CN112135824A - 作为免疫调节剂的杂环化合物 - Google Patents
作为免疫调节剂的杂环化合物 Download PDFInfo
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- CN112135824A CN112135824A CN201980033784.9A CN201980033784A CN112135824A CN 112135824 A CN112135824 A CN 112135824A CN 201980033784 A CN201980033784 A CN 201980033784A CN 112135824 A CN112135824 A CN 112135824A
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- Prior art keywords
- methyl
- compound
- pyrimidin
- ylamino
- benzo
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- 239000002955 immunomodulating agent Substances 0.000 title abstract description 3
- 229940121354 immunomodulator Drugs 0.000 title abstract description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 308
- 238000000034 method Methods 0.000 claims abstract description 100
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 72
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 201000010099 disease Diseases 0.000 claims abstract description 34
- 201000011510 cancer Diseases 0.000 claims abstract description 31
- 208000015181 infectious disease Diseases 0.000 claims abstract description 20
- 208000035475 disorder Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- -1 C3-6Cycloalkyl radical Chemical class 0.000 claims description 339
- 150000003839 salts Chemical class 0.000 claims description 98
- 125000005605 benzo group Chemical group 0.000 claims description 93
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 82
- 150000003254 radicals Chemical class 0.000 claims description 47
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 42
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 41
- 102000008096 B7-H1 Antigen Human genes 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000006413 ring segment Chemical group 0.000 claims description 11
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 230000028993 immune response Effects 0.000 claims description 7
- 230000003993 interaction Effects 0.000 claims description 7
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 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
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 4
- 230000001965 increasing effect Effects 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- ARRUIUNMLVKZBV-BVRKHOPBSA-N (3R)-1-[[7-cyano-2-[3-[3-[[2-cyclopropyl-7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C1CC1)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1C[C@@H](CC1)C(=O)O ARRUIUNMLVKZBV-BVRKHOPBSA-N 0.000 claims description 3
- ABIMOFDDUILTQA-QLWXXVCSSA-N (3R)-1-[[7-cyano-2-[3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-6-methyl-1,7-naphthyridin-8-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1N=C(C=C2C=C(C=NC=12)CN1C[C@@H](CC1)O)C)C)C)CN1C[C@@H](CC1)C(=O)O ABIMOFDDUILTQA-QLWXXVCSSA-N 0.000 claims description 3
- LLCKWXCPDAUVGI-QHKNHCAJSA-N (3R)-1-[[7-cyano-2-[3-[3-[[6-(difluoromethyl)-3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]-3-methylpyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1N=C(C=C2C=C(C=NC=12)CN1C[C@@H](CC1)O)C(F)F)C)C)CN1C[C@@](CC1)(C(=O)O)C LLCKWXCPDAUVGI-QHKNHCAJSA-N 0.000 claims description 3
- FKXSQBPXYLKXMF-GDLZYMKVSA-N 1-[[2-[3-[3-[[2-amino-7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-7-cyano-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound NC=1N=C(C2=C(N=1)C=C(C=N2)CN1C[C@@H](CC1)O)NC=1C(=C(C=CC=1)C1=C(C(=CC=C1)C=1OC2=C(N=1)C=C(C=C2C#N)CN1CCC(CC1)C(=O)O)C)C FKXSQBPXYLKXMF-GDLZYMKVSA-N 0.000 claims description 3
- HDKXKNNLHFFDGW-VZUYHUTRSA-N 1-[[7-cyano-2-[3-[3-[[2-(difluoromethyl)-7-[[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]methyl]pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C(F)F)C=C(C=N2)CN1C[C@](CC1)(C)O)C)C)CN1CCC(CC1)C(=O)O HDKXKNNLHFFDGW-VZUYHUTRSA-N 0.000 claims description 3
- FBJBIASQJRTZDW-SSEXGKCCSA-N 1-[[7-cyano-2-[3-[3-[[2-(hydroxymethyl)-7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)CO)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1CCC(CC1)C(=O)O FBJBIASQJRTZDW-SSEXGKCCSA-N 0.000 claims description 3
- FGVCQETUXBHOKS-VZUYHUTRSA-N 1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CN1C[C@](CC1)(C)O)C)C)CN1CCC(CC1)C(=O)O FGVCQETUXBHOKS-VZUYHUTRSA-N 0.000 claims description 3
- BOPQFSYHHMTBMG-GDLZYMKVSA-N 1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C(F)(F)F)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1CCC(CC1)C(=O)O BOPQFSYHHMTBMG-GDLZYMKVSA-N 0.000 claims description 3
- UWRISMWEBPQKNV-WJOKGBTCSA-N 1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1CCC(CC1)C(=O)O UWRISMWEBPQKNV-WJOKGBTCSA-N 0.000 claims description 3
- FGVCQETUXBHOKS-QLKFWGTOSA-N 1-[[7-cyano-2-[3-[3-[[7-[[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CN1C[C@@](CC1)(C)O)C)C)CN1CCC(CC1)C(=O)O FGVCQETUXBHOKS-QLKFWGTOSA-N 0.000 claims description 3
- HPSVVUAGIVJRDH-QHCPKHFHSA-N 1-[[7-cyano-2-[3-[3-[[7-[[[(2S)-1-hydroxypropan-2-yl]amino]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CN[C@H](CO)C)C)C)CN1CCC(CC1)C(=O)O HPSVVUAGIVJRDH-QHCPKHFHSA-N 0.000 claims description 3
- MSVVAVYEUNATQL-QHCPKHFHSA-N 1-[[7-cyano-2-[3-[3-[[7-[[[(2S)-2-hydroxypropyl]amino]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]piperidine-4-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CNC[C@H](C)O)C)C)CN1CCC(CC1)C(=O)O MSVVAVYEUNATQL-QHCPKHFHSA-N 0.000 claims description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 3
