:2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-羧酸(6f)
2-((1-phenylpyrrolidin-3-yl)amino)pyrimidine-5-carboxylic acid(6f)
將化合物6e(1.2g,4.5mmol)溶於20毫升異丙醇和5毫升水中,加入氫氧化鉀(1.26g,22.5mmol),反應混合物回流3小時。TLC監測反應完全後,濃縮反應液,加水稀釋,用乙酸乙酯萃取,有機相加硫酸氫鉀水溶液調pH至4-5,再用乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮得到化合物6f(510mg,40%)。LC-MS(ESI):m/z=285.2[M+H]+.
第六步:3-側氧基-3-(2-(2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-羰基)肼基)丙酸乙酯(6g)
ethyl 3-oxo-3-(2-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidine-5-carbonyl)hydrazineyl)propanoate(6g)
將化合物6f(500mg,1.76mmol)溶於DMF(10mL)中,再加入HATU(802mg,2.11mmol)和DIPEA(681mg,5.28mmol),攪拌反應10分鐘,然後再加入3-肼基-3-側氧基丙酸乙酯(309mg,2.11mmol),室溫攪拌隔夜。將反應液倒入水中(200mL),乙酸乙酯(50mL×3)萃取,飽和鹽水洗滌,無水硫酸鈉乾燥,減壓濃縮得到化合物6g(400mg,55%)。LC-MS(ESI):m/z=413.2[M+H]+.
第七步:2-(5-(2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(6h)
ethyl 2-(5-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(6h)
將化合物6g(1.0g,2.4mmol)溶于無水四氫呋喃(15mL)中,加入伯吉斯試劑(1.15g,4.9mmol),在室溫攪拌,在氮氣保護下反應1小時。TLC監測反應完全後,加水和乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮後,再柱層析(PE/EA=1/1),得到化合6h(300mg,32%)。LC-MS(ESI):m/z=395.2[M+H]+.
第八步:2-(5-(2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(6i)
2-(5-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(6i)
將化合物6h(250mg,0.63mmol)溶於9毫升THF和3毫升水中,加入一水氫氧化鋰(133mg,3.17mmol),室溫攪拌,反應1小時。TLC監測反應完
全後,濃縮反應液,加水稀釋,用乙酸乙酯萃取,再將水層加硫酸氫鉀水溶液調pH至4-5,用乙酸乙酯萃取,有機層用飽和鹽水洗滌,無水硫酸鈉乾燥,濃縮得到化合物6i(120mg,52%)。LC-MS(ESI):m/z=367.2[M+H]+.
第九步:2-(5-(2-((1-苯基吡咯啶-3-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物6)
2-(5-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 6)
將化合物6i(120mg,0.33mmol)溶於3毫升DMF中,加入CDI(64mg,0.39mmol),室溫攪拌30分鐘,另將4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(212mg,1.32mmol)溶於2毫升DMF,加入DIEA(170mg,1.32mmol)再將該溶液加入到6i的反應液中,反應1h,先用HPLC(乙腈和水)進行分離,再矽膠柱層析(MeOH/DCM=1/8)分離純化,得到化合物6(11mg,7%)。
LC-MS(ESI):m/z=473.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.83-8.79(m,2H),8.38(d,1H),7.15(t,2H),6.61-6.52(m,3H),4.81(s,1H),4.68-4.62(m,2H),4.41(d,2H),3.85-3.83(m,2H),3.62-3.58(m,1H),3.34-3.28(m,1H),3.24-3.20(m,1H),2.92-2.89(m,1H),2.76-2.73(m,1H),2.34-2.29(m,1H),2.10-2.05(m,1H).
化合物7:2-(5-(2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物7)
2-(5-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-
yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 7)
第一步:(5-溴-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯(7b)
tert-butyl(5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate(7b)
將起始物質7a(20g,68.2mmol)溶解於200mL的甲醇中,然後加入一縮二碳酸二第三丁酯(16.4g,75.1mmol)以及三乙胺(20.7g,204.6mmol),室溫攪拌隔夜,點板檢測反應完全,旋掉大部分溶劑,加入300mL的飽和碳酸氫鈉溶液,然後用300mL的乙酸乙酯萃取三次,合併有機相,用無水硫酸鈉乾燥旋幹,得到白色固體7b(21g,收率71.2%)。LC-MS(ESI):m/z=313.2[M+H]+.
第二步:(5-環丙基-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯(7c)
tert-butyl(5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)carbamate(7c)
在250mL的單口瓶中加入化合物7b(6.0g,19.2mmol),用甲苯(60mL)和水(6mL)溶解,加入環丙基硼酸(2.2g,25.0mmol)、磷酸鉀(8.2g,38.4mmol)、Pd2(dba)3(1.8g,1.9mmol)、Xphos(1.8g,3.8mmol),用氮氣置換3次,100℃反應5h,用水溶液(100mL)淬滅,EA萃取(50mL×3),合併有機相,用飽和氯化鈉洗滌(5mL×1),用無水硫酸鈉乾燥,減壓濃縮,柱層析(PE:EA=4:1)得化合物7c(6.2g,粗品),直接用於下一步反應。LC-MS(ESI):m/z=218.2[M-55]+.
第三步:5-環丙基-2,3-二氫-1H-茚-2-胺(7d)
5-cyclopropyl-2,3-dihydro-1H-inden-2-amine(7d)
在250mL的單口瓶中加入化合物7c(6.2g,粗品),用DCM(50mL)溶解,加入TFA(50mL),室溫攪拌18h,用飽和碳酸氫鈉(10mL)調節pH到9,DCM(50mL×2)萃取,合併有機相,用飽和氯化鈉洗滌(5mL×1),用無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析(PE/EA=2/1)分離純化,得化合物7d(2.3g,68%)。LC-MS(ESI):m/z=174.2[M+H]+.
第四步:5-溴-N-(5-環丙基-2,3-二氫-1H-茚-2-基)嘧啶-2-胺(7e)
5-bromo-N-(5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine(7e)
在100mL的單口瓶中加入化合物7d(2.3g,11.9mmol),用EtOH(15mL)溶解,加入DIPEA(3.8g,29.7mmol)、5-溴-2-氯嘧啶(3.8g,29.7mmol),在90℃攪拌3h,冷卻至室溫,抽濾,乾燥得白色固體化合物7e(2.2g,56%)。LC-MS(ESI):m/z=330.1[M+H]+.
第五步:2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸甲酯(7f)
methyl 2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-
yl)amino)pyrimidine-5-carboxylate(7f)
在250mL的高壓釜中加入化合物7e(2.2g,6.7mmol),用甲醇(20mL)和DMF(20mL)溶解,加入Pd(dppf)Cl2(2.0g,2.7mmol),一氧化碳置換3次,在20atm和100℃反應10h,用矽藻土過濾,濃縮,矽膠柱層析(PE/EA=3/1)分離純化,得到白色固體化合物7f(0.45g,22%)。LC-MS(ESI):m/z=310.3[M+H]+.
第六步:2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸(7g)
2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylicacid(7g)
在100mL的茄形瓶中加入化合物7f(0.45g,1.5mmol),THF(5mL)和水(5mL)溶解,室溫攪拌反應3h,用HCl(1M)調節pH到4-5,過濾得白色固體化合物7g(0.36g,84%)。
LC-MS(ESI):m/z=296.2[M+H]+.
第七步:3-(2-(2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-3-側氧基丙酸乙酯(7h)
ethyl 3-(2-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazineyl)-3-oxopropanoate(7h)
在100mL的茄形瓶中加入化合物7g(0.36g,1.2mmol),用DMF(5mL)溶解,加入DIPEA(0.39g,3.0mmol)、HATU(0.6g,1.6mmol),室溫攪拌10分鐘,加入3-側氧基-3-肼基丙酸乙酯(0.36g,1.2mmol),室溫繼續攪拌反應隔夜,加入水(10mL),用EA(2x20mL)萃取,矽膠柱層析(PE/EA=2/3)分離純化,得到白色固體化合物7h(0.6g)。LC-MS(ESI):m/z=424.3[M+H]+.
第八步:2-(5-(2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(7i)
ethyl 2-(5-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(7i)
將化合物7h(550mg,1.3mmol)溶於二氯甲烷(10mL)和DMF(2mL)中,加入三乙胺(328mg,3.3mmol),冰浴下加入對甲苯磺醯氯(297mg,1.56mmol),再升至室溫,攪拌,在氮氣保護下反應4小時。TLC監測反應完全後,加碳酸氫鈉水溶液和二氯甲烷萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,矽膠柱層析(PE/EA=1/1)分離純化,得到化合7i(200mg,38%)。LC-MS(ESI):m/z=406.2[M+H]+.
第九步:2-(5-(2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(7j)
2-(5-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(7j)
將化合物7i(200mg,0.49mmol)溶於9毫升THF和3毫升水中,加入一水氫氧化鋰(104mg,2.5mmol),室溫攪拌,反應1小時。TLC監測反應完全後,濃縮反應液,加水稀釋,用乙酸乙酯萃取,再將水層加硫酸氫鉀水溶液調pH至4-5,用乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮得到化合物7j(140mg,76%)。LC-MS(ESI):m/z=378.2[M+H]+.
第十步:2-(5-(2-((5-環丙基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物7)
2-(5-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 7)
將化合物7j(120mg,0.32mmol)溶於3毫升DMF中加入CDI(62
mg,0.38mmol),室溫攪拌30分鐘,再將4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(205mg,1.28mmol)溶於2毫升DMF,用DIEA(165mg,1.28mmol)游離,加入到6i的反應液中反應1h,先用製備型HPLC(乙腈和水)分離,再用矽膠製備板分離(MeOH/DCM(v/v)=1/8)純化,得到化合物7(5mg,3%)。
LC-MS(ESI):m/z=484.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 14.63(s,1H),8.82-8.79(m,2H),8.36(d,1H),7.08(d,1H),6.92-6.87(m,2H),4.81-4.66(m,3H),4.41(d,2H),3.86-3.82(m,2H),3.25-3.21(m,2H),2.91-2.88(m,3H),2.78-2.76(m,1H),1.90-1.86(m,1H),0.91-0.89(m,2H),0.62-0.60(m,2H).
實例8:2-((5-(5-(2-(6,7-二氫-1H-[1,2,3]三唑並[4,5-c]吡啶-5(4H)-基)-2-側氧基乙基)-1,3,4-噁二唑-2-基)嘧啶-2-基)胺基)-2,3-二氫-1H-茚-5-甲腈(化合物8)
2-((5-(5-(2-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-2-oxoethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-5-carbonitrile(compound 8)
第一步:(5-溴-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯(8b)
tert-butyl(5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate(8b)
將化合物8a(28.9g,98.6mmol)溶於甲醇(500ml)中,加入三乙胺(29.9g,296mmol),室溫攪拌10分鐘後分次加入(Boc)2O(21.5g,98.6mmol),加畢,室溫攪拌隔夜;反應液減壓蒸幹,剩餘物加水600ml攪拌1小時後過濾,濾餅乾燥後,得到化合物8b(30.0g,97.4%)。
第二步:(5-氰基-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯(8c)
tert-butyl(5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate(8c)
將化合物8b(6.8g,21.8mmol)溶於DMF(80ml)中,加入Zn(CN)2(3.5g,29.9mmol),用氮氣置換3次後,加入Pd(PPh3)4(3.9g,3.4mmol),用氮氣置換3次後,升溫至100℃攪拌隔夜;反應液加壓蒸去DMF,剩餘物矽膠柱層析(PE/EA=5/1)分離純化,得到8c(4.8g,85.2%)。LC-MS(ESI):m/z=259.3[M+H]+.
第三步:2-胺基-2,3-二氫-1H-茚-5-甲腈鹽酸鹽(8d)
2-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride(8d)
將8c(4.8g,18.6mmol)置於100ml單口瓶中,加入HCl-二氧六環(60ml),加畢,室溫攪拌隔夜,反應液加壓蒸幹,得到化合物8d(3.6g,100%)。
第四步:2-((5-溴嘧啶-2-基)胺基)-2,3-二氫-1H-茚-5-甲腈(8e)
2-((5-bromopyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-5-carbonitrile(8e)
將化合物8d(3.6g,18.6mmol)和5-溴嘧啶-2-胺(3.2g,18.6mmol)溶于無水乙醇(100ml)中,加入DIPEA(12.0g,93.0mmol),加畢,升溫至90℃攪拌隔夜;反應液減壓蒸幹,剩餘物加水100ml,攪拌30分鐘後過濾,濾餅乾燥,
得到化合物8e(5.1g,87.0%)。LC-MS(ESI):m/z=315.3[M+H]+.
第五步:2-((5-氰基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸甲酯(8f)
methyl 2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate(8f)
將化合物8b(4.0g,12.7mmol)置於高壓釜中,加入DMF(30ml),MeOH(30ml)和DIPEA(4.9g,38.1mmol),最後加入Pd(dppf)Cl2.CH2Cl2(490mg,0.6mmol),加畢,用一氧化碳置換3次後,通入一氧化碳至壓力為3.0MPa,加熱至110℃反應15小時,反應液減壓蒸幹,剩餘物矽膠柱層析(PE/EA=4/1)分離純化,得到8f(2.8g,74.9%)。LC-MS(ESI):m/z=295.3[M+H]+.
第六步:2-((5-氰基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸(8g)
2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid(8g)
將8f(2.8g,9.5mmol)置於100ml單口瓶中,依次加入甲醇/水=1/1(40ml)和LiOH.H2O(2.0g,47.5mmol),加畢,室溫攪拌5小時後減壓蒸去甲醇,水相用1N稀鹽酸調pH=5,攪拌10分鐘後過濾,濾餅乾燥,得到化合物8g(2.5g,93.9%)。
第七步:3-(2-(2-((5-氰基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-3-側氧基丙酸乙酯(8h)
Ethyl 3-(2-(2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazinyl)-3-oxopropanoate(8h)
將8g(2.5g,8.9mmol)和3-側氧基-3-肼基丙酸乙酯(1.4g,9.3mmol)溶於DMF(50ml)中,依次加入DIPEA(2.3g,17.8mmol)和HATU(4.1g,10.7mmol),加畢室溫攪拌隔夜;反應液加水80ml,乙酸乙酯萃取4次,有機相
用飽和NaCl水溶液洗3次,用無水硫酸鈉乾燥,過濾,濾液減壓蒸幹,剩餘物用矽膠柱層析(PE/EA=2/1)分離純化,得到化合物8h(1.9g,52.3%)。
第八步:2-(5-(2-((5-氰基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(8i)
Ethyl 2-(5-(2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(8i)
將化合物8h(1.9g,6.8mmol)溶于無水THF(30ml)中,加入伯吉斯試劑(3.2g,13.6mmol),加畢,室溫攪拌隔夜;反應液減壓蒸幹,剩餘物矽膠柱層析(PE/EA=2/1)分離純化,得到化合物8i(1.0g,37.7%)。LC-MS(ESI):m/z=391.2[M+H]+.
第九步:2-(5-(2-((5-氰基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(8j)
2-(5-(2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(8j)
將化合物8i(1.0g,2.6mmol)溶於THF/H2O=2/1(15ml)中,加入LiOH.H2O(328mg,7.8mmol),加畢,室溫攪拌隔夜;反應液減壓蒸去THF,水相用1N稀鹽酸調pH=5,攪拌10分鐘後過濾,濾餅乾燥得8j(0.8g,84.9%)。
第十步:2-((5-(5-(2-(6,7-二氫-1H-[1,2,3]三唑並[4,5-c]吡啶-5(4H)-基)-2-側氧基乙基)-1,3,4-噁二唑-2-基)嘧啶-2-基)胺基)-2,3-二氫-1H-茚-5-甲腈(化合物8)
2-((5-(5-(2-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-2-oxoethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-5-carbonitrile(compound 8)
將8j(0.8g,2.2mmol)和4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶
鹽酸鹽(707mg,4.4mmol)溶於DMF(20ml),依次加入DIPEA(1.4g,11mmol)和HATU(988mg,2.6mmol),加畢,室溫攪拌隔夜;反應液緩慢滴入冰水中,攪拌2分鐘後過濾,濾餅用矽膠柱層析(DCM/MeOH=15/1)分離純化,得到化合物8(47mg,4.6%)。
1H NMR(400MHz,DMSO-d 6)δ 8.81(brs,2H),8.42(d,1H),7.69(s,1H),7.63(d,1H),7.45(s,1H),8.81(s,1H),4.77-4.72(m,1H),4.68(s,1H),4.43(s,1H),4.39(S,1H),3.87-381(m,2H),3.41-3.32(m,1H),3.06-2.97(m,2H),2.91(t,1H),2.75(t,1H)。LC-MS(ESI):m/z=469.1[M+H]+。
化合物9:2-(5-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物9)
2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 9)
第一步:(5-甲醯基-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯(9b)
tert-butyl(5-formyl-2,3-dihydro-1H-inden-2-yl)carbamate(9b)
將起始物質8b(10g,32.1mmol)溶解於400mL的無水四氫呋喃中,然後在零下78℃的條件下加入正丁基鋰(2.5M,32mL,80.1mmol),將反應混合物在同樣的溫度下攪拌30分鐘,然後在零下78度的條件下加入DMF(12.5mL,160.5mmol),混合物被慢慢恢復到室溫,然後再攪拌15分鐘。反應完成後,加入飽和氯化銨溶液,再用乙酸乙酯萃取三次,合併有機相,用無水硫酸鈉乾燥,旋幹,用矽膠柱層析(PE/EA=6/1)分離純化,得到白色固體9b(5.8g,收率69%)。LC-MS(ESI):m/z=262.2[M+H]+.
