CN109310671A - 布鲁顿酪氨酸激酶抑制剂 - Google Patents
布鲁顿酪氨酸激酶抑制剂 Download PDFInfo
- Publication number
- CN109310671A CN109310671A CN201780007631.8A CN201780007631A CN109310671A CN 109310671 A CN109310671 A CN 109310671A CN 201780007631 A CN201780007631 A CN 201780007631A CN 109310671 A CN109310671 A CN 109310671A
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- CN
- China
- Prior art keywords
- base
- pyridine
- pyrazolo
- ketone
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940125814 BTK kinase inhibitor Drugs 0.000 title abstract description 4
- -1 iso-aryl Chemical group 0.000 claims description 202
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 180
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 115
- 150000001875 compounds Chemical class 0.000 claims description 98
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 77
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 30
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 150000003053 piperidines Chemical class 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 150000003235 pyrrolidines Chemical class 0.000 claims description 18
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical class 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- LCSWGJWPSRRFRS-UHFFFAOYSA-N 3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridine Chemical compound O(C1=CC=CC=C1)C1=CC=C(C=C1)C1=NNC2=C1C=NC=C2 LCSWGJWPSRRFRS-UHFFFAOYSA-N 0.000 claims description 13
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- NPDIDUXTRAITDE-UHFFFAOYSA-N 1-methyl-3-phenylbenzene Chemical compound CC1=CC=CC(C=2C=CC=CC=2)=C1 NPDIDUXTRAITDE-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 206010011224 Cough Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 150000001336 alkenes Chemical class 0.000 claims description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 235000003642 hunger Nutrition 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- KIFIMFJZRQZTSX-UHFFFAOYSA-N [O].FC1=CC(=CC=C1)OC Chemical compound [O].FC1=CC(=CC=C1)OC KIFIMFJZRQZTSX-UHFFFAOYSA-N 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 claims description 2
- WSDVFNMANDYYKD-UHFFFAOYSA-N 3-(4-phenylmethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C1=NNC2=C1C=NC=C2 WSDVFNMANDYYKD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- AYIPJDGFBWHUQM-UHFFFAOYSA-N C1=CC=C(C=C1)OC2=CC=C(C=C2)C3=C4C(=CN=C3)C=NN4 Chemical compound C1=CC=C(C=C1)OC2=CC=C(C=C2)C3=C4C(=CN=C3)C=NN4 AYIPJDGFBWHUQM-UHFFFAOYSA-N 0.000 claims description 2
- AFMFEHBPECNLRI-UHFFFAOYSA-N COC1=CC(Cl)=CC=C1.[O] Chemical compound COC1=CC(Cl)=CC=C1.[O] AFMFEHBPECNLRI-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical class C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 239000005864 Sulphur Substances 0.000 claims 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 230000001404 mediated effect Effects 0.000 claims 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- PBHWPIJZSZDIED-UHFFFAOYSA-N 1-fluoropyrrole Chemical compound FN1C=CC=C1 PBHWPIJZSZDIED-UHFFFAOYSA-N 0.000 claims 1
- WQDDXVGJRSTLED-UHFFFAOYSA-N 1-methyl-4-phenylpiperazine Chemical compound C1CN(C)CCN1C1=CC=CC=C1 WQDDXVGJRSTLED-UHFFFAOYSA-N 0.000 claims 1
- NFYCGFPFIVPLHI-UHFFFAOYSA-N 1-methylpiperazine;piperazine Chemical compound C1CNCCN1.CN1CCNCC1 NFYCGFPFIVPLHI-UHFFFAOYSA-N 0.000 claims 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 claims 1
- SOLFRBJAWBBBSB-UHFFFAOYSA-N CC1=C(C=CC=C1)C.[O] Chemical compound CC1=C(C=CC=C1)C.[O] SOLFRBJAWBBBSB-UHFFFAOYSA-N 0.000 claims 1
- YCWZKUIASGPYIN-UHFFFAOYSA-N [O].CC1=C(C=CC=C1)F Chemical compound [O].CC1=C(C=CC=C1)F YCWZKUIASGPYIN-UHFFFAOYSA-N 0.000 claims 1
- DEZOTUBHVZKDMZ-UHFFFAOYSA-N [O].COC1=CC=CC=C1 Chemical compound [O].COC1=CC=CC=C1 DEZOTUBHVZKDMZ-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical class 0.000 claims 1
- 229960003896 aminopterin Drugs 0.000 claims 1
- 229940124623 antihistamine drug Drugs 0.000 claims 1
- 239000000739 antihistaminic agent Substances 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 229940046731 calcineurin inhibitors Drugs 0.000 claims 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 claims 1
- 229960000681 leflunomide Drugs 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 239000002585 base Substances 0.000 description 219
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
- 239000000243 solution Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 239000000047 product Substances 0.000 description 34
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical compound C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
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- 150000003839 salts Chemical class 0.000 description 18
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- JYCGXZGGVUKKNQ-UHFFFAOYSA-N tert-butyl formate piperazine Chemical compound C(C)(C)(C)OC=O.N1CCNCC1 JYCGXZGGVUKKNQ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
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- 238000001291 vacuum drying Methods 0.000 description 1
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Abstract
布鲁顿酪氨酸激酶抑制剂具有以下通式(I):
Description
本申请要求于2016年1月21日提交的美国申请No.62/281,252的优先权,其全文以引用的方式并入本文。
技术领域
本发明涉及布鲁顿酪氨酸激酶抑制剂,包括制备这些抑制剂的方法,以及含有这样的抑制剂的药物组合物。
背景技术
布鲁顿酪氨酸激酶(BtK)在B细胞内的信号转导过程中起重要作用,也是B细胞生存、分化、增生和活化的一个影响因素。目前,有B细胞或肥大细胞参与的疾病的治疗方法是需要的。BtK也参与了肥大细胞活化和血小板的生理功能。因此,针对B细胞或肥大细胞参与的疾病如:过敏类疾病、自身免疫疾病、炎症性疾病、血栓栓塞性疾病和癌症的治疗中,BtK抑制剂是有效的。
发明内容
本文所述的Btk抑制剂具有以下通式(I):
在结构式(I)中,A是N或CR1;B,C和D各自为N或C-H,其条件是只有A, B,C和D中的一个或两个可以是N;R1是氢,氨基,OH,CN,-NHOH或CONH2;R2是
-X-E符合下列条件之一:(1)X是O、OCRaRb、S(O)、S(O)2、CRaRb、CRaRbO、NRc(C=O)、C=ONRc或一个化学键;E为氢、芳基或具有一至三个R5取代基的杂芳基,或一个3-7元饱和或部分不饱和碳环,或一个8-10元饱和、部分不饱和或芳香双环,或一个具有1-4个任意选定的氮、氧或硫原子的5-6元单杂芳环,或一个具有1-3个任意选定的氮、氧或硫原子的4-7元饱和或不饱杂环,或一个具有1-5个任意选定的氮、氧或硫原子的7-10元环饱和或不饱双环,或一个具有1-5个任意选定的氮、氧或硫原子的8-10 元芳香杂双环;或(2)-X-E为氢、卤原子、-ORa、-O(CH2)1-4Ra、-CN或-NO2;R4和R5各自独立地选自氢、卤素、羟基、氰基、OCF3、OCF2H、C1-6烷基且可含有一至五个独立的氟取代基、C3-6环烷基且可含有一至五个独立的氟取代基、C1-4烷氧基且可含有一至五个独立的氟取代基、C1-4烷硫基且可含有一至五个独立的氟取代基、C1-4烷基磺酰基且可含有一至五个独立的氟取代基、羧基、C1-4烷氧基羰基和C1-4烷基羰基;Ra和Rb为各自独立的氢、氟或C1-3烷基且可含有一至五个独立的氟取代基;Rc为氢或C1-3烷基且可含有一至五个独立的氟取代基;R3可为一具有双键的基团;
进一步描述,可以是上述结构的异构体或互变异构体、药学上可接受的制剂混合物或药学上可接受的前体药物。
一方面,在式(I)中,E是芳基,异芳基,羧基,杂环基,任何一个基团可含有一至三个R5取代基。
在另一方面,在式(I)中,R3选自以下基团:
Y是C(=O),C(=O),NHC(=O),S(=O)2或NHS(=O)2;R6,R7和R8是各自独立的氢,卤素,氰基,C1-4烷基,C1-6烷氧基,C1-8烷基氨基烷基,或C 1-4烷基苯基;或R7和R8一起形成键。
在另一方面,在式(I)中,R3选自以下结构:
Y是C(=O),OC(=O),NHC(=O),S=O,S(=O)2或NHS(=O)2;
R6,R7,R8是各自独立的氢,卤素,氰基,C1-4烷基,C1-6烷氧烷基,C1-8烷基氨基烷基,或C1-4烷基苯基,或R7和R8一起形成键。
另一方面,在式(I)中,R3选自以下结构:
另一方面,在式(I)中,A为CR1,B,C,D中有一个为N。
另一方面,在式(I)中,A是CR1,B为N,C和D是C-H。
另一方面,本文所述的是一种药物组合物,所述药物组合物包含治疗有效量的所述的式(I)化合物的治疗有效量和药学上可接受的赋形剂。
另一方面,本文所述的是一种用于治疗自身免疫性疾病的方法,包括向有需要的受试者施用含有治疗有效量的所述的式(I)化合物的组合物。
另一方面,本文中描述的Btk抑制剂选自下面的化合物:
(R)-1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2- 烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H- 吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3- (3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基) 丙基-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c] 吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(萘-1-基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(苯并[d][1,3]二氧杂环戊烯-4-基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R) -1-(3-(3-(4-(3-氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1- 酮;(R)-1-(3-(3-(4-(间甲苯基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷- 1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氯-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基) 吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氟苯氧基)苯基)-1H-吡唑并 [4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二甲基苯氧基) 苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3- 二氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1- (3-(3-(4-(3-氯-2-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2- 烯-1-酮;(R)-1-(3-(3-(4-(3-氯-2-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基) 哌啶-1-基)丙-2-烯-1-酮;1-(3-((3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基) 