- AEOCEZNNXNJSQE-VOLSFDEHSA-N (3R)-1-[[7-cyano-2-[3-[3-[[2-(difluoromethyl)-7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]-3-methylpyrrolidine-3-carboxylic acid Chemical compound CC1=C(NC2=NC(=NC3=CC(CN4CC[C@@H](O)C4)=CN=C23)C(F)F)C=CC=C1C1=CC=CC(C2=NC3=C(O2)C(=CC(CN2CC[C@](C)(C2)C(O)=O)=C3)C#N)=C1C AEOCEZNNXNJSQE-VOLSFDEHSA-N 0.000 claims description 2
- BBNDMJLFRODJDG-IXCJQBJRSA-N (3R)-1-[[7-cyano-2-[3-[3-[[2-(difluoromethyl)-7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C(F)F)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1C[C@@H](CC1)C(=O)O BBNDMJLFRODJDG-IXCJQBJRSA-N 0.000 claims description 2
- AJMVAOKZKQTANQ-OCQXTOTRSA-N (3R)-1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]-3-methylpyrrolidine-3-carboxylic acid Chemical compound CC1=NC2=CC(CN3CC[C@@](C)(O)C3)=CN=C2C(NC2=C(C)C(=CC=C2)C2=CC=CC(C3=NC4=C(O3)C(=CC(CN3CC[C@](C)(C3)C(O)=O)=C4)C#N)=C2C)=N1 AJMVAOKZKQTANQ-OCQXTOTRSA-N 0.000 claims description 2
- RBIRYSWFJHPWOM-LIIBOVGXSA-N (3R)-1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CN1C[C@](CC1)(C)O)C)C)CN1C[C@@H](CC1)C(=O)O RBIRYSWFJHPWOM-LIIBOVGXSA-N 0.000 claims description 2
- POKUBRPIWKCYMV-GIEABIOQSA-N (3R)-1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]-3-methylpyrrolidine-3-carboxylic acid Chemical compound Cc1c(Nc2nc(nc3cc(CN4CC[C@@H](O)C4)cnc23)C(F)(F)F)cccc1-c1cccc(-c2nc3cc(CN4CC[C@](C)(C4)C(O)=O)cc(C#N)c3o2)c1C POKUBRPIWKCYMV-GIEABIOQSA-N 0.000 claims description 2
- VGHINJDXVFDAHT-IXCJQBJRSA-N (3R)-1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C(F)(F)F)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1C[C@@H](CC1)C(=O)O VGHINJDXVFDAHT-IXCJQBJRSA-N 0.000 claims description 2
- QMSKZSYBUKOPKH-SBEKKQRLSA-N (3R)-1-[[7-cyano-2-[3-[3-[[7-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-2-methylpyrido[3,2-d]pyrimidin-4-yl]amino]-2-methylphenyl]-2-methylphenyl]-1,3-benzoxazol-5-yl]methyl]-3-methylpyrrolidine-3-carboxylic acid Chemical compound C(#N)C1=CC(=CC=2N=C(OC=21)C=1C(=C(C=CC=1)C1=C(C(=CC=C1)NC=1C2=C(N=C(N=1)C)C=C(C=N2)CN1C[C@@H](CC1)O)C)C)CN1C[C@@](CC1)(C(=O)O)C QMSKZSYBUKOPKH-SBEKKQRLSA-N 0.000 claims description 2
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
公开了式(I′)化合物、使用所述化合物作为免疫调节剂的方法和包含此类化合物的药物组合物。所述化合物可用于治疗、预防或改善例如癌症或感染的疾病或病症。
Description
本申请主张2018年3月30日提交的美国临时申请No.62/650,821和2018年6月21日提交的美国临时申请No.62/687,964号的权益,每个临时申请以引用的方式整体并入本文中。
发明领域
本申请涉及医药活性化合物。本公开提供了化合物以及其组合物和使用方法。所述化合物调节PD-1/PD-L1蛋白质/蛋白质相互作用并且可用于治疗包括感染性疾病和癌症的多种疾病。
发明背景
免疫系统在控制和根除例如癌症的疾病中起着重要作用。然而,癌细胞常常发展躲避或抑制免疫系统的策略以利于其生长。一种此类机制是改变在免疫细胞上表达的共刺激和共抑制分子的表达(Postow等人,J.Clinical Oncology 2015,1-9)。已经证明阻断例如PD-1的抑制免疫检查点的信号传导是一种有前景和有效的治疗模式。
程序性细胞死亡蛋白-1(PD-1)又称CD279,是一种在活化T细胞、自然杀伤T细胞、B细胞和巨噬细胞上表达的细胞表面受体(Greenwald等人,Annu.Rev.Immunol 2005,23:515-548;Okazaki和Honjo,Trends Immunol 2006,(4):195-201)。其充当内部负反馈系统以防止T细胞活化,这又会降低自身免疫性并且促进自身耐受性。此外,还知道PD-1在抑制如癌症和病毒感染的疾病中的抗原特异性T细胞反应中起到关键作用(Sharpe等人,NatImmunol 2007 8,239-245;Postow等人,J.Clinical Oncol 2015,1-9)。
PD-1的结构由细胞外免疫球蛋白可变样结构域、接着跨膜区和细胞内结构域组成(Parry等人,Mol Cell Biol 2005,9543-9553)。细胞内结构域含有两个位于基于免疫受体酪氨酸的抑制基元和基于免疫受体酪氨酸的转换基序中的磷酸化位点,这表明PD-1负调节T细胞受体介导的信号。PD-1具有两种配体PD-L1和PD-L2(Parry等人,Mol Cell Biol2005,9543-9553;Latchman等人,Nat Immunol 2001,2,261-268),并且所述配体的差异在于其表达模式。在巨噬细胞和树突状细胞上,响应于脂多糖和GM-CSF治疗,PD-L1蛋白质上调,而在T细胞和B细胞上,在T细胞受体和B细胞受体信号传导后上调。PD-L1也在几乎所有肿瘤细胞上均高度表达,并且所述表达在IFN-γ治疗之后进一步增加(Iwai等人,PNAS2002,99(19):12293-7;Blank等人,Cancer Res 2004,64(3):1140-5)。事实上,肿瘤PD-L1表达状态已经显示在多种肿瘤类型中是预后的(Wang等人,Eur J Surg Oncol 2015;Huang等人,Oncol Rep 2015;Sabatier等人,Oncotarget 2015,6(7):5449-5464)。相比之下,PD-L2表达更受限制并且主要由树突状细胞表达(Nakae等人,J Immunol 2006,177:566-73)。在T细胞上PD-1与其配体PD-L1和PD-L2的连接递送出抑制IL-2和IFN-γ产生以及T细胞受体活化后所诱发的细胞增殖的信号(Carter等人,Eur J Immunol 2002,32(3):634-43;Freeman等人,J Exp Med 2000,192(7):1027-34)。所述机制包括募集SHP-2或SHP-1磷酸酶以抑制T细胞受体信号传导,例如Syk和Lck磷酸化(Sharpe等人,Nat Immunol2007,8,239-245)。PD-1信号传导轴的活化也会减弱PKC-θ活化环磷酸化,PKC-θ活化环磷酸化是活化NF-κB和AP1通路以及产生例如IL-2、IFN-γ和TNF的细胞因子所必需的(Sharpe等人,Nat Immunol 2007,8,239-245;Carter等人,Eur J Immunol 2002,32(3):634-43;Freeman等人,J Exp Med 2000,192(7):1027-34)。
来自临床前动物研究的数条证据表明PD-1和其配体负调节免疫反应。已经证明缺乏PD-1的小鼠发生狼疮样肾小球性肾炎和扩张型心肌病(Nishimura等人,Immunity 1999,11:141-151;Nishimura等人,Science 2001,291:319-322)。使用LCMV慢性感染模型,已经证明PD-1/PD-L1相互作用抑制病毒特异性CD8 T细胞的效应功能的活化、扩增和获得(Barber等人,Nature 2006,439,682-7)。总的来说,这些数据支持发展阻断PD-1介导的抑制信号传导级联以加强或“拯救”T细胞反应的治疗性方法。因此,需要阻断PD-1/PD-L1蛋白质/蛋白质相互作用的新化合物。
发明内容
本公开尤其提供一种式(I′)化合物,
或其药学上可接受的盐或立体异构体,其中构成变量在本文中定义。
本发明还提供了一种式(I)化合物:
或其药学上可接受的盐或立体异构体,其中构成变量在本文中定义。
本发明还提供了一种药物组合物,所述药物组合物包含本文公开的化合物或其药学上可接受的盐或立体异构体以及一种或多种药学上可接受的赋形剂或载体。
本发明还提供了抑制PD-1/PD-L1相互作用的方法,所述方法包括向患者施用本文公开的化合物或其药学上可接受的盐或立体异构体。
本发明还提供了治疗与PD-1/PD-L1相互作用的抑制相关的疾病或病症的方法,所述方法包括向有需要的患者施用治疗有效量的本文公开的化合物或其药学上可接受的盐或立体异构体。
本发明还提供了增强、刺激和/或增加患者中的免疫反应的方法,所述方法包括向有需要的患者施用治疗有效量的本文公开的化合物或其药学上可接受的盐或立体异构体。
具体实施方式
I.化合物
本公开尤其提供了式(I’)化合物:
或其药学上可接受的盐或立体异构体,其中:
环A为氮杂环丁烷基、吡咯烷基或哌啶基;
X1为CH或N;
R1为甲基或卤基;
R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、OH、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基或4至6元杂环烷基-C1-2烷基-,其中所述4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各具有一或两个选自O和N的杂原子作为环原子,并且其中R2的所述C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代;