第二步:(5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯
(9c)
tert-butyl(5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)carbamate(9c)
在250mL的單口瓶中加入化合物9b(5.8g,22.2mmol)和二氯甲烷(100mL),在零下10℃加入DAST(7.2g,44.4mmol),升至室溫反應48h,用水溶液(100mL)淬滅,用二氯甲烷萃取(50mL×3),合併有機相,用飽和氯化鈉洗滌(50mL×1),用無水硫酸鈉乾燥,減壓濃縮,矽膠柱層析(PE/EA=9/1)分離純化,得到白色固體9c(4.2g,67%)。LC-MS(ESI):m/z=284.2[M-55]+.
第三步:5-(二氟甲基)-2,3-二氫-1H-茚-2-胺(9d)
5-(difluoromethyl)-2,3-dihydro-1H-inden-2-amine(9d)
室溫下,向化合物9c(4.2g,14.8mmol)中加入4N的鹽酸1,4-二氧六環溶液(60mL)。攪拌反應1小時。反應完後濃縮,得到9d(3.3g粗品)直接用於下一步。LC-MS(ESI):m/z=184.2[M+H]+.
第四步:2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸甲酯(9e)
methyl 2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate(9e)
在100mL的單口瓶中加入化合物9d(3.3g,18.0mmol),用NMP(40mL)溶解,加入DIPEA(7.0g,54.1mmol)、2-氯嘧啶-5-羧酸甲酯(3.1g,18.0mmol),在100℃攪拌2h,冷卻至室溫,倒入水中,有固體析出,抽濾,乾燥得到淡黃色固體化合物9e(2.5g,44%)。LC-MS(ESI):m/z=320.1[M+H]+.
第五步:2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸(9f)
2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-
yl)amino)pyrimidine-5-carboxylic acid(9f)
在100mL的茄形瓶中加入化合物9e(2.5g,7.84mmol),用THF(30mL)和水(20mL)溶解,加入氫氧化鈉(940mg,23.51mmol),回流攪拌反應3h,濃縮掉四氫呋喃,用HCl(1M)調節pH到4-5,過濾得到白色固體化合物9f(2.0g,84%)。LC-MS(ESI):m/z=306.2[M+H]+.
第六步:3-(2-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-3-側氧基丙酸乙酯(9g)
ethyl 3-(2-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazineyl)-3-oxopropanoate(9g)
在100mL的茄形瓶中加入化合物9f(3.6g,11.76mmol),用DMF(50mL)溶解,加入DIPEA(4.55g,35.29mmol)、HATU(6.7g,17.64mmol),室溫攪拌10分鐘,加入3-側氧基-3-肼基丙酸乙酯(2.06g,14.11mmol),室溫繼續攪拌反應隔夜,倒入水中,有黃色固體析出,過濾,濾餅烘乾得到黃色固體化合物9g(4.0g,78%)。LC-MS(ESI):m/z=434.3[M+H]+.
第七步:2-(5-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(9h)
ethyl 2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(9h)
將化合物9g(4.0g,9.24mmol)溶于無水四氫呋喃(50mL)中,加入伯吉斯試劑(4.4g,18.48mmol),在氮氣保護下70℃反應1小時。TLC監測反應完全後,加水和乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,矽膠柱層析(PE/EA=1/1)分離純化,得到化合物9h(2.8g,73%)。LC-MS(ESI):m/z=416.2[M+H]+.
第八步:2-(5-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-
5-基)-1,3,4-噁二唑-2-基)乙酸(9i)
2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(9i)
將化合物9h(2.8g,6.75mmol)溶於30毫升THF和10毫升水中,加入一水氫氧化鋰(850mg,20.24mmol),室溫攪拌,反應1小時。TLC監測反應完全後,濃縮反應液,加水稀釋,用乙酸乙酯萃取,再將水層加硫酸氫鉀水溶液調pH至4-5,用乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮得到化合物9i(2.3g,88%)。LC-MS(ESI):m/z=388.2[M+H]+.
第九步:2-(5-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物9)
2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 9)
將化合物9i(387mg,1.0mmol)溶於5毫升DMF中加入CDI(195mg,1.2mmol),室溫攪拌30分鐘,再將4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(482mg,3.0mmol)溶於2毫升DMF,用DIEA(516mg,4.0mmol)游離,加入到9i的反應液中反應1h,倒入水中,用DCM/MeOH/MeCN的混合溶劑萃取,旋幹,先用HPLC(乙腈和水)進行分離,再矽膠柱層析分離(THF/DCM=1/3)純化,得到化合物9(70mg,14%)。LC-MS(ESI):m/z=494.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.83-8.79(m,2H),8.38-8.36(m,1H),7.40(d,3H),6.97(t,1H),4.81-4.68(m,3H),4.43-4.39(m,2H),3.87-3.81(m,2H),3.35-3.31(m,2H),3.02-2.72(m,4H).
實例10:N-(2,3-二氫-1H-茚-2-基)-2-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)苯並[d]噁唑-5-甲醯胺(化合物10)
N-(2,3-dihydro-1H-inden-2-yl)-2-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)benzo[d]oxazole-5-carboxamide(compound 10)
第一步:2-(2-乙氧基-2-側氧基乙基)苯並[d]噁唑-5-羧酸第三丁酯(10c)
tert-butyl 2-(2-ethoxy-2-oxoethyl)benzo[d]oxazole-5-carboxylate(10c)
將3-胺基-4-羥基苯甲酸第三丁酯(10a)(3g,14.34mmol)、3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽10b(3.37g,17.20mmol)溶解在乙醇(20mL)中並在80℃下攪拌隔夜。反應完成後,將反應冷卻至室溫,減壓濃縮乙醇,然後將殘餘物溶於二氯甲烷中,用蒸餾水洗滌有機相,分離各層,將有機相減壓濃縮,得到目標化合物(10c),呈白色固體(4g,91.37%)。LC-MS(ESI):m/z=306.1[M+H]+
第二步:2-(2-乙氧基-2-側氧基乙基)苯並[d]噁唑-5-羧酸(10d)
2-(2-ethoxy-2-oxoethyl)benzo[d]oxazole-5-carboxylic acid(10d)
將化合物10c(4.9g,4.5mmol)在二氯甲烷(10mL)中的溶液加入三
氟乙酸(2mL)中,在室溫下攪拌3小時。反應完成後,向其中加入飽和碳酸氫鈉水溶液以調節pH值為中性,然後用二氯甲烷萃取。依次用水和飽和鹽水洗滌有機層,無水硫酸鈉乾燥,濃縮,得到標題化合物10d,呈淡黃色固體(3.9g,97.51%)。LC-MS(ESI):m/z=250.3[M+H]+
第三步:2-(5-((2,3-二氫-1H-茚-2-基)胺甲醯基)苯並[d]噁唑-2-基)乙酸乙酯(10f)
ethyl 2-(5-((2,3-dihydro-1H-inden-2-yl)carbamoyl)benzo[d]oxazol-2-yl)acetate(10f)
在單口瓶中,依次加入化合物10d(1.2g,4.81mmol),DMF(20mL),HATU(2.2g,5.78mmol),N,N-二異丙基乙胺(1.3g,10mmol),攪拌反應15分鐘後加入化合物1B(0.77g,5.78mmol),繼續室溫下攪拌反應1小時。反應完成後,用水(30mL)稀釋,並用乙酸乙酯萃取。用水和飽和鹽水洗滌有機層,用無水硫酸鈉乾燥,濃縮。矽膠柱層析(DCM:MeOH=60:1)分離,得到目標化合物10f,呈白色固體(1.2g,68.4%)。LC-MS(ESI):m/z=365.3[M+H]+
第四步:2-(5-((2,3-二氫-1H-茚-2-基)胺甲醯基)苯並[d]噁唑-2-基)乙酸(10g)
2-(5-((2,3-dihydro-1H-inden-2-yl)carbamoyl)benzo[d]oxazol-2-yl)acetic acid(10g)
向化合物10f(1.2g,3.29mmol)在四氫呋喃(10mL)和水(5mL)的混合溶劑中添加氫氧化鋰(0.44g,11mmol),並且將混合物在室溫下攪拌1小時。反應完成後,將混合物用10%檸檬酸水溶液處理以調節pH=6,然後用乙酸乙酯萃取。有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,殘留物用乙醚打漿得到目標化合物10g,呈黃色固體(1.0g,90.2%)。LC-MS(ESI):m/z=337.2[M+H]+
第五步:N-(2,3-二氫-1H-茚-2-基)-2-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)苯並[d]噁唑-5-甲醯胺(化合物10)
N-(2,3-dihydro-1H-inden-2-yl)-2-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)benzo[d]oxazole-5-carboxamide(compound 10)
在室溫下,向化合物10g(0.12g,0.35mmol)、氯化四甲基脲六氟磷酸鹽(0.12g,0.42mmol)、N-甲基咪唑(0.04g,0.52mmol)的N,N-二甲基甲醯胺(10mL)溶液中依次地緩慢添加中間物1i(0.11g,0.61mmol)、N,N-二異丙基乙胺(0.13g,1mmol),並將混合物在室溫下在氮氣保護下攪拌3h。反應完成後,將反應混合物用水(30mL)稀釋,並用乙酸乙酯萃取(50mLx2)。用飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮得到粗品。粗品通過矽膠柱層析(DCM:MeOH=25:1)分離純化,得到化合物1015mg,9.5%)。
LC-MS(ESI):m/z=443.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.77-8.75(m,1H),8.26-8.24(m,1H),7.96-7.93(m,1H),7.77-7.73(m,1H),7.25-7.22(m,2H),7.18-7.13(m,2H),4.81-4.69(m,3H),4.43-4.40(m,2H),3.88-3.81(m,2H),3.31-3.32(m,2H),3.03-2.97(m,2H),2.87-2.74(m,2H).
實例11:1-(2,3-二氫-1H-茚-2-基)-3-(2-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)苯並[d]噁唑-6-基)脲(化合物11)
1-(2,3-dihydro-1H-inden-2-yl)-3-(2-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)benzo[d]oxazol-6-yl)urea(compound 11)
第一步:2-(6-硝基苯並[d]噁唑-2-基)乙酸乙酯(11c)
ethyl 2-(6-nitrobenzo[d]oxazol-2-yl)acetate(11c)
將化合物11a(2.00g,12.98mmol)、化合物11b((2.03g,12.98mmol))溶於四氫呋喃(40mL)中,冰浴下緩慢加入Cs2CO3(8.46g,25.95mmol),氮氣置換後,在45℃反應5小時。反應完成後冷卻至室溫,加水,用乙酸乙酯萃取三次,飽和鹽水洗,無水硫酸鈉乾燥,旋幹,矽膠柱層析(PE:EA=40:1)分離純化,得到(11c)(3.00g,92.4%)。LC-MS(ESI):m/z=251.1[M+H]+。1H NMR(400MHz,CDCl3)δ 8.45(d,1H),8.32(dd,1H),7.85-7.80(m,1H),4.27(q,2H),4.10-4.05(m,2H),2.04(s,1H),1.31(dd,3H).
第二步:2-(6-胺基苯並[d]噁唑-2-基)乙酸乙酯(11d)
ethyl 2-(6-aminobenzo[d]oxazol-2-yl)acetate(11d)
將化合物11c(1.6g,6.4mmol)溶於甲醇中,加入Pd/C(160mg),置換氫氣後,反應隔夜。DCM:MeOH=10:1顯示反應完全。過濾反應液,減壓濃縮後,得到(11d)(1.18g,84%)。
第三步:2-(6-(3-(2,3-二氫-1H-茚-2-基)脲基)苯並[d]噁唑-2-基)乙酸乙酯(11f)
ethyl 2-(6-(3-(2,3-dihydro-1H-inden-2-yl)ureido)benzo[d]oxazol-2-yl)acetate(11f)
將化合物11d(1.18g,5.36mmol)、化合物1B(1.09g,6.43mmol)溶于無水二氯甲烷中,加入三光氣(557mg,1.88mmol),緩慢滴加DIPEA(2.71g,26.8mmol),室溫反應10min。反應完成後,將反應液用飽和氯化銨淬滅,並用乙酸乙酯(30mLx2)萃取。有機相用飽和鹽水洗,無水硫酸鈉乾燥,過濾,濃縮。矽膠柱層析(DCM:MeOH=60:1)分離純化,得到為白色固體的產物11f(1.15g,56.6%)。
第四步:2-(6-(3-(2,3-二氫-1H-茚-2-基)脲基)苯並[d]噁唑-2-基)乙酸(11g)
2-(6-(3-(2,3-dihydro-1H-inden-2-yl)ureido)benzo[d]oxazol-2-yl)acetic acid(11g)
將化合物11f(1.15g,3.03mmol)溶於甲醇中,緩慢滴加氫氧化鋰的水溶液(318mg,7.58mmol),室溫反應。反應完成後,將混合物濃縮加水過濾,濾液用HCl調節pH=3-4,並用乙酸乙酯(30mLx2)萃取。有機相用飽和鹽水洗,無水硫酸鈉乾燥,過濾,濃縮。得白色固體為產物11g(1.0g,93.9%)。
第五步:1-(2,3-二氫-1H-茚-2-基)-3-(2-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)苯並[d]噁唑-6-基)脲(化合物11)
1-(2,3-dihydro-1H-inden-2-yl)-3-(2-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)benzo[d]oxazol-6-yl)urea(compound 11)
將化合物11g(400mg,1.138mmol)、11h(212mg,1.707mmol)溶
於DMF中,加入HATU(866mg,2.277mmol),滴加DIPEA(0.79ml,5.692mmol),室溫反應。反應完成後,將混合物用水稀釋,並用乙酸乙酯萃取。有機層用飽和鹽水洗,無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(DCM:MeOH=15:1)分離純化,得到化合物11(386mg,74.1%)。
LC-MS(ESI):m/z=458.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.58(d,1H),7.94(dd,1H),7.54-7.48(m,1H),7.25(dt,2H),7.18-7.13(m,2H),7.08(m,1H),6.50(d,1H),4.80(s,1H),4.68(s,1H),4.49-4.39(m,1H),4.30(d,2H),3.91-3.80(m,2H),3.22(d,1H),3.18(d,1H),2.88-2.72(m,4H).
實例12:1-(6,7-二氫-1H-[1,2,3]三唑並[4,5-c]吡啶-5(4H)-基)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-甲氧基嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酮(化合物12)
1-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethanone(compound 12)
第一步:2-((2,3-二氫1H-茚2-基)胺基)-4-甲氧基嘧啶-5-羧酸乙酯(12c)
ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidine-5-carboxylate(12c)
將2-氯-4-甲氧基嘧啶-5-羧酸乙酯(12a)(2.2g,10mmol)、2-胺基茚滿(1B)(1.33g,10mmol)和N,N-二異丙基乙胺(2.6g,20mmol)溶解在乙醇(20mL)中並在90℃下攪拌2小時。反應完成後,將混合物冷卻至室溫,過濾所得固體,用乙醇(20mL)洗滌,乾燥,得到標題化合物(12c),呈米色固體(1.4g,45%)。LC-MS(ESI):m/z=314.1[M+H]+。
第二步:2-((2,3-二氫-1H-茚-2-基)胺基)-4-甲氧基嘧啶-5-羧酸(12d)
2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidine-5-carboxylic acid(12d)
向化合物2-((2,3-二氫1H-茚2-基)胺基)-4-甲氧基嘧啶-5-羧酸乙酯((12c)(1.2g,4.5mmol)在四氫呋喃(30mL)和蒸餾水(10mL)中的溶液中添加氫氧
化鋰(1.08g,27mmol),將反應將混合物在室溫下攪拌15小時。反應完成後,向其中添加2N鹽酸水溶液以調節pH值為3,然後用乙酸乙酯萃取。用飽和鹽水洗滌有機層,用無水硫酸鈉乾燥,濃縮,得到標題化合物(12d)1.05g,呈淡黃色固體。LC-MS(ESI):m/z=286.2[M+H]+
第三步:3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-甲氧基嘧啶-5-羰基)肼基)-3-側氧基丙酸乙酯(12f)
ethyl 3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidine-5-carbonyl)hydrazinyl)-3-oxopropanoate(12f)
在0℃下,向化合物(12d)(1.05g,3.7mmol)的N,N-二甲基甲醯胺(30mL)溶液中依次地緩慢添加化合物(2e)(0.65g,4mmol)、N,N-二異丙基乙胺(1.3g,10mmol)和HATU(1.52g,4mmol),並將混合物在室溫下在氮氣流下攪拌1小時。反應完成後,將反應混合物冷卻至室溫,用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取。用飽和鹽水洗滌有機層,用無水硫酸鈉乾燥,濃縮。矽膠柱層析分離,得到標題化合物(12f),呈白色固體(1.21g,79%)。LC-MS(ESI):m/z=414.2[M+H]+
第四步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-甲氧基嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(12g)
ethyl 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(12g)
在0℃下,向化合物(12f)(1.21g,2.9mmol)的無水四氫呋喃(50mL)溶液中添加N-(三乙基銨磺醯基)胺基甲酸甲酯(1.6g,5.5mmol),並且將混合物在70℃和氮氣氣氛下攪拌2小時。反應完成後,將混合物冷卻至室溫,用蒸餾水(80mL)稀釋,並用乙酸乙酯萃取。用飽和鹽水洗滌有機層,用無水硫酸鈉
乾燥,濃縮。殘餘物矽膠柱層析分離純化,得到標題化合物(12g),呈黃色固體(0.86g,75%)。
LC-MS(ESI):m/z=396.2[M+H]+
第五步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-甲氧基嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(12h)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(12h)
向化合物(12g)(0.86g,2.2mmol)在四氫呋喃(10mL)和蒸餾水(5mL)的混合溶劑中的溶液中添加氫氧化鋰(0.44g,11mmol),並且將混合物在室溫下攪拌2小時。反應完成後,將混合物用2N鹽酸水溶液處理以調節pH為2或更低,然後用乙酸乙酯萃取。有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,殘留物用乙醚打漿,得到目標化合物12h,呈黃色固體(0.59g,73%)。LC-MS(ESI):m/z=368.2[M+H]+
第六步:1-(6,7-二氫-1H-[1,2,3]三唑並[4,5-c]吡啶-5(4H)-基)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-甲氧基嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酮(化合物12)
1-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethanone(compound 12)
在0℃下,向化合物(12h)(0.12g,0.33mmol)的N,N-二甲基甲醯胺(10mL)溶液中依次地緩慢添加中間物1i(0.11g,0.66mmol)、N,N-二異丙基乙胺(0.5mL)和HATU(0.14g,0.36mmol),並將混合物在室溫下在氮氣保護下攪拌3h。反應完成後,將反應混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取(50mLx2)。用飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。通過矽
膠柱層析分離純化,得到化合物12(14mg)。
LC-MS(ESI):m/z=474.2[M+H]+。
1H NMR(400MHz,CDCl3)δ 8.61(s,1H),8.24(s,1H),7.79(s,1H),7.33-7.12(m,4H),4.87(s,2H),4.19(s,3H),4.06-3.85(m,3H),3.49-3.40(m,4H),3.10-2.85(m,4H).