甲基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基) -1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2- 甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;1-(4-(3- (4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3- (4-(3-氟-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮; N-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)苯基)丙烯酰胺;(R)-1-(3- (3-(4-(3-异丙氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1- 酮;(R)-1-(3-(3-(4-(2,3-二甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶 -1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3- c]吡啶-1-基)哌啶-1-基)丁-2-炔-1-酮;1-(6-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)- 1H-吡唑并[4,3-c]吡啶-1-基)-2-氮杂-螺[3.3]庚-2-基)丙-2-烯-1-酮;(R)-1-(3-(7-氯 -3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯 -1-酮;(R)-1-(1-丙烯酰基吡咯烷-3-基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-7-腈;(R)-1-(3-(3-(4-(环己基氧基)苯基)-1H-吡唑并[4,3-c]吡啶 -1-基)哌啶-1-基)丙-2-烯-1-酮;1-(6-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)-2-氮杂-螺[3.3]庚烷吡啶-2-基)丙-2-烯-1-酮;(R)-1-(3-(3- (4-((2,3-二氢-1H-茚-4-基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基) 丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3- c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-((3-氯苯基)硫基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(3-氯-4- 苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4- (3-氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(S)-1- (3-(3-(4-(间甲苯基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1- 酮;(R)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷 -1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-2H-吡唑并[4,3-c] 吡啶-2-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)- 1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3- (4-(2,3-二氯苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2烯-1-酮; (S)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基) 丙-2烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基) 哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-1H-吡唑并[4,3- c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-((2-氟苄基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-((2- 氟苄基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-4- (1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(3-甲氧基苄基)苯甲酰胺;(R)-4-(1-(1-丙烯酰基-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(3-甲氧基苄基)苯甲酰胺;(R)-1-(3-(3-(3'-甲基[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-丙-2-烯-1-酮;(R)-1-(3-(3-(3'-甲基-[1,1'-联苯]-4-基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3'-甲基[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷哌嗪-1-基)丙-2-烯-1-酮;N-{4-[1-(1-丙烯酰基-吡咯烷-3-基) -1H-吡唑并[4,3-c]吡啶-3-基]-苯基}-3-三氟甲基-(4-(1-(1-丙烯酰基-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)苯基)-3-(三氟甲基)苯甲酰胺;(R)-1-(3-(5-乙酰基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,5,6,7-四氢-1H-吡唑并[4,3-C]吡啶-1-基)吡咯烷-1-基)丙- 2-烯-1-酮;(R)-1-(3-(5-丙烯酰-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,5,6,7-四氢- 1H-吡唑并[4,3-C]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3- 甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1- 基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2-甲氧基苯氧基)苯基)- 1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氟-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;1-(3-(3-(4-苯氧基苯基) -1H-吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;1-(3-((3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)甲基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(4-氨基-3-(4-苯氧基苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(4-氨基 -3-(4-苯氧基苯基)-1H-吲唑-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3- 氯-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)- 1-(3-(3-(4-(3-甲氧基-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基) 丙-2-烯-1-酮;(R)-1-(3-(3-(4-((3-氟苯基)硫基)苯基)-1H-吡唑并[4,3-c]吡啶 -1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基-2-甲基苯氧基)苯基) -1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氯-2- 甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1- (3-(3-(3-氟-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮; (R)-1-(3-(3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙- 2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3- c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基苯氧基)苯基) -1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-氟-3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯;(R)-1-(3-(7-(二氟甲基) -3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯 -1-酮;R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-氟-1H-吡唑并[4,3-c]吡啶-1- 基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1--(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基) -7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4- (4-甲基-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)- 1-(3-(7-氟-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1- 基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-([1,4'-联哌啶]-1'-基)苯基) -1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;1-(3-(3-(4- (2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2- 烯-1-酮;(R)-1-(3-(3-(4-(4-(甲基磺酰基)哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-4-(1-(1-(丁-2-炔酰基)哌啶-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(吡啶-2-基)苯甲酰胺;(R)-1-(3- (7-(二氟甲基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-异丙氧基 -1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-乙氧基-3-(4-(2- 氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R) -(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)(2-甲苯磺酰基-2-氮杂螺[3.3]庚-6-基)甲酮;(R)-1-(3-(3-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R) -1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-丁氧基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)- 1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R) -1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-4-甲基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶 -1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H- 吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-乙氧基-3-(4- (2-氟3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮; (R)-1-(3-(3--(4-(2-氯-3-甲氧基苯氧基)苯基)-7-乙氧基-1H-吡唑并[4,3-c]吡啶- 1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基) -7-乙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-羟基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮; (R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-丙氧基-1H-吡唑并[4,3-c]吡啶-1- 基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-丁氧基-3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯 -3-甲氧基苯氧基)苯基)-7-异丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-(2-羟基乙氧基)-1H-吡唑并[4,3-c]吡啶-1-基基)哌啶-1-基)丙-2-烯-1-酮;1-((3R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-((四氢呋喃-3-基)氧基)-1H-吡唑并[4,3-C]吡啶-1-基)哌啶-1-基) 丙-2-烯-1-酮;1-((3R)-3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-((四氢呋喃 -3-基)氧基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-(2- 氨基乙氧基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基基)哌啶 -1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基-2-丙氧基苯氧基)苯基)-7-丙氧基 -1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-1-酮;1-(3-(3- (4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基) -2-羟基丙-1-酮;2-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3- c]吡啶-1-基)哌啶-1-基)-2-氧代乙酸;2-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基) -7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)-2-氧代乙酸;3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)环己烷甲酸;4-(3-(4-(2- 氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)环己烷羧酸;(E)-2- (3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶 -1-羰基)-4,4-二甲基戊-2-烯腈;1-(2-((3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;(E)-2-(2-((3- (4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)吡咯烷 -1-羰基)-4,4-二甲基戊-2-烯腈;(R)-1-(3-(7-(2-(二甲氨基)乙氧基)-3-(4-(2- 氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R) -1-(3-(7-(2-(二甲氨基)乙氧基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并 [4,3-c]吡啶-1-基)哌啶-1-基)丁-2-炔-1-酮;4-(3-(4-苯甲酰氨基苯基)-1H-吡唑并[4,3- c]吡啶-1-基)环己烷甲酸;(3-([1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷羧酸。(S)-1-(3-(3-(4-(1-苯基乙烯基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶 -1-基)丙-2-烯-1-酮;3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷甲酸; 4-(3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷羧酸。