R3选自(R)-3-羟基-3-甲基吡咯烷-1-基、(S)-3-羟基-3-甲基吡咯烷-1-基、(R)-3-羟基吡咯烷-1-基、(S)-3-羟基吡咯烷-1-基、(R)-2-羟基-2-甲基-乙基氨基、(S)-2-羟基-2-甲基-乙基氨基、(R)-2-羟基-1-甲基-乙基氨基和(S)-2-羟基-1-甲基-乙基氨基;并且
R4为H或C1-3烷基;并且
R5为C(O)OH、C(O)N(CH3)2、C(O)NH(CH3)或C(O)NH(CH2)2C(O)OH。
在一些实施方案中,本文提供了式(I)化合物:
或其药学上可接受的盐或立体异构体,其中:
环A为氮杂环丁烷基、吡咯烷基或哌啶基;
X1为CH或N;
R1为甲基或卤基;
R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、OH、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基或4至6元杂环烷基-C1-2烷基-,其中所述4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各具有一或两个选自O和N的杂原子作为环原子,并且其中R2的所述C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代;
R3选自(R)-3-羟基-3-甲基吡咯烷-1-基、(S)-3-羟基-3-甲基吡咯烷-1-基、(R)-3-羟基吡咯烷-1-基、(S)-3-羟基吡咯烷-1-基、(R)-2-羟基-2-甲基-乙基氨基、(S)-2-羟基-2-甲基-乙基氨基、(R)-2-羟基-1-甲基-乙基氨基和(S)-2-羟基-1-甲基-乙基氨基;并且
R4为H或C1-3烷基。
在一些实施方案中,环A为吡咯烷基。在一些实施方案中,环A为哌啶基。在其它实施方案中,环A为哌啶基。
在一些实施方案中,部分选自4-羧基哌啶-1-基、3-羧基吡咯烷-1-基、3-甲基-3-羧基吡咯烷-1-基、4-(N,N-二甲基氨基羰基)哌啶-1-基、4-(N-甲基氨基羰基)哌啶-1-基和4-(2-羧基乙基氨基羰基)哌啶-1-基,其中波形线指示与分子的其余部分的连接点。
在一些实施方案中,部分为3-羧基吡咯烷-1-基,其中波形线指示与分子的其余部分的连接点。在一些实施方案中,3-羧基吡咯烷-1-基为(R)-3-羧基吡咯烷-1-基。在一些实施方案中,3-羧基吡咯烷-1-基为(S)-3-羧基吡咯烷-1-基。
在一些实施方案中,部分为3-甲基-3-羧基吡咯烷-1-基,其中波形线指示与分子的其余部分的连接点。在一些实施方案中,3-甲基-3-羧基吡咯烷-1-基为(R)-3-甲基-3-羧基吡咯烷-1-基。在一些实施方案中,3-甲基-3-羧基吡咯烷-1-基为(S)-3-甲基-3-羧基吡咯烷-1-基。
在一些实施方案中,部分选自4-羧基哌啶-1-基、(R)-3-羧基吡咯烷-1-基、(S)-3-羧基吡咯烷-1-基、(R)-3-甲基-3-羧基吡咯烷-1-基和(S)-3-甲基-3-羧基吡咯烷-1-基,其中波形线指示与分子的其余部分的连接点。
在一些实施方案中,X1为N。在一些实施方案中,X1为CH。
在一些实施方案中,R1为CH3或Cl。在一些实施方案中,R1为CH3。在一些实施方案中,R1为卤基(例如F、Cl或Br)。在一些实施方案中,R1为Cl。
在一些实施方案中,R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、OH、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基或哌啶-1-基甲基,其中R2的所述C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、-NH-C1-4烷基、-N(C1-4烷基)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基和哌啶-1-基甲基各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代。
在一些实施方案中,R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、OH、NH2、-NH-C1-4烷基或-N(C1-4烷基)2,其中R2的所述C1-4烷基、C1-4烷氧基、-NH-C1-4烷基和-N(C1-4烷基)2各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代。
在一些实施方案中,R2为C3-6环烷基、C3-6环烷基-C1-2烷基-、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基或哌啶-1-基甲基,其中R2的所述C3-6环烷基、C3-6环烷基-C1-2烷基-、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基和哌啶-1-基甲基各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代。
在一些实施方案中,R2为甲基、乙基、异丙基、甲氧基、乙氧基、CF3、CHF2、CFH2、OCF3、OCHF2、OCH2F、环丙基、环丁基、环己基、环丙基甲基、环丁基甲基、环己基甲基、OH、NH2、NHCH3、N(CH3)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基或哌啶-1-基甲基,其中R2的所述甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环己基、环丙基甲基、环丁基甲基、环己基甲基、NHCH3、N(CH3)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基和哌啶-1-基甲基各任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。
在一些实施方案中,R2为甲基、乙基、异丙基、甲氧基、乙氧基、CF3、CHF2、CFH2、OCF3、OCHF2、OCH2F、OH、NH2、NHCH3或N(CH3)2,其中R2的所述甲基、乙基、异丙基、甲氧基、乙氧基、NHCH3和N(CH3)2各任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。
在一些实施方案中,R2为环丙基、环丁基、环己基、环丙基甲基、环丁基甲基、环己基甲基、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基或哌啶-1-基甲基,其中R2的所述环丙基、环丁基、环己基、环丙基甲基、环丁基甲基、环己基甲基、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基和哌啶-1-基甲基各任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。
在一些实施方案中,R2为CH3、CF3、CHF2、CH(CH3)2、NH2、环丙基或CH2OH。
在一些实施方案中,R2为C1-4烷基或C1-4卤基烷基,所述每个基团任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。
在一些实施方案中,R2为C1-4烷基或C1-4卤基烷基。在一些实施方案中,R2为CH3、CF3、CHF2或CH(CH3)2。在一些实施方案中,R2为C1-4烷基,例如CH3和CH(CH3)2。在一些实施方案中,R2为CH3。在一些实施方案中,R2为CH(CH3)2。在一些实施方案中,R2为C1-4卤基烷基,例如CF3、CHF2和CH2F。在一些实施方案中,R2为C1-4卤基烷基,例如CF3和CHF2。在一些实施方案中,R2为CF3。在一些实施方案中,R2为CHF2。在一些实施方案中,R2为CH2F。
在一些实施方案中,R2为NH2、NHCH3或N(CH3)2,其中R2的所述NHCH3和N(CH3)2各任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。在一些实施方案中,R2为NH2。
在一些实施方案中,R2为环丙基、环丁基或环己基,其中R2的所述环丙基、环丁基和环己基各任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。在一些实施方案中,R2为任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代的环丙基。在一些实施方案中,R2为环丙基。
在一些实施方案中,R3为(R)-3-羟基-3-甲基吡咯烷-1-基或(S)-3-羟基-3-甲基吡咯烷-1-基。在一些实施方案中,R3为(R)-3-羟基吡咯烷-1-基或(S)-3-羟基吡咯烷-1-基。在一些实施方案中,R3为(R)-2-羟基-2-甲基-乙基氨基或(S)-2-羟基-2-甲基-乙基氨基。在一些实施方案中,R3为(R)-2-羟基-1-甲基-乙基氨基或(S)-2-羟基-1-甲基-乙基氨基。
在一些实施方案中,R4为H或CH3。在一些实施方案中,R4为H。在一些实施方案中,R4为C1-3烷基,例如CH3。
在一些实施方案中,本文提供的化合物为式II化合物:
或其药学上可接受的盐或立体异构体,其中R2、R3、R4和环A如本文中所述。
在一些实施方案中,本文提供的化合物为式III化合物:
或其药学上可接受的盐或立体异构体,其中R2、R3和环A如本文中所述。
在一些实施方案中,本文提供的化合物为式IV化合物:
或其药学上可接受的盐或立体异构体,其中R2、R3、R4和环A如本文中所述。
在一些实施方案中,本文提供的化合物为式V化合物:
或其药学上可接受的盐或立体异构体,其中R2、R3和环A如本文中所述。
在一些实施方案中,所述化合物选自:
1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((-2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(7-((-3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;和
1-((7-氰基-2-(3′-(7-((-3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸,
或其药学上可接受的盐或立体异构体。
在一些实施方案中,所述化合物选自:
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-4-甲基哌啶-4-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-N,N-二甲基哌啶-4-甲酰胺;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-N-甲基哌啶-4-甲酰胺;
3-(1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酰胺基)丙酸;
1-((7-氰基-2-(3′-(2-环丙基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
1-((2-(3′-(2-氨基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-7-氰基苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(2-(羟基甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
1-((7-氰基-2-(3′-(3-((3-羟基吡咯烷-1-基)甲基)-6-甲基-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;和
1-((7-氰基-2-(3′-(6-(二氟甲基)-3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸,