實例13:2-((2,3-二氫-1H-茚-2-基)胺基)-5-(5-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)-1,3,4-噁二唑-2-基)煙腈(化合物13)
2-((2,3-dihydro-1H-inden-2-yl)amino)-5-(5-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile(compound 13)
第一步:5-碘-6-側氧基-1,6-二氫吡啶-3-羧酸乙酯(13b)
ethyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate(13b)
向化合物13a(10.0g,59.8mmol)的N,N-二甲基甲醯胺(100mL)溶液中加入N-碘代丁二醯亞胺(14.8g,65.8mmol),將混合物在70℃下攪拌16小
時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯(100mLx3)萃取。用飽和鹽水(50mL)洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物13b,呈白色固體(10.0g,57%)。LC-MS(ESI):m/z=294.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ 12.48(s,1H),8.36(s,1H),8.08(s,1H),4.24(q,2H),1.28(t,3H).
第二步:5-氰基-6-側氧基-1,6-二氫吡啶-3-羧酸乙酯(13c)
ethyl 5-cyano-6-oxo-1,6-dihydropyridine-3-carboxylate(13c)
向化合物13b(5.0g,17.1mmol)的N,N-二甲基甲醯胺(10mL)溶液中加入氰化鋅(4.0g,34.1mmol)和四(三苯基膦)鈀(0.99g,0.86mmol),將混合物在110℃下攪拌4小時。反應完成後,將混合物用水(100mL)稀釋,並用乙酸乙酯(100mLx4)萃取。用飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物13c,呈白色固體(1.3g,40%)。
LC-MS(ESI):m/z=193.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 13.12(s,1H),8.46(s,1H),8.34(s,1H),4.26(q,2H),1.29(t,3H).
第三步:6-氯-5-氰基煙酸乙酯(13d)
ethyl 6-chloro-5-cyanonicotinate(13d)
向化合物13c(1.3g,6.8mmol)的1,4-二氧六環(10mL)溶液中加入三氯氧磷(6ml),將混合物在100℃下攪拌2小時。反應完成後,將反應液濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~1:1)分離純化,得到標題化合物13d,呈白色固體(0.9g,64%)。LC-MS(ESI):m/z=211.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 9.12(s,1H),8.91(s,1H),4.38(q,2H),1.35(t,3H).
第四步:5-氰基6-((2,3-二氫-1H-茚-2-基)胺基)煙酸乙酯(13f)
ethyl 5-cyano-6-((2,3-dihydro-1H-inden-2-yl)amino)nicotinate(13f)
向化合物13d(0.9g,4.2mmol)的N,N-二甲基甲醯胺(10mL)溶液中加入1B(1.1g,6.4mmol)和碳酸銫(2.8g,8.5mmol),將混合物在110℃下攪拌2小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯(30mLx3)萃取。用飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物13f,呈類白色固體(1.25g,96%)。
LC-MS(ESI):m/z=308.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),8.32(s,1H),8.06(s,1H),7.23-7.20(m,2H),7.17-7.14(m,2H),4.96-4.92(m,1H),4.28(q,2H),3.25(dd,2H),3.06(dd,2H),1.30(t,3H).
第五步:5-氰基-6-((2,3-二氫-1H-茚-2-基)胺基)煙醯肼(13g)
5-cyano-6-((2,3-dihydro-1H-inden-2-yl)amino)nicotinohydrazide(13g)
向化合物13f(0.7g,2.0mmol)的乙醇(10mL)溶液中加入水合肼(4ml),將混合物在80℃反應16小時。反應完成後,將反應液過濾,乙醇洗滌。旋幹,得到標題化合物13g,呈灰色固體(350mg,63%)。LC-MS(ESI):m/z=294.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),8.32(s,1H),8.06(s,1H),7.23-7.20(m,2H),7.17-7.14(m,2H),4.96-4.92(m,1H),4.28(q,2H),3.25(dd,2H),3.06(dd,2H),1.30(t,3H).
第六步:3-(2-(5-氰基-6-((2,3-二氫-1H-茚-2-基)胺基)煙醯基)肼基)-3-側氧基丙酸第三丁酯(13i)
tert-butyl 3-(2-(5-cyano-6-((2,3-dihydro-1H-inden-2-
yl)amino)nicotinoyl)hydrazineyl)-3-oxopropanoate(13i)
向化合物13g(0.35g,1.2mmol)的N,N-二甲基甲醯胺(6mL)溶液中加入13h(0.23g,1.4mmol)、2-(7-氮雜苯並三唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.54g,1.4mmol)和N,N-二異丙基乙胺(0.39g,3.0mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用二氯甲烷(20mLx3)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。得到標題化合物13i,呈棕色固體(720mg)。LC-MS(ESI):m/z=434.1[M-H]+。
第七步:2-(5-(5-氰基-6-((2,3-二氫-1H-茚-2-基)胺基)吡啶-3-基)-1,3,4-噁二唑-2-乙酸第三丁酯(13j)
tert-butyl 2-(5-(5-cyano-6-((2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)acetate(13j)
向化合物13i(0.72g,1.7mmol)的二氯甲烷(10mL)溶液中加入4-甲苯磺醯氯(0.63g,3.3mmol)和N,N,N’,N’-四甲基-1,6-己二胺(0.57g,3.3mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用二氯甲烷(30mL)稀釋。用飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。得到標題化合物13j,呈灰色固體(150mg,兩步收率30%)。LC-MS(ESI):m/z=418.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),8.42(s,1H),8.03(d,1H),7.24-7.22(m,2H),7.17-7.15(m,2H),4.98-4.92(m,1H),8.12(s,2H),3.27(dd,2H),3.06(dd,2H),1.43(s,9H).
第八步:2-(5-(5-氰基-6-((2,3-二氫-1H-茚-2-基)胺基)吡啶-3-基)-1,3,4-噁二唑-2-基)乙酸(13k)
2-(5-(5-cyano-6-((2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)acetic acid(13k)
向化合物13j(0.15g,0.36mmol)的二氯甲烷(6mL)溶液中加入TFA(4ml),將混合物在室溫下反應16小時。反應完成後,將反應液用二氯甲烷
(20mL)稀釋。用飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮,得到標題化合物13k,呈灰色固體(120mg,92%)。LC-MS(ESI):m/z=362.1[M+H]+
第九步:2-((2,3-二氫-1H-茚-2-基)胺基)-5-(5-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)-1,3,4-噁二唑-2-基)煙腈(化合物13)
2-((2,3-dihydro-1H-inden-2-yl)amino)-5-(5-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile(compound 13)
向化合物13k(0.12g,0.33mmol)的N,N-二甲基甲醯胺(6mL)溶液中依次地緩慢添加化合物1i(0.11g,0.66mmol)、N,N-二異丙基乙胺(0.21g,1.7mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(0.26g,0.50mmol),並將混合物在室溫下攪拌2h。反應完成後,往反應液加入二氯甲烷(20mL),並且用水(20mL)稀釋,用二氯甲烷萃取(20mLx3)。用飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:二氯甲烷:乙酸乙酯:甲醇=1:0:0~2:10:1)分離純化,得到白化合物13(20mg,13%)。LC-MS(ESI):m/z=468.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.84(dd,1H),8.39(dd,1H),8.02(d,1H),7.24-7.20(m,2H),7.17-7.14(m,2H),4.98-4.92(m,1H),4.81(s,1H),4.68(s,1H),4.41(d,1H),3.27(dd,2H),3.06(dd,2H),2.91(t,1H),2.75(t,1H).
實例14:N-(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)-1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-甲醯胺(化合物14)
N-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(compound 14)
第一步:2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸甲酯(14b)
methyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate(14b)
將起始物質14a(8.63g,50mmol)溶解於200mL的NMP中,然後加入2,3-二氫-1H-茚-2-胺鹽酸鹽(8.48g,50mmol)以及DIEA(14.2g,110mmol),在100℃攪拌反應2小時。將反應液倒入(600mL)水中,有大量固體析出,過濾,濾餅烘乾,得到化合物14b(9.8g,73%)。LC-MS(ESI):m/z=270.2[M+H]+。
第二步:2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-碳醯肼(14c)
2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide(14c)
在250mL的單口瓶中加入化合物14b(8.5g,31.6mmol)和乙醇(100mL),再加入水合肼(39.5g,632mmol),室溫攪拌隔夜,有大量固體析出,然後再過濾,濾餅烘乾得到化合物14c(6.8g,80%)。LC-MS(ESI):m/z=270.2[M+H]+.
第三步:(1-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼-1-羰基)環丙基)胺基甲酸第三丁酯(14d)
tert-butyl(1-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazine-1-carbonyl)cyclopropyl)carbamate(14d)
將化合物14c(6.8g,25.28mmol)溶於DMF(80mL)中,再加入HATU(14.41g,37.92mmol)和DIPEA(9.78g,75.84mmol),攪拌反應10分鐘,然後再加入1-((第三丁氧羰基)胺基)環丙烷-1-羧酸(5.09g,25.28mmol),室溫攪拌隔夜。將反應液倒入水中(250mL),有大量固體析出,過濾,濾餅烘乾得到化合物14d(8.0g,70%)。LC-MS(ESI):m/z=453.2[M+H]+.
第四步:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)胺基甲酸第三丁酯(14e)
tert-butyl(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)carbamate(14e)
將化合物14d(4.0g,8.85mmol)溶于無水四氫呋喃(50mL)中,加入伯吉斯(Burgess)試劑(4.22g,17.7mmol)加熱至70℃,氮氣保護下反應1h。反應完全後,加水和乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,矽膠柱層析(PE/EA=1/1)分離純化,得到化合14e(2.1g,55%)。LC-MS(ESI):m/z=435.1[M+H]+.
第五步:5-(5-(1-胺基環丙基)-1,3,4-噁二唑-2-基)-N-(2,3-二氫-1H-茚-2-基)嘧啶-2-胺(14f)
5-(5-(1-aminocyclopropyl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine(14f)
室溫下,向化合物14e(500mg,1.15mmol)中加入4N的鹽酸1,4-二氧六環溶液(10mL)。攪拌反應1小時。反應完後濃縮,得到14f(400mg粗品)直
接用於下一步。LC-MS(ESI):m/z=335.2[M+H]+.
第六步:N-(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)-1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-甲醯胺(化合物14)
N-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(compound 14)
將化合物14f(400mg,1.19mmol)溶於5毫升DME中,加入三乙胺(721mg,7.14mmol)和CDI(193mg,1.19mmol),室溫攪拌1h,再加入4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(191mg,1.19mmol),反應隔夜,倒入水中有固體析出,固體直接用矽膠柱層析(MeOH/DCM=1/8)分離純化,得到化合物14(70mg,12%)。
LC-MS(ESI):m/z=485.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.75(d,2H),8.35(d,1H),7.87(s,1H),7.23-6.95(m,4H),4.73-4.67(m,1H),4.55(s,2H),3.70-3.67(m,2H),3.29-3.25(m,2H),2.96-2.91(m,2H),2.75-2.74(m,2H),1.55-1.52(m,2H),1.31-1.28(m,2H).
實例15:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)(3,4,6,7-四氫-5H-咪唑並[4,5-c]吡啶-5-基)甲酮(化合物15)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone(compound15)
第一步:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)(3,4,6,7-四氫-5H-咪唑並[4,5-c]吡啶-5-基)甲酮(化合物15)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone(compound 15)
將4e(100mg,0.28mmol)溶於DMF(2mL)中,冰浴降溫至0℃。攪拌下加入4,5,6,7-四氫-3H-咪唑並[4,5-c]吡啶二鹽酸鹽(70mg,0.36mmol)。加入HATU(136mg,0.36mmol),逐滴滴入三乙胺(0.4mL,2.75mmol),室溫攪拌隔夜。加入水(50mL),用乙酸乙酯萃取(50mL×2)萃取。合併有機相,用水(100mL)洗滌一次。用硫酸鈉乾燥、過濾、旋幹,將殘留物用矽膠柱層析分離純化,得到化合物15(30mg,23%)。
LC-MS(ESI):m/z=469.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),8.77(m,2H),8.47-8.27(m,1H),7.48(s,1H),7.33-7.18(m,2H),7.18-7.03(m,2H),4.79-4.61(m,1H),4.48(s,2H),3.81(s,2H),3.29-3.23(m,2H),2.93(dd,2H),2.64-2.52(m,2H),1.72-1.63(m,2H),1.63-1.48(m,2H).
實例16:N-(1H-苯並[d][1,2,3]三唑-5-基)-1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙烷-1-甲醯胺(化合物16)
N-(1H-benzo[d][1,2,3]triazol-5-yl)-1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxamide(compound 16)
第一步:N-(1H-苯並[d][1,2,3]三唑-5-基)-1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙烷-1-甲醯胺(化合物16)
N-(1H-benzo[d][1,2,3]triazol-5-yl)-1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxamide(compound 16)
將化合物4e(130mg,0.3577mmol)、16h(72mg,0.5366mmol)溶於DMF中,加入HATU(272mg,0.7155mmol),滴加DIPEA(0.25ml,13.789mmol),室溫反應。反應完成後,將混合物用水稀釋,並用乙酸乙酯萃取。有機層用飽和鹽水洗,無水硫酸鈉乾燥,濃縮。通過矽膠柱層析分離純化,得到化合物16(65mg,37.89%)。
LC-MS(ESI):m/z=480.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.80(d,2H),8.39(t,1H),7.75(d,1H),7.25-7.19(m,4H),7.17-7.13(m,2H),7.09(s,1H),6.96(s,1H),6.83(dd,1H),4.69(dd,1H),3.27(dd,2H),2.93(dd,2H),2.07(dd,2H),1.97(dd,2H)。
實例17:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2,2-二氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物17)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2,2-difluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 17)
往燒瓶中加入二異丙胺(0.038g,0.38mmol)和四氫呋喃(4ml),在-78℃下滴加n-BuLi(0.15ml,0.38mmol),攪拌0.5h後,往燒瓶中滴加化合物17a(0.036g,0.075mmol)的四氫呋喃(2ml)溶液並在-78℃攪拌0.5h。然後往反應液中滴加N-氟代雙苯磺醯胺(0.12g,0.38mmol)的四氫呋喃(2ml)溶液並在-78℃攪拌0.5h。然後繼續攪拌至室溫。反應完成後,將反應混合物用飽和氯化銨(20mL)溶液淬滅,並用二氯甲烷萃取(30mLx3)。用飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:二氯甲烷:乙酸乙酯:甲醇=1:0:0~2:10:1)分離純化,得到化合物17(7mg,18%)。
LC-MS(ESI):m/z=480.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.95(s,1H),8.89(s,1H),8.59(d,2H),7.24-7.22(m,2H),7.18-7.14(m,2H),4.84(s,2H),4.76-4.71(m,1H),3.99(s,1H),3.93(s,1H),3.29(dd,2H),2.95(dd,2H),2.87-2.83(m,2H).
實例18:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)(4-(甲磺醯基)哌嗪-1-基)甲酮(化合物18)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)(4-(methylsulfonyl)piperazin-1-yl)methanone(compound 18)
第一步:(1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丙基)(4-(甲磺醯基)哌嗪-1-基)甲酮(化合物18)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)(4-(methylsulfonyl)piperazin-1-yl)methanone(compound 18)
將4e(100mg,0.28mmol)溶於DMF(2mL)中,冰浴降溫至0℃。攪拌下加入1-(甲磺醯基)哌嗪三氟乙酸鹽(100mg,0.36mmol)。加入HATU(136mg,0.36mmol),逐滴滴入三乙胺(0.4mL,2.75mmol),室溫攪拌隔夜。加入水(50mL),攪拌均勻,析出固體,抽濾,將固體用矽膠柱層析分離純化,得到化合物18(20mg,14%)。
LC-MS(ESI):m/z=510.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.83(d,2H),8.39(d,1H),7.25-7.19(m,2H),7.18-7.11(m,2H),4.76-4.64(m,1H),3.73-3.54(m,4H),3.34-3.30(m,1H),3.28-3.23(m,1H),3.20-3.07(m,4H),2.94(dd,2H),2.89(s,3H),1.73-1.62(m,2H),1.62-1.49(m,2H).