具体实施方式
本文所述的方法包括向需要的受试者施用含有治疗有效量的本文所述的一种或多种 Btk抑制剂化合物的组合物。
前药是指当将这样的前药给予哺乳动物受试者时,在体内释放根据式I的活性母体药物的任何化合物。式I化合物的前药是通过修饰存在于式I化合物中的官能团以使得修饰官能团可在体内裂解以释放母体化合物的方式制备的。前药可以通过修饰存在于化合物中的官能团,使得修饰在常规操作或在体内裂解为母体化合物而制备。
互变异构体是指由分子的一个原子的质子移动到另一个原子的现象产生的化合物。互变异构体还指以平衡存在的两种或多种结构异构体之一,并且容易从一种异构体形式转化为另一种异构体形式。本领域普通技术人员将认识到其它互变异构的环原子排列是可能的。这些化合物的所有这些异构形式明确地包括在本公开内容中。
同分异构体是指具有相同分子式但其原子键合的性质或顺序或其原子在空间排列方面不同的化合物。在其原子的空间排列上不同的异构体称为立体异构体。彼此不是镜像的立体异构体被称为非对映异构体,彼此不可重叠的镜像的那些被称为对映异构体。当化合物具有不对称中心时,例如,其键合四个不同的基团,一对对映异构体是可能的。手性化合物可以作为单独的对映异构体或作为其混合物存在。除非另外指明,该描述旨在包括单独的立体异构体以及混合物。
本公开的某些化合物可以以非溶剂化形式以及溶剂化形式存在,包括水合形式。溶剂合物是指通过溶剂分子与式I化合物的组合形成的组合物。溶剂可以是有机化合物、无机化合物或其混合物。
药学上可接受的盐表示在医学判断范围内适合用于接触人和低等动物的组织而没有不适当的毒性、刺激和过敏反应等的那些盐,并且具有合理的利益/风险比。它们可以在本发明化合物的最终分离和纯化期间获得,或者通过使游离碱官能团与合适的无机酸如盐酸、磷酸或硫酸,或与有机酸如例如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸或甲磺酸等。酸官能团可以与有机或无机碱如氢氧化钠、氢氧化钾或氢氧化锂反应。
治疗有效量是指有效抑制布鲁顿酪氨酸激酶并因此产生所需治疗效果的本发明化合物或组合物的量。
本文所用的术语中,烷基是指具有指定范围内的碳原子数的单价直链或支链饱和脂族烃基。例如,C1-6烷基是指任何己基烷基和戊基烷基异构体以及正、异、仲和叔丁基、正和异丙基、乙基和甲基。烷基还包括其中一个或多个氢被氘代替的饱和脂族烃基,例如:CD3。
术语支链烷基是指如上定义的烷基,除了在指定范围内的直链烷基。如本文所定义,支链烷基包括烷基通过仲碳或叔碳连接到化合物其余部分的烷基化合物。例如:异丙基是支链烷基。
术语环烷基是指具有指定范围内的碳原子数的烷烃的任何单环。例如,C3-6环烷基是指环丙基、环丁基、环戊基和环己基。
术语卤素是指氟、氯、溴和碘(或者称为氟基、氯基、溴基和碘基)。
术语卤代烷基是指其中一个或多个氢原子被卤素(即F、Cl、Br和/或I)替代的如上定义的烷基。例如,C1-6卤代烷基是指具有一个或多个卤素取代基的如上定义的C1至C6直链或支链烷基。术语氟烷基具有类似的含义,除了卤素取代基限于氟。合适的氟烷基包括(CH2)0-4CF3系列。
C(O)或CO指的是羰基;术语S(O)2或SO2是指磺酰基;术语S(O)指的是亚磺酰基。
术语芳基是指苯基、萘基、四氢萘基、茚基、二氢茚基等。特别感兴趣的芳基是苯基。
术语杂芳基是指(i)含有1至4个独立地选自N、O和S的5或6元杂芳环,或 (ii)选自喹啉基、异喹啉基和喹喔啉基的杂二环。合适的5-和6-元杂芳环包括如吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、三嗪基、噻吩基、呋喃基、咪唑基、吡唑基、三唑基、四唑基、恶唑基、异恶唑基、恶二唑基、氧杂三唑基、噻唑基、异噻唑基和噻二唑基。一类感兴趣的杂芳基由(i)含有1至3个独立地选自N,O和S的5-和6-元杂芳环,和(ii)选自喹啉基、异喹啉基和喹喔啉基的杂二环。特别感兴趣的杂芳基是吡咯基、咪唑基、吡啶基、吡嗪基、喹啉基、异喹啉基和喹喔啉基。
在本发明范围内的4-至7-元饱和杂环的实例包括如氮杂环丁烷基、哌啶基、吗啉基、硫代吗啉基、噻唑烷基、异噻唑烷基、恶唑烷基、异恶唑烷基、吡咯烷基、咪唑烷基、哌嗪基、四氢呋喃基、四氢噻吩基、吡唑烷基、六氢嘧啶基、噻嗪基、硫氮杂环庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢吡喃基、四氢噻喃基和二氧杂环己烷基。在本发明范围内的4-至7-元不饱和杂环的实例包括对应于前述句子中所列的饱和杂环的单不饱和杂环,其中单键被双键代替(例如,碳-碳单键被碳-碳双键代替)。
应当理解,上面列出的特定环不限制可用于本发明的环。这些环仅仅是代表性的。
用于制备本发明化合物的合成方法在以下方案、方法和实施例中说明。原料是可商购的或可以根据本领域已知的或如本文所述的方法制备。通过下面所示的具体实施例说明本发明的化合物。然而,这些具体实施例不应被解释为本发明的唯一种类。这些实施例进一步说明了制备本发明化合物的细节,本领域技术人员将容易地理解,可以使用这些条件和方法的已知变化来制备这样的化合物。
结构式I
结构式I中Btk抑制剂化合物可以通过有机化学领域中熟知的方法来制备。用于这些化合物合成的起始原料既可以合成又可以从商业来源获得,例如中国化学试剂公司,或Sigma-Aldrich化学中国公司,但不局限于此。本文所述的化合物,以及使用的技术、材料和具有不同取代基的其它相关化合物的合成可以在下面专业书中得到描述,例如:高等有机化学第4版,(1992威利);凯里和桑德博格,高等有机化学第4版,A卷和B 卷(普利纳姆2000、2001年);菲泽和菲泽的有机合成试剂,1-17卷(约翰威利父子, 1991年);罗德碳化合物,第1-5卷和增刊(Elsevier科学出版社,1989);有机反应, 1-40卷(约翰威利父子,1991年);Larock综合有机转化(VCH出版公司,1989)。本文所述的化合物的其它合成方法可以在国际专利WO 2013/010868A1中找到,也可以在刘建等的ACS Medicinal Chemisty Letters 10(2016)198-203中找到。本申请中使用化学术语的定义可以在这些参考中找到(如果本文没有另外定义)。作为指导,以下合成方法也可以使用。
在合成步骤中,也许有必要或希望保护所涉及的任何分子中敏感或反应性基团,这通常需要用常规的保护基,诸如那些在T.W Greene和P.G.M.Wutts“有机合成中的保护基”第3版,John Wiley&Sons,1999描述的方法来实现;保护基可以选择性地在适当的阶段中用熟知的方法除去。反应的产物是可以分离和纯化的,如果需要的话,使用常规技术,但不限于,过滤、蒸馏结晶、色谱等。这些化合物可用常规手段,包括物理常数和光谱数据来表征。
本文描述的化合物可以具有一个或多个手性中心并且每个中心可以存在R或S构型。本文提供的化合物包括所有非对映体、对映体和差向异构体以及其适当的混合物。
例如从Btk抑制剂结构式(I)化合物可以是1H-吡唑并[4,3-c]吡啶衍生物。具体地,式中I的Btk抑制剂化合物可以是,如化合物F,其中R1-R2具有前面定义的含义。在方案I和II中所示的一般合成路线可以为合成F的合成方法提供一个非限制性的例子。
方案I
参照方案I,可将其中FG为官能团(例如酯,保护的苯胺,保护的酚,溴化物)的不同的醛(B)加入到一系列取代的邻卤代芳香族A中以形成醇,接着在丙酮中用CrO3氧化产物C,得到苯甲酰基D,D与(NH2)2-H2O在回流下环化以获得关键中间体吲唑 E。中间体E通过光延反应与R2OH偶联或通过置换R2OTs得到中间体G,然后使用适当取代的苯基硼酸(相应的硼酸酯也可以使用)通过金属催化剂偶联反应衍生的中间体 G直接提供所需的化合物F。在典型的程序中,将中间体G,铜催化剂(例如Cu(OAc) 2),碱(例如TEA,DIPEA等)和芳基硼酸或芳基硼酸酯在合适的溶剂,例如DCM或甲苯中反应以形成化合物F(FG被转换为XAr定义的基团)。
方案II
参照方案II,化合物F能够从另一途径得到,在无水THF中用LDA选择性邻位锂化并与DMF反应,得到醛H,其在回流条件下与(NH2)2-H2O反应,得到关键中间体吲唑I,然后用Br2/I2区域选择性溴化或碘化,或者NBS/NIS得到化合物J,化合物J的 1位氮通过光延反应与R2OH偶联或通过置换R2OTs得到中间体K,然后使用适当取代的苯基硼酸(也可以使用相应的硼酸酯)得到的关键中间体G或直接提供所需的化合物 F。从G到F转移方式在之前已经显示了一个类似的合成方式,由金属催化剂偶联反应生成衍生物(方案I)。
另一方面,化合物F可以从其中FG是官能团(例如酯,被保护的苯胺,被保护的酚,溴化物)的化合物G获得,其可以容易地转化成为XAr定义的基团。非限制性的合适的官能团的例子中的化合物G为苄基醚,二苄基芳烃或甲酯,其可以用碱或Pd/C/H 2进行处理,以形成关键中间体G-1a,G-2a,G-3a,然后按方案III形成相应的化合物F- 1,F-2,F-3,F-4。
方案III
化合物F的保护基进行脱保护基团的反应在方案IV中是已知的,并且可以通过下面描述的方法来进行。这里的实例有:(a)酸性条件下脱除Boc保护基团(b)氢化去除苄基保护基。用这些条件脱除保护基后,与酰氯缩合,但不限于酰氯,芳酰基氯化物也可以,最后提供化合物F-b。
方案IV
通用的实验条件:
制备薄层层析(PTLC)在20cmx20cm板上进行(500μm厚的硅胶)。硅胶柱层析法在Biotage柱层析系统或一般的玻璃柱上进行。1H和31P NMR谱在布鲁克Avanced III 400MHz核磁谱仪获得,温度为298K,化学位移(PPM)用氘代溶剂质子峰标定:δ=7.26 ppm的氯仿和δ=3.30ppm的甲醇或CD3OD。LCMS数据是在安捷伦1260Infinity或6120 四极杆质谱仪上得到。LC流动相为乙腈(A)和水(B),含有0.01%甲酸,洗脱梯度为 5~95%6分钟,60~95%5分钟,80-100%5分钟和85~100%10分钟使用SB-C18 50 mm×4.6mm×2.7μm毛细管柱。质谱(MS)采用电喷雾离子质谱(ESI)。所有的温度是摄氏度,除非另有说明。
高效液相色谱质谱条件分析:
LC1:柱:SB-C18 50mm×4.6mm×2.7μm
温度:50℃
洗脱:5:95V/V乙腈/水+0.01%甲酸6分钟。
流速:1.5mL/min,进样量5μL
检测:PDA,200-600nm
MS:质量范围150至750amu;正离子电喷雾电离
LC2:柱:SB-C18 50mm×4.6mm×2.7μm
温度:50℃
洗脱:5:95至95:5V/V乙腈/水+0.05%TFA超过3分钟
流速:1.5mL/min,进样量5μL
检测:PDA,200-600nm
MS:质量范围150至750amu;正离子电喷雾电离
LC3:柱:SB-C18 50mm×4.6mm×2.7μm
温度:50℃
洗脱:10:90至98:2V/V乙腈/水+0.05%TFA超过3.75分钟。
流速:1mL/min,进样量10μL
检测:PDA,200-600nm
MS:质量范围150至750amu,正离子电喷雾电离
英文缩写词列表:
AcOH=乙酸;Alk=烷基;Ar=基;Boc=叔丁氧羰基;br=宽的单峰;DCM=二氯甲烷;d=双重峰;dd=个双重峰;DBU=1,8-二氮杂双环[5.4.0]十一碳-7-烯;DCM =二氯甲烷;DEAD=偶氮二甲酸二乙酯;DMF=N,N-二甲基甲酰胺;DMSO=二甲基亚砜;ESI=电喷雾电离;EtOAc=乙酸乙酯;EDCI=1-乙基-(3-二甲基氨基丙基) 碳酰二亚胺盐酸盐;ESI=电喷雾电离;Et=乙基;Et3N=三乙胺;EtOAc=醋酸乙酯; EtOH=乙醇;h=小时;HPLC=高效液相色谱法;HOAc=醋酸;LiOH=氢氧化锂; m=多重峰;Me=甲基;MeCN=乙腈;MeOH=甲醇;MgSO4=硫酸镁;min=分钟; MS=质谱;NaOH=氢氧化钠;NMI=N-甲基咪唑;1H-NMR=核磁共振氢谱;PE=石油醚;PG=保护组;Ph=苯基;rt=室温;s=单峰;t=三重峰;TBME=二甲基叔丁基醚;TFA=三氟乙酸;THF=四氢呋喃;Ts=对甲苯磺酰基。
本发明的化合物可以通过以下详述的通用方法制备。在某些实施方案中,本文提供的是制备本文所描述的酪氨酸激酶抑制剂化合物的方法。在某些实施方案中,本文描述的化合物是使用下面的合成方案合成。在其他实施方案中,化合物合成使用下面描述的类似方法合成,只是起始原料不同。所有关键中间体也是按照下列方法制备。
中间体1:(4-(2-氯-3-甲氧基苯氧基)苯基)硼酸
步骤A:2-氯-3-羟基苯甲醛(1)
在搅拌下,向3-羟基苯甲醛(5g,40.98mmol)的AcOH(10mL)悬浮液中小心加入t-BuOCl(5mL,45.08mmol)。将其冷却并搅拌16h,产生白色沉淀。过滤固体,用 H2O洗涤并干燥,得到目标产物(3g,46.9%)。1H-NMR(400MHz,CDCl 3):δ10.66 (br,1H),10.33(s,1H),7.31-7.25(m,3H)。
步骤B:2-氯-3-羟基苯甲醛(2)
向2-氯-3-羟基苯甲醛1(3.4g,21.66mmol)的DMF(22mL)溶液中加入K2CO3(3.59 g,26mmol),然后加入MeI(2mL,32.5mmol),混合物在室温下搅拌18小时。在真空浓缩后,将残余物溶于乙酸乙酯中,用H2O,盐水洗涤,Na2SO4干燥并浓缩。通过硅胶柱色谱法用乙酸乙酯/己烷(1/5)纯化,得到目标产物(3.5g,95.1%)。1H-NMR(400 MHz,CDCl3):δ10.53(s,1H),7.53(d,J=7.6Hz,1H),7.36-7.32(m,1H),7.01(d,J= 8.8Hz,1H),3.95(s,3H)。
步骤C:2-氯-3-羟基苯甲醛(3)
向2-氯-3-甲氧基苯甲醛2(2g,11.7mmol)的DCM(50mL)溶液中加入3-氯过氧苯甲酸(3g,17.5mmol)。将该混合物在40℃下搅拌12h。过滤后,残留物被浓缩到一个碱液中,在18mL的MeOH中脱盐,然后在冷却下加入5mL的10%NaOH。在10℃下搅拌45 分钟后,用旋转蒸发器在30℃条件下除去甲醇,加入22mL5%氢氧化钠,冷却后加入浓盐酸,EA(3×20)萃取,H2O,5%NaHCO3洗涤,Na2SO 4干燥并真空浓缩,得到目标化合物(1.2g,66.6%)。1H-NMR(400MHz,CDCl3):δ7.14-7.10(m,1H),6.67(d,J=8.4 Hz,1H),6.51(d,J=8.4Hz,1H),5.62(s,1H),3.89(s,3H)
步骤D:1-(4-溴苯氧基)-2-氯-3-甲氧基苯(4)
3(1.5g,9.5mmol),CuI(0.182g,0.95mmol),N,N-二甲基甘氨酸盐酸盐(0.396 g,2.85mmol),Cs2CO3(6.2g,19mmol)中加入1-溴-4-碘苯(2.68g,9.5mmol)的二恶烷(40mL)溶液。将混合物在N 2保护下于105℃下搅拌18小时,将混合物过滤,浓缩并用EA萃取。将有机层用水和盐水洗涤,无水Na2SO4干燥,并通过快速色谱法纯化,得到目标产物(1.2g,40.4%)。1H-NMR(400MHz,CDCl3):δ7.43-7.39(m,2H),7.18- 7.15(m,1H),6.85-6.75(m,3H),6.65-6.15(m,1H),3.93(s,3H).
步骤E:1-(4-溴苯氧基)-2-氯-3-甲氧基苯(5)
在N2下,将4(1.2g,3.85mmol)的THF(30mL)溶液冷却至-78℃,在此温度下逐滴加入n-BuLi(1.82mL,4.61mmol)。混合物在-78℃下搅拌30分钟。在相同温度下逐滴加入硼酸三异丙酯(0.868g,4.61mmol)。15分钟后,将混合物置于室温并搅拌2小时,然后加入2N HCl调节至pH=5并搅拌30分钟,然后将混合物用EA萃取。将有机层用水和盐水洗涤,无水Na2SO4干燥,得到目标粗产物(0.4g粗品)。
实施例1:(R)-1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1–酮
步骤A:(4-(苄氧基)苯基)-(4-氯吡啶-3-基)甲醇(2)
在N2下,将二异丙胺(4.1mL,29.8mmol)的干燥的四氢呋喃(64mL)溶液冷却至-78℃,缓慢滴加2.5M n-BuLi(15mL,29.8mmol),滴加完毕后,在0℃下搅拌1 小时。溶液冷却至-78℃,滴加4-氯吡啶1(3.07g,27.1mmol)的干燥的THF(10mL) 溶液,滴加完毕后在此温度下搅拌4小时。滴加4-苄氧基苯甲醛(5.75g,27.1mmol) 的干燥的THF(10mL)溶液,滴加完毕后,回温至室温搅拌过夜。加入H2O(100mL) 淬灭,用Et2O(3×50mL)萃取,Na2SO4干燥,过滤,浓缩,柱层析分离(DCM/MeOH =200:1–50/1),获得产物2(2.5g,产率28.46%)。
1H-NMR(400MHz,CDCl3):δ8.86(s,1H),8.36(d,J=4Hz,1H),7.39-7.23(m, 8H),6.94(d,J=8.0Hz,2H),6.12(s,1H),5.03(s,2H),2.98(s,1H),2.16(s,1H).
LCMS:m/z=326,.328[M+H]+.
步骤B:(4-(苄氧基)苯基)-(4-氯吡啶-3-基)甲酮(3)
在小的反应瓶中加入2(1g,3.07mmol)的干燥的丙酮(10mL),降温至0℃,小心加入CrO3(0.92g,9.23mmol),将所得溶液在室温下搅拌直至原料完全消耗(3h),用异丙醇(6mL)淬灭,并搅拌30min,加入饱和NaHCO3(50mL),经硅藻土过滤沉淀的铬盐,滤液用DCM(6×15mL)萃取,浓缩,柱层析(DCM/MeOH=200:1),获得产物 3(0.7g,产率70.7%)。
1H-NMR(400MHz,CDCl3):δ8.61(d,J=8Hz,1H),8.58(S,1H),7.79(d,J= 8Hz,2H),7.44-7.35(m,6H),7.04(d,J=8Hz,2H),5.15(s,2H).
LCMS:m/z=324,326[M+H]+.