或其药学上可接受的盐或立体异构体。
在一些实施方案中,所述化合物选自本文提供的实例。
进一步了解,为了清楚起见,在分开实施方案的上下文中描述的本发明的某些特征也可以组合提供于单个实施方案中(而所述实施方案意图如同以多重从属形式书写一般组合)。相反地,为了简便起见,在单个实施方案的上下文中描述的本发明的多种特征还可以分开或呈任何合适的子组合提供。因此,预期描述为式(I)化合物的实施方案的特征可以任何合适组合进行组合。
在本说明书中的多个地方,化合物的某些特征是以组或以范围公开。特别意图此类公开内容包括此类组和范围的成员的每个单独子组合。举例来说,术语“C1-6烷基”特别意图单独公开(不限于)甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
其中n为整数的术语“n员”通常描述成环原子数目为n的部分中成环原子的数目。举例来说,哌啶基为6元杂环烷基环的一实例,吡唑基为5元杂芳环的一实例,吡啶基为6元杂芳环的一实例,并且1,2,3,4-四氢-萘为10元环烷基的一实例。
在本说明书的多个地方,可描述界定二价连接基团的变量。特别意图每个连接取代基包括连接取代基的正向与反向形式。举例来说,-NR(CR′R″)n-包括-NR(CR′R″)n-与-(CR′R″)nNR-,并且意图公开每个单独形式。在结构需要连接基团的情况下,针对所述基团所列出的马库什变量(Markush variable)应理解为连接基团。举例来说,如果结构需要连接基团并且针对所述变量的马库什基团定义列出“烷基”或“芳基”,那么应了解“烷基”或“芳基”分别表示连接亚烷基或亚芳基。
术语“取代”意指原子或原子团作为附接于另一基团的“取代基”形式上替换氢。除非另外指示,否则术语“取代”是指任何程度的取代,例如单取代、二取代、三取代、四取代或五取代(在允许此类取代的情况下)。取代基是独立地选择的,并且取代可以在任何化学上可行的位置进行。应了解,给定原子上的取代受价数限制。应了解,给定原子上的取代产生化学上稳定的分子。词组“任选地取代”意指未取代或取代。术语“取代”意指去除氢原子并且被取代基置换。单个二价取代基(例如氧代基)可以置换两个氢原子。
术语“Cn-m”指示包括终点的范围,其中n和m为整数且指示碳数。实例包括C1-4、C1-6等等。
单独或与其它术语组合使用的术语“烷基”是指可为直链或具支链的饱和烃基。术语“Cn-m烷基”是指具有n至m个碳原子的烷基。烷基在形式上对应于一个C-H键被烷基与化合物其余部分的连接点替代的烷烃。在一些实施方案中,烷基含有1至6个碳原子、1至4个碳原子、1至3个碳原子或1至2个碳原子。烷基部分的实例包括(但不限于)例如以下的化学基团:甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基;高级同系物,例如2-甲基-1-丁基、正戊基、3-戊基、正己基、1,2,2-三甲基丙基等等。
单独或与其它术语组合使用的术语“烯基”是指与具有一个或多个碳-碳双键的烷基对应的直链或具支链烃基。烯基在形式上对应于一个C-H键被烯基与化合物其余部分的连接点替代的烯烃。术语“Cn-m烯基”是指具有n至m个碳原子的烯基。在一些实施方案中,烯基部分含有2至6个、2至4个或2至3个碳原子。烯基实例包括(但不限于)乙烯基、正丙烯基、异丙烯基、正丁烯基、仲丁烯基等等。
单独或与其它术语组合使用的术语“炔基”是指与具有一个或多个碳碳三键的烷基对应的直链或具支链烃基。炔基在形式上对应于一个C-H键被烷基与化合物其余部分的连接点替代的炔烃。术语“Cn-m炔基”是指具有n至m个碳的炔基。炔基实例包括(但不限于)乙炔基、丙炔-1-基、丙炔-2-基等等。在一些实施方案中,炔基部分含有2至6个、2至4个或2至3个碳原子。
单独或与其它术语组合使用的术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上对应于两个C-H键被亚烷基与化合物其余部分的连接点替代的烷烃。术语“Cn-m亚烷基”是指具有n至m个碳原子的亚烷基。亚烷基的实例包括(但不限于)乙-1,2-二基、丙-1,3-二基、丙-1,2-二基、丁-1,4-二基、丁-1,3-二基、丁-1,2-二基、2-甲基-丙-1,3-二基等等。
单独或与其它术语组合使用的术语“烷氧基”是指式-O-烷基的基团,其中所述烷基如上所定义。术语“Cn-m烷氧基”是指烷基具有n至m个碳的烷氧基。烷氧基实例包括甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)、叔丁氧基等等。在一些实施方案中,烷基具有1至6个、1至4个或1至3个碳原子。
术语“氨基”是指式-NH2的基团。
术语“氨甲酰基”是指式-C(O)NH2的基团。
单独或与其它术语组合使用的术语“羰基”是指-C(=O)-基团,其也可以写成C(O)。
术语“氰基”或“腈”是指式-C≡N的基团,其也可以写成-CN。
单独或与其它术语组合使用的术语“卤基”或“卤素”是指氟、氯、溴和碘。在一些实施方案中,“卤基”是指选自F、Cl或Br的卤素原子。在一些实施方案中,卤基为F。
如本文所用的术语“卤烷基”是指其中一个或多个氢原子已被卤素原子置换的烷基。术语“Cn-m卤烷基”是指具有n至m个碳原子和至少一个至至多{2(n至m)+1}个卤素原子的Cn-m烷基,所述卤素原子可以相同或不同。在一些实施方案中,卤素原子为氟原子。在一些实施方案中,卤烷基具有1至6个或1至4个碳原子。卤烷基实例包括CF3、C2F5、CHF2、CCl3、CHCl2、C2Cl5等等。在一些实施方案中,卤烷基为氟烷基。
单独或与其它术语组合使用的术语“卤烷氧基”是指式-O-卤烷基的基团,其中卤烷基如上所定义。术语“Cn-m卤烷氧基”是指卤烷氧基,其中卤烷基具有n至m个碳。卤烷氧基实例包括三氟甲氧基等等。在一些实施方案中,卤烷氧基具有1至6个、1至4个或1至3个碳原子。
术语“氧代基”是指作为二价取代基的氧原子,当附接于碳时形成羰基,或当附接于杂原子时,形成亚砜基或砜基,或N-氧化物基团。在一些实施方案中,杂环基团可任选地被1个或2个氧代基(=O)取代基取代。
术语“硫离子基”是指作为二价取代基的硫原子,当附接于碳时形成硫羰基(C=S)。
术语“芳香族”是指具有一个或多个多不饱和环并且具有芳香族特性(即具有(4n+2)个离域π(π)电子,其中n为整数)的碳环或杂环。
单独或与其它术语组合使用的术语“芳基”是指可为单环或多环(例如具有2个稠环)的芳香族烃基。术语“Cn-m芳基”是指具有n至m个环碳原子的芳基。芳基包括例如苯基、萘基、二氢茚基、茚基等等。在一些实施方案中,芳基具有6至约10个碳原子。在一些实施方案中,芳基具有6个碳原子。在一些实施方案中,芳基具有10个碳原子。在一些实施方案中,芳基为苯基。在一些实施方案中,芳基为萘基。
本文中使用的术语“杂原子”意指包括硼、磷、硫、氧和氮。
单独或与其它术语组合使用的术语“杂芳基”或“杂芳香族”是指具有至少一个选自硼、磷、硫、氧和氮的杂原子环成员的单环或多环芳香族杂环。在一些实施方案中,杂芳环具有1个、2个、3个或4个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中,杂芳基部分中的任何成环N可为N-氧化物。在一些实施方案中,杂芳基具有5-14个包括碳原子的环原子和1个、2个、3个或4个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中,杂芳基具有5-14个或5-10个包括碳原子的环原子和1个、2个、3个或4个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中,杂芳环具有5-6个环原子和1个或2个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中,杂芳基为五元或六元杂芳环。在其它实施方案中,杂芳基为八元、九元或十元稠合双环杂芳环。杂芳基实例包括(但不限于)吡啶基(pyridinyl)(吡啶基(pyridyl))、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、唑基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基、喹啉基、异喹啉基、萘啶基(包括1,2-萘啶、1,3-萘啶、1,4-萘啶、1,5-萘啶、1,6-萘啶、1,7-萘啶、1,8-萘啶、2,3-萘啶和2,6-萘啶)、吲哚基、苯并噻吩基、苯并呋喃基、苯并异噁唑基、咪唑并[1,2-b]噻唑基、嘌呤基等等。
五元杂芳环为具有五个环原子的杂芳基,其中一个或多个(例如1个、2个或3个)环原子独立地选自N、O和S。示例性五元环杂芳基包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、异噻唑基、异噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基和1,3,4-噁二唑基。
六元杂芳环为具有六个环原子的杂芳基,其中一个或多个(例如1个、2个或3个)环原子独立地选自N、O和S。示例性六元环杂芳基为吡啶基、吡嗪基、嘧啶基、三嗪基和哒嗪基。
单独或与其它术语组合使用的术语“环烷基”是指非芳香族烃环系统(单环、双环或多环),包括环化烷基和烯基。术语“Cn-m环烷基”是指具有n至m个环成员碳原子的环烷基。环烷基可包括单环或多环(例如具有2个、3个或4个稠环)基团和螺环。环烷基可具有3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个或14个成环碳(C3-14)。在一些实施方案中,环烷基具有3至14个成员、3至10个成员、3至6个环成员、3至5个环成员或3至4个环成员。在一些实施方案中,环烷基为单环。在一些实施方案中,环烷基为单环或双环。在一些实施方案中,环烷基为C3-6单环环烷基。环烷基的成环碳原子可任选地经氧化形成氧代基或硫离子基。环烷基还包括亚环烷基。在一些实施方案中,环烷基为环丙基、环丁基、环戊基或环己基。环烷基的定义中还包括具有一个或多个与环烷基环稠合(即与环烷基环共享一键)的芳香族环的部分,例如环戊烷、环己烷的苯并或噻吩基衍生物等等。含有稠合芳环的环烷基可以通过任何成环原子,包括稠合芳环的成环原子进行附接。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、降冰片基、降蒎烷基、降蒈烷基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。在一些实施方案中,环烷基为环丙基、环丁基、环戊基或环己基。
单独或与其它术语组合使用的术语“杂环烷基”是指可任选地含有一个或多个亚烯基作为环结构的一部分,具有至少一个独立地选自硼、氮、硫、氧和磷的杂原子环成员并且具有4-14个环成员、4-10个环成员、4-7个环成员或4-6个环成员的非芳香族环或环系统。术语“杂环烷基”内包括单环4元、5元、6元和7元杂环烷基。杂环烷基可以包括单环或双环或多环(例如具有两个或三个稠环或桥环)环系统或螺环。在一些实施方案中,杂环烷基为具有1个、2个或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可任选地氧化形成氧代基或硫离子基或其它氧化键联(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等),或氮原子可以季铵化。杂环烷基可以通过成环碳原子或成环杂原子附接。在一些实施方案中,杂环烷基含有0至3个双键。在一些实施方案中,杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即与杂环烷基环共享一键)的芳环的部分,例如哌啶、吗啉、氮杂卓的苯并或噻吩基衍生物等。含有稠合芳环的杂环烷基可以通过任何成环原子,包括稠合芳环的成环原子进行附接。杂环烷基的实例包括氮杂环丁烷基、氮杂环庚烷基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代基哌嗪基、吡喃基、吡咯烷基、奎宁环基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、托品烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基和硫吗啉基。