實例19:N-2-((2,3-二氫-1H-茚-2基)胺基)嘧啶-5基)-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)噁唑-4-甲醯胺(化合物19)
N-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)oxazole-4-carboxamide(compound 19)
第一步:2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)噁唑-4-羧酸乙酯(19a)
Ethyl 2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)oxazole-4-carboxylate(19a)
將2-氯噁唑-4-羧酸乙酯(350mg,2mmol)、化合物1i(320mg,2mmol)和N,N-二異丙基乙胺(1.3g,10mmol)溶解在DMF(10mL)中並在90℃下攪拌2小時。反應完成後,將混合物冷卻至室溫,加水淬滅(10mlx2),二氯甲烷萃取(20mlx2),飽和鹽水洗滌(20ml),乾燥,旋幹,矽膠柱層析分離純化,得到標題化合物(19a)(350mg,67%)。
LC-MS(ESI):m/z=264.1[M+H]+.
第二步:2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)噁唑-4-羧酸(19b)
2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)oxazole-4-carboxylic acid(19b)
向單口瓶中依次加入化合物19a(350mg,1.33mmol)、四氫呋喃(2mL)、甲醇(5ml),蒸餾水(2mL)和一水合氫氧化鋰(300mg,7mmol),並且在室溫攪拌3h。向反應中加入稀鹽酸淬滅反應,用二氯甲烷(50mL×2)萃取,合併後有機相用無水硫酸鈉乾燥,減壓濃縮,得到粗品化合物19b(280mg,89%),粗
品可直接用於下一步反應。
LC-MS(ESI):m/z=236.1[M+H]+.
第三步:N-2-((2,3-二氫-1H-茚-2基)胺基)嘧啶-5基)-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)噁唑-4-甲醯胺(化合物19)
N-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)oxazole-4-carboxamide(compound 19)
氮氣保護下,向單口瓶中依次加入化合物19b(100mg,0.42mmol),DMF(10mL),HATU(190mg,0.5mmol),DIPEA(91mg,0.7mmol),中間物1(113mg,0.5mmol),室溫下攪拌3h。向反應中加入水溶液(30mL)淬滅反應,萃取,靜置分層,水相用二氯甲烷(100mL×2)洗滌,合併後有機相用無水硫酸鈉乾燥,減壓濃縮得到粗品,矽膠柱層析分離純化,得到化合物19(20mg,11%)。
LC-MS(ESI):m/z=444.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 7.81(s,3H),7.27(s,1H),6.42-6.41(m,3H),6.35-6.33(m,3H),3.94-3.91(m,2H),3.20-3.17(m,4H),2.19-2.10(m,5H).
實例20:1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丁基)(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)甲酮(化合物20)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclobutyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone(compound 20)
第一步:1-(乙氧羰基)環丁烷-1-羧酸(20b)
1-(ethoxycarbonyl)cyclobutane-1-carboxylic acid(20b)
室溫下,向已知化合物20a(10.0g,50mmol)中加入乙醇(44mL),再加入氫氧化鉀(2.8g,50mmol),室溫攪拌16h。用6N HCl調pH至5-6,加水和EA萃取,EA相用飽和鹽水洗,用無水硫酸鈉乾燥,減壓濃縮後,得到20b(8.5g,99%)。LC-MS(ESI):m/z=173.1[M+H]+.
第二步:2-(1-(乙氧羰基)環丁烷-1-羰基)肼-1-羧酸第三丁酯(20c)
tert-butyl-2-(1-(ethoxycarbonyl)cyclobutane-1-carbonyl)hydrazine-1-carboxylate(20c)
室溫下,向化合物20b(3.0g,17.4mmol)中加入二氯甲烷(30mL)、第三丁氧羰基肼(2.5g,19.2mmol)、HATU(7.3g,19.2mmol)和DIEA(6.7
g,52.2mmol),室溫攪拌2小時。加水和DCM萃取,DCM相用飽和鹽水洗,用無水硫酸鈉乾燥,減壓濃縮後殘留物以矽膠柱層析(PE:EA=5:1)分離純化,得到20c(4.0g,81%)。LC-MS(ESI):m/z=231.1[M+H-56]+.
第三步:1-(肼基羰基)環丁烷-1-羧酸乙酯(20d)
ethyl 1-(hydrazinecarbonyl)cyclobutane-1-carboxylate(20d)
向化合物20c(4.0g,14mmol)中加入HCl/二氧六環溶液(50mL),室溫下攪拌2小時。減壓濃縮後得到20d粗品(2.6g)。
第四步:1-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼-1-羰基)環丁烷-1-羧酸乙酯(20f)
ethyl 1-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazine-1-carbonyl)cyclobutane-1-carboxylate(20f)
室溫下,向中間物4a(1.8g,7.0mmol)中依次加入二氯甲烷(20mL)、化合物20d(1.6g,8.4mmol)、HATU(2.95g,7.7mmol)、DIEA(1.6g,21.0mmol),室溫攪拌2小時。用水稀釋反應液,二氯甲烷萃取,有機相用飽和鹽水(50mL)洗,用無水硫酸鈉乾燥,減壓濃縮後殘留物用矽膠柱層析(PE:EA=2:1)分離純化,得到20f(1.5g,50%)。LC-MS(ESI):m/z=424.2[M+H]+.
第五步:1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丁烷-1-羧酸乙酯(20g)
Ethyl 1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclobutane-1-carboxylate(20g)
室溫下,向化合物20f(0.8g,1.9mmol)中依次加入二氯甲烷(10mL)、N1,N1,N6,N6-四甲基己烷-1,6-二胺(0.49g,2.8mmol)和對甲苯磺醯氯(0.54g,2.8mmol),室溫攪拌2小時,加水稀釋,二氯甲烷萃取,二氯甲烷相用飽和鹽
水(20mL)洗,用無水硫酸鈉乾燥,減壓濃縮後殘留物用矽膠柱層析(PE:EA=1:1)分離提純,得到20g(500mg,76.6%)。
第六步:1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丁烷-1-羧酸(20h)
1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclobutane-1-carboxylic acid(20h)
室溫下,向化合物20g(0.5g,1.23mmol)中依次加入四氫呋喃(5mL)、水(1mL)和LiOH(0.26g,6.15mmol),室溫攪拌2小時。用1N稀鹽酸調pH至5-6,乙酸乙酯萃取,乙酸乙酯相用飽和鹽水(20mL)洗,用無水硫酸鈉乾燥,減壓濃縮後得到20h(0.45g,96.7%)。LC-MS(ESI):m/z=378.2[M+H]+.
第七步:1-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)環丁基)(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)甲酮(化合物20)
(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)cyclobutyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone(compound 20)
室溫下,向化合物20h(0.45g,1.2mmol)中依次加入DMF(2mL)、HATU(0.55g,1.44mmol)、1i(0.4g,2.5mmol)和DIEA(0.67g,3.6mmol)。室溫攪拌2小時,加水稀釋,用乙酸乙酯萃取,有機相用飽和鹽水(20mL)洗滌,用無水硫酸鈉乾燥,減壓濃縮後殘留物用矽膠柱層析(DCM:MeoH=100:1-20:1)分離純化,得到化合物20(0.012g,1.7%)。
1H NMR(400MHz,CDCl3)δ 12.36(s,1H),8.86-8.47(m,2H),7.18-7.16(m,2H),7.19-7.10(m,2H),6.18-5.94(m,1H),4.82-4.78(m,2H),4.44(s,1H),3.91-3.89(m,1H),3.59-3.57(m,1H),3.37-3.31(m,2H),2.97-2.77(m,7H),2.57-2.55(m,1H),2.21-2.13(m,1H),1.95-1.93(m,1H)。LC-MS(ESI):m/z=484.2
[M+H]+.
化合物21:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物21)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)oxazol-4-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 21)
第一步:2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-羧酸乙酯(21b)
ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)oxazole-4-carboxylate(21b)
在250mL的單口瓶中加入化合物(21a)(5.0g,26.5mmol),用乙醇(50mL)溶解,室溫下加入DIEA(13.7g,106mmol)和2,3-二氫-1H-茚-2-胺鹽酸鹽(6.75g,39.8mmol),加完後升至85℃反應3小時,反應完全後,減壓濃縮,粗產品不用純化直接用於下一步。LC-MS(ESI):m/z=273.1[M+H]+.
第二步:2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-羧酸(21c)
2-((2,3-dihydro-1H-inden-2-yl)amino)oxazole-4-carboxylic acid
(21c)
在250mL的單口瓶中加入化合物(21b)(7.0g,25.7mmol)和LiOH(5.13g,129mmol),用甲醇(50mL),水(50mL)和四氫呋喃(50mL)溶解,在室溫反應3小時,反應完全後,加水100mL減壓濃縮除去有機溶劑,然後用4N鹽酸調節pH=2-3。大量固體析出,過濾。濾餅用水20mLx3洗滌。濾餅用甲苯帶水三次,濃縮至幹,得到化合物21c(5.0g,79.6%)。LC-MS(ESI):m/z=245.1[M+H]+.
第三步:3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-羰基肼基)-3-側氧基丙酸乙酯(21d)
ethyl 3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)oxazole-4-carbonyl)hydrazineyl)-3-oxopropanoate(21d)
在100mL的單口瓶中加入化合物21c(2.0g,8.19mmol),用DCM(20mL)溶解,加入HATU(4.05g,10.6mmol)、三乙胺(2.45g,24.6mmol)和3-肼基-3-側氧基丙酸乙酯(1.56g,10.6mmol),室溫反應16h,用水溶液(10mL)洗滌,室溫攪拌10min後用DCM萃取(5mL×3),合併有機相,飽和氯化鈉洗滌(5mL×1),無水硫酸鈉乾燥,減壓濃縮,得到化合物21d(3.5g,粗品),直接用於下一步反應。LC-MS(ESI):m/z=373.1[M+H]+。
第四步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-基)-1,3,4-噁二唑-2-基)乙酸乙酯(21e)
ethyl 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)oxazol-4-yl)-1,3,4-oxadiazol-2-yl)acetate(21e)
在100mL的單口瓶中加入化合物21d(3.5g),用DCM(40mL)溶解,室溫下加入TsCl(3.6g,19mmol)和N1,N1,N6,N6-四甲基己烷-1,6-二胺(3.2g,19mmol),然後室溫反應隔夜。用水溶液(40mL)洗滌,室溫攪拌10min後用DCM萃
取(50mL×3),合併有機相,飽和氯化鈉洗滌(5mL×1),用無水硫酸鈉乾燥,減壓濃縮,用矽膠柱層析分離純化,得到化合物21e(0.6g,1.7mmol)。LC-MS(ESI):m/z=355.2[M+H]+.
第五步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-基)-1,3,4-噁二唑-2-基)乙酸(21f)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)oxazol-4-yl)-1,3,4-oxadiazol-2-yl)acetic acid(21f)
在100mL的單口瓶中加入化合物(21e)(0.3g,0.847mmol)和LiOH(0.169g,4.23mmol),用甲醇(10mL),水(10mL)和四氫呋喃(10mL)溶解,室溫反應3小時,反應完全後,加水20mL減壓濃縮除去有機溶劑,然後用4N鹽酸調節pH=2-3。乙酸乙酯20mLx3萃取。合併有機相,濃縮得到化合物21f(0.2g,0.61mmol,72%)。LC-MS(ESI):m/z=327.0[M+H]+.
第六步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)噁唑-4-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物21)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)oxazol-4-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 21)
在100mL的單口瓶中加入化合物21f(0.20g,0.61mmol),用DMF(5mL)溶解,加入PyBop(0.431g,0.827mmol)、DIPEA(0.317g,2.45mmol)和4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(0.197g,1.23mmol),室溫反應16h,用水溶液(20mL)洗滌,室溫攪拌10min後用乙酸乙酯萃取(20mL×3),合併有機相,飽和氯化鈉洗滌(5mL×1),無水硫酸鈉乾燥,減壓濃縮,用矽膠柱層析(DCM:MeOH=20:1)分離純化,得到化合物21(0.016g,0.038mmol,6%)。
LC-MS(ESI):m/z=433.2[M+H]+。
1H NMR(400MHz,CD3OD)δ 8.03(d,1H),7.21(dd,2H),7.14(dd,2H),4.86(s,1H),4.53(dd,1H),4.37(d,2H),3.96(dd,2H),3.37(d,2H),3.34(d,2H),2.97(t,2H),2.92(d,1H),2.85(t,1H).
實例22:5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-2-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)噁唑-4-甲腈(化合物22)
5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)oxazole-4-carbonitrile(compound 22)
第一步:5-胺基-2-甲基噁唑-4-甲腈(22b)
5-amino-2-methyloxazole-4-carbonitrile(22b)
將化合物22a(500mg,1.98mmol)、乙醯氯(312mg,3.95mmol)和NMP(5mL)加入微波管中,微波加熱至120℃反應1.5小時。反應完成後,反應體系加入水中,並用乙酸乙酯(50mLx3)萃取。有機層用無水硫酸鈉乾燥,濃縮。通過用矽膠柱層析分離純化,得到標題化合物22b,呈淡黃色固體(170mg,70%)。
1H NMR(400MHz,CDCl3)δ 4.79(s,2H),2.33(s,3H).
第二步:5-溴-2-甲基噁唑-4-甲腈(22c)
5-bromo-2-methyloxazole-4-carbonitrile(22c)
將化合物22b(200mg,1.63mmol)加入乙腈(10mL)溶液中,冰浴下依次添加溴化銅(725mg,3.26mmol)、亞硝酸第三丁酯(335mg,3.26mmol),將混合物在冰浴下攪拌1小時。反應完成後,混合物用飽和碳酸氫鈉(30mL)溶液稀釋,乙酸乙酯(50mL)萃取,有機相用無水硫酸鈉乾燥,過濾,濾液減壓濃縮後通過矽膠柱層析(石油醚:乙酸乙酯=10:1)純化,分離得到化合物22c(100mg,33%)。
1H NMR(400MHz,CDCl3)δ 2.52(s,3H).
第三步:5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-2-甲基噁唑-4-甲腈(22d)
5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-methyloxazole-4-carbonitrile(22d)
將化合物22c(400mg,2.14mmol)加入二氧六環(10mL)和水(1mL)的混合溶劑中,然後加入N-(2,3-二氫-1H-茚-2-基)-5-(4,4,5-三甲基-1,3,2-二氧雜醇-2-基)嘧啶-2-胺(691mg,2.14mmol),碳酸鉀(591mg,4.28mmol),Pd(dppf)Cl2(73mg,0.1mmol),氮氣保護,升溫至100℃攪拌3h。待反應冷至室溫,過濾,濾液濃縮後通過矽膠柱層析(石油醚:乙酸乙酯=2:1)分離純化,得到22d(400mg,59%)。
LC-MS(ESI):m/z=318.1[M+H]+.
第四步:2-(4-氰基-5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)噁唑-2-基)乙酸甲酯(22e)
methyl 2-(4-cyano-5-(2-((2,3-dihydro-1H-inden-2-
yl)amino)pyrimidin-5-yl)oxazol-2-yl)acetate(22e)
將二異丙胺(127mg,1.26mmol)加入無水四氫呋喃(3mL)中,在氮氣保護和冰浴下加入正丁基鋰(0.5mL,1.26mmol,2.5M),攪拌半小時。然後將溫度降至-78℃,然後加入用四氫呋喃溶解的22d(200mg,0.63mmol),繼續攪拌半小時後,加入碳酸二甲酯(114mg,1.26mmol),攪拌半小時後,升至室溫攪拌半小時。反應完成後,用飽和的氯化銨水溶液淬滅反應,並用乙酸乙酯(80mL)萃取。有機層用無水硫酸鈉乾燥,濃縮。通過用矽膠柱層析(石油醚:乙酸乙酯=1:2)分離純化,得到標題化合物22e,呈黃色固體(110mg,47%)。LC-MS(ESI):m/z=376.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 7.23-7.26(m,4H),7.19-7.22(m,2H),6.42-6.43(m,1H),4.89-4.93(m,1H),3.93(s,2H),3.80(m,3H),3.41-3.47(m,2H),2.93-2.98(m,2H).
第五步:2-(4-氰基-5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)噁唑-2-基)乙酸(22f)
2-(4-cyano-5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)oxazol-2-yl)acetic acid(22f)
將化合物22e(110mg,0.29mmol)溶於的二氧六環(2mL)和水(1mL)的混合溶液中,然後加入水合氫氧化鋰(24mg,0.58mmol),室溫攪拌,TLC監測反應完全後,用1M稀鹽酸調pH至5~6,直接濃縮至幹,得到標題化合物22f的粗品,該粗品直接用於下一步反應。LC-MS(ESI):m/z=362.1[M+H]+
第六步:5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-2-(2-側氧基-2-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙基)噁唑-4-甲腈(化合物22)
25-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-(2-oxo-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)oxazole-4-carbonitrile(compound 22)
在0℃下,向化合物22f(100mg,0.28mmol)的N,N-二甲基甲醯胺
(3mL)溶液中依次地緩慢添加化合物1i(66mg,0.42mmol)、N,N-二異丙基乙胺(0.5mL)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(160mg,0.42mmol),室溫下攪拌反應,反應完成後,將反應混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取(50mLx2)。用飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。通過用矽膠柱層析(DCM:THF=1:1)分離純化,得到化合物22(12mg,9%)。
LC-MS(ESI):m/z=468.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.70-8.73(m,2H),8.46(d,1H),7.21-7.24(m,2H),7.14-7.17(m,2H),4.68-4.78(m,4H),4.33(d,2H),3.82-3.83(m,1H),3.26-3.32(m,2H),2.88-2.97(m,3H),2.72-2.74(m,1H).