步骤C:3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶(4)
向(4-(苄氧基)苯基)-(4-氯吡啶-3-基)甲酮(3)(0.7g,2.16mol)的无水乙醇(5ml)搅拌溶液中加入水合肼(1.08g,17.3mol),将该溶液加热回流3小时,然后冷却,滤出产物并连续用水和甲醇洗涤,得到目标产物(0.54g,产率83%)。
1H-NMR(400MHz,DMSO-d6):δ13.48(br,1H),9.39(s,1H),8.37(d,J=8Hz, 1H),8.01(d,J=8Hz,2H),7.56-7.35(m,6H),7.18(d,J=8Hz,2H),5.20(S,2H).
LCMS:m/z=302[M+H]+.
步骤D:(R)-叔丁基3-(3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-羧酸酯(5)
向100mL的三口圆底烧瓶中加入3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶(4)(0.5g,1.66mmol)的N,N-二甲基甲酰胺(41mL)溶液,(S)-3-(甲苯磺酰氧基)吡咯烷-1-羧酸叔丁酯(0.68g,1.99mmol)和Cs2CO3(0.97g,2.98mmol)。将所得溶液在 60℃下搅拌12h,加入100mL水淬灭。EA萃取,合并有机层。将有机物用盐水洗涤,无水NaHCO3干燥。真空除去溶剂,残余物通过硅胶柱色谱(梯度:DCM/MeOH=200: 1至100:1)纯化,得到标题产物(0.7g,收率89.7%)。
1H-NMR(400MHz,CDCl3):δ9.32(br,1H),8.45(br,1H),7.85-7.83(m,2H), 7.37-7.36(m,1H),7.04-7.02(m,2H),5.18-5.15(m,1H),3.96-3.79(m,3H),3.63-3.59 (m,1H),2.89(br,1H),2.45(br,1H),1.47(s,9H).
LCMS:m/z=471[M+H]+.
步骤E:将(R)-叔丁基3-(3-(4-羟基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(6)
(R)-叔丁基3-(3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-羧酸酯(3)(0.7g,1.48mmol)和10%Pd/C(0.1g)的MeOH(15mL)悬浮液在50psi H2下氢化3h。将悬浮液通过硅藻土过滤,并浓缩。将残余物真空干燥,得到目标化合物(0.48 g,产率85.7%)。
LCMS:m/z=381[M+H]+。
步骤F:(R)-叔丁基3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-羧酸酯(7)
(R)-叔丁基3-(3-(4-羟基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(6)(50mg,0.1mmol),苯基硼酸(25.4mg,0.2mmol),TEA(21mg,0.2mmol) 和4A分子筛(0.1g)加入到DCM(10mL)的小瓶中,一次性加入醋酸铜(Ⅱ)(18.8 mg,0.1mmol)。混合物室温搅拌约22h,真空除去挥发性组分,加入H2O,EA萃取,用硅胶柱层析法(梯度:DCM/MeOH=100/1-50/1),得到目标产品(40mg,产率88.8%)。
LCMS:m/z=457[M+H]+。
步骤G:(R)-1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基) 丙-2-烯-1-酮(8)
(R)-3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)-吡咯烷-1-甲酸叔丁酯 (7)(40mg,0.087mmol)一次性加入到CF 3COOH/DCM=4/1(5mL)中。该混合物在室温下搅拌约1小时。真空除去挥发性组分,得到粗的目标产物(30mg),并直接用于下一步而无需进一步纯化。LCMS:m/z=357[M+H]+
0℃,在搅拌情况下,向(R)-3-(4-苯氧基苯基)-1-(吡咯烷-3-基)-1H-吡唑并[4,3- c]吡啶(8)(30mg,0.087mmol)和TEA(44mg,0.43mmol)的DCM(5mL)溶液中加入丙烯酰氯(8.7mg,0.095mmol)的DCM(1mL)溶液。将反应混合物搅拌1h,倒入盐水,DCM萃取。干燥有机层,浓缩,重结晶(DCM/MeOH=100/1),得到目标产物 (16mg,产率45.7%)。1H-NMR(400MHz,CDCl3):δ9.35(br,1H),8.49(br,1H), 7.95-7.91(m,2H),7.40-7.36(m,3H),7.15-7.08(m,5H),6.53-6.42(m,2H),5.76-5.71 (m,1H),5.27-5.15(m,1H),4.17-4.03(m,3H),3.85-3.82(m,1H),2.79-2.49(m,2H). LCMS:m/z=411.2[M+H]+。
实施例2:(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮
步骤A:1H-吡唑并[4,3-c]吡啶(2)
向搅拌的1H-吡唑并[4,3-c]吡啶(1)(17g,0.12mol)的无水乙醇(120mL)溶液中加入水合肼(80%)(75g,1.2mol)。将溶液加热回流5h,真空除去EtOH,并用EA (10×100mL)萃取混合物。合并有机相,用Na2SO 4干燥。在真空下除去挥发性组分,残余物通过硅胶柱色谱(梯度:DCM/MeOH=200:1-50/1)纯化,得到目标产物(8g,产率57.1%)。
1H-NMR(400MHz,CDCl3):δ13.48(br,1H),9.18(s,1H),8.44(d,J=6.0Hz,1H),8.25(s,1H),7.45(d,J=6.0Hz,1H).LCMS:m/z=120[M+H]+。
步骤B:3-溴-1H-吡唑并[4,3-c]吡啶(3)
室温下,向1H-吡唑并[4,3-c]吡啶(2)(8g,67.2mmol)的AcOH(100.0mL)溶液中加入溴(5.1mL,0.1mol)。反应液在室温下搅拌72小时,用10%NaOH(aq.)淬灭至pH=12。分离有机物,EA(10×100mL)萃取水相。合并有机相,用Na2SO4干燥,真空除去挥发性组分,残余物通过硅胶柱色谱法(梯度:DCM/MeOH=200:1-50/1)纯化,得到目标产物(4.5g,收率34.3%)。
1H-NMR(400MHz,CDCl3):δ13.32(br,1H),9.06(s,1H),8.54(d,J=5.6Hz,1H),7.43(d,J=5.6Hz,1H).LCMS:m/z=198,200[M+H]+
步骤D:(R)-3-(3-溴-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-甲酸叔丁酯(4)
向100mL的圆底烧瓶中加入3-溴-1H-吡唑并[4,3-c]吡啶(3)(2g,10mmol)的DMF(20mL)溶液,(S)-(甲苯磺酰氧基)哌啶-1-甲酸叔丁酯(4.3g,12mmol)和Cs2CO3 (5.9g,18mmol)。所得溶液在65℃下搅拌24h,加入100mL水淬灭。所得溶液用EA 萃取,合并有机层。有机物用盐水洗涤,经无水NaHCO3干燥。真空除去溶剂,残余物通过硅胶柱色谱(梯度:DCM/MeOH=200:1至100:1)纯化,得到目标产物(0.8g,收率21.0%)。
1H-NMR(400MHz,CDCl3):δ8.97(s,1H),8.48(d,J=5.6Hz,1H),7.36(d,J =5.6Hz,1H),4.43-4.38(m,3H),3.2(br,1H),2.88-2.81(m,1H),2.30-2.17(m,2H), 1.95-1.91(m,1H),1.72-1.62(m,1H),1.46(s,9H)。
LCMS:m/z=382[M+H]+.
步骤E:(R)-3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基) 哌啶-1(5)
在N2及搅拌情况下,向4(100mg,0.262mmol)和(4-(2-氯-3-甲氧基苯氧基)苯基)硼酸(109.9mg,0.393mmol)的甲苯(5mL)和水(1mL)溶液中加入K2CO3(72 mg,0.524mmol),然后加入(Ph3P)4Pd(30mg)。混合物回流8小时,直到原料消失。将反应混合物冷却至室温。通过旋转蒸发除去二恶烷。将残余物倒入水中并用EA萃取。有机层用Na2SO4干燥,过滤并在真空下除去溶剂,将残余物通过使用100:1- 50:1DCM:MeOH的硅胶色谱纯化,得到目标产物(50mg)。LCMS:m/z=534.2[M+H]+
步骤F:(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡啶-3-基)丙-2-烯-1-酮(6)
将中间体5(50mg,0.093mmol)一次性加入到CF3COOH/DCM=4/1(5mL)中。该混合物在室温下搅拌约2小时。真空除去挥发性组分,得到目标粗产物,直接用于下一步而无需进一步纯化。
0℃下,将丙烯酰氯(8.5mg,0.095mmol)的DCM(1mL)溶液加入到搅拌的前述的粗产物中,TEA(44mg,0.43mmol)的DCM(5mL)溶液中。将反应混合物搅拌1小时,倒入盐水中并用DCM萃取。将有机层干燥,浓缩并用DCM/MeOH=100/1重结晶,得到目标产物(29mg,产率65%)。
1H-NMR(400MHz,CDCl3):δ9.35(s,1H),8.45(d,J=5.6Hz,1H),7.93(d,J= 8.4Hz,2H),7.45-7.34(m,1H),7.24-7.20(m,2H),7.11(d,J=8.4Hz,2H),6.80(d,J =8.4Hz,1H),6.73(d,J=8.4Hz,2H),6.68-6.53(m,1H),6.38-6.34(m,1H),5.77-5.69 (m,1H),4.94-4.91(m,0.5H),4.72-4.48(br,1.4H),4.25-4.07(m,1H),3.96(s,3H), 3.80-3.78(m,0.6H),3.24-3.22(m,1H),2.91(br,0.4H),2.50-2.47(m,1H),2.30-2.28(m, 1H),2.06-2.02(m,1H),1.73-1.71(m,1H)。
LCMS:m/z=489.2[M+H]+。
实施例3:(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶 -1-基)基)丙-2-烯-1-酮:
步骤A:1-(4-溴苯氧基)-2-氟-3-甲氧基苯(1)
向1-溴-4-碘苯(20.7g,73mmol,1.0eq)的二恶烷(180mL)溶液中加入2-氟-3-甲氧基苯酚(10.4g,73mmol,1.0eq),CuI(1.39g,7.3mmol,0.1eq),N,N-二甲基甘氨酸盐酸盐(2.03g,14.6mmol,0.2eq),Cs2CO3(35.9g,109.5mmol,1.5eq)。将混合物在N2保护下于100℃搅拌15小时,过滤,浓缩,EA萃取,有机层用水和盐水洗涤,无水Na 2SO 4干燥,浓缩并将残余物通过硅胶柱色谱法得到目标产物1(9.2g,42.4%)。
1H-NMR(400MHz,CDCl3):δ7.59(d,J=7.6Hz,1H),7.41(d,J=8.0Hz,1H), 7.00-7.04(m,1H),6.87(d,J=8.0Hz,1H),6.74-6.81(m,2H),6.62-6.66(m,1H),3.92 (s,3H)。
步骤B:(4-(2-氟-3-甲氧基苯氧基)苯基)硼酸
在N2下,将1(9.2g,30.96mmol,1.0eq)的THF(100mL)溶液冷却至-78℃,在相同温度下逐滴加入n-BuLi(16.1mL,40.25mmol,1.3eq),混合物在此温度下搅拌50分钟。在相同温度下逐滴加入硼酸三异丙酯(7.57g,40.25mmol,1.3eq),15分钟后,将混合物放置至室温并搅2小时,然后加入1N HCl调节至pH=5.0并搅拌30分钟。混合物用EA萃取,将有机层用水和盐水洗涤,无水Na2SO4干燥,过滤并浓缩,得到目标粗产物2(7.8g,95.8%)。
步骤C:(R)-3-(3-溴-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(3)
向100mL的圆底烧瓶中加入3-溴-1H-吡唑并[4,3-c]吡啶(2.45g,23.34mmol,1.0eq) 的DMF(40mL)溶液,(S)-(甲苯磺酰氧基)哌啶-1-甲酸叔丁酯(5.06g,14.48mmol,1.2eq)和Cs2CO3(6.1g,18.55mmol,1.5eq)。将所得溶液在65℃下搅拌12小时,加入 100mL水淬灭。EA(80mL×3)萃取,合并有机层。将有机物用盐水洗涤,无水Na2CO3干燥。真空除去溶剂,残余物通过硅胶柱色谱(DCM/MeOH=200:1-100:1)纯化,得到目标产物(3.5g,收率76.9%)。
1H-NMR(400MHz,CDCl3):δ8.98(s,1H),8.50(d,J=4.8Hz,1H),7.32(d,J =5.6Hz,1H),3.91(s,1H),3.76-3.80(m,2H),3.53-3.59(m,1H),2.59(s,1H),2.38- 2.44(m,1H),1.48(s,9H)。
LCMS:m/z=367[M+H]+。
步骤D:(R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基) (4)
向3(430mg,1.17mmol,1.0eq)和2(460mg,1.76mmol,1.5eq)的二恶烷(20mL) 和水(3mL)的溶液中加入K2CO3(324mg,2.34mmol,2.0eq)和(Ph3P)4Pd(30mg)。混合物回流6小时,直至原料消失。冷却至室温。通过旋转蒸发除去二恶烷。将残余物倒入水中并用EA萃取。有机层用Na2SO4干燥,过滤并通过旋转蒸发除去溶剂。用硅胶色谱法(DCM:MeOH=100:1-50:1)纯化残余物,得到目标产物(0.5g,产率84.4%)。
1H-NMR(400MHz,CDCl3):δ9.33(s,1H),8.46(d,J=5.2Hz,1H),7.94(d,J= 8.4Hz,2H),7.34(d,J=5.6Hz,1H),7.14(d,J=8.8Hz,2H),7.03-7.08(m,1H),6.80- 6.84(m,1H),6.71-6.75(m,1H),5.18(s,1H),3.94(s,6H),3.59(s,1H),2.64(s, 1H),2.41-2.46(m,1H),1.47(s,9H).