在某些地方,定义或实施方案是指特定环(例如氮杂环丁烷环、吡啶环等)。除非另外指示,否则这些环可附接于任何环成员,条件为不超过原子价数。举例来说,氮杂环丁烷环可在环的任何位置附接,而氮杂环丁烷-3-基环在3位附接。
本文所述的化合物可为不对称的(例如具有一个或多个立构中心)。除非另外指示,否则预期为例如对映异构体和非对映异构体的所有立体异构体。含有经不对称取代的碳原子的本发明的化合物可以呈光学活性或消旋形式分离。本领域中已知如何从无光学活性的起始物质制备光学活性形式的方法,例如通过拆分外消旋混合物或通过立体选择性合成。烯烃、C=N双键等等的许多几何异构体也可以存在于本文所述的化合物中,并且本发明中涵盖所有此类稳定异构体。描述本发明化合物的顺式与反式几何异构体并且可以呈异构体混合物或呈分开异构体形式分离。
化合物的外消旋混合物的拆分可以通过本领域中已知的许多方法中的任一种进行。一种方法包括使用作为光学活性成盐有机酸的手性拆分酸进行分步再结晶。适用于分步再结晶法的拆分剂为例如光学活性酸,例如D和L形式的酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或多种光学活性樟脑磺酸(例如β-樟脑磺酸)。其它适合于分步结晶法的拆分剂包括α-甲基苯甲胺的立体异构纯形式(例如S和R形式,或非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷等等。
外消旋混合物的拆分也可以通过在装填有光学活性拆分剂(例如二硝基苯甲酰基苯基甘氨酸)的柱上洗脱来进行。合适洗脱溶剂组成可由本领域的技术人员决定。
在一些实施方案中,本发明的化合物具有(R)-构型。在其它实施方案中,化合物具有(S)-构型。在具有超过一个手性中心的化合物中,除非另外指示,否则化合物中的每个手性中心可独立地为(R)或(S)。
本发明的化合物还包括互变异构形式。互变异构形式由单键与相邻双键交换同时伴随质子迁移产生。互变异构形式包括质子转移互变异构体,其为具有相同经验式和总电荷的异构质子化状态。质子转移互变异构体实例包括酮-烯醇对、酰胺-亚氨酸对、内酰胺-内酰亚胺对、烯胺-亚胺对和其中质子可占据杂环系统的两个或更多个位置的环状形式,例如1H-咪唑和3H-咪唑、1H-1,2,4-三唑、2H-1,2,4-三唑和4H-1,2,4-三唑、1H-异吲哚和2H-异吲哚以及1H-吡唑和2H-吡唑。互变异构形式可处于平衡或通过适当取代而在空间上锁定成一种形式。
本发明的化合物也可以包括在中间物或最终化合物中存在的原子的所有同位素。同位素包括具有相同原子序数但质量数不同的那些原子。举例来说,氢同位素包括氚和氘。本发明的化合物的一个或多个组成原子可被天然或非天然丰度的原子同位素置换或取代。在一些实施方案中,化合物包括至少一个氘原子。举例来说,本发明的化合物中的一个或多个氢原子可被氘置换或取代。在一些实施方案中,化合物包括两个或更多个氘原子。在一些实施方案中,化合物包括1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个或12个氘原子。用于将同位素包括于有机化合物中的合成方法是本领域中已知的。
如本文所用的术语“化合物”意指包括所描绘的结构的所有立体异构体、几何异构体、互变异构体和同位素。所述术语也意指本发明的化合物,无论其如何制备,例如通过合成、通过生物方法(例如代谢或酶促转变)或它们的组合。
所有化合物和其药学上可接受的盐连同例如水和溶剂的其它物质一起存在(例如水合物和溶剂化物),或可以是分离的。当处于固态时,本文所述的化合物和其盐可以呈多种形式存在,并且可例如采取溶剂合物形式,包括水合物。化合物可以呈任何固态形式,例如多晶型物或溶剂合物,因此除非另外清楚指示,本说明书中对化合物和其盐的提及应理解为涵盖化合物的任何固态形式。
在一些实施方案中,本发明的化合物或其盐是基本上分离的。“基本上分离的”意指化合物至少部分或基本上与形成或检测到其的环境分离。部分分离可包括例如富集本发明的化合物的组合物。基本上分离可包括含有至少约50重量%、至少约60重量%、至少约70重量%、至少约80重量%、至少约90重量%、至少约95重量%、至少约97重量%或至少约99重量%本发明的化合物或其盐的组合物。
本文中词组“药学上可接受”用以指在合理医学判断范围内,适合与人类和动物的组织接触使用而无过度毒性、刺激、过敏反应或其它问题或并发症,与合理利益/风险比相称的那些化合物、物质、组合物和/或剂型。
如本文所用的表述“周围温度”和“室温”是本领域中所了解的,并且一般是指温度、例如反应温度约为进行反应的房间的温度,例如约20℃至约30℃。
本发明还包括本文所述的化合物的药学上可接受的盐。术语“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过将所存在的酸或碱部分转变成其盐形式而被改性。药学上可接受的盐的实例包括(但不限于)例如胺的碱性残余物的无机酸盐或有机酸盐;例如羧酸的酸性残余物的碱金属盐或有机盐;等等。本发明的药学上可接受的盐包括例如由无毒无机酸或有机酸形成的母体化合物的无毒盐。本发明的药学上可接受的盐可以通过常规化学方法由含有碱性或酸性部分的母体化合物合成。一般来说,此类盐可以通过使这些化合物的游离酸或游离碱形式与化学计算量的适当碱或酸在水中或有机溶剂中或两者的混合物中反应来制备;一般来说,非水性介质,如乙醚、乙酸乙酯、醇(例如甲醇、乙醇、异丙醇或丁醇)或乙腈(MeCN)是优选的。合适盐的清单见于Remington′sPharmaceutical Sciences,第17版,(Mack Publishing Company,Easton,1985),第1418页;Berge等人,J.Pharm.Sci.,1977,66(1),1-19;和Stahl等人,Handbook ofPharmaceutical Salts:Properties,Selection,and Use,(Wiley,2002)。在一些实施方案中,本文所述的化合物包括N-氧化物形式。
II.合成
本发明的化合物,包括其盐,可以使用已知的有机合成技术制备并且可以根据许多可能合成途径中的任一种合成。
用于制备本发明的化合物的反应可在有机合成领域的技术人员容易选择的合适溶剂中进行。合适溶剂可基本上不与起始物质(反应物)、中间物或产物在进行反应的温度,例如可在溶剂冷冻温度至溶剂沸点温度范围内的温度下反应。给定反应可在一种溶剂中或超过一种溶剂的混合物中进行。取决于具体的反应步骤,熟练技术人员可选择适于具体的反应步骤的溶剂。
本发明的化合物的制备可涉及多种化学基团的保护和脱除保护基。本领域的技术人员容易地确定对保护和脱除保护基的需要和适当保护基的选择。保护基化学描述于例如下列中:Kocienski,Protecting Groups,(Thieme,2007);Robertson,Protecting GroupChemistry,(Oxford University Press,2000);Smith等人,March′s Advanced OrganicChemistry:Reactions,Mechanisms,and Structure,第6版(Wiley,2007);Peturssion等人,“Protecting Groups in Carbohydrate Chemistry”,J.Chem.Educ.,1997,74(11),1297;和Wuts等人,Protective Groups in Organic Synthesis,第4版,(Wiley,2006)。
反应可根据本领域中已知的任何合适方法监测。举例来说,产物形成可以通过光谱手段,例如核磁共振谱法(例如1H或13C)、红外光谱分析、分光光度法(例如UV-可见光分光光度法)、质谱分析法或通过色谱法,例如高效液相色谱法(HPLC)或薄层色谱法(TLC)监测。
III.化合物的用途
本公开的化合物可抑制PD-1/PD-L1蛋白质/蛋白质相互作用的活性,因此,可用于治疗与PD-1活性相关的疾病和病症以及与PD-L1,包括其与例如PD-1和B7-1(CD80)的其它蛋白质的相互作用相关的疾病和病症。在某些实施方案中,本公开的化合物或其药学上可接受的盐或立体异构体可用于治疗性施用以增强、刺激和/或增加在癌症、慢性感染或败血症中的免疫性,包括增强对接种疫苗的反应。在一些实施方案中,本公开提供了一种用于抑制PD-1/PD-L1蛋白质/蛋白质相互作用的方法。所述方法包括向个体或患者施用式(I)或如本文所述的任一式的化合物,或如权利要求书任一项中所叙述和本文所述的化合物,或其药学上可接受的盐或立体异构体。本公开的化合物可以单独使用,与其它药剂或疗法组合使用,或作为辅助疗法或新辅助疗法,用于治疗包括癌症或感染性疾病的疾病或病症。对于本文所述的用途,可使用任一本公开的化合物,包括其任一实施方案。
本公开的化合物抑制PD-1/PD-L1蛋白质/蛋白质相互作用,导致PD-1通路阻断。PD-1的阻断可增强包括人类的哺乳动物中对癌细胞和感染性疾病的免疫反应。在一些实施方案中,本公开提供了使用式(I)化合物或其盐或立体异构体在体内治疗个体或患者,由此抑制癌性肿瘤的生长。式(I)或如本文所述的任一式的化合物,或如权利要求书任一项中所叙述和本文所述的化合物,或其盐或立体异构体,可用于抑制癌性肿瘤的生长。可替代地,式(I)或如本文所述的任一式的化合物,或如权利要求书任一项中所叙述和本文所述的化合物,或其盐或立体异构体,可结合如下所述的其它剂或标准癌症治疗使用。在一个实施方案中,本公开提供了一种用于抑制体外肿瘤细胞生长的方法。所述方法包括使体外肿瘤细胞接触式(I)或如本文所述的任一式的化合物,或如权利要求书任一项中所叙述和本文所述的化合物,或其盐或立体异构体。在另一实施方案中,本公开提供了一种用于抑制个体或患者中肿瘤细胞生长的方法。所述方法包括向有需要的个体或患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,或如权利要求书任一项中所叙述和本文所述的化合物,或其盐或立体异构体。
在一些实施方案中,本文提供了一种用于治疗癌症的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物,或其盐。癌症的实例包括生长可使用本公开的化合物来抑制的癌症和通常对免疫疗法起反应的癌症。
在一些实施方案中,本公开提供了一种增强、刺激和/或增加患者中的免疫反应的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物或组合物,或其盐。
可使用本公开的化合物治疗的癌症的实例包括(但不限于)骨癌、胰腺癌、皮肤癌、头部或颈部癌症、皮肤或眼内恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、睪丸癌、子宫癌、输卵管癌、子宫内膜癌瘤、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病(Hodgkin′s Disease)、非霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞白血病)、幼年实体瘤、淋巴球性淋巴瘤、膀胱癌、肾或尿道癌、肾盂癌、中枢神经系统(CNS)赘瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊椎轴肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏肉瘤(Kaposi′s sarcoma)、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的癌症)和所述癌症的组合。本公开的化合物也可以用于治疗转移性癌症,特别是表达PD-L1的转移性癌症。