實例23:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物23)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 23)
第一步:3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-2-氟-3-側氧基丙酸乙酯(23b)
ethyl 3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazinyl)-2-fluoro-3-oxopropanoate(23b)
將化合物4b(6g,22.3mmol)和3-乙氧基-2-氟-3-側氧基丙酸(3.34g,22.3mmol)加入N,N-二甲基甲醯胺(100mL)溶液中,然後依次地緩慢添加N,N-二異丙基乙胺(5.75g,44.6mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(11g,28.99mmol),室溫下攪拌反應,LCMS監測反應完全。反應完成後,將反應混合物用蒸餾水(200mL)稀釋,並用乙酸乙酯萃取(200mLx2)。用蒸餾水和飽和鹽水(100mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。粗品通過矽膠柱層析(石油醚:乙酸乙酯=1:2)純化分離,得到白色固體化合物23b(3.4g,38%)。LC-MS(ESI):m/z=402.1[M+H]+
第二步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟乙酸乙酯(23c)
ethyl 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoroacetate(23c)
將化合物23b(2.4g,5.99mmol)加入無水四氫呋喃(80mL)溶液中,然後加入伯吉斯試劑(1.71g,7.18mmol),升至75℃攪拌2小時。反應完成後,冷卻,通過矽膠柱層析法(石油醚:乙酸乙酯=1:1)純化殘餘物,得到標題化合物23c呈白色固體(1.6g,70%)。LC-MS(ESI):m/z=384.1[M+H]+
第三步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟乙酸(23d)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoroacetic acid(23d)
將化合物23c(1.5g,3.92mmol)溶於二氧六環(15mL)和水(4mL)的混合溶液中,然後加入水合氫氧化鋰(329mg,7.84mmol),室溫攪拌,TLC監測反應完全後,用1M稀鹽酸調pH至3~4,用乙酸乙酯萃取,無水硫酸鈉乾燥,過濾,濃縮後得標題化合物23d呈淡黃色固體(1.4g,100%)。LC-MS(ESI):m/z=356.1[M+H]+
第四步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物23)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 23)
在0℃下,向化合物23d(100mg,0.28mmol)的N,N-二甲基甲醯胺(3mL)溶液中依次地緩慢添加1i(90mg,0.56mmol)、N,N-二異丙基乙胺(108mg,0.84mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(160mg,0.42
mmol),室溫下攪拌反應,LCMS監測反應完全。反應完成後,將反應混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取(50mL*3)。用蒸餾水和飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(DCM:THF=1:1)純化,得到化合物23(16mg,12%)。
LC-MS(ESI):m/z=462.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.77-8.90(m,2H),8.50-8.51(m,1H),7.22-7.24(m,2H),7.11-7.17(m,2H),4.60-4.82(m,3H),3.76-3.88(m,2H),3.23-3.32(m,2H),2.90-2.97(m,2H),2.67-2.89(m,3H).
實例24:1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)-2-(5-(2-((5-(三氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙-1-酮(化合物24)
1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethan-1-one(compound 24)
第一步:2-(羥基亞胺基)-6-(三氟甲基)-2,3-二氫-1H-茚-1-酮(24b)
2-(hydroxyimino)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one
(24b)
將化合物24a(18g,90mmol)和亞硝酸正丁酯(10.8g,90mmol)加入到無水甲醇(270mL)溶液中,然後加入濃鹽酸(4.5mL),升至75℃攪拌10小時。反應完成後,將反應液冷卻濃縮至幹,固體用少量的乙酸乙酯洗滌後,將固體烘乾得化合物24b(13g,63%)。LC-MS(ESI):m/z=230.1[M+H]+
第二步:5-(三氟甲基)-2,3-二氫-1H-茚-2-胺(24c)
5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-amine(24c)
向250mL高壓釜中依次加入化合物24b(5g,21.8mmol)、冰醋酸(100mL)和濃硫酸(5mL)的混合溶劑,鈀碳(500mg),並充入4MPa的氫氣,升溫至95℃攪拌15h。待反應冷至室溫,矽藻土過濾,濾液濃縮後通過矽膠柱層析(DCM:MeOH=10:1)分離提純,得到24c(1.2g,27%)。LC-MS(ESI):m/z=202.1[M+H]+
第三步:2-(5-(2-((5-(三氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(24d)
ethyl 2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(24d)
將化合物24c(400mg,1.99mmol)和2-(5-(2-氯嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(533mg,1.99mmol)加入NMP(10mL)溶液中,然後加入DIPEA(770mg,5.97mmol),升溫至100℃攪拌2小時。冷卻,將反應混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取(50mLx2)。用蒸餾水和飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。矽膠柱層析純化殘餘物,得到標題化合物24d,呈棕色油狀物(120mg,14%)。LC-MS(ESI):m/z=434.1[M+H]+
第四步:2-(5-(2-((5-(三氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-
5-基)-1,3,4-噁二唑-2-基)乙酸(24e)
2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(24e)
將化合物24d(120mg,0.28mmol)溶於的二氧六環(2mL)和水(1mL)的混合溶液中,然後加入水合氫氧化鋰(35mg,0.84mmol),室溫攪拌,TLC監測反應完全後,減壓濃縮至幹,然後用1M稀鹽酸調pH至5~6,過濾,固體烘乾後的標題化合物24e,呈棕色固體(75mg,66%)。LC-MS(ESI):m/z=406.1[M+H]+
第五步:1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)-2-(5-(2-((5-(三氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙-1-酮(化合物24)
1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethan-1-one(compound 24)
在0℃下,向化合物24e(75mg,0.19mmol)的N,N-二甲基甲醯胺(3mL)溶液中依次緩慢添加化合物1i(61mg,0.38mmol)、N,N-二異丙基乙胺(0.5mL)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(108mg,0.29mmol),室溫下攪拌反應,LCMS監測反應完全。反應完成後,將反應混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯萃取(50mLx4)。用蒸餾水和飽和鹽水(50mL)洗滌有機層,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(DCM:THF=1:1)純化,得到化合物24(18mg,19%)。
LC-MS(ESI):m/z=512.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.81-8.83(m,2H),8.42(d,1H),7.59(s,1H),.44-7.52(m,2H),4.81(s,1H),4.74-4.79(m,1H),4.69(s,1H),4.41(d,
2H),3.83-3.86(m,2H),3.35-3.41(m,2H),2.99-3.05(m,2H),2.90-2.91(m,1H),2.74-2.75(m,1H).
實例25:1-(6,7-二氫-1H-[1,2,3]三唑並[4,5-c]吡啶-5(4H)-基)-2-(5-(2-((5,6-二氫-4H-環戊並[b]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酮(化合物25)
1-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-2-(5-(2-((5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethanone(compound 25)
第一步:(Z)-5-(羥基亞胺基)-4H-環戊並[b]噻吩-6(5H)-酮(25b)
(Z)-5-(hydroxyimino)-4H-cyclopenta[b]thiophen-6(5H)-one(25b)
將化合物25a(4.0g,28.9mmol)溶於甲醇(60ml)中,升溫至40℃,快速加入亞硝酸正丁酯(3.3g,32.0mmol)和鹽酸(1.6ml),加畢,保持40℃攪拌2小時後減壓蒸去甲醇,剩餘物加入PE/EtOH=10/1(30ml),攪拌5分鐘後,過濾,
濾餅乾燥,得到化合物25b(2.5g,52.1%)。
第二步:(6-側氧基-5,6-二氫-4H-環戊並[b]噻吩-5-基)胺基甲酸第三丁酯(25c)
tert-butyl(6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)carbamate(25c)
將化合物25b(2.5g,15.0mmol)溶於MeOH(50ml)中,加入Pd/C(0.5g)和(Boc)2O(3.9g,18.0mmol),加畢,用氮氣置換3次後,通入H2,室溫攪拌隔夜;反應液過濾,濾液減壓蒸幹,剩餘物矽膠柱層析(PE/EA=5/1)純化,得到25c(2.6g,68.4%)。
第三步:4H-環戊並[b]噻吩-5-基胺基甲酸第三丁酯(25d)
tert-butyl 4H-cyclopenta[b]thiophen-5-ylcarbamate(25d)
將NaBH4(783mg,20.6mmol)置於100ml單口瓶,加入THF(2.5ml),室溫滴加25c(2.6g,10.3mmol)的甲醇溶液(10ml),加畢,室溫攪拌隔夜,反應液加水(30ml),攪拌10分鐘後EA萃取3次,合併有機相,用飽和NaCl水溶液洗1洗,無水硫酸鈉乾燥,過濾,濾液減壓蒸幹得化合物25d(2.2g,91.7%)。
第四步:4H-環戊並[b]噻吩-5(6H)-亞胺(25e)
4H-cyclopenta[b]thiophen-5(6H)-imine(25e)
將化合物25d(2.2g,9.3mmol)溶於DCM(30ml)中,加入三氟醋酸(1.0g),冰浴冷卻至0℃,滴加Et3SiH(1.1g),加畢,緩慢恢復至室溫攪拌2小時,反應液減壓蒸幹,剩餘物加入乙醚(30ml),攪拌10分鐘後過濾,濾餅乾燥,得到化合物25e(1.2g,94.5%)。
第五步:5,6-二氫-4H-環戊並[b]噻吩-5-胺(25f)
5,6-dihydro-4H-cyclopenta[b]thiophen-5-amine(25f)
將化合物25e(1.2g,8.7mmol)溶於甲醇(50ml)中,加入Pd/C(1.2g),加畢,用氫氣置換3次,室溫攪拌隔夜;LC-MS監測反應完畢,反應液過濾,濾液減壓蒸幹得25f(0.8g,66.7%)。LC-MS(ESI):m/z=140.1[M+H]+.
第六步:2-(5-(2-((5,6-二氫-4H-環戊並[b]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(25g)
Ethyl 2-(5-(2-((5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(25g)
將25f(200mg,1.4mmol)和中間物2(376mg,1.4mmol)置於100ml單口瓶,加入NMP(30ml)和DIPEA(80mg,4.2mmol),加畢,升溫至100℃,攪拌反應2小時,LC-MS監測反應完畢,反應液以矽膠柱層析(PE/EA=2/1)純化,得到化合物25g(180mg,34.6%)。LC-MS(ESI):m/z=372.2[M+H]+.
第七步:2-(5-(2-((5,6-二氫-4H-環戊並[b]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(25h)
2-(5-(2-((5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(25h)
將25g(180mg,0.5mmol)溶於THF(5ml)和H2O(2ml)中,加入LiOH.H2O(63mg,1.5mmol),加畢,室溫攪拌3小時;反應液減壓蒸幹,剩餘物加水5ml,用2N稀鹽酸調節pH=5,乙酸乙酯萃取4次,合併有機相,用無水硫酸鈉乾燥,過濾,濾液減壓蒸幹得化合物25h(150mg,87.2%)。LC-MS(ESI):m/z=344.1[M+H]+.
第八步:1-(6,7-二氫-1H-[1,2,3]三唑並[4,5-c]吡啶-5(4H)-基)-2-(5-(2-((5,6-二氫-4H-環戊並[b]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酮
(化合物25)
1-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-2-(5-(2-((5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethanone(compound 25)
將化合物25h(50mg,0.15mmol)溶於DMF(5ml),加入CDI(29mg,0.18mmol),在室溫攪拌10分鐘後加入三乙胺(606mg,6mmol)和1i(61mg,0.38mmol)的DMF溶液2ml,加畢,室溫攪拌2小時,過濾,濾液經矽膠柱層析純化(DCM/MeOH=15/1),得到化合物25(40mg,59.7%)。
LC-MS(ESI):m/z=450.2[M+H]+。
1H NMR(400MHz,DMSO-d 6)δ 14.72(m,1H),8.84-8.77(m,2H),8.53(d,1H),7.37(d,1H),6.89(d,1H),5.16-5.07(m,1H),4.81(s,1H),4.68(s,1H),4.43(s,1H),4.39(s,1H),3.87-3.81(m,2H),3.35-3.32(m,1H),3.18-3.12(m,1H),2.92-2.83(m,2H),2.78-2.72(m,2H).
實例26:2-(5-(2-((5,6-二氫-4H-環戊並[c]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物26)
2-(5-(2-((5,6-dihydro-4H-cyclopenta[c]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-on(compound 26)
第一步:噻吩-3,4-二基二甲醇(26b)
thiophene-3,4-diyldimethanol(26b)
在500mL的單口瓶中加入化合物26a(10g,58.1mmol)溶於40mL的THF中,在零度下加入硼烷的THF溶液(145mL,145mmol,1.0M),再室溫攪拌隔夜,用100毫升THF/H2O(1:1)淬滅反應,再加入150毫升飽和碳酸氫鈉溶液,用EA(100mL×3)萃取,合併有機相,飽和氯化鈉洗滌(100mL),無水硫酸鈉乾燥,減壓濃縮,得到化合物26b(5.1g,產率61%)。LC-MS(ESI):m/z=145.2[M+H]+.
第二步:3,4-雙(氯甲基)噻吩(26c)
3,4-bis(chloromethyl)thiophene(26c)
將化合物26b(5.1g,35.4mmol)溶於60毫升DCM中,在冰浴下加入氯化亞碸(6mL),再升至室溫,反應隔夜。TLC監測反應完全後,用冰水萃滅反應,用DCM萃取,用飽和碳酸氫鈉和鹽水洗滌,無水硫酸鈉乾燥,旋幹,通過矽膠柱層析(PE/EA=10/1)分離純化,得到化合物26c(2.6g,41%)。LC-MS
(ESI):m/z=181.1[M+H]+.
第三步:4H-環戊並[c]噻吩-5,5(6H)-二羧酸二乙酯(26d)
diethyl 4H-cyclopenta[c]thiophene-5,5(6H)-dicarboxylate(26d)
將丙二酸二乙酯(6.5g,40.9mmol)溶于無水THF(100mL)中,在冰浴的條件下加入60%氫化鈉(4.1g,102.2mmol),然後冰浴下攪拌30分鐘,回流的情況下,再加入化合物26c(7.4g,40.9mmol),繼續反應3h。用水萃滅反應,用乙酸乙酯(50mL×3)萃取,飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,通過矽膠柱層析(PE/EA=6/1)分離純化,得到化合物26d(6.0g,55%)。LC-MS(ESI):m/z=269.2[M+H]+。
第四步:5,6-二氫-4H-環戊並[c]噻吩-5-羧酸乙酯(26e)
ethyl 5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylate(26e)
將化合物26d(5.2g,19.4mmol)溶於DMSO(40mL)中,加入水(2mL),再加入氯化鈉固體(5.2g),加熱至回流,反應5小時。冷至室溫,加水和乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,矽膠柱層析(PE/EA=10/1)分離純化,得到化合物26e(2.0g,52%)。LC-MS(ESI):m/z=197.2[M+H]+.
第五步:5,6-二氫-4H-環戊並[c]噻吩-5-羧酸(26f)
5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid(26f)
將化合物26e(2.0g,10.2mmol)溶於15毫升乙醇和5毫升水中,加入氫氧化鉀(1.71g,30.6mmol),室溫攪拌,反應1小時。TLC監測反應完全後,濃縮反應液,加水稀釋,用乙醚萃取,水相再用4N HCl調至pH小於5用DCM萃取,鹽水洗滌有機相,無水硫酸鈉乾燥,過濾,旋幹,得到化合物26f(1.3g,76%)。LC-MS(ESI):m/z=169.2[M+H]+.
第六步:(5,6-二氫-4H-環戊並[c]噻吩-5-基)胺基甲酸第三丁酯(26g)
tert-butyl(5,6-dihydro-4H-cyclopenta[c]thiophen-5-yl)carbamate(26g)
將化合物26f(1.1g,6.5mmol)溶于10毫升第三丁醇中,再依次加入三乙胺(661mg,6.5mmol)和DPPA(1.8g,6.5mmol)氮氣保護下回流反應隔夜,冷至室溫濃縮,通過矽膠柱層析(PE/EA=2/1)分離,得到化合物26g(1.2g,77%)。LC-MS(ESI):m/z=184.2[M-55]+.
第七步:5,6-二氫-4H-環戊並[c]噻吩-5-胺鹽酸鹽(26h)
5,6-dihydro-4H-cyclopenta[c]thiophen-5-amine hydrochloride(26h)
將化合物26g(1.2g,5.0mmol)溶於20毫升4N的1,4-二氧六環溶液中,室溫攪拌,反應1小時。TLC監測反應完全後,濃縮,得到化合物26h(755mg,86%)。LC-MS(ESI):m/z=140.2[M+H]+.
第八步:2-(5-(2-((5,6-二氫-4H-環戊並[c]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(26i)
ethyl 2-(5-(2-((5,6-dihydro-4H-cyclopenta[c]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(26i)
在100mL的單口瓶中加入化合物26h(177mg,1.0mmol),用NMP(4mL)溶解,加入DIPEA(387mg,3.0mmol)、中間物2(268mg,1.0mmol),在100℃攪拌2h,冷卻至室溫,倒入水中,有固體析出,抽濾,乾燥,得到淡黃色固體化合物26i(205mg,55%)。LC-MS(ESI):m/z=372.2[M+H]+.
第九步:2-(5-(2-((5,6-二氫-4H-環戊並[c]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(26j)
2-(5-(2-((5,6-dihydro-4H-cyclopenta[c]thiophen-5-
yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(26j)
將化合物26i(205mg,0.55mmol)溶於5毫升THF和2毫升水中,加入一水氫氧化鋰(69mg,1.65mmol),室溫攪拌,反應1小時。TLC監測反應完全後,濃縮反應液,加水稀釋,用乙醚萃取兩遍,水相再加4N鹽酸水溶液調pH至4-5,用二氯甲烷萃取,用無水硫酸鈉乾燥,過濾,旋幹,得到化合物26j(165mg,87%)。LC-MS(ESI):m/z=344.2[M+H]+.
第十步:2-(5-(2-((5,6-二氫-4H-環戊並[c]噻吩-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物26)
2-(5-(2-((5,6-dihydro-4H-cyclopenta[c]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 26)
將化合物26j(165mg,0.48mmol)溶於3毫升DMF中加入CDI(94mg,0.58mmol),室溫攪拌30分鐘,再將4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(231mg,1.44mmol)溶於2毫升DMF,用DIPEA(248mg,1.92mmol)游離,加入到26j的反應液中反應1h,直接矽膠柱層析(MeOH/DCM=10/1)分離,得到化合物26(25mg,12%)。
LC-MS(ESI):m/z=450.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.84-8.78(m,2H),8.46(d,1H),7.06(s,2H),4.95-4.90(m,1H),4.81(s,1H),4.68(s,1H),4.41(d,2H),3.87-3.81(m,2H),3.14-3.08(m,2H),2.69(t,1H),2.74-2.67(m,3H).