LCMS:m/z=505[M+H]+.
步骤E:(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡啶-3-基)丙-2-烯-1-酮(5):
向中间体4(870mg,1.73mmol,1.0eq)的DCM(30mL)一次性加入TFA(2.5mL)。将该混合物在室温下搅拌约1.5h。真空下除去挥发性组分,得到粗的目标产物,直接用于下一步而无需进一步纯化。将粗产物溶于DCM(20mL)中,向该溶液中加入TEA直至PH=8.0,然后逐滴加入丙烯酰氯(187mg,2.07mmol,1.2eq)的DCM(3.0mL)溶液。反应混合物搅拌0.5小时,倒入水,DCM萃取。将有机层用无水Na2SO4干燥,过滤并浓缩,将残余物通过硅胶柱色谱法(DCM/MeOH=200:1-50:1)纯化,得到目标产物 (400mg,产率50.6%)。
1H-NMR(400MHz,CDCl3):δ9.34(d,J=4.4Hz,1H),8.47-8.49(m,1H),7.90- 7.94(m,2H),7.34(d,J=4.8Hz,1H),7.12-7.14(m,2H),7.03-7.07(m,1H),6.80-6.84 (m,1H),6.71-6.75(m,1H),6.40-6.52(m,2H),5.69-5.75(m,1H),5.20-5.23(m,1H), 4.06-4.17(m,3H),3.94(s,3H),3.81-3.85(m,1H),2.47-2.78(m,2H).LCMS:m/z= 459.1[M+H]+。
实施例4:(R)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)基)丙-2-烯-1-酮
步骤A:(R)-3-(3-(4-(2-氯-3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(2)
向1(80mg,0.22mmol,1.0eq)和相应的硼酸(88mg,0.33mmol,1.5eq)的甲苯(10mL)和水(2mL)的溶液中加入K2CO3(61mg,0.44mmol,2.0eq)和(Ph3P)4Pd(25mg, 0.1eq)。将混合物回流6小时,直到原料消失。反应混合物冷却至室温,通过旋转蒸发除去甲苯,将残余物倒入水中并用EA萃取。有机层用Na2SO4干燥,过滤并通过旋转蒸发除去溶剂。产物用硅胶色谱法(DCM:MeOH=100:1-50:1)纯化,得到目标产物(90mg,产率81%)。
LCMS:m/z=509[M+H]+.
步骤B:(R)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基) 基)丙-2-烯-1-酮:
将中间体2(90mg,0.18mmol,1.0eq)溶于DCM(4mL)中,一次性加入TFA(1 mL)。混合物在室温下搅拌约1.5小时。真空下除去挥发性组分,得到粗的目标产物,其直接用于下一步而无需进一步纯化。将粗产物溶解于DCM(4mL)中,向该溶液中加入 TEA直到PH=8.0,然后逐滴加入丙烯酰氯(16mg,0.18mmol,1.0eq)的DCM(1.0mL) 溶液。反应混合物搅拌0.5h,倒入水中并用DCM萃取。有机层用无水Na2SO4干燥,过滤并浓缩,将残余物用硅胶柱色谱法(DCM/MeOH=200:1-50:1)纯化,得到目标产物(40 mg,产率50%)。
1H-NMR(400MHz,CDCl3):δ9.35(d,J=4.1Hz,1H),8.49(t,J=5.9Hz,1H),7.96(dd,J=8.2,6.0Hz,2H),7.41–7.31(m,1H),7.25–7.17(m,1H),7.13(dd,J=8.6Hz, 2.5Hz,2H),7.00(t,J=8.4Hz,1H),6.87(d,J=8.3Hz,1H),6.48(ddd,J=14.5Hz,13.7, 7.2Hz,2H),5.83–5.65(m,1H),5.38–5.15(m,1H),4.26–3.94(m,3H),3.95–3.69 (m,1H),2.85–2.42(m,2H).LCMS:m/z=463.2[M+H]+.
实施例5:(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3- c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤A:4-(2-氟-3-甲氧基苯氧基)苯甲醛(1)
向4-溴苯甲醛(6.99g,38mmol,1.2eq)的1,4-二氧六环(100mL)溶液中加入2- 氟-3-甲氧基苯酚(4.5g,32mmol,1.0eq),CuI(0.60g,3.2mmol,0.1eq),N,N- 二甲基甘氨酸盐酸盐(1.32g,9.5mmol,0.3eq),Cs2CO3(20.59g,60mmol,2eq),将混合物在N2保护下于100℃搅拌15h。过滤,浓缩,EtOAc萃取。将有机层用水和盐水洗涤,无水Na2SO4干燥并通过硅胶柱色谱法纯化,得到目标产品(4.1g,52.6%)。
1H-NMR(400MHz,CDCl3):δ9.9(s,1H),7.85-7.83(m,2H),7.26-7.04(m,3H), 6.89-6.85(m,1H),6.77-6.73(m,1H),3.92(s,3H).
步骤B:4,5-(二氯吡啶-3-基)-(4-(2-氟-3-甲氧基苯氧基)苯基)-甲醇(2)
在-78℃下,向二异丙基胺(2.1mL,15.1mmol,1.1eq)的无水THF(24mL)溶液中加入2.5M BuLi的己烷溶液(8.2mL,20.0mmol,1.3eq)。混合物升温至0℃并搅拌约1h,再将溶液冷却至-78℃并加入3,4-二氯吡啶(2.0g,13.7mmol,1eq)的无水THF (5mL)溶液。反应混合物再搅拌4h,然后加入相应的4-(2-氟-3-甲氧基苯氧基)苯甲醛(3.36g,13.7mmol,1eq),室温搅拌过夜。用H2O(25mL)破坏过量的LDA,Et2 O(3×50mL)萃取。合并有机相,Na2SO4干燥,真空除去挥发性组分,残余物通过硅胶柱色谱法(梯度:DCM/MeOH=200:1-50/1)纯化,得到目标产物(4.5g,收率83.6%)。
1H-NMR(400MHz,CDCl3):δ8.78(s,1H),8.55(s,1H),7.30(d,J=8.0Hz,2H), 7.02(d,J=8.0Hz,2H),6.98-6.66(m,3H),6.12(s,1H),3.93(s,3H).
LCMS:m/z=394.1[M+H]+.
步骤C:(4,5-二氯吡啶-3-基)-4-(2-氟-3-甲氧基苯氧基)苯基)-甲酮(3)
将4,5-二氯吡啶-3-基-4-(2-氟-3-甲氧基苯氧基)苯基)甲醇(2)(1g,2.5mmol)的无水丙酮(10mL)溶液冷却至0℃,小心多次加入CrO3(0.92g,9.23mmol),将所得溶液在室温下搅拌直至原料完全消失(3h),2-丙醇(6mL)淬灭,搅拌30min。最后加入饱和的NaHCO3溶液(50mL)以生成铬盐,经硅藻土过滤并用CH2Cl2(6×15mL)洗涤。真空除去溶剂,残余物通过硅胶柱色谱(梯度:DCM/MeOH=200:1)纯化,得到目标产物(0.69g,产率70.7%)。
LCMS:m/z=392.1[M+H]+.
步骤D:7-氯-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶(4)
向搅拌的(4-(苄氧基)苯基)-(4-氯吡啶-3-基)甲酮(3)(0.7g,1.77mol)的无水乙醇(5mL)溶液中加入水合肼(1.08g,17.3mol),加热回流3h,冷却,滤出产物,连续用水和甲醇洗涤,得到目标产物(0.54g,收率83%)。
1H-NMR(400MHz,CD3OD):δ9.30(s,1H),8.37(s,1H),8.01(d,J=8Hz,2H), 7.13-7.3.74(m,4H),7.18(d,J=8Hz,2H),3.92(S,3H).
LCMS:m/z=370.1[M+H]+.
步骤E:(R)-3-(7-氯-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶 -1-基)吡咯烷-1-羧酸酯(5)
向100mL的三口圆底烧瓶中加入3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶(4)(0.52g,1.41mmol)的N,N-二甲基甲酰胺(41mL)溶液,(S)-3-(甲苯磺酰氧基) 吡咯烷-1-羧酸叔丁酯(0.68g,1.99mmol)和Cs2CO3(0.97g,2.98mmol)。将所得溶液在60℃下搅拌12h,加入100mL水淬灭,EA萃取,合并有机层。有机物用盐水洗涤,无水NaHCO3干燥。真空除去溶剂,残余物通过硅胶柱色谱(梯度:DCM/MeOH=200:1 至100:1)纯化,得到目标产物(0.68g,收率90%)。
LCMS:m/z=539.1[M+H]+.
步骤F:(R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(6)
在N2条件下,向(R)-3-(7-氯-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3- c]吡啶-1-基酯)吡咯烷-1-甲酸叔丁酯(100mg,0.18mmol),甲基硼酸(12.2mg,0.20mmol),K3PO4·H2O(102mg,0.44mmol),三环己基膦(10.09mg,0.036mmol)的甲苯(10.0mL)和水(2mL)溶液中加入二乙基氧化钯(5mg,0.018mmol)。反应液升至100℃搅拌过夜,然后冷却至室温。加入水(100mL),EtOAc萃取,合并的有机物用盐水洗涤,经MgSO4干燥并真空浓缩,得到粗化合物。残余物用硅胶柱色谱法(DCM/ MeOH=200:1-50:1)纯化,得到目标产物(25mg,产率26%)。
LCMS:m/z=519.1[M+H]+.
步骤G:(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮(7)
(R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3-c]吡啶-1-基) 哌嗪-1-甲酸叔丁酯(25mg,0.048mmol)一次性加入到CF3COOH/DCM=4/1(5mL) 中,将混合物在室温下搅拌约1h,真空除去挥发性组分得到粗产物(20mg),并直接用于下一步而无需进一步纯化。
LCMS:m/z=419[M+H]+.
0℃下,将丙烯酰氯(4.3mg,0.048mmol)的DCM(1mL)溶液加入到搅拌的(R) -3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1-(吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶和 TEA(44mg,0.43mmol)的DCM(5mL)溶液中,将反应混合物搅拌1小时,倒入盐水中并用DCM萃取。将有机层干燥,浓缩并用DCM/MeOH=100/1重结晶,得到目标产物(11mg,产率50%)。
1H-NMR(400MHz,CDCl3):δ9.18(br,1H),8.21(br,1H),7.89-7.86(m,2H), 7.26-7.02(m,3H),6.83-6.49(m,2H),6.43-6.41(m,2H),5.74-5.71(m,1H),5.34-5.29 (m,1H),4.13-3.93(m,6H),2.73-2.19(m,4H),2.04-2.00(m,2H).
LCMS:m/z=473.2[M+H]+.