在一些实施方案中,可用本公开的化合物治疗的癌症包括黑色素瘤(例如转移性恶性黑色素瘤、皮肤黑色素瘤)、肾脏癌(例如透明细胞癌)、前列腺癌(例如激素难治性前列腺腺癌)、乳腺癌(例如乳腺浸润性癌)、结肠癌、肺癌(例如非小细胞肺癌和小细胞肺癌)、鳞状细胞头颈部癌(例如头颈部鳞状细胞癌)、尿路上皮癌(例如膀胱癌、非肌层浸润性膀胱癌(NMIBC))和具有高微卫星不稳定性(MSI高)的癌症。另外,本公开包括生长可使用本公开的化合物抑制的难治性或复发性恶性病。
在一些实施方案中,可使用本公开的化合物治疗的癌症包括(但不限于)实体瘤(例如前列腺癌、结肠癌、食道癌、子宫内膜癌、卵巢癌、子宫癌、肾脏癌、肝脏癌、胰腺癌、胃癌、乳腺癌、肺癌、头颈部癌、甲状腺癌、胶质母细胞瘤、肉瘤、膀胱癌等)、血液癌症(例如淋巴瘤、白血病(例如急性淋巴母细胞性白血病(ALL)、急性髓细胞性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓细胞性白血病(CML))、DLBCL、套细胞淋巴瘤、非霍奇金淋巴瘤(包括复发性或难治性NHL和复发性滤泡性NHL)、霍奇金淋巴瘤或多发性骨髓瘤)和所述癌症的组合。
在一些实施方案中,可使用本公开的化合物治疗的癌症包括(但不限于)胆管细胞癌、胆管癌、胆道癌、三阴性乳腺癌、横纹肌肉瘤、小细胞肺癌、平滑肌肉瘤、肝细胞癌、尤文氏肉瘤(Ewing’s sarcoma)、脑癌、脑肿瘤、星形细胞瘤、神经母细胞瘤、纤维神经瘤、基底细胞癌、软骨肉瘤、上皮样肉瘤、眼癌、输卵管癌、胃肠癌、胃肠道间质瘤、毛细胞白血病、肠癌、胰岛细胞癌、口癌、口腔癌、咽喉癌、喉癌、唇癌、间皮瘤、颈癌、鼻腔癌、眼癌、眼部黑色素瘤、骨盆癌、直肠癌、肾细胞癌、唾液腺癌、鼻窦癌、脊椎癌、舌癌、小管癌、尿道癌和输尿管癌。
在一些实施方案中,本公开的化合物可用于治疗镰状细胞病和镰状细胞贫血。
在一些实施方案中,可使用本公开的化合物治疗的疾病和适应症包括(但不限于)血液癌症、肉瘤、肺癌、胃肠癌、泌尿生殖道癌症、肝癌、骨癌、神经系统癌症、妇科癌症和皮肤癌。
例示性血液癌症包括淋巴瘤和白血病,例如急性淋巴母细胞性白血病(ALL)、急性髓细胞性白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞白血病(CLL)、慢性髓细胞性白血病(CML)、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤、非霍奇金淋巴瘤(包括复发性或难治性NHL和复发性滤泡性NHL)、霍奇金淋巴瘤、骨髓增生性疾病(例如原发性骨髓纤维化(PMF)、真性红细胞增多症(PV)和原发性血小板增多症(ET))、骨髓增生异常综合征(MDS)、T细胞急性淋巴母细胞性淋巴瘤(T-ALL)和多发性骨髓瘤(MM)。
例示性肉瘤包括软骨肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、血管肉瘤、纤维肉瘤、脂肪肉瘤、粘液瘤、横纹肌瘤、横纹肉瘤、纤维瘤、脂肪瘤、错构瘤和畸胎瘤。
例示性肺癌包括非小细胞肺癌(NSCLC)(例如鳞状细胞NSCLC)、小细胞肺癌、支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(支气管)癌、支气管腺瘤、软骨瘤错构瘤和间皮瘤。
例示性胃肠癌包括食道癌(癌瘤、鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌瘤、淋巴瘤、平滑肌肉瘤、腺癌)、胰腺癌(导管腺癌、胰岛瘤、胰升糖素瘤、胃泌素瘤、类癌瘤、胰血管活性肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、纤维神经瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)和结肠直肠癌(例如结肠直肠腺癌)。
例示性泌尿生殖道癌症包括肾癌(腺癌、威尔姆斯瘤(Wilm′s tumor)[肾母细胞瘤])、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)和睪丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤)。在一些实施方案中,癌症为泌尿道癌(例如乳头状肾癌、睪丸生殖细胞癌、难染肾细胞癌、透明细胞肾癌或前列腺癌)。
例示性肝癌包括肝细胞瘤(肝细胞癌)、胆管细胞癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤和血管瘤。
例示性骨癌包括例如骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、软骨骨瘤(骨软骨性外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤。
例示性神经系统癌症包括颅骨癌(骨瘤、血管瘤、肉芽瘤、黄瘤、畸形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶质瘤病)、脑癌(星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、胶质母细胞瘤、多形性胶质母细胞瘤、寡树突细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)和脊髓癌(纤维神经瘤、脑膜瘤、胶质瘤、肉瘤)以及神经母细胞瘤和莱-杜二氏病(Lhermitte-Duclos disease)。
例示性妇科癌症包括子宫癌(子宫内膜癌)、子宫颈癌(子宫颈癌瘤、肿瘤前子宫颈非典型增生)、卵巢癌(卵巢癌瘤(浆液性囊腺癌、浆液性腺癌、粘液性囊腺癌、未分类癌瘤)、颗粒细胞-卵泡膜细胞肿瘤、支持-间质细胞肿瘤(Sertoli-Leydig cell tumor)、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄样肉瘤(胚胎性横纹肌肉瘤)和输卵管癌(癌瘤)。
例示性皮肤癌包括黑色素瘤、基底细胞癌、鳞状细胞癌(例如皮肤鳞状细胞癌)、卡波西氏肉瘤、发育异常痣、脂肪瘤、血管瘤、皮肤纤维瘤和瘢痕瘤。在一些实施方案中,可使用本公开的化合物治疗的疾病和适应症包括(但不限于)镰状细胞病(例如镰状细胞贫血)、三阴性乳腺癌(TNBC)、骨髓增生异常综合征、睪丸癌、胆管癌、食道癌和尿路上皮癌。
利用本公开的化合物阻断PD-1通路也可以用于治疗感染,例如病毒、细菌、真菌和寄生虫感染。本公开提供了一种用于治疗感染(例如病毒感染)的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物,其盐。引起本公开的方法可治疗的感染的病毒的实例包括(但不限于)人类免疫缺陷病毒、人乳头瘤病毒、流感病毒、甲型、乙型、丙型或丁型肝炎病毒、腺病毒、痘病毒、单纯疱疹病毒、人类巨细胞病毒、严重急性呼吸道综合征病毒、埃博拉病毒(ebola virus)和麻疹病毒。在一些实施方案中,引起本公开的方法可治疗的感染的病毒包括(但不限于)肝炎(甲型、乙型或丙型)病毒、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II和CMV、爱泼斯坦巴尔病毒(Epstein Barr virus))、腺病毒、流感病毒、黄病毒、埃可病毒(echovirus)、鼻病毒、柯萨奇病毒(coxsackie virus)、冠状病毒(cornovirus)、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒(dengue virus)、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒、肺结核病毒和虫媒病毒性脑炎病毒。
本公开提供了一种用于治疗细菌感染的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物,或其盐。引起本公开的方法可治疗的感染的致病细菌的非限制性实例包括衣原体属(chlamydia)、立克次氏体细菌(rickettsial bacteria)、分枝杆菌属(mycobacteria)、葡萄球菌属(staphylococci)、链球菌属(streptococci)、肺炎球菌属(pneumonococci)、脑膜炎球菌(meningococci)和淋球菌(conococci)、克雷伯氏杆菌属(klebsiella)、变形杆菌(proteus)、沙雷氏菌属(serratia)、假单胞菌属(pseudomonas)、军团杆菌(legionella)、白喉杆菌、沙门氏菌(salmonella)、杆菌属、霍乱菌、破伤风菌、肉毒中毒菌、炭疽菌、瘟疫菌、钩端螺旋体病(leptospirosis)菌和莱姆病细菌(Lyme′sdisease bacteria)。
本公开提供了一种用于治疗真菌感染的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物,或其盐。引起本公开的方法可治疗的感染的致病真菌的非限制性实例包括念珠菌属(Candida)(白色念珠菌(Candida albicans)、克柔念珠菌(Candida krusei)、光滑念珠菌(Candida glabrata)、热带念珠菌(Candida tropicalis)等)、新型隐球菌(Cryptococcus neoformans)、曲霉属(Aspergillus)(烟曲霉(Aspergillus fumigatus)、黑曲霉(Aspergillus niger)等)、毛霉菌目(Genus Mucorales)(毛霉属(mucor)、犁头霉属(absidia)、根霉属菌(rhizophus))、申克孢子丝菌(Sporothrix schenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis)和荚膜组织胞浆菌(Histoplasma capsulatum)。
本公开提供了一种用于治疗寄生虫感染的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物,或其盐。引起本公开的方法可治疗的感染的致病寄生物的非限制性实例包括痢疾内变形虫(Entamoeba histolytica)、结肠小袋虫(Balantidium coli)、福氏耐格里阿米巴原虫(Naegleriafowleri)、棘阿米巴属(Acanthamoeba sp.)、蓝氏贾第鞭毛虫(Giardia lambia)、隐孢子虫属(Cryptosporidium sp.)、肺炎肺囊虫(Pneumocystiscarinii)、间日疟原虫(Plasmodium vivax)、果氏巴贝虫(Babesia microti)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、杜氏利什曼虫(Leishmaniadonovani)、刚地弓形虫(Toxoplasma gondi)和巴西钩虫(Nippostrongylusbrasiliensis)。
本公开提供了一种用于治疗神经变性疾病或病症的方法。所述方法包括向有需要的患者施用治疗有效量的式(I)或如本文所述的任一式的化合物,如权利要求书任一项中所叙述和本文所述的化合物,或其盐。神经变性疾病或病症的非限制性实例包括阿尔茨海默病(Alzheimer’s disease)、帕金森病(Parkinson’s disease)、亨廷顿病(Huntington’sdisease)、朊病毒病(prion disease)、运动神经元疾病、脊髓小脑性共济失调和脊髓性肌萎缩。
相信式(I)化合物或其任一实施方案可具有令人满意的药理学概况和有前景的生物药学特性,例如毒物学概况、代谢和药物动力学特性、溶解性和渗透性。应了解,适当生物药学特性的测定在本领域的技术人员的知识范围内,例如测定在细胞中的细胞毒性或某些标靶或通道的抑制以测定潜在毒性。
术语“个体”或“患者”可互换使用,是指任何动物,包括哺乳动物,优选为小鼠、大鼠、其它啮齿动物、兔、犬、猫、猪、牛、羊、马或灵长类动物,并且最优选为人。