實例27:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)丙-1-酮(化合 物27)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)propan-1-one(compound 27)
第一步:3-乙氧基-2-氟-2-甲基-3-側氧基丙酸(27b)
3-ethoxy-2-fluoro-2-methyl-3-oxopropanoic acid(27b)
將化合物27a(10.0g,52mmol)溶于無水乙醇(100mL)中,再加入氫氧化鉀(2.92g,52mmol)。在加熱回流反應4小時。冷至室溫,濃縮乙醇,加入水和乙醚,水相再用4N的鹽酸將pH調到3-4,用乙酸乙酯(50mL×3)萃取,有機相用飽和鹽水洗滌,用無水硫酸鈉乾燥,過濾,濃縮,得到化合物27b(5.5g,64%)。LC-MS(ESI):m/z=165.2[M+H]+.
第二步:3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-2-氟-2-甲基-3-側氧基丙酸乙酯(27c)
ethyl 3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazineyl)-2-fluoro-2-methyl-3-oxopropanoate(27c)
將化合物27b(1.8g,11mmol)溶於DMF(80mL)中,再加入HATU
(5.7g,15mmol)和DIPEA(3.87g,30mmol),攪拌反應10分鐘,然後再加化合物4b(2.69g,10mmol),室溫攪拌隔夜。將反應液倒入水中(250mL),有大量固體析出,過濾,濾餅烘乾得到化合物27c(2.4g,58%)。LC-MS(ESI):m/z=416.2[M+H]+.
第三步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟丙酸乙酯(27d)
ethyl 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoropropanoate(27d)
將化合物27c(2.48g,5.98mmol)溶于無水四氫呋喃(25mL)中,加入伯吉斯試劑(4.27g,17.93mmol),在室溫攪拌,在氮氣保護下回流反應1小時。
TLC監測反應完全後,加水和乙酸乙酯萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,矽膠柱層析(PE/EA=1/1)純化,得到化合物27d(1.2g,50%)。LC-MS(ESI):m/z=398.2[M+H]+.
第四步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟丙酸(27e)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoropropanoic acid(27e)
將化合物27d(1.2g,3.02mmol)溶於9毫升THF和3毫升水中,加入一水氫氧化鋰(381mg,9.07mmol),在室溫攪拌,反應1小時。TLC監測反應完全後,濃縮反應液,加水稀釋,用乙醚萃取,再將水層加4N鹽酸水溶液調pH至4-5,用二氯甲烷萃取,有機層用飽和鹽水洗滌,用無水硫酸鈉乾燥,濃縮,得到化合物27e(850mg,76%)。LC-MS(ESI):m/z=370.2[M+H]+.
第九步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)丙-1-酮(化合 物27)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-
yl)propan-1-one(compound 27)
將化合物27e(123mg,0.33mmol)溶於3毫升無水DCM中,加入草醯氯(64mg,0.5mmol)和催化量的DMF,室溫攪拌30分鐘,再將4,5,6,7-四氫-1H-[1,2,3]三唑並[4,5-c]吡啶鹽酸鹽(133mg,0.83mmol)溶於3毫升無水DMSO中,加入三乙胺(134mg,1.32mmol),再將此溶液加入到上述反應液中反應1h,濃縮掉DCM,再矽膠柱層析(THF/DCM=1/3純化,得到化合物27(40mg,26%)。
LC-MS(ESI):m/z=476.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.92-8.81(m,2H),8.50(d,1H),7.24-7.14(m,4H),4.76-4.69(m,3H),4.00-3.90(m,2H),3.32-3.26(m,2H),2.99-2.95(m,2H),2.83-2.81(m,2H),2.16-2.07(m,3H).
實例28:2-(5-(2-((5-(呋喃-3-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物28)
2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-
[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 28)
第一步:2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸甲酯(28c)
methyl 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate(28c)
向化合物28a(3.0g,10.71mmol)的乙醇(30mL)溶液中加入28b(2.0g,10.71mmol)和三乙胺(4.3g,42.87mmol),將混合物在80℃下攪拌4小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯(30mLx3)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1),得到標題化合物28c,呈類白色固體(3.7g,100%)。LC-MS(ESI):m/z=348.1,350.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.79(s,1H),8.73(s,1H),8.44(d,1H),7.42(s,1H),7.33(d,1H),7.18(d,1H),4.73-4.66(m,1H),3.80(s,3H),3.27-3.20(m,2H),2.96-2.86(m,2H).
第二步:2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羧酸(28d)
2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-
carboxylic acid(28d)
將化合物28c(5.0g,14.36mmol)溶於四氫呋喃(50mL)/甲醇(5ml)和蒸餾水(5ml)中,再加入LiOH(1.0g,43.08mmol);然後,在室溫下反應16小時。反應完成後,冷卻,加酸調pH=3,再加乙酸乙酯50mLx3萃取,有機相用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到類白色固體目標化合物28d(4.5g,94%)。LC-MS(ESI):m/z=334.1,336.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 12.67(s,1H),8.77(s,1H),8.71(s,1H),8.31(d,1H),7.42(s,1H),7.33(m,1H),7.18
(d,1H),4.73-4.67(m,1H),3.31-3.17(m,2H),2.96-2.85(m,2H).
第三步:3-(2-(2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-3-側氧基丙酸乙酯(28e)
Ethyl 3-(2-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazinyl)-3-oxopropanoate(28e)
向化合物28d(0.35g,1.2mmol)的N,N-二甲基甲醯胺(6mL)溶液中加入2e(0.23g,1.4mmol)、2-(7-氮雜苯並三唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.54g,1.4mmol)和N,N-二異丙基乙胺(0.39g,3.0mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用二氯甲烷(20mLx3)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。得到標題化合物28e,呈棕色固體(720mg)。LC-MS(ESI):m/z=460.1,462.1[M-H]+。
第四步:2-(5-(2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(28f)
Ethyl 2-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(28f)
向化合物28e(1.0g,2.16mmol)的二氯甲烷(20mL)溶液中加入4-甲苯磺醯氯(0.83g,4.33mmol)和N,N,N’,N’-四甲基-1,6-己二胺(1.12g,6.49
mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用二氯甲烷(30mL)稀釋。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1),得到標題化合物28f,呈灰色固體(550mg,兩步收率42%)。LC-MS(ESI):m/z=444.1,446.1,[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.81(s,1H),8.43(d,1H),7.43(s,1H),7.33(d,1H),7.19(d,1H),4.74-4.69(m,1H),4.23(s,2H),4.17(q,2H),3.33-3.22(m,2H),2.98-2.87(m,2H),1.22(t,3H).
第五步:2-(5-(2-((5-(呋喃-3-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(28g)
Ethyl 2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(28g)
向化合物28f(0.54g,1.22mmol)的二氧六環/水(10ml/1ml)溶液中加入化合物28i(0.15g,1.33mmol)、磷酸三鉀一水合物(1.23g,3.65mmol)和二(三苯基膦)二氯化鈀(0.04g,0.06mmol),將混合物在90℃下攪拌4小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯(20mLx4)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮,通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1),得到標題化合物28g,呈淡黃色固體(0.3g,56%)。LC-MS(ESI):m/z=432.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),8.81(s,1H),8.43(d,1H),8.12(s,1H),7.71(t,1H),7.48(s,1H),7.41(d,1H),7.24(d,1H),6.92(s,1H),4.77-4.72(m,1H),4.23(s,2H),4.17(q,2H),3.34-3.26(m,2H),3.00-2.95(m,2H),1.22(t,3H).
第六步:2-(5-(2-((5-(呋喃-3-基)-2,3-二氫-1H-茚-2-基)胺基]嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(28h)
2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(28h)
將化合物28g(0.3g,0.70mmol)溶於四氫呋喃(6mL)/甲醇(2ml)
和蒸餾水(2ml)中,再加入LiOH(0.05g,2.09mmol);然後,在室溫下反應3小時。反應完成後,加水20mL,加酸調pH=3,再加DCM(30mLx3)萃取,有機相用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到目標化合物28h(0.25g,96%)。LC-MS(ESI):m/z=404.2[M+H]+
第七步:2-(5-(2-((5-(呋喃-3-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物28)
2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 28)
向化合物28h(0.25g,0.62mmol)的N,N-二甲基甲醯胺(8mL)溶液中依次地緩慢添加化合物1i(0.40g,2.48mmol)、N,N-二異丙基乙胺(0.40g,3.1mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(0.48g,0.93mmol),並將混合物在室溫下攪拌2h。反應完成後,往反應液加入二氯甲烷(20mL)和蒸餾水(20mL)稀釋,並用二氯甲烷萃取(20mLx3)。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:二氯甲烷:乙酸乙酯:甲醇=1:0:0~2:10:1)得到化合物28(52mg,18%)。LC-MS(ESI):m/z=510.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.85(s,1H),8.79(s,1H),8.40(d,1H),8.12(s,1H),
7.71(,1H),7.48(s,1H),7.41(d,1H),7.23(d,1H),6.92(s,1H),4.81(s,1H),4.77-4.71(m,1H),4.68(s,1H),4.41(d,2H),3.87-3.81(m,2H),3.30(m,2H),2.97(m,
2H),2.91(t,1H),2.74(t,1H).
實例29:2-(5-(2-((6,7-二氫-5H-茚並[5,6-d][1,3]二氧雜環戊烯-6-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物29)
2-(5-(2-((6,7-dihydro-5H-indano[5,6-d][1,3]dioxol-6-
yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-
[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 29)
第一步:2-(5-(2-((6,7-二氫-5H-茚並[5,6-d][1,3]二氧雜環戊烯-6-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(29b)
ethyl 2-(5-(2-((6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(29b)
將29a(180mg,1.02mmol)溶於乙醇(3mL)中,加入中間物2(546mg,2.03mmol),再加入DIPEA(0.51ml,3.05mmol),升溫至50℃,攪拌4小時。加入1mol/L的稀鹽酸(50mL),用二氯甲烷萃取(50mL×2)萃取,合併有機相,用水(100mL)洗滌一次。用硫酸鈉乾燥、過濾、旋幹,得到棕黑色固體粗品29b(200mg)。LC-MS(ESI):m/z=410.2[M+H]+.
第二步:2-(5-(2-((6,7-二氫-5H-茚並[5,6-d][1,3]二氧雜環戊烯-6-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(29c)
2-(5-(2-((6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(29c)
將粗品29b(200mg)溶於甲醇(1.5mL),加入THF(1.5mL),再加入KOH(275mg,4.91mmol)的水(1.5mL)溶液,加熱至回流攪拌隔夜。冷卻,加入水(50mL),用稀鹽酸(1moL/L)調pH約為6,用乙酸乙酯萃取(50mL×2)萃取,合併有機相,用水(100mL)洗滌一次。硫酸鈉乾燥、過濾、旋幹,得到灰黑色固
體粗品29c(205mg)。LC-MS(ESI):m/z=382.1[M+H]+.
第三步:2-(5-(2-((6,7-二氫-5H-茚並[5,6-d][1,3]二氧雜環戊烯-6-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物29)
2-(5-(2-((6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 29)
將粗品29c(205mg)溶於DMF(1.5mL),加入4,5,6,7-四氫-3H-[1,2,3]三唑並[4,5-c]吡啶 鹽酸鹽(169mg,1.05mmol),再滴加三乙胺(0.73mL,5.25mmol),加入BOP(348mg,0.79mmol),室溫攪拌隔夜。加入水(50mL),用稀鹽酸(2moL/L)調節pH約為6,用乙酸乙酯萃取(50mL×2)萃取,合併有機相,用水(100mL)洗滌一次。硫酸鈉乾燥、過濾、旋幹,得到棕色油狀物。矽膠柱層析分離純化,得到化合物29(20mg)。
LC-MS(ESI):m/z=488.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 9.00-8.62(m,2H),8.37(d,1H),6.79(s,2H),5.94(d,2H),4.81(s,1H),4.74-4.66(m,2H),4.41(d,2H),3.89-3.79(m,2H),3.18(dd,2H),2.90(t,1H),2.82(dd,2H),2.77-2.71(m,1H).
實例30:2-(5-(2-((2,4,5,6-四氫-1H-環丁並[f]茚-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物30)
2-(5-(2-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 30)
第一步:(E)-5-(羥基亞胺基)-1,2,5,6-四氫-4H-環丁並[f]茚-4-酮(30b)
(E)-5-(hydroxyimino)-1,2,5,6-tetrahydro-4H-cyclobuta[f]inden-4-one(30b)
將中間物30a(300mg,1.90mmol)溶於甲醇(5mL),加入濃鹽酸(0.3mL),然後滴加亞硝酸特戊酯(244mg,2.09mmol),室溫攪拌3小時。大量白色固體析出,過濾,濾餅用少量甲醇潤洗,減壓旋幹,得到白色固體30b(300mg,84.5%)。LC-MS(ESI):m/z=188.1[M+H]+.
第二步:5-胺基-1,2,5,6-四氫-4H-環丁並[f]茚-4-酮(30c)
5-amino-1,2,5,6-tetrahydro-4H-cyclobuta[f]inden-4-one(30c)
將30b(300mg,1.6mmol)溶於醋酸(10mL)中,加入4N鹽酸二氧六環(1ml),再加入濕鈀碳(100mg),用氫氣球置換氫氣三次。氫氣氛圍下室溫反應隔夜。反應完後過濾、旋幹,得到灰白色固體粗品30c(250mg)。LC-MS(ESI):m/z=174.1[M+H]+.
第三步:2,4,5,6-四氫-1H-環丁並[f]茚-5-胺(30d)
2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-5-amine(30d)
將粗品30c(250mg)溶於DCM(10mL)中,加入三乙基氫矽烷
(5mL),再滴加三氟化硼乙醚(5mL),45℃反應16小時。反應完全後濃縮,然後加入碳酸氫鈉水溶液鹼化,用乙酸乙酯萃取(30mL×2),合併有機相,硫酸鈉乾燥、過濾、旋幹,得到紅褐色固體30d(200mg)。LC-MS(ESI):m/z=160.2[M+H]+.
第四、五、六步
2-(5-(2-((2,4,5,6-四氫-1H-環丁並[f]茚-5-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物30)
2-(5-(2-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 30)
參考化合物29第一步至第三步的合成方法製備得到化合物30。
LC-MS(ESI):m/z=470.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ 8.89-8.73(m,2H),8.34(d,1H),6.93(s,2H),4.75(d,2H),4.65(dd,2H),4.41(d,2H),3.91-3.79(m,2H),3.26-3.20(m,2H),3.04(s,4H),2.92-2.84(m,3H),2.74(t,1H).
實例31:2-(5-(2-((5-乙炔基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物31)
2-(5-(2-((5-ethynyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 31)
第一步:(5-((三甲基矽基)乙炔基)-2,3-二氫-1H-茚-2-基)胺基甲酸第三丁酯(31a)
tert-butyl(5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-inden-2-yl)carbamate(31a)
將化合物8b(1.0g,3.203mmol),雙三苯基膦二氯化鈀(450mg,0.6406mmol)、碘化亞銅(61mg,0.3203mmol)溶於DMF(32ml)中,加入三乙胺(1.12ml,8.008mmol),三甲基乙炔基矽(378mg,3.844mmol),氮氣保護後90℃反應約6h。應完成後冷卻至室溫,過濾並用乙酸乙酯洗,加水後以乙酸乙酯萃取。有機相用飽和鹽水洗,用無水硫酸鈉乾燥,過濾,濃縮。矽膠柱層析(PE:EA=5:1)純化,得到白色固體產物31a(640mg,61%)。
第二步:5-((三甲矽基)乙炔基)-2,3-二氫-1H-茚-2-胺(31b)
5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-inden-2-amine(31b)
將化合物31a(640mg,1.94mmol)溶於鹽酸-1,4-二氧六環(20ml)中,室溫反應。反應完成後,濃縮。得白色固體產物31b(420mg,95%)。
第三步:2-(5-(2-((5-((三甲矽基)乙炔基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯(31c)
ethyl 2-(5-(2-((5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(31c)
將化合物31b(420mg,1.83mmol),中間物2(541mg,2.01mmol)溶於NMP(20ml)中,加入DIPEA(591mg,4.575mmol),氮氣保護後80℃反應約4h。反應完成後,加水(100ml)以乙酸乙酯萃取。有機相用飽和鹽水洗,無水硫酸鈉乾燥,過濾,濃縮。矽膠柱層析(DCM:MeOH=60:1)純化,得到白色固體產物31c(640mg,79%)。
第四步:2-(5-(2-((5-乙炔基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(31d)
2-(5-(2-((5-ethynyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(31d)
將化合物31c(640mg,1.77mmol)溶於甲醇中,緩慢滴加氫氧化鋰的水溶液(149mg,3.54mmol),室溫反應。反應完成後,將混合物濃縮加水過濾,濾液用HCl調節pH=3-4,並用乙酸乙酯(30mLx2)萃取。有機相用飽和鹽水洗,用無水硫酸鈉乾燥,過濾,濃縮,得到白色固體產物31d(480mg,95%)。
第五步:2-(5-(2-((5-乙炔基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物31)
2-(5-(2-((5-ethynyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 31)
將化合物31d(480mg,1.328mmol)、1i(427mg,2.657mmol)溶於DMF中,加入HATU(616mg,1.594mmol),滴加DIPEA(1.12ml,6.64mmol),室溫反應。反應完成後,將混合物用水稀釋,並用乙酸乙酯萃取。有機層用飽和
鹽水洗,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(DCM:MeOH=40:1)純化,得到化合物31(9mg)。LC-MS(ESI):m/z=468.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.80(s,2H),8.39(d,1H),7.34(s,1H),7.26(q,2H),4.81(s,1H),4.71(dd,2H),4.41(d,2H),4.06(s,1H),3.89-3.80(m,2H),3.29(m,2H),2.93(m,3H),2.75(t,1H).