实施例6:(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮
步骤A:(4-氯-5-氟-吡啶-3-基)(4-(2-氟-3-乙氧基苯氧基)苯基)甲醇(1)
在-65℃,氮气条件下,向4-氯-3-氟吡啶(6.4.0g,49mmol,1.2eq)的无水THF(100mL)溶液中缓慢滴加LDA(2N,25.6mL)。加完后,将所得溶液在该温度下搅拌4.0h。然后在相同温度下小心加入4-(2-氟-3-甲氧基苯氧基)苯甲醛(10.0g,41mmol,1.0eq) 的无水THF(20mL)溶液。之后反应液在室温(15℃)下搅拌1.0h,通过TLC和LCMS 检测。反应混合物用水淬灭,然后倒入水中,用乙酸乙酯萃取,用水和盐水洗涤。有机层用无水Na2SO4干燥,浓缩,得到粗产物1,用于下一步骤而无需进一步纯化。LCMS:m/z =378.1[M+H]+.
步骤B:(4-氯-5-氟吡啶-3-基)(4-(2-氟-3-甲氧基苯氧基)苯基)甲酮(2)
在冰浴下,向1(10.0g(粗),26.53mmol,1.0eq)的DCM溶液中缓慢加入Dess-Martin(22.5g,53.05mmol,2.0eq),将所得溶液在15度下搅拌4.0h,通过TLC和 LCMS检测。向反应混合物中加入饱和NaHCO3溶液,过滤。滤液倒入水中,DCM萃取,饱和NaHCO3,Na2SO3溶液,水和盐水洗涤。无水Na2SO4干燥,浓缩,得到粗产物2(10.0 g),用于下一步而无需进一步纯化。LCMS:m/z=376.1[M+H]+.
步骤C:7-氟-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶(3)
向2(48g,128mmol,1.0eq)的EtOH(300mL)溶液中加入N2H4·H2O(64g,1.28 mol,10.0eq)。将所得溶液在90℃下搅拌2.5h。通过TLC和LCMS监测反应,并将反应混合物冷却至室温,然后过滤,沉淀用EtOH和EA洗涤,真空干燥得到纯产物3(33.3 g)。
1H-NMR(400MHz,D6-DMSO):δ9.24-9.23(d,J=2.0Hz,1H),8.39-8.38(d,J=2.4Hz,1H),8.08-8.06(d,J=8.8Hz,2H),7.22-7.17(m,1H),7.14-7.06(m,3H),6.86-6.82(m,1H),3.90(s,3H).
LCMS:m/z=354.1[M+H]+.
步骤D:(R)-3-(7-氟-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-甲酸叔丁酯(4)
将3(20g,57mmol,1.0eq),(S)-3-(甲苯磺酰氧基)哌啶-1-甲酸叔丁酯(40 g,113mmol,2.0eq),碳酸铯(37g,113mmol,2.0eq)的DMF(20mL)溶液在60℃下搅拌60h,通过LC-MS监测反应。将反应混合物冷却至室温,倒入水中,乙酸乙酯萃取,水和盐水洗涤。有机层经无水Na2SO4干燥,浓缩。产物通过硅胶柱色谱(DCM: MeOH=200:1至150:1)纯化,得到4(17g)。1H-NMR(400MHz,CDCl3):δ9.09 (s,1H),8.30-8.29(d,J=3.2Hz,1H),7.91-7.89(d,J=8.4Hz,2H),7.14-7.12(d,J=8.4 Hz,2H),7.08-7.03(m,1H),6.84-6.80(m,1H),6.74-6.71(m,1H),4.75-4.73(m,1H), 4.13-4.11(m,3H),3.93(s,3H),3.41-3.38(m,1H),2.92-2.86(m,1H),2.44-2.29(m, 2H),1.95-1.86(m,1H),1.73-1.70(m,1H),1.47-1.42(m,9H).
LCMS:m/z=537.2[M+H]+.
步骤E:(R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-羧酸叔丁酯(5)
将4(15g,28.0mmol,1.0eq),MeONa(15g,280mmol,10.0eq)的MeOH(120 mL)溶液加入到250mL密封管中,在100℃下搅拌过夜。通过TLC和LC-MS监测反应。将反应混合物冷却至室温,倒入水中,乙酸乙酯萃取,水和盐水洗涤。有机层用无水 Na2SO4干燥,浓缩,得到粗产物。产物通过硅胶柱色谱法(DCM:MeOH=150:1至100: 1)纯化,得到5(13.2g)。
1H-NMR(400MHz,CDCl3):δ8.94(s,1H),7.99(s,1H),7.91-7.89(d,J=8.8Hz, 2H),7.13-7.11(d,J=8.8Hz,2H),7.06-7.01(m,1H),6.82-6.78(m,1H),6.73-6.69(m, 1H),5.06-5.04(m,1H),4.14-4.11(m,1H),4.08(s,3H),3.93(s,3H),3.37(s,1H), 2.89-2.83(m,1H),2.30-2.24(m,2H),1.92(s,1H),1.70-1.67(m,1H),1.48-1.44(m, 11H).
LCMS:m/z=549.2[M+H]+.
步骤F:(R)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1-(哌啶-3-基)-1H-吡唑并[4,3-c]吡啶(6)
在18℃,向5(13g,23.7mmol)的DCM(100mL)溶液中加入TFA(14mL),搅拌4.0h,通过LC-MS和TLC监测反应。将反应混合物真空浓缩,得到粗产物6(5.5 g),用于下一步而无需进一步纯化。
LCMS:m/z=449.2[M+H]+.
步骤G:(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮(7)
在-30℃,向6(5.5g,粗品),TEA(2.2g,21.9mmol,2.0eq)的无水DCM(50mL) 溶液中加入丙烯酰氯(40mg/mL,在无水DCM中),所得溶液在18℃下搅拌30min,通过LC-MS和TLC监测。反应混合物用水淬灭,然后倒入水中,DCM萃取,水和盐水洗涤。有机溶液经无水Na2SO4干燥,浓缩。产物通过硅胶柱色谱法(DCM:MeOH=200:1至 150:1至100:1)纯化,得到7(3.2g)。1H-NMR(400MHz,CDCl3):δ8.95(s,1H), 8.00(s,1H),7.91-7.89(d,J=8.8Hz,2H),7.14-7.11(d,J=8.4Hz,2H),7.06-7.02(m,1H), 6.83-6.79(m,1H),6.73-6.70(m,1H),6.64-6.61(m,1H),6.34-6.30(m,1H),5.73-5.67 (m,1H),5.07-4.66(m,2H),4.29-4.06(m,4H),3.93(m,3H),3.625-2.82(m,2H),2.32- 1.72(m,4H).
LCMS:m/z=503.2[M+H]+.
下表中显示的实施例7-99按照上面通用方法中概述的程序制备,并在实施例1-6中详述。
实施例100:(R)-1-(3-(3-(4-((2-氟苄基)氧基)苯基)-1H-吡唑并[4,3-c] 吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤A:3-(4-((2-氟苄基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷- 1-甲酸((R)-3-1)
向100mL的圆底烧瓶中加入(R)-叔丁基-3-(3-(4-羟基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(30mg,0.078mmol)的DMF(3mL)溶液,1-(溴甲基) -2-氟苯(22mg,0.117mmol)和Cs2CO3(51.3mg,0.16mmol),将所得溶液在室温下搅拌3h,加入100mL水淬灭。EtOAc萃取,并合并有机层,有机物用盐水洗涤,无水Na2SO4干燥。真空除去溶剂,残余物通过硅胶柱色谱(梯度:DCM/MeOH=200:1-100:1)纯化,得到目标产物(30mg,收率80%)。LCMS:m/z=489.2[M+H]+.
步骤B:(R)-1-(3-(3-(4-((2-氟苄基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮(2)
将(R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3-c]吡啶-1- 基)哌嗪-1-甲酸叔丁酯(30mg,0.061mmol)一次性加入到CF3COOH/DCM=4/1(5mL) 中,混合物在室温下搅拌约1小时,真空除去挥发性组分,得到目标粗产物(24mg),并直接用于下一步而无需进一步纯化。
LCMS:m/z=389.2[M+H]+.
将丙烯酰氯(5.5mg,0.061mmol)的DCM(1mL)溶液加入到搅拌的(R)-3-(4 -((2-氟苄基)氧基)苯基)-1-(吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶(24mg,0.061mmol) 和TEA(44mg,0.43mmol)的DCM(5mL)溶液中。将反应混合物搅拌1h,倒入盐水,DCM萃取,干燥有机层,浓缩,并从DCM/MeOH=100/1重结晶,得到目标产物 (13mg,产率50%)。
1H-NMR(400MHz,CDCl3):δ9.18(br,1H),8.48(br,1H),7.93-7.89(m,2H), 7.55-7.52(m,1H),7.34-7.26(m,2H),7.20-7.09(m,4H),6.52-6.40(m,2H),5.75-5.70 (m,1H),5.27-5.23(m,1H),5.22(s,1H),4.16-4.07(m,3H),3.82-3.80(m,1H),2.89- 2.49(m,2H).
LCMS:m/z=443.2[M+H]+.
下表中所示的实施例101,102是按照以上通用方法中概述的和在实施例100中详述的方法制备的。
实施例103:(R)-4-(1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N- (3-甲氧基苄基)
步骤A:(R)-3-(3-(4-(甲氧基羰基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-羧酸叔丁酯(1)
在N2及搅拌情况下,向(R)-3-(3-溴-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-羧酸叔丁酯(105mg,0.286mmol,1.0eq)和4-(甲氧基羰基)苯基)硼酸(77mg,0.429mmol,1.5eq)的二恶烷(8.0mL)和水(1.0mL)中加入K2CO3(79mg,0.572mmol,2.0eq)和 (Ph3P)4Pd(20mg),混合物回流5.5h,直到原料消失,反应混合物冷却至室温,通过旋转蒸发除去二恶烷。将残余物倒入水中,EA萃取,有机层用Na2SO4干燥,过滤并真空除去溶剂,残余物用硅胶色谱法(DCM:MeOH=100:1-50:1)纯化,得到目标产物(90 mg,收率77.4%)。
1H-NMR(400MHz,CDCl3):δ9.45(s,1H),8.53(s,1H),8.19(d,J=8.4Hz, 2H),8.04-8.11(m,3H),5.20(s,1H),3.97(s,3H),3.93(s,3H),3.61(s,1H),2.62- 2.66(m,1H),2.46(d,J=6.0Hz,1H),1.48(s,9H).
LCMS:m/z=423[M+H]+.
步骤B:(R)-4-(1-(1-(叔丁氧基羰基)吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基) 苯甲酸(2)
向1(90mg,0.213mmol,1.0eq)的THF(5.0mL)和EtOH(5.0mL)溶液中加入 LiOH(45mg,1.067mmol,5.0eq),混合物在室温下搅拌,直到原料消失,加入水,然后加入1N HCl调节至pH=5.0,EA萃取混合物,有机层用水和盐水洗涤,无水Na2SO4干燥,过滤并浓缩,得到目标粗产物2(75mg,86.2%),其不经纯化即可用于下一步骤。
LCMS:m/z=409[M+H]+.
步骤C:(R)-3-(3-(4-((3-甲氧基苄基)氨基甲酰基)苯基)-1H-吡唑并[4,3-c] 吡啶-1-基)吡咯烷-1-羧酸叔丁酯(3):
向50mL的圆底烧瓶中加入2(75mg,0.184mmol,1.0eq)的THF(5.0mL)溶液, (3-甲氧基苯基)甲胺(38mg,0.276mmol,1.5eq)和TEA(47mg,0.46mmol,2.5eq), HATU(84mg,0.221mmol,1.2eq),所得溶液在室温下搅拌1.5h,加入30mL水淬灭, EA(20mL×3)萃取,合并有机层,用盐水洗涤,无水Na2SO4干燥,真空除去溶剂,残余物通过硅胶柱色谱法(DCM/MeOH=100:1-50:1),得到目标产物(85mg,收率 87.7%)。
1H-NMR(400MHz,CDCl3):δ9.37(s,1H),8.48(s,1H),8.07(d,J=7.6Hz, 1H),7.94(d,J=7.6Hz,1H),7.38(s,1H),7.26-7.32(m,1H),6.94-6.99(m,2H),6.86 (d,J=8.4Hz,1H),6.48(s,1H),5.19(s,1H),4.67(d,J=5.2Hz,2H),3.78-3.93(m, 6H),3.60(s,1H),2.64(d,J=6.0Hz,1H),2.46(d,J=7.6Hz,1H),1.47(s,9H)。
LCMS:m/z=528[M+H]+.