词组“治疗有效量”是指活性化合物或药剂引起由研究员、兽医、医学博士或其它临床医师在组织、系统、动物、个体或人中所寻求的生物或医学反应的量。
如本文所用,术语“治疗(treating)”或“治疗(treatment)”是指以下中一种或多种:(1)抑制疾病;例如抑制经历或发生疾病、疾患或病症的病变或症状的个体中的疾病、疾患或病症(即阻止病理和/或症状进一步发展);和(2)改善疾病;例如改善经历或发生疾病、疾患或病症的病变或症状的个体中的疾病、疾患或病症(即逆转病理和/或症状),例如降低疾病的严重度。
在一些实施方案中,本发明的化合物可用于预防发生本文中提及的任一疾病或降低发生疾病的风险;例如预防易感染疾病、疾患或病症但尚未经历或显现疾病的病变或症状的个体中发生疾病、疾患或病症或降低发生疾病、疾患或病症的风险。
组合疗法
癌细胞生长和存活会受多个生物学通路功能障碍影响。因此,将不同机制的抑制剂,例如酶抑制剂、信号转导抑制剂、染色质动力学的抑制剂或免疫反应调节剂组合可用于治疗此类疾患。靶向超过一个信号传导通路(或超过一种涉及给定信号传导通路的生物分子)可降低细胞群体中出现抗药性的可能性,和/或减小治疗毒性。
本公开的化合物可与用于治疗例如癌症或感染的疾病的一种或多种疗法组合使用。可用组合疗法治疗的疾病和适应症的实例包括如本文所述的疾病和适应症。癌症的实例包括实体瘤和非实体瘤,例如液体肿瘤、血液癌症。感染的实例包括病毒感染、细菌感染、真菌感染或寄生虫感染。举例来说,本公开的化合物可与以下激酶的一种或多种抑制剂组合用于治疗癌症:Akt1、Akt2、Akt3、BCL2、CDK、TGF-βR、PKA、PKG、PKC、CaM-激酶、磷酸化酶激酶、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IDH2、IGF-1R、IR-R、PDGFαR、PDGFβR、PI3K(α、β、γ、δ和多重性或选-择性)、CSF1R、KIT、FLK-II、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、PARP、Ron、Sea、TRKA、TRKB、TRKC、TAM激酶(Axl、Mer、Tyro3)、FLT3、VEGFR/Flt2、Flt4、EphA1、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK和B-Raf。在一些实施方案中,本公开的化合物可与一种或多种以下抑制剂组合用于治疗癌症或感染。可与本公开的化合物组合用于治疗癌症和感染的抑制剂的非限制性实例包括FGFR抑制剂(FGFR1、FGFR2、FGFR3或FGFR4,例如培米替尼(pemigatinib)(INCY54828)、INCB62079)、JAK抑制剂(JAK1和/或JAK2,例如鲁索利替尼(ruxolitinib)、巴瑞克替尼(baricitinib)或伊它替尼(itacitinib)(INCB39110))、IDO抑制剂(例如艾帕卡(epacadostat)、NLG919或BMS-986205、MK7162)、LSD1抑制剂(例如INCB59872和INCB60003)、TDO抑制剂、PI3K-δ抑制剂(例如帕萨里斯(Parsaclisib)(INCB50465)和INCB50797)、PI3K-γ抑制剂(例如PI3K-γ选择性抑制剂)、Pim抑制剂(例如INCB53914)、EGFR抑制剂(又称ErB-1或HER-1;例如埃罗替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、奥希替尼(orsimertinib)、西妥昔单抗(cetuximab)、耐昔妥珠单抗(necitumumab)或帕尼单抗(panitumumab))、VEGFR抑制剂或通路阻断剂(例如贝伐单抗(bevacizumab)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、阿西替尼(axitinib)、瑞戈非尼(regorafenib)、帕纳替尼(ponatinib)、卡博替尼(cabozantinib)、阿西替尼、凡德他尼、雷莫芦单抗(ramucirumab)、乐伐替尼(lenvatinib)、阿柏西普(ziv-aflibercept))、PARP抑制剂(例如奥拉帕尼(olaparib)、卢卡帕尼(rucaparib)、维利帕尼(veliparib)、拉唑帕尼(talazoparib)或尼拉帕尼(niraparib))、CSF1R抑制剂、TAM受体酪氨酸激酶(Tyro-3、Axl和Mer)、腺嘌呤核苷受体拮抗剂(例如A2a/A2b受体拮抗剂)、HPK1抑制剂、趋化因子受体抑制剂(例如CCR2或CCR5抑制剂)、SHP1/2磷酸酶抑制剂、组蛋白脱乙酰酶抑制剂(HDAC)(例如HDAC8抑制剂)、血管生成抑制剂、白细胞介素受体抑制剂、含布罗莫结构域和额外末端结构域的家族成员抑制剂(例如布罗莫结构域抑制剂或BET抑制剂,例如INCB54329和INCB57643)、精氨酸酶抑制剂(INCB001158)、PARP抑制剂(例如卢卡帕尼或奥拉帕尼)、西曲替尼(sitravatinib)、B-Raf抑制剂-MEK抑制剂组合(例如恩考芬尼(encorafenib)加尼美替尼(binimetinib)、达拉非尼(dabrafenib)加曲美替尼(trametinib)或考比替尼(cobimetinib)加威罗菲尼(vemurafenib))和腺嘌呤核苷受体拮抗剂或它们的组合。
在一些实施方案中,本公开的化合物可与TLR7激动剂(例如咪喹莫特(imiquimod))组合。
本公开的化合物还可以与其它癌症治疗方法,例如化学疗法、放射疗法、靶向肿瘤的疗法、辅助疗法、免疫疗法或外科手术组合使用。免疫疗法的实例包括细胞因子治疗(例如干扰素、GM-CSF、G-CSF、IL-2)、CRS-207免疫疗法、癌症疫苗、单克隆抗体、双特异性或多特异性抗体、抗体药物偶联物、过继性T细胞转移、Toll受体激动剂、STING激动剂、RIG-I激动剂、溶瘤病毒疗法和免疫调节小分子,包括沙利度胺(thalidomide)或JAK1/2抑制剂、PI3Kδ抑制剂等等。化合物可以与一种或多种抗癌药物,例如化学治疗剂组合施用。化学治疗剂的实例包括以下任一个:阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿仑单抗(alemtuzumab)、阿利维A酸(alitretinoin)、别嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、阿那曲唑(anastrozole)、三氧化二砷、天冬酰胺酶、阿扎胞苷(azacitidine)、贝伐单抗、贝沙罗汀(bexarotene)、巴瑞克替尼、博莱霉素(bleomycin)、硼替佐米(bortezomib)、静脉内用白消安(busulfan intravenous)、口服用白消安(busulfanoral)、二甲睪酮(calusterone)、卡培他滨(capecitabine)、卡铂(carboplatin)、卡莫司汀(carmustine)、西妥昔单抗、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、环磷酰胺、阿糖胞苷、达卡巴嗪(dacarbazine)、放线菌素D、达特肝素钠(dalteparin sodium)、达沙替尼(dasatinib)、道诺霉素(daunorubicin)、地西他滨(decitabine)、地尼白介素(denileukin)、地尼白介素-白喉毒素连接物(denileukin diftitox)、右雷佐生(dexrazoxane)、多西紫杉醇(docetaxel)、多柔比星(doxorubicin)、屈他雄酮丙酸盐(dromostanolone propionate)、依库珠单抗(eculizumab)、表柔比星(epirubicin)、埃罗替尼(erlotinib)、雌氮芥(estramustine)、依托泊苷磷酸盐(etoposide phosphate)、依托泊苷、依西美坦(exemestane)、芬太尼柠檬酸盐(fentanyl citrate)、非格司亭(filgrastim)、氟尿苷、氟达拉滨(fludarabine)、氟尿嘧啶、氟维司群(fulvestrant)、吉非替尼、吉西他滨(gemcitabine)、吉妥单抗(gemtuzumabozogamicin)、戈舍瑞林乙酸盐(goserelin acetate)、组氨瑞林乙酸盐(histrelinacetate)、替伊莫单抗(ibritumomab tiuxetan)、伊达比星(idarubicin)、异环磷酰胺、伊马替尼甲磺酸盐(imatinib mesylate)、干扰素α2a、伊立替康(irinotecan)、拉帕替尼二甲苯磺酸盐(lapatinib ditosylate)、来那度胺(lenalidomide)、来曲唑(letrozole)、甲酰四氢叶酸、亮丙瑞林乙酸盐(leuprolide acetate)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、氮芥(meclorethamine)、甲地孕酮乙酸盐(megestrol acetate)、美法仑(melphalan)、巯基嘌呤、胺甲喋呤(methotrexate)、甲氧沙林(methoxsalen)、丝裂霉素C、米托坦(mitotane)、米托蒽醌(mitoxantrone)、南诺龙苯丙酸盐(nandrolonephenpropionate)、奈拉滨(nelarabine)、诺非单抗(nofetumomab)、奥沙利铂(oxaliplatin)、太平洋紫杉醇(paclitaxel)、帕米膦酸盐(pamidronate)、帕尼单抗、培门冬酶(pegaspargase)、聚乙二醇化非格司亭(pegfilgrastim)、培美曲塞二钠(pemetrexeddisodium)、喷司他丁(pentostatin)、哌泊溴烷(pipobroman)、普卡霉素(plicamycin)、丙卡巴肼(procarbazine)、奎纳克林(quinacrine)、拉布立酶(rasburicase)、利妥昔单抗(rituximab)、鲁索利替尼(ruxolitinib)、索拉非尼、链脲霉素(streptozocin)、舒尼替尼、舒尼替尼顺丁烯二酸盐、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睪内酯(testolactone)、沙利多迈、硫鸟嘌呤、噻替派(thiotepa)、拓扑替康(topotecan)、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、维A酸、尿嘧啶氮芥、戊柔比星(valrubicin)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、伏立诺他(vorinostat)和唑来膦酸盐(zoledronate)。
其它抗癌剂包括例如曲妥珠单抗(Herceptin)的抗体治疗剂、针对例如CTLA-4(例如伊匹单抗(ipilimumab))、4-1BB(例如乌瑞鲁单抗(urelumab)、乌托米单抗(utomilumab))的共刺激分子的抗体、针对PD-1和PD-L1的抗体或针对细胞因子(IL-10、TGF-β等)的抗体。可与本公开的化合物组合用于治疗癌症或例如病毒、细菌、真菌和寄生虫感染的感染的针对PD-1和/或PD-L1的抗体的实例包括(但不限于)纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、阿特珠单抗(atezolizumab)、度伐鲁单抗(durvalumab)、阿利库单抗(avelumab)和SHR-1210。