實例32:2-(5-(2-((5-(1-甲基-1H-吡唑-4-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物32)
2-(5-(2-((5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 32)
第一步:2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-碳醯肼(32b)
2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide(32b)
向化合物32a(3.6g,2.0mmol)的乙醇(40mL)溶液中加入水合肼(16ml),將混合物在80℃反應16小時。反應完成後,將反應液過濾,乙醇洗滌。旋幹,得到標題化合物32b,呈灰色固體(3.5g,100%)。LC-MS(ESI):m/z=348.1,350.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 9.57(s,1H),8.69(s,2H),8.05(d,1H),7.42(s,1H),7.32(d,1H),7.18(d,1H),4.69-4.64(m,1H),4.40(s,2H),3.28-3.16(m,2H),2.94-2.83(m,2H).
第二步:3-(2-(2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-羰基)肼基)-3-側氧基丙酸第三丁酯(32d)
tert-butyl 3-(2-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazineyl)-3-oxopropanoate(32d)
向化合物32b(1.0g,2.87mmol)的N,N-二甲基甲醯胺(10mL)溶液中加入32c(0.55g,3.45mmol)、2-(7-氮雜苯並三唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(1.30g,3.45mmol)和N,N-二異丙基乙胺(0.93g,7.18mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用二氯甲烷(20mLx3)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。得到標題化合物32d,呈棕色固體(1.8g粗產品)。LC-MS(ESI):m/z=490.1,492.1[M-H]+。
第三步:2-(5-(2-((5-溴-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸第三丁酯(32e)
tert-butyl 2-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(32e)
向化合物32d(1.8g,3.67mmol)的二氯甲烷(20mL)溶液中加入4-甲苯磺醯氯(1.95g,10.20mmol)和N,N,N’,N’-四甲基-1,6-己二胺(2.11g,12.23mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用二氯甲烷(30mL)
稀釋。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)純化,得到標題化合物32e,呈灰色固體(450mg,兩步收率33%)。LC-MS(ESI):m/z=472.1,474.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.80(s,1H),8.42(d,1H),7.43(s,1H),7.33(d,1H),7.19(d,1H),4.76-4.67(m,1H),4.12(s,2H),3.23-3.23(m,2H),2.98-2.87(m,2H),1.43(s,9H).
第四步:2-(5-(2-((5-(1-甲基-1H-吡唑-4-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸第三丁酯(32g)
tert-butyl 2-(5-(2-((5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(32g)
向化合物32e(0.4g,0.8mmol)的二氧六環/水(10ml/1ml)溶液中,加入化合物32f(0.2g,0.9mmol),磷酸三鉀一水合物(1.23g,3.65mmol)和二(三苯基膦)二氯化鈀(0.04g,0.06mmol),將混合物在90℃下攪拌4小時。反應完成後,將混合物用蒸餾水(100mL)稀釋,並用乙酸乙酯(100mLx4)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物32g,呈白色固體(0.2g,53%)。LC-MS(ESI):m/z=473.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.81(s,1H),8.42(d,1H),8.06(s,1H),7.78(s,1H),7.42(s,1H),7.35(d,1H),
7.19(d,1H),4.76-4.70(m,1H),4.11(s,2H),3.85(s,3H),3.23-3.24(m,2H),2.98-2.89(m,2H),1.43(s,9H).
第五步:2-(5-(2-((5-(1-甲基-1H-吡唑-4-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(32h)
2-(5-(2-((5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(32h)
向化合物32g(0.2g,0.42mmol)的二氯甲烷(6mL)溶液中加入三氟乙酸(4ml),將混合物在室溫下反應16小時。反應完成後,將反應液用二氯甲
烷(20mL)稀釋。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮,得到標題化合物32h,呈灰色固體(165mg,94%)。LC-MS(ESI):m/z=418.1[M+H]+。
第六步:2-(5-(2-((5-(1-甲基-1H-吡唑-4-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物32)
2-(5-(2-((5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 32)
向化合物32h(0.25g,0.60mmol)的N,N-二甲基甲醯胺(6mL)溶液中依次地緩慢添加化合物1i(0.29g,1.8mmol)、N,N-二異丙基乙胺(0.40g,3.1mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(0.48g,0.93mmol),並將混合物在室溫下攪拌2h。反應完成後,往反應液加入二氯甲烷(20mL)和蒸餾水(20mL)稀釋,並用二氯甲烷萃取(20mLx3)。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:二氯甲烷:乙酸乙酯:甲醇=1:0:0~2:10:1)純化,得到化合物32(19mg,6%)。
LC-MS(ESI):m/z=524.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 8.85(s,1H),8.80(s,1H),8.39(d,1H),8.06(s,1H),7.80(s,1H),7.42(s,1H),7.34(d,1H),7.19(d,1H),4.81(s,1H),4.75-4.70(m,1H),4.68(s,1H),4.43(s,1H),4.39(s,1H),3.87-3.83(m,5H),3.32-3.23(m,2H),2.98-2.89(m,3H),2.74(t,1H).
實例33:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物33)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 33)
第一步:2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-羧酸乙酯(33c)
Ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidine-5-carboxylate(33c)
向化合物33a(2.0g,7.86mmol)的乙醇(40mL)溶液中,加入1B(1.6g,9.43mmol)和三乙胺(3.18g,31.42mmol),將混合物在80℃下攪拌4小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用乙酸乙酯(30mLx3)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物33c,呈類白色固體(3.0g,100%)。LC-MS(ESI):m/z=352.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.96-8.86(m,2H),7.22(s,2H),7.17-7.14(m,2H),4.74-4.65(m,1H),4.28(q,2H),3.25(dd,2H),3.06(m,2H),1.29(t,3H).
第二步:2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-碳醯
肼(33d)
2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidine-5-carbohydrazide(33d)
向化合物33c(1.0g,2.85mmol)的乙醇(10mL)溶液中加入水合肼(6ml),將混合物在在80℃反應16小時。反應完成後,將反應液過濾,乙醇洗滌。旋幹,得到標題化合物33d,呈灰色固體(400mg,42%)。LC-MS(ESI):m/z=338.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.52(s,1H),7.22(t,1H),7.17-7.14(m,2H),7.11-7.08(m,2H),4.68-4.53(m,1H),3.68(s,1H),3.26(dd,1H),3.01(dd,2H),2.91(dd,1H),2.56(dd,2H).
第三步:3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-羰基)肼基)-3-側氧基丙第三丁酸酯(33f)
tert-butyl 3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidine-5-carbonyl)hydrazinyl)-3-oxopropanoate(33f)
向化合物33d(0.40g,1.0mmol)的N,N-二甲基甲醯胺(6mL)溶液中加入33e(0.20g,1.2mmol)、2-(7-氮雜苯並三唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(0.50g,1.2mmol)和N,N-二異丙基乙胺(0.4g,3.0mmol),將混合物在在室溫下反應2小時。反應完成後,將混合物用蒸餾水(30mL)稀釋,並用二氯甲烷(20mLx3)萃取。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。得到標題化合物33f,呈棕色固體(800mg粗產品)。LC-MS(ESI):m/z=480.1[M-H]+
第四步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸第三丁酯(33g)
tert-butyl 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetate(33g)
向化合物33f(0.8g,2.0mmol)的二氯甲烷(10mL)溶液中加入4-
甲苯磺醯氯(0.80g,4.0mmol)和N,N,N’,N’-四甲基-1,6-己二胺(0.90g,5.0mmol),將混合物在室溫下反應2小時。反應完成後,將混合物用二氯甲烷(30mL)稀釋。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:石油醚:乙酸乙酯=1:0~0:1)分離純化,得到標題化合物33g,呈灰色固體(200mg,兩步收率37%)。LC-MS(ESI):m/z=462.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ 8.96(s,1H),8.28(s,1H),7.24-7.21(m,2H),7.17-7.13(m,2H),4.76-4.67(m,1H),4.14(s,2H),3.30(dd,1H),3.17(dd,1H),2.97(dd,1H),2.75(dd,1H),1.39(s,9H).
第五步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸(33h)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid(33h)
向化合物33g(0.20g,0.43mmol)的二氯甲烷(6mL)溶液中加入TFA(4ml),將混合物在室溫下反應16小時。反應完成後,將反應液用二氯甲烷(20mL)稀釋。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮,得到標題化合物33h,呈灰色固體(150mg,86%)。LC-MS(ESI):m/z=406.1[M+H]+。
第六步:2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-4-(三氟甲基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物33)
2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-(trifluoromethyl)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 33)
向化合物33h(0.25g,0.62mmol)的N,N-二甲基甲醯胺(6mL)溶液中依次地緩慢添加化合物1i(0.40g,2.48mmol)、N,N-二異丙基乙胺(0.40g,
3.10mmol)和苯並三唑-1-基-氧基-三吡咯啶基鏻六氟磷酸鹽(0.48g,0.93mmol),並將混合物在室溫下攪拌2h。反應完成後,往反應液加入二氯甲烷(20mL)和蒸餾水(20mL)稀釋,並用二氯甲烷萃取(20mLx3)。用蒸餾水和飽和鹽水洗滌有機相,用無水硫酸鈉乾燥,濃縮。通過矽膠柱層析(溶離劑:二氯甲烷:乙酸乙酯:甲醇=1:0:0~2:10:1)分離純化,得到化合物33(50mg,13%)。
LC-MS(ESI):m/z=512.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ 9.01-8.87(m,2H),7.24-7.22(m,2H),7.17-7.15(m,2H),4.80(s,1H),4.74-4.71(m,1H),4.68(s,1H),4.44(d,2H),3.86-3.81(m,2H),3.30(dd,2H),2.97(dd,2H),2.89(t,1H),2.74(t,1H).
實例34和35:(S)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)-2-(5-(2-((5-(三氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙-1-酮(化合物34)和(R)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)-2-(5-(2-((5-(三氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)乙-1-酮(化合物35)
(S)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethan-1-one(compound 34)and(R)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethan-1-one(compound 35)
化合物24通過對掌性HPLC解析,得到化合物34和化合物35(對
掌性HPLC解析方法:儀器名稱:MG II製備型SFC(SFC-14);層析柱:ChiralPak AD,250×30mmI.D.,10μm;移動相:A(針對CO2)和B(針對異丙醇)(0.1%NH3H2O);梯度:B 40%;流速:80mL/min;柱壓:100bar;柱溫:38℃;吸收波長:220nm循環時間:~8min)。
化合物34滯留時間:3.635min
LC-MS(ESI):m/z=512.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ 8.81-8.83(m,2H),8.42(d,1H),7.59(s,1H),.44-7.52(m,2H),4.81(s,1H),4.74-4.79(m,1H),4.69(s,1H),4.41(d,2H),3.83-3.86(m,2H),3.35-3.41(m,2H),2.99-3.05(m,2H),2.90-2.91(m,1H),2.74-2.75(m,1H).
化合物35滯留時間:5.492min
LC-MS(ESI):m/z=512.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ 8.81-8.83(m,2H),8.42(d,1H),7.59(s,1H),.44-7.52(m,2H),4.81(s,1H),4.74-4.79(m,1H),4.69(s,1H),4.41(d,2H),3.83-3.86(m,2H),3.35-3.41(m,2H),2.99-3.05(m,2H),2.90-2.91(m,1H),2.74-2.75(m,1H).
實例36和37:(S)-2-(5-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物36)和(R)-2-(5-(2-((5-(二氟甲基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物37)
(S)-2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 36)and(R)-2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 37)
化合物9通過對掌性HPLC解析,得到化合物36和化合物37(對掌性HPLC解析方法:儀器名稱:MG II製備型SFC(SFC-1);層析柱:ChiralPak AD,250×30mm I.D.,10μm;移動相:A(針對CO2)和B(針對異丙醇);梯度:B 50%;流速:80mL/min;柱壓:100bar;柱溫:38℃;吸收波長:220nm循環時間:~7min)。
化合物36滯留時間:3.832min
LC-MS(ESI):m/z=494.3[M+H]+,1H NMR(400MHz,DMSO-d6)δ 8.83-8.79(m,2H),8.38-8.36(m,1H),7.40(d,J=28Hz,3H),6.97(t,J=56Hz,1H),4.81-4.68(m,3H),4.43-4.39(m,2H),3.87-3.81(m,2H),3.35-3.31(m,2H),3.02-2.72(m,4H).
化合物37滯留時間:5.717min
LC-MS(ESI):m/z=494.3[M+H]+,1H NMR(400MHz,DMSO-d6)δ 8.83-8.79(m,2H),8.38-8.36(m,1H),7.40(d,J=28Hz,3H),6.97(t,J=56Hz,1H),4.81-4.68(m,3H),4.43-4.39(m,2H),3.87-3.81(m,2H),3.35-3.31(m,2H),3.02-2.72(m,4H).
實例38和39:(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-
1,3,4-噁二唑-2-基)-2-氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)丙-1-酮和(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-2-氟-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)丙-1-酮(化合物38和化合物39)
(S)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)propan-1-one和(R)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)propan-1-one(compound 38and compound 39)
化合物27通過對掌性HPLC解析,得到化合物38(峰1)和化合物39(峰2)(對掌性HPLC解析方法:儀器名稱:MG II製備型SFC(SFC-14);層析柱:纖維素-2,250×30mmI.D.,5μm;移動相:A(針對CO2)和B(針對乙醇)(0.1%NH3H2O);梯度:B 45%;流速:60mL/min;柱壓:100bar;柱溫:38℃;吸收波長:220nm循環時間:~9min)。
峰1滯留時間為:4.300min,LC-MS(ESI):m/z=476.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ 8.92-8.81(m,2H),8.50(d,J=8Hz,1H),7.24-7.14(m,4H),4.76-4.69(m,3H),4.00-3.90(m,2H),3.32-3.26(m,2H),2.99-2.95(m,2H),2.83-2.81(m,2H),2.16-2.07(m,3H).
峰2滯留時間為:5.784min,LC-MS(ESI):m/z=476.2[M+H]+,
1H NMR(400MHz,DMSO-d6)δ 8.92-8.81(m,2H),8.50(d,J=8Hz,1H),7.24-7.14(m,4H),4.76-4.69(m,3H),4.00-3.90(m,2H),3.32-3.26(m,2H),2.99-2.95(m,2H),2.83-2.81(m,2H),2.16-2.07(m,3H).
實例40和41:(S)-2-(5-(2-((5-乙炔基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮和(R)-2-(5-(2-((5-乙炔基-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物40和化合物41)
(S)-2-(5-(2-((5-ethynyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one and(R)-2-(5-(2-((5-ethynyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 40 and compound 41)
化合物31通過對掌性HPLC解析,得到化合物40(峰1)和化合物41(峰2)(對掌性HPLC解析方法:儀器名稱:MG II製備型SFC(SFC-14);層析柱:纖維素-2,250×30mmI.D.,5μm;移動相:A(針對CO2)和B(針對乙醇)(0.1%NH3H2O);梯度:B45%;流速:60mL/min;柱壓:100bar;柱溫:38℃;吸收波長:220nm循環時間:~9min)。
峰1滯留時間為:7.004min,LC-MS(ESI):m/z=468.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ 14.63(s,1H),8.80(s,2H),8.39(d,1H),7.34(s,1H),7.26(q,2H),4.81(s,1H),4.71(dd,2H),4.41(d,2H),4.07-4.04(m,1H),3.89-3.79(m,2H),3.27(d,2H),2.99-2.88(m,3H),2.75(s,1H).
峰2滯留時間為:8.086min,LC-MS(ESI):m/z=468.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ 14.65(s,1H),8.80(s,2H),8.39(d,1H),7.34(s,1H),7.30-7.21(m,2H),4.81(s,1H),4.77-4.63(m,2H),4.41(d,2H),4.06(s,1H),3.89-3.78(m,2H),3.27(d,2H),2.93(dt,3H),2.75(t,1H).