步骤D:(R)-4-(1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(3- 甲氧基苄基):
向中间体3(85mg,0.157mmol,1.0eq)的DCM(8.0mL)溶液中一次性加入TFA(1.5mL),将该混合物在室温下搅拌约1.5小时,在真空下除去挥发性组分,得到粗产物TFA盐的目标产物,直接用于下一步而无需进一步纯化。将粗产物溶于DCM(7.0mL) 中,向溶液中加入TEA直到PH=8.0,然后逐滴加入丙烯酰氯(17mg,0.188mmol, 1.2eq)的DCM(1.0mL)溶液,将反应混合物搅拌0.5h,倒入水中并用DCM萃取,有机层用无水Na2SO4干燥,过滤并浓缩,将残余物用硅胶板(DCM/MeOH=50:1)纯化,得到目标产物(20mg,产率25.8%)。
1H-NMR(400MHz,CD3OD):δ9.82(s,1H),8.62(s,1H),8.35(d,J=6.0Hz,1H), 8.18(d,J=8.0Hz,2H),8.08(d,J=8.0Hz,2H),7.25-7.29(m,1H),6.97(d,J=8.0Hz, 2H),6.84(d,J=8.0Hz,1H),6.61-6.79(m,1H),6.32-6.38(m,1H),5.77-5.85(m,2H), 4.60(s,2H),4.28(d,J=4.0Hz,1H),4.00(d,J=6.8Hz,1H),3.80(s,3H),2.62-2.75 (m,2H).
LCMS:m/z=482.2[M+H]+.
下表中所示实施例104-105按照以上通用方法中概述的程序并在实施例103中详述的方法制备的。
实施例106:(R)-1-(3-(3-(3'-甲基-[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1- 基)哌啶-1-基)丙-2-烯-1-酮:
步骤A:(R)-3-(3-(3'-甲基-[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶 -1-羧酸叔丁酯(1):
在N2及搅拌情况下,向(R)-3-(3-溴-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-甲酸叔丁酯(66.5mg,0.175mmol,1.0eq)和(3'-甲基-[1,1'-联苯]-4-基)硼酸(55.5mg,0.262mmol,1.5eq)的二恶烷(7.0mL)和水(1.0mL)中加入K2CO3(60.4mg,0.436mmol, 2.0eq)和Pd[Ph3P]4(15mg)。将该混合物回流6.0h,并将反应混合物冷却至室温,通过旋转蒸发除去二恶烷,将残余物倒入水中并用EA萃取,有机层用Na2SO4干燥,过滤并通过旋转蒸发除去溶剂,产物用硅胶色谱法(DCM:MeOH=100:1-50:1)纯化,得到目标产物(70mg,产率85.7%)。
LCMS:m/z=469[M+H]+.
步骤B:(R)-1-(3-(3-(3'-甲基-[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基) 哌啶-1-基)丙-2-烯-1-酮(2):
向中间体1(70mg,0.15mmol,1.0eq)的DCM(5.0mL)溶液中一次性加入TFA(1.0mL),该混合物在室温下搅拌约1.5h,真空下除去挥发性组分,得到目标粗产物的 TFA盐,并直接用于下一步而无需进一步纯化。将粗产物溶于DCM(5.0mL)中,加入 TEA直至PH=8.0,然后逐滴加入丙烯酰氯(20mg,0.224mmol,1.5eq)的DCM(1.0 mL)溶液。将反应混合物搅拌0.5h,倒入水中并用DCM萃取。有机层用无水Na2SO4干燥,过滤并浓缩,将残余物用硅胶板(DCM/MeOH=50:1)纯化,得到目标产物(20mg,产率31.7%)。
1H-NMR(400MHz,CDCl3):δ9.40(s,1H),8.48(s,1H),8.06(d,J=8.0Hz,2H), 7.76(d,J=8.4Hz,2H),7.35-7.48(m,4H),7.20(d,J=7.6Hz,1H),6.56-6.69(m,1H), 6.34-6.39(m,1H),5.70-5.78(m,1H),4.95(d,J=11.2Hz,0.5H),4.66(d,J=7.2Hz, 0.5H),4.50(d,J=10.4Hz,1H),4.08-4.23(m,1H),3.84(s,0.5H),3.21-3.30(m,1H), 2.93(s,0.5),2.30(d,J=11.2Hz,1H),1.74(s,1H).
LCMS:m/z=423[M+H]+.
下表中所示的实施例107-115是按照上面通用方法中概述的,并在实施例106中详述的方法制备的。
实施例116:N-{4-[1-(1-丙烯酰基-吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基]- 苯基}-3-三氟甲基-苯甲酰胺:
步骤A:(R)-3-(3-(4-氨基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-羧酸叔丁酯(1)
在N2及搅拌情况下,向(R)-3-(3-溴-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-甲酸叔丁酯(77mg,0.209mmol,1.0eq)和4-氨基苯基硼酸(57mg,0.418mmol,2.0eq) 的二恶烷(8.0mL)和水(1.0mL)中加入K2CO3(87mg,0.628mmol,3.0eq)和(Ph3P) 4Pd(20mg),混合物回流5.5h,直到原料消失。将反应混合物冷却至室温,旋转蒸发除去二恶烷。将残余物倒入水中并用EA萃取,有机层用Na2SO4干燥,过滤,真空除去溶剂,硅胶色谱法(DCM:MeOH=100:1-50:1)纯化残余物,得到目标产物(77mg,产率 96.8%)。
LCMS:m/z=380[M+H]+.
步骤B:(R)-3-(3-(4-((3-(三氟甲基)苯基)氨基)苯基)-1H-吡唑并[4,3-c] 吡啶-1-基)(2)
向1(77mg,0.203mmol,1.0eq)的DCM(5.0mL)溶液中逐滴加入3-(三氟甲基) 苯甲酰氯(51mg,0.243mmol,1.2eq)的DCM(2.0mL)溶液。将混合物在室温下搅拌 2.0h,加入水,DCM萃取,有机层用水和盐水洗涤,无水Na2SO4干燥,过滤并浓缩,产物用硅胶色谱纯化(DCM:MeOH=100:1-50:1),得到目标产物(60mg,56.5%)。
LCMS:m/z=524[M+H]+.
步骤C:(R)-1-(3-(3-(4-((3-(三氟甲基)苯基)氨基)苯基)-1H-吡唑并[4,3- c]吡啶-1-基)丙-1-烯-1-酮(3)
向中间体2(60mg,0.115mmol,1.0eq)的DCM(8.0mL)中一次性加入TFA(1.0 mL),该混合物在室温下搅拌约1.5h,真空除去挥发性组分,得到目标粗产物的TFA盐,并直接用于下一步而无需进一步纯化。将粗产物溶于DCM(5.0mL)中,加入TEA直到 PH=8.0,然后逐滴加入丙烯酰氯(12mg,0.133mmol,1.2eq)的DCM(1.0mL)溶液,反应混合物搅拌0.5h,倒入水中并用DCM萃取,有机层用无水Na2SO4干燥,过滤并浓缩,将残余物用硅胶板(DCM/MeOH=50:1)纯化,得到目标产物(19mg,产率34.7%)。
1H-NMR(400MHz,CDCl3):δ9.34(d,J=14.0Hz,1H),9.09(d,J=6.0Hz,1H), 8.15-8.47(m,3H),7.77-7.95(m,5H),7.58-7.62(m,1H),7.35-7.39(m,1H),6.37-6.54 (m,2H),5.69-5.75(m,1H),5.21-5.30(m,1H),4.38(d,J=9.6Hz,1H),4.01-4.18(m, 3H),3.80-3.85(m,1H),2.47-2.75(m,2H).
LCMS:m/z=506.2[M+H]+.
下表中所示的下列另外的实施例117按照以上通用方法中概述的程序,并在实施例 116中详述的方法制备的。
其他实施例118-123是按照以上通用方法中的步骤或报道的文献制备的。
Btk激酶和其他激酶的测定
BTK激酶的测活方法是利用均相时间分辨荧光技术。该方法的反应是在384浅孔板中,反应总体积是15μL。激酶、抑制剂、ATP和1μM肽底物在Hepes 50mM(pH=7.0), NaN30.02%,BSA 0.01%,Orthocanadate 0.1mM的缓冲液中进行,反应1小时后,向体系中加入能够识别底物磷酸化的抗体和XL-665以及含有60mM EDTA的1x检测缓冲液(Cisbio),使混合物温育1小时。激酶的反应信号通过PE公司的多孔板检测仪进行检测。参数设置是激发光330纳米,发射光615纳米和665纳米。通过665纳米和615纳米的信号比值间接反映BTK的活力。反应中设置8个不加酶的背景孔和两个不含化合物的全酶活性孔。IC50的值通过公式:Y=100/(1+10^((LogIC50-X)*HillSlope))获得。在BTK 反应体系中,ATP的浓度为80μM,BTK的浓度是3.4nM。
在LYN反应体系中,ATP的浓度是20μM,LYN的浓度是0.12nM。在LCK反应体系中,ATP的浓度是20μM,LCK的浓度是0.2nM。在BLK反应体系中,ATP的浓度是20μM,BLK的浓度是0.6nM。
实施例127
下表显示了本发明中的BTK抑制分析中所选化合物的活性。化合物编号对应于在先前的表的化合物编号。指定为活性化合物的“A”,提供的IC50≤10nM;具有活性的化合物被指定为“B”的,提供的IC50=10-100nM;具有活性的化合物被指定为“C”的,提供的IC50=100-1000nM;具有活性的化合物被指定为“D”的,提供的IC50=1000-10000nM;具有活性的化合物被指定为“E”的,提供的IC50≥10000nM。
实施例128
下表显示了本发明中的BTK,BLK,LYN,LCK抑制测定所选化合物的活性。化合物编号对应于在先前的表的化合物编号。指定为活性化合物的“A”,提供的IC50≤10nM;具有活性的化合物被指定为“B”的,提供的IC50=10-100nM;具有活性的化合物被指定为“C”的,提供的IC50=100-1000nM;具有活性的化合物被指定为“D”的,提供的IC50=1000- 10000nM;具有活性的化合物被指定为“E”的,提供的IC50≥10000nM;其命名为“N/A”的活性的化合物不可用。
表2
化合物 | BTK IC<sub>50</sub> | BLK IC<sub>50</sub> | LYN IC<sub>50</sub> | LCK IC<sub>50</sub> | EGFR IC<sub>50</sub> |
1 | A | A | E | D | C |
6 | A | B | D | D | C |
钙流分析
钙流信号是通过FDSS7000EX(Hamamatsu Photonics)读板机检测。首先,待测化合物用DMSO稀释,在0至10μM的Ca2+缓冲液(稀释因子为0.1)中稀释至适当浓度,向各孔中加入5μL(6X)(最终DMSO浓度为每孔0.1%)。然后在384孔板的每个孔中加入12.5μL2X染料上样溶液(Fluo-4NP钙测定试剂盒,Invitrogen)。之后,将在补充有 10%FBS(Invitrogen)的RPM1640培养基中活跃生长的Ramos细胞(ATCC)洗涤并且重新置于测定缓冲液(来自Fluo-4NP钙测定试剂盒,Invitrogen)中至大约6.4x106/ml (80000细胞/12.5μL,在384孔板中)。孔板在37℃温育30分钟,然后在室温下再温育 30分钟。这些孔板即已准备好用于实验。转移和10秒基线荧光记录后,立即用山羊抗人 IgM抗体(10μg/ml;Jackson ImmunoResearch)刺激化合物处理的细胞,并在FDSS中读取240秒。通过使用定制的Excel(Microsoft,Redmond,WA)模板计算信号与基线处指定的经调整的相对荧光单位之间的差异,以确定IgM诱导的钙的流入及其对化合物的抑制。下表显示了结果。指定为“A”的活性化合物提供了IC50≤10nM;指定为“B”的活性化合物提供了IC50=10-100nM;指定为“C”的活性化合物提供了IC50=100-1000nM。
下表显示了结果,指定为活性的化合物“A”提供的IC50≤10nM;活性的化合物被指定为“B”的提供的IC50=10-100nM;指定为“C”的活性化合物提供的IC50=100-1000nM。
表3
细胞水平的BTK占位实验
对于人类B细胞的PCI-33380标记,在标记前将106个Jeko-1细胞与化合物预温育1.5小时。然后用5μM的PCI-33380处理细胞1小时。洗涤,在含有样品还原剂的Ripa 缓冲液中裂解,并通过使用Typhoon扫描仪9500(GE Healthcare)(Ex,532nm;Em, 555nm)的SDS/PAGE和荧光凝胶扫描进行分析。印迹凝胶之后,通过用Btk抗体(CST) 的标准Western印迹检测总Btk水平。
通过使用荧光标记的衍生物PCI-33380,我们发现,化合物77在浓度25nM,化合物3,78,79,80,83在浓度50nM,化合物2,4,17,41,43,69,71,73,98和99 在浓度100nM时足以完全占据在人套细胞淋巴瘤细胞系Jeko-1细胞中培养的Btk的活性位点。
BTK在体内的占有率
用于分析化合物口服给药4小时后Babc/L小鼠的Btk占有率。采用小鼠外周血分离试剂盒(天津浩洋生物制品有限公司),从Babc/L小鼠中分离外周血单个核细胞 (PBMCs)(1mL,2只小鼠)。将脾脏加工成脾细胞,然后在红细胞裂解缓冲液(来自小鼠外周血分离试剂盒)中温育5分钟。然后如细胞测定中所述通过荧光凝胶扫描对 PBMC或脾细胞进行PCI-33380-标记且裂解物分析。化合物2,3,4,71在单次口服剂量为10mg/kg时,Babc/L小鼠体内BTK占位效果显示完全;化合物73,91在单次口服剂量为5mg/kg时,Babc/L小鼠体内BTK占位效果显示完全。
Claims (13)
1.一种具有以下结构式(I)的化合物:
其中:
A是N或CR1;
B,C和D各自为N或C-H,其条件是只有一个或两个的A,B,C和D可以是N;
R1是氢,氨基,OH,CN,-NHOH或CONH2;
R2是
-X-E是下列条件之一:
(1)X是O,OCRaRb,S(O),S(O)2,CRaRb,NRc(C=O),C=ONRc或键和E为氢,芳基或具有一至三个R5取代基取代的杂芳基;或一个3-7元饱和或部分不饱和碳环,8-10元双环饱和,部分不饱和或芳基环,具有1-4个任意选定氮,氧或硫杂原子的5-6元单环杂芳基环,一个4-7元饱和或不饱和且具有1-3个任意选定氮,氧或硫杂原子的部分杂环,7-10元双环饱和或不饱的具有1-5个任意选定氮,氧或硫的杂原子的杂环,或具有1-5个任意选定氮,氧或硫的杂原子的8-10元双环杂环;或
(2)-X-E为氢,卤素,-ORa,-O(CH2)1-4Ra,-CN,-NO2;
R4和R5各自独立地选自氢,卤素,羟基,氰基,OCF3,OCF2H,C1-6烷基,此烷基可含有一至五个独立的氟取代基,C3-6环烷基,此环烷基可含有一至五个独立的氟取代基,C1-4烷氧基,此烷氧基可含有一至五个独立的氟取代基,C1-4烷硫基,可含有一至五个独立的氟取代基,C1-4烷基磺酰基,可含有一至五个独立的氟和羧基取代基,C1-4烷氧基羰基,和C1-4烷基羰基;
Ra和Rb各自独立地为氢,氟,或C1-3烷基,可含有一至五个独立的氟取代基;
Rc为氢或C1-3烷基,可含有一至五个独立的氟取代基;
R3可为一具有双键的基团;
其异构体或其互变异构体,其药学上可接受的溶剂化物,或其药学上可接受的前体药物。
2.如权利要求1所述的化合物,在式(I)中,E是芳基,异芳基,羧基,杂环基,任何一个基团可含有一至三个R5取代基取代。
3.如权利要求1所述的化合物,在式(I)中,其中R3选自以下基团:
Y是C(=O),OC(=O),NHC(=O),S(=O)2,或NHS(=O)2;
R6,R7和R8各自独立地是氢,卤素,氰基,C1-4烷基,C1-6烷氧基,C1-8烷基氨基烷基,或C1-4烷基苯基;或R7和R8一起形成键。
4.如权利要求3所述的化合物,在式(I)中,R3选自以下组中的化合物:
Y是C(O);OC(=O),NHC(=O),S=O,S(=O)2,或NHS(=O)2;
R6,R7,R8各自独立地是氢,卤素,氰基,C1-4烷基,C1-6烷氧基,C1-8烷基氨基烷基,或C1-4烷基苯基;并且R7和R8一起形成键。
5.如权利要求3所述的化合物,在式(I)中,R3选自以下组中的化合物:
6.如权利要求1所述的化合物,其中A为CR1,B,C,D中有一个为N。
7.如权利要求1的所述的化合物,其中A是CR1,B为N,C和D是C-H。