實例42和43:(S)-2-(5-(2-((5-(呋喃-3-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮和(R)-2-(5-(2-((5-(呋喃-3-基)-2,3-二氫-1H-茚-2-基)胺基)嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(1,4,6,7-四氫-5H-[1,2,3]三唑並[4,5-c]吡啶-5-基)乙-1-酮(化合物42和化合物43)
(S)-2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one and(R)-2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one(compound 42 and compound 43)
化合物28通過對掌性HPLC解析,得到化合物42(峰1)和化合物43(峰2)(對掌性HPLC解析方法:儀器名稱:MG II製備型SFC(SFC-14);層析柱:纖維素-2,250×30mmI.D.,5μm;移動相:A(針對CO2)和B(針對Ethanol)
(0.1%NH3H2O);梯度:B 45%;流速:60mL/min;柱壓:100bar;柱溫:38℃;吸收波長:220nm循環時間:~9min)。
峰1滯留時間為:4.886min,LC-MS(ESI):m/z=510.1[M+H]+。
峰2滯留時間為:5.716min,LC-MS(ESI):m/z=510.1[M+H]+。
生物測試
1、ATX抑制活性
實驗對象:待測化合物。
通過檢測混合人血漿中LPA的生成檢測ATX活性。采肝素抗凝全血離心後收血漿。95-μL血漿中加入5-μL梯度稀釋的待測化合物或DMSO,37℃培養2h後加入終止液(40mM磷酸氫二鈉緩衝液,含有緩衝溶液(含30mM檸檬酸,pH=4)。培養前後血漿中LPA用LC-MS-MS檢測。
LPA(18:2)&(20:4)LC-MS-MS分析方法
1 試驗方法
1.1 儀器
1.2 層析條件和質譜條件
層析條件
質譜條件
1.3 血漿樣品預處理
用1.5mL的EP管,取3.0μL標曲和質控的工作液加入到27.0μL水中,渦旋混勻之後,加入400μL的內標溶液,渦旋混勻之後,低溫4℃,離心10min。取180μL上清于96孔板中,等待進樣。
1.4 線性範圍
1.4.1 Stock溶液
精密吸取10μL的待測試化合物(10mg/ml)于EP管中,加入990μL的DMSO溶液,渦旋至全部溶解,得到100μg/mL的溶液。
1.4.2 工作液
溶劑:正丁醇
標曲系列工作液濃度:5μg/mL,2μg/mL,1μg/mL,500ng/mL,
200ng/mL,100ng/mL,50ng/mL,20ng/mL,10ng/mL
質控工作液濃度:4μg/mL,800ng/mL,30ng/mL
1.4.3 內標溶液(溶劑:正丁醇)
LPA17:025.0ng.mL-1
ATX受體活性抑制率通過以下方式計算:抑制率%=((LPAc-LPA0)-(LPAi-LPA0))/(LPAc-LPA0)*100%,其中LPAc為加入DMSO後培養2h血漿中LPA含量,LPA0為加入DMSO培養前血漿中LPA含量,LPAi為加入受試化合物培養2h後血漿中LPA含量。
测试结果:本发明化合物对ATX受体显示有抑制活性,实施例化合物对LPA 18:2/20:4細胞的IC50值在0.01-20nM范围內。其中,部分实施例的测试结果如表1所示:
結論:本發明化合物對於ATX受體顯示了較高的抑制活性。
2.小鼠藥動學測試
實驗目的:本試驗通過單劑量靜脈和灌胃給予受試物於C57小鼠,測定小鼠血漿中化合物35、37和38的濃度,評價受試物在小鼠體內藥代特徵和生物可用度。
試驗動物:雄性C57小鼠,20-25g,6~8周齡,18只/化合物。購于成都達碩實驗動物有限公司。
試驗方法:試驗當天,18只C57小鼠按體重隨機分組。給藥前1天禁食不禁水12~14h,給藥後4h給食。
取樣
於給藥前及給藥後異氟烷麻醉經眼眶取血0.08ml,置於EDTAK2離心管中。5000rpm,4℃離心10min,收集血漿。
G1組採集血漿時間點:0,5,15,30min,1,2,4,6,8,24h。
G2組採集血漿時間點:0,15,30min,1,2,4,6,8,24h。
分析檢測前,所有樣品存於-80℃。
樣品前處理
取30μL血漿樣品、標曲和質控樣品,加入200μL的含內標乙腈溶液,渦旋混勻之後,4℃,12000rpm離心10min。取上清于96孔板中,LC-MS/MS分析。
主要藥動學參數用WinNonlin 8.0軟體非房室模型分析。實驗結果如下表所示:
結論:本發明化合物具有較高的生物可用度和良好的藥動學特
徵。
Claims (32)
- 一種式(I)所示的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,L1為鍵、-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-或-C(O)-(CR3R4)c-C=CR7-;W為-C(=X)-或含有1-3個選自N、O或S雜原子的3-6員伸雜環基;X為O、S或NRx,其中Rx為H或氰基;每個R1至R6獨立地選自H、鹵素、C1-4烷基或C3-6環烷基;每個R7和R8獨立地選自H、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R1和R2、R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;a、c和e獨立地選自0-5的整數,b和d獨立地為0或1;Ra'和Ra"獨立地為H或C1-4烷基;n為1-2的整數;X1和X2獨立地為N或CRA1,且不同時為CRA1,X3為S、O或NRA1;X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA或-ORA;RA為C1-4烷基、C3-6環烷基、C3-6環烷基氧基、C1-4烷氧基、C1-4鹵代烷基、C1-4鹵代烷氧基或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、環烷基氧基、烷氧基、鹵代烷基、鹵代烷氧基和雜環基視情況進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;Y1為O、S或NRB3;Cy具有結構:,其中,長示單鍵或雙鍵,Z1為C或N,環E為含有1-3個選自N、O或S雜原子的5員雜環,環D為含有0-3個選自N、O或S雜原子的6員環;所述5員雜環和6員環獨立視情況被1-3個RB2取代;每個RB1和RB2獨立地選自H、側氧基、OH、鹵素、氰基、C1-4烷基、鹵代C1-4烷基、C1-4烷基氧基或C3-6環烷基;RB3選自H、C1-4烷基或C3-6環烷基;作為選擇,A上的基團RA1和B上的基團RB1與其連接的原子一起形成含有1-3個選自N、S、O雜原子的6-10員雜環;f為0-3的整數;L2為-O-、-NR9-、-C(O)NR9-、-NR9C(O)NR9-、-(CR10R11)g-、-NR9-(CR10R11)g-或鍵,其中g為1-3的整數;R9為H或C1-4烷基;每個R10和R11獨立地為H、鹵素、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R10和R11與其連接的碳原子形成3-6員碳環;Z2和Z3各自獨立地為CRM或N,Z4為O、S或NRM1;每個RM獨立地為H、C1-4烷基、C1-4烷氧基烷基、氰基、C3-6環烷基、C3-6環烷基氧基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6烯基、C2-6炔基、-NRM1,含有1-3個選自N、O或S雜原子的3-6員雜環基或鹵素,所述烷基、烯基、炔基和環烷基各自視情況被1-3個選自鹵素、氰基、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基或C1-4烷基的基團取代;作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的3-6員碳環或3-6員雜環基;Rm為H、C1-4烷基或鹵代C1-4烷基;Rm'為C1-4烷基或鹵代C1-4烷基;RM1為H、C1-4烷基、C3-6環烷基、C1-4鹵代烷基或C1-4烷氧基烷基;RM2為鹵代C1-4烷氧基;每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;h為0-3的整數;i為0、1或2;當M1為,L1為-C(O)-CH2-,A為,B為或,L2為-NH-,M2為時,A至少有一個取代基RA1選自氰基、鹵素、C3-4環烷基氧基、環丙基甲基氧基、C1-4鹵代烷氧基、環丙基甲基、-C1-4烷基-O-C1-4烷基、-NHC(O)RA、-C(O)NHRA、-C(O)-C3-6環烷基、、、、、、或;
- 如請求項1所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:a、c和e獨立地選自0-3的整數,b和d獨立地為0或1;W為-C(=X)-或含有1-2個選自N、O雜原子的5員伸雜環基,其中X為O、S或NRx,Rx為氰基;每個R1至R6獨立地選自H、鹵素、C1-4烷基,R7和R8獨立地選自H或C1-4烷基;作為選擇,同碳原子上的R3和R4、或R5和R6與其連接的碳原子一起形成3-4員碳環,所述碳環視情況被1-2個選自鹵素或C1-2烷基的取代基取代;RA為C1-4烷基、C3-4環烷基或含有1-2個選自N、O雜原子的4-6員雜環基,所述烷基和雜環基各自視情況進一步地被1-5個選自C3-4環烷基、C1-4烷基、鹵素、-S(O)2C1-2烷基、-OC1-2烷基或氰基的基團取代。
- 如請求項1或2所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:L1為-C(=O)-(NH)d-CR3R4-,其中d為0或1,R3和R4中至少有一個為鹵素,或R3和R4及其連接的碳原子一起形成3-4員碳環;或者L1為-C(=S)-CR3R4-,其中R3和R4獨立地選自H、鹵素或C1-4烷基;或者L1為-C(=N-CN)-CR3R4-,其中R3和R4獨立地選自H、鹵素或C1-4烷基;或者L1為-C(O)-CR3R4-C=CR7-,其中R3和R4獨立地選自H、鹵素或C1-4烷基,R7為H或C1-4烷基;或者L1為-W-(CR3R4)c-,其中W為含有1-2個選自N、O雜原子的5員伸雜環基,c為0-3的整數。
- 如請求項1或2所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,L2為-C(O)NR9-、-NR9C(O)NR9-、-O-、或-CR10R11-,R10和R11中至少一個為鹵素或C1-4烷基,或R10和R11與其連接的碳原子形成3-4員碳環。
- 如請求項1或2所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:A為C3-6伸環烷基、C2-4伸炔基、、、、-RaC(O)NRa'-或,其中X1為N或CRA1,X3為S、O或NRA1,每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA或-ORA,Ra為,Ra'為H或C1-4烷基;或者
- 如請求項1或2所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,所述化合物如(VI)所示:其中,L1為-C(=O)-(CR3R4)c-(NR8)d-、c為0-3的整數,d為0或1,R3、R4和R8獨立地選自H、C1-3烷基或鹵素,R3和R4與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;Cy具有結構:,其中,表示單鍵或雙鍵,Z1為C或N,環E為含有1-3個選自N、O或S雜原子的5員雜環,環D為飽和或不飽和的含有0-3個選自N、O或S雜原子的6員環;所述5員雜環和6員環獨立視情況被1-3個RB2取代;每個RB2獨立地選自H、鹵素、氰基、C1-4烷基或鹵代C1-4烷基;L2為-NH-或鍵。
- 如請求項1或2所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中:當M2為時,h不為0,且至少有一個RM為鹵代C1-4烷基、氰基、C3-6環烷基、C2-6炔基或含有1-3個選自N、O或S雜原子的3-6員雜環基;所述烷基視情況被1-3個選自鹵素或氰基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基或C1-4烷基的基團取代;或者,作為選擇,M2 中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3選自N、O或S雜原子的3-6員碳環或3-6員雜環基;
- 如請求項1所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,L1為-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-;W為-C(=X)-,X為O或S;a、b為0,c為1或2,d、e為0;每個R3和R4獨立地選自H、鹵素或C1-4烷基,且不同時為H;L2為-NR9-,R9為H;每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;h為0、1或2;每個RM獨立地為H或C1-4烷基,所述烷基視情況被1-3個鹵素取代。
- 如請求項1所述的式(I)的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,L1為鍵或-(CR1R2)a-(NR7)b-W-(CR3R4)c-(NR8)d-(CR5R6)e-;W為-C(=X)-;X為O、S或NRx,Rx為H或氰基;每個R1至R6獨立地選自H、鹵素、C1-4烷基或C3-6環烷基;每個R7和R8獨立地選自H、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R1和R2、R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環,所述碳環視情況被1-4個選自鹵素或C1-4烷基的取代基取代;a、c和e獨立地選自0、1、2和3,b和d獨立地為0或1;Ra'和Ra"獨立地為H或C1-4烷基;n為1或2;X1和X2獨立地為N、NRA1或CRA1,且不同時為CRA1;X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;每個RA1獨立地為H、氰基、-RA、鹵素、-C1-4烷基RA、-NHC(O)RA、-C(O)RA、-C1-4烷基-O-C1-4烷基、-NHRA、-C(O)NHRA、-ORA的取代基取代;RA為C1-4烷基、C3-6環烷基或含有1-3個選自N、O或S雜原子的3-6員雜環基,所述烷基、環烷基、雜環基視情況進一步地被1-6個選自C3-6環烷基、C1-4烷基、鹵素、-S(O)2C1-4烷基、-OC1-4烷基或氰基的基團取代;每個RB1和RB2獨立地選自H、OH、鹵素、氰基、C1-4烷基、鹵代C1-4烷基、C1-4烷基氧基或C3-6環烷基;L2為-O-、-NR9-、-(CR10R11)g-、-NR9-(CR10R11)g-或鍵,g為1-3的整數;R9為H或C1-4烷基;每個R10和R11獨立地為H、鹵素、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R10和R11與其連接的碳原子形成3-6員碳環;Z2、Z3為CRM或N,Z4為O、S或NRM1;每個RM獨立地為H、C1-4烷基、氰基、C3-6環烷基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6炔基、含有1-3個選自N、O或S雜原子的3-6員雜環基、或鹵素;所述烷基、炔基、環烷基視情況被1-3個選自鹵素、氰基、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-4烷基的基團取代;Rm為H、C1-4烷基、鹵代C1-4烷基,Rm'為C1-4烷基、鹵代C1-4烷基;作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-2選自N、O或S雜原子的3-6員碳環或3-6員雜環基;RM1為H、C1-4烷基或C3-6環烷基;RM2為鹵代C1-4烷氧基;每個R12獨立地為H、鹵素、C1-4烷基、C3-6環烷基或鹵代C1-4烷基;h為0-3的整數;i為0、1或2;
- 如請求項19所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,L1為鍵或-W-(CR3R4)c-;W為-C(=X)-;X為O或S;每個R3和R4獨立地選自H、鹵素或C1-4烷基;作為選擇,同碳原子上的R3和R4與其連接的碳原子一起形成3-6員碳環;c選自0、1和2;Ra'和Ra"為H或C1-4烷基;n為1或2;X1和X2獨立地為N、NRA1或CRA1,且不同時為CRA1;X4、X5和X6獨立地為N、NRA1、S、O或CRA1,且不同時為CRA1;每個RA1獨立地為H;RB1和RB2均為H;L2為-NR9-或-NR9-(CR10R11)g-,g為1-3的整數;R9為H;每個R10和R11獨立地為H;Z2、Z3為CRM,Z4為O或S;每個RM獨立地為H、C1-4烷基、C3-6環烷基、-SRm'、-S(O)2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C2-6炔基、含有1-3個選自N、O或S雜原子的3-6員雜環基或鹵素;所述烷基、炔基、環烷基視情況被1-3個選自鹵素、C1-4烷氧基、鹵代C1-4烷基或鹵代C1-4烷氧基的基團取代,所述雜環基視情況被1-3個選自鹵素、側氧基、C1-4烷基的基團取代;Rm為H或C1-4烷基,Rm'為C1-4烷基;作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-2選自N、O或S雜原子的3-6員碳環或3-6員雜環基;RM2為鹵代C1-4烷氧基;h為0、1或2;i為0、1或2。
- 如請求項20所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,c為1或2,同碳原子上的R3和R4與其連接的碳原子一起形成3-6員碳環。
- 如請求項1或2所述的含氮雜環化合物,其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,其中,L1為-W-(CR3R4)c-或-W-(NR8)d-(CR5R6)e-;W為-C(=X)-;X為O或S;每個R3、R4、R5和R6獨立地選自H、鹵素或C1-4烷基;每個R8獨立地選自H、C1-4烷基或C3-6環烷基;作為選擇,同碳原子上的R3和R4、或R5和R6與其連接的碳原子一起形成3-6員碳環;C和e選自0或1,d為1;X1和X2獨立地為N或CRA1,且不同時為CRA1;RA1為氰基、C1-4烷基、-RA或鹵素;RA為C3-6環烷基、C3-6環烷基氧基、C1-4烷氧基、C1-4鹵代烷基、C1-4鹵代烷氧基,所述環烷基、環烷基氧基、烷氧基、鹵代烷基、鹵代烷氧基視情況進一步地被1-3個選自C1-4烷基、鹵素、氰基的基團取代;RB1和RB2均為H;L2為-NR9-;R9為H或C1-4烷基;Z2、Z3為CRM或N,Z4為O或S;每個RM獨立地為H、C1-4烷基、C1-4烷氧基烷基、氰基、C3-6環烷基、C3-6環烷基氧基、C2-6烯基、C2-6炔基、-NRM1、或含有1-3個選自N、O或S雜原子的3-6員雜環基;所述烷基、烯基、炔基、環烷基視情況被1-3個選自鹵素、氰基的基團取代,所述雜環基視情況被1-3個選自鹵素或C1-4烷基的基團取代;作為選擇,M2中相鄰環碳原子上的兩個RM與它們連接的碳原子一起形成含有0-3個選自N、O或S雜原子的3-6員碳環或3-6員雜環基;RM1為H、C1-4烷基、C3-6環烷基、C1-4鹵代烷基或C1-4烷氧基烷基;每個R12獨立地為H、鹵素或C1-4烷基;h為0-3的整數;i為0、1或2。
- 一種醫藥組合物,其特徵在於,含有醫藥有效量的如請求項1-27中任意一項所述的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,以及醫藥上可接受的輔料和/或載劑。
- 如請求項1-27任意一項所述的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,或者如請求項28所述的組合物在製備治療/預防自分泌運動因子介導的疾病的藥物中的用途。
- 如請求項1-27任意一項所述的含氮雜環化合物,或其立體異構物、溶劑合物、氘代物、醫藥上可接受的鹽或共晶,或者如請求項28所述的組合物在治療或預防自分泌運動因子介導的疾病的中的用途。
- 如請求項29或30所述的用途,其中,所述自分泌運動因子介導的疾病選自心血管病症、癌症、代謝紊亂、腎臟病症、肝臟病症、炎症性病症、神經系統病症、呼吸系統病症、纖維化疾病、眼部病症、膽汁淤積和其他形式的慢性瘙癢症以及急性或慢性器官移植排斥。
- 如請求項31所述的用途,其中,所述炎症性病症選自關節炎、特應性皮炎、關節炎和哮喘。
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CN115232147B (zh) * | 2022-08-09 | 2023-10-13 | 南方科技大学 | 一种作为HIF-2α激动剂的杂环衍生物 |
KR20240028959A (ko) * | 2022-08-25 | 2024-03-05 | 주식회사 레고켐 바이오사이언스 | 오토탁신 저해 화합물 및 이를 함유하는 약제학적 조성물 |
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TW201520219A (zh) * | 2013-03-12 | 2015-06-01 | Lilly Co Eli | 咪唑並吡啶化合物 |
TW201446768A (zh) * | 2013-03-15 | 2014-12-16 | Biogen Idec Inc | S1p及/或atx調節劑 |
TW201500356A (zh) * | 2013-04-12 | 2015-01-01 | Lilly Co Eli | 二氫吡啶并嘧啶化合物 |
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