8.如权利要求1所述的化合物,选自下面的化合物:(R)-1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲基-1H-吡唑并[4,3-c]吡啶-1-基)1-丙基-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(萘-1-基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(苯并[d][1,3]二氧杂环戊烯-4-基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(间甲苯基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氯-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R) -1-(3-(3-(4-(2,3-二甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氯-2-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氯-2-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;1-(3-((3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;1-(4-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;N-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)苯基)丙烯酰胺;(R)-1-(3-(3-(4-(3-异丙氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基),但-2-炔-1-酮;1-(6-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)-2-氮杂-螺[3.3]庚-2-基)丙-2-烯-1-酮;(R)-1-(3-(7-氯-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(1-丙烯酰基吡咯烷-3-基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-7-甲腈;(R)-1-(3-(3-(4-(环己基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1--酮;1-(6-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)-2-氮杂-螺[3.3]庚烷吡啶-2-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-((2,3-二氢-1H-茚-4-基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-((3-氯苯基)硫基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙丙-2-烯-1-酮;(S)-1-(3-(3-(3-氯-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-(3-氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-(间甲苯基氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-(2-氯-3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2烯-1-酮;(S)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2烯-1-酮;(R)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-2H-吡唑并[4,3-c]吡啶-2-基)哌啶-1-基)丙-2-烯-1-酮;(S)-1-(3-(3-(4-(2,3-二氯苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-((2-氟苄基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-((2-氟苄基)氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙丙-2-烯-1-酮;(R)-4-(1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(3-甲氧基苄基)苯甲酰胺;(R)-4-(1-(1-丙烯酰基-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(3-甲氧基苄基)苯甲酰胺;(R)-1-(3-(3-(3'-甲基[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶丙-2-烯-1-酮:(R)-1-(3-(3-(3'-甲基-[1,1'-联苯]-4-基)-2H-吡唑并[4,3-c]吡啶-2-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3'-甲基[1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷哌嗪-1-基)丙-2-烯-1-酮;N-{4-[1-(1-丙烯酰基-吡咯烷-3-基)-1H-吡唑并[4,3-c]吡啶-3-基]-苯基}-3-三氟甲基--(4-(1-(1-丙烯酰基-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)苯基)-3-(三氟甲基)苯甲酰胺;(R)-1-(3-(5-乙酰基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,5,6,7-四氢-1H-吡唑并[4,3-C]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(5-丙烯酰-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,5,6,7-四氢-1H-吡唑并[4,3-C]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲基苯氧基)苯基) -1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟-2-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氟-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;1-(3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮;1-(3-((3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)甲基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(4-氨基-3-(4-苯氧基苯基)-1H-吲唑-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(4-氨基-3-(4-苯氧基苯基)-1H-吲唑-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氯-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-((3-氟苯基)硫基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氯-2-甲基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氟-4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-氟-3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯;(R)-1-(3-(7-(二氟甲基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-氟-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1--(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(4-甲基-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-氟-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(4-甲基哌哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-([1,4'-联哌啶]-1'-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(4-(甲基磺酰基)哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-4-(1-(1-(丁-2-炔酰基)哌啶-3-基)-1H-吡唑并[4,3-c]吡啶-3-基)-N-(吡啶-2-基)苯甲酰胺;(R)-1-(3-(7-(二氟甲基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-异丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-乙氧基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)(2-甲苯磺酰基-2-氮杂螺[3.3]庚-6-基)甲酮;(R)-1-(3-(3-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-丁氧基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-4-甲基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-乙氧基-3-(4-(2-氟3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3--(4-(2-氯-3-甲氧基苯氧基)苯基)-7-乙氧基-1H-吡唑并[4,3-c]吡啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-乙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-羟基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-丁氧基-3-(4-(2-氯-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-异丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-(2-羟基乙氧基)-1H-吡唑并[4,3-c]吡啶-1-基基)哌啶-1-基)丙-2-烯-1-酮;1-((3R)-3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-((四氢呋喃-3-基)氧基)-1H-吡唑并[4,3-C]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;1-((3R)-3-(3-(4-(2-氯-3-甲氧基苯氧基)苯基)-7-((四氢呋喃-3-基)氧基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-(2-氨基乙氧基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(3-甲氧基-2-丙氧基苯氧基)苯基)-7-丙氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-1-酮;1-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)-2-羟基丙-1-酮;2-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)-2-氧代乙酸;2-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)-2-氧代乙酸;3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)环己烷甲酸;4-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)环己烷羧酸;(E)-2-(3-(3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-羰基)-4,4-二甲基戊-2-烯腈;1-(2-((3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮;(E)-2-(2-((3-(4-(2-氟-3-甲氧基苯氧基)苯基)-7-甲氧基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)吡咯烷-1-羰基)-4,4-二甲基戊-2-烯腈;(R)-1-(3-(7-(2-(二甲氨基)乙氧基)-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;(R)-1-(3-(7-(2-(二甲氨基)乙氧基) -3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丁-2-炔-1-酮;4-(3-(4-苯甲酰氨基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷甲酸;(3-([1,1'-联苯]-4-基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷羧酸。(S)-1-(3-(3-(4-(1-苯基乙烯基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)哌啶-1-基)丙-2-烯-1-酮;3-(3-(4-苯氧基苯基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷甲酸;4-(3-(4-(苄氧基)苯基)-1H-吡唑并[4,3-c]吡啶-1-基)环己烷羧酸。
9.一种包含治疗有效量的权利要求1至8的化合物和药学上可接受的赋形剂的药物组合物。
10.一种治疗自身免疫性疾病的方法,其包括向有需要的受试者施用含有治疗有效量的权利要求1至8的化合物的组合物。
11.权利要求1-8的用途,其与选自以下的治疗剂组合施用:抗癌药物,类固醇药物,甲氨蝶呤,来氟米特,抗TNF药剂,钙调磷酸酶抑制剂,抗组胺药物及其混合物。
12.一种用于预防或治疗癌症、肿瘤、炎性疾病、自身免疫疾病或免疫介导的疾病的药物组合物,其包含治疗有效量的权利要求1-8的化合物和药学上可接受的赋形剂。
13.一种治疗自身免疫性疾病、癌症、肿瘤、炎性疾病或免疫介导的疾病的方法,其包括向有需要的受试者施用含有治疗有效量的权利要求1-8的化合物和其它治疗剂的组合物。
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CN109310671B (zh) | 2021-08-06 |
EP3405192A4 (en) | 2019-07-03 |
AU2017208998B2 (en) | 2021-07-15 |
US10662187B2 (en) | 2020-05-26 |
EP3405192A1 (en) | 2018-11-28 |
JP6950897B2 (ja) | 2021-10-13 |
CA3009669C (en) | 2023-08-08 |
JP2019502763A (ja) | 2019-01-31 |
IL260691B (en) | 2022-07-01 |
KR20180135885A (ko) | 2018-12-21 |
IL260691A (zh) | 2018-09-20 |
EA201891626A1 (ru) | 2019-04-30 |
ZA201805439B (en) | 2019-11-27 |
CA3009669A1 (en) | 2017-07-27 |
BR112018014705A2 (pt) | 2018-12-11 |
AU2017208998A1 (en) | 2018-08-09 |
MX2018008815A (es) | 2019-03-28 |
US20190062328A1 (en) | 2019-02-28 |
WO2017127371A1 (en) | 2017-07-27 |
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