本公开的化合物可与一种或多种免疫检查点抑制剂组合用于治疗例如癌症或感染的疾病。示例性免疫检查点抑制剂包括针对例如以下的免疫检查点分子的抑制剂:CBL-B、CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM、精氨酸酶、CD137(又称4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、TIGIT、CD112R、VISTA、PD-1、PD-L1和PD-L2。在一些实施方案中,免疫检查点分子为选自CD27、CD28、CD40、ICOS、OX40、GITR和CD137的刺激性检查点分子。在一些实施方案中,免疫检查点分子为选自A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3和VISTA的抑制性检查点分子。在一些实施方案中,本文中提供的化合物可与一种或多种选自KIR抑制剂、TIGIT抑制剂、LAIR1抑制剂、CD160抑制剂、284抑制剂和TGFRβ抑制剂的剂组合使用。
在一些实施方案中,免疫检查点分子的抑制剂为抗PD1抗体、抗PD-L1抗体或抗CTLA-4抗体。
在一些实施方案中,免疫检查点分子的抑制剂为PD-1的抑制剂,例如抗PD-1单克隆抗体。在一些实施方案中,抗PD-1单克隆抗体为纳武单抗、派姆单抗(又称MK-3475)、皮利珠单抗(pidilizumab)、SHR-1210、PDR001或AMP-224。在一些实施方案中,抗PD-1单克隆抗体为纳武单抗或派姆单抗。在一些实施方案中,抗PD1抗体为派姆单抗。
在一些实施方案中,免疫检查点分子的抑制剂为PD-L1的抑制剂,例如抗PD-L1单克隆抗体。在一些实施方案中,抗PD-L1单克隆抗体为BMS-935559、MEDI4736、MPDL3280A(又称RG7446)或MSB0010718C。在一些实施方案中,抗PD-L1单克隆抗体为MPDL3280A或MEDI4736。
在一些实施方案中,免疫检查点分子的抑制剂为CTLA-4的抑制剂,例如抗CTLA-4抗体。在一些实施方案中,抗CTLA-4抗体为伊匹单抗或曲美木单抗(tremelimumab)。
在一些实施方案中,免疫检查点分子的抑制剂为LAG3的抑制剂,例如抗LAG3抗体。在一些实施方案中,抗LAG3抗体为BMS-986016、LAG525或INCAGN2385。
在一些实施方案中,免疫检查点分子的抑制剂为TIM3的抑制剂,例如抗TIM3抗体。在一些实施方案中,抗TIM3抗体为INCAGN2390、MBG453或TSR-022。
在一些实施方案中,免疫检查点分子的抑制剂为GITR的抑制剂,例如抗GITR抗体。在一些实施方案中,抗GITR抗体为TRX518、MK-4166、INCAGN1876、MK-1248、AMG228、BMS-986156、GWN323或MEDI1873。
在一些实施方案中,免疫检查点分子的抑制剂为OX40抑制剂,例如抗OX40抗体或OX40L融合蛋白。在一些实施方案中,抗OX40抗体为MEDI0562、MOXR-0916、PF-04518600、GSK3174998或BMS-986178。在一些实施方案中,OX40L融合蛋白为MEDI6383。
本发明的化合物还可以与一种或多种消炎剂、类固醇、免疫抑制剂或治疗性抗体组合使用。
式(I)或如本文所述的任一式的化合物、如权利要求书任一项中所叙述和本文所述的化合物或其盐可与另一免疫原性剂组合,所述免疫原性剂例如癌细胞、纯化的肿瘤抗原(包括重组蛋白、肽和碳水化合物分子)、细胞和经编码免疫刺激细胞因子的基因转染的细胞。可使用的肿瘤疫苗的非限制性实例包括黑色素瘤抗原的肽,例如gp100、MAGE抗原、Trp-2、MARTI和/或酪氨酸酶的肽,或被转染以表达细胞因子GM-CSF的肿瘤细胞。
式(I)或如本文所述的任一式的化合物、如权利要求书任一项中所叙述和本文所述的化合物或其盐可与用于治疗癌症的疫苗接种方案组合使用。在一些实施方案中,肿瘤细胞被转导以表达GM-CSF。在一些实施方案中,肿瘤疫苗包括来自与人类癌症有关的病毒(例如人乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西氏疱疹肉瘤病毒(KHSV))的蛋白质。在一些实施方案中,本公开的化合物可与例如从肿瘤组织本身分离的热休克蛋白的肿瘤特异性抗原组合使用。在一些实施方案中,式(I)或如本文所述的任一式的化合物、如权利要求书任一项中所叙述和本文所述的化合物或其盐可与活化有效抗肿瘤反应的树突状细胞免疫接种组合使用。
本公开的化合物可与使表达Feα或Feγ受体的效应细胞靶向至肿瘤细胞的双特异性大环肽组合使用。本公开的化合物也可以与活化宿主免疫反应的大环肽组合。
本公开的化合物可与骨髓移植组合用于治疗多种造血来源肿瘤。
式(I)或如本文所述的任一式的化合物、如权利要求书任一项中所叙述和本文所述的化合物或其盐可与刺激对病原体、毒素和自体抗原的免疫反应的疫苗组合使用。这种治疗方法特别适用的病原体的实例包括当前无有效疫苗的病原体或常规疫苗不完全有效的病原体。这些病原体包括(但不限于)HIV病原体、肝炎(甲型、乙型和丙型)病原体、流感病原体、疱疹病原体、贾第鞭毛虫属(Giardia)、疟疾病原体、利什曼虫、金黄色葡萄球菌(Staphylococcus aureus)、绿脓杆菌(Pseudomonas Aeruginosa)。
引起本公开的方法可治疗的感染的病毒包括(但不限于)人乳头瘤病毒、流感病毒、甲型、乙型、丙型或丁型肝炎病毒、腺病毒、痘病毒、单纯疱疹病毒、人类巨细胞病毒、严重急性呼吸道综合征病毒、埃博拉病毒、麻疹病毒、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II和CMV、爱泼斯坦巴尔病毒)、黄病毒、埃可病毒、鼻病毒、柯萨奇病毒、冠状病毒、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒和虫媒病毒性脑炎病毒。
引起本公开的方法可治疗的感染的致病细菌包括(但不限于)衣原体属、立克次氏体细菌、分枝杆菌属、葡萄球菌属、链球菌属、肺炎球菌属、脑膜炎球菌和淋球菌、克雷伯氏杆菌属、变形杆菌、沙雷氏菌属、假单胞菌属、军团杆菌、白喉杆菌、沙门氏菌、杆菌属、霍乱菌、破伤风菌、肉毒中毒菌、炭疽菌、瘟疫菌、钩端螺旋体病菌和莱姆病细菌。
引起本公开的方法可治疗的感染的致病真菌包括(但不限于)念珠菌属(白色念珠菌、克柔念珠菌、光滑念珠菌、热带念珠菌等)、新型隐球菌、曲霉属(烟曲霉、黑曲霉等)、毛霉菌目(毛霉属、犁头霉属、根霉属菌)、申克孢子丝菌、皮炎芽生菌、巴西副球孢子菌、粗球孢子菌和荚膜组织胞浆菌。
引起可用本公开的方法治疗的感染的致病寄生物包括(但不限于)痢疾内变形虫、结肠小袋虫、福氏耐格里阿米巴原虫、棘阿米巴属、蓝氏贾第鞭毛虫、隐孢子虫属、肺炎肺囊虫、间日疟原虫、果氏巴贝虫、布氏锥虫、克氏锥虫、杜氏利什曼虫、刚地弓形虫和巴西钩虫。
当向患者施用超过一种药剂时,所述药剂可以同时、分开、依序或组合(例如对于超过两种剂)施用。
IV.配制、剂型和施用
当用作药物时,本公开的化合物可以呈药物组合物形式施用。因此,本公开提供了一种组合物,所述组合物包含式(I)或如本文所述的任一式的化合物、如权利要求书任一项中所叙述和本文所述的化合物或其药学上可接受的盐或其任一实施方案,和至少一种药学上可接受的载体或赋形剂。这些组合物可以制药领域众所周知的方式制备,并且可以通过多种途径施用,这取决于指示局部还是全身治疗和待治疗的区域。施用可为局部施用(包括经皮、表皮、经眼和粘膜,包括鼻内、阴道和直肠递送)、经肺施用(例如通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内或鼻内)、经口施用或不经肠施用。不经肠施用包括静脉内、动脉内、皮下、腹膜内、肌肉内施用或注射或输注;或颅内,例如鞘内或心室内施用。不经肠施用可以呈单次推注剂量形式,或可例如通过连续灌注泵。用于局部施用的药物组合物和制剂可包括经皮贴片、软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾、液体和粉剂。常规医药载体、水性、粉末或油性基剂、增稠剂等等可为需要或合乎需要的。
本发明还包括药物组合物,其含有本公开的化合物或其药学上可接受的盐作为活性成分,以及一种或多种药学上可接受的载体或赋形剂。在一些实施方案中,组合物适合于局部施用。在制造本发明的组合物时,活性成分通常与赋形剂混合,用赋形剂稀释,或装入此类载体内,呈例如胶囊、药囊、纸剂或其它容器形式。当赋形剂充当稀释剂时,其可为固体、半固体或液体物质,充当活性成分的媒介物、载体或介质。因此,组合物可以呈片剂、丸剂、粉剂、糖锭、药囊、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆、气雾剂(呈固体形式或于液体介质中)、软膏(含有例如至多10重量%的活性化合物)、软和硬明胶胶囊、栓剂、无菌可注射溶液和无菌包装粉剂的形式。
在制备制剂时,活性化合物在与其它成分组合前可进行研磨,以提供适当粒度。如果活性化合物基本上不溶,那么其可研磨至小于200目的粒度。如果活性化合物基本上溶于水,那么粒度可以通过研磨来调整以在制剂中基本上均匀分布,例如约40目。
本发明的化合物可使用已知的研磨程序,例如湿磨来研磨,以获得适合于片剂形成和其它制剂类型的粒度。本发明化合物的细粉状(纳米颗粒)制剂可以通过本领域中已知的方法制备,参见例如WO2002/000196。
合适赋形剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、褐藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂可另外包括:润滑剂,例如滑石、硬脂酸镁和矿物油;润湿剂;乳化剂和悬浮剂;防腐剂,例如羟苯甲酸甲酯和羟苯甲酸丙酯;甜味剂;和调味剂。通过采用本领域中已知的程序,本发明的组合物可以被配制成使活性成分在施用患者之后快速、持续或延迟释放。
在一些实施方案中,药物组合物包含硅化微晶纤维素(SMCC)和至少一种本文所述的化合物或其药学上可接受的盐。在一些实施方案中,硅化微晶纤维素包含约98%微晶纤维素和约2%二氧化硅w/w。
在一些实施方案中,组合物为包含至少一种本文所述的化合物或其药学上可接受的盐和至少一种药学上可接受的载体或赋形剂的持续释放组合物。在一些实施方案中,组合物包含至少一种本文所述的化合物或其药学上可接受的盐和至少一种选自微晶纤维素、乳糖单水合物、羟丙基甲基纤维素和聚氧化乙烯的组分。在一些实施方案中,组合物包含至少一种本文所述的化合物或其药学上可接受的盐和微晶纤维素、乳糖单水合物和羟丙基甲基纤维素。在一些实施方案中,组合物包含至少一种本文所述的化合物或其药学上可接受的盐和微晶纤维素、乳糖单水合物和聚氧化乙烯。在一些实施方案中,组合物还包含硬脂酸镁或二氧化硅。在一些实施方案中,微晶纤维素为Avicel PH102TM。在一些实施方案中,乳糖单水合物为Fast-flo 316TM。在一些实施方案中,羟丙基甲基纤维素为羟丙基甲基纤维素2208K4M(例如Methocel K4 M PremierTM)和/或羟丙基甲基纤维素2208K100LV(例如Methocel K00LVTM)。在一些实施方案中,聚氧化乙烯为聚氧化乙烯WSR 1105(例如PolyoxWSR 1105TM)。
在一些实施方案中,使用湿式造粒工艺产生组合物。在一些实施方案中,使用干式造粒工艺产生组合物。
组合物可以呈单位剂型配制,每剂含有约5至约1,000mg(1g),更通常约100mg至约500mg活性成分。在一些实施方案中,每剂含有约10mg活性成分。在一些实施方案中,每剂含有约50mg活性成分。在一些实施方案中,每剂含有约25mg活性成分。术语“单位剂型”是指适合呈单一剂量用于人类受试者和其它哺乳动物的物理离散单元,每个单元含有经计算以产生所需治疗效果的预定量的活性物质以及合适药物赋形剂。
用于配制药物组合物的组分具有高纯度且基本上不含可能有害的污染物(例如至少是国家食品级,一般至少是分析级,并且更典型地至少是医药级)。尤其对于人类食用来说,组合物优选根据如美国食品与药物管理局(U.S.Food and Drug Administration)的适用规定中所定义的优良制造规范标准制造或配制。举例来说,合适制剂可为无菌的,和/或基本上等渗的,和/或完全遵守美国食品与药物管理局的所有优良制造规范规定。
活性化合物可在宽剂量范围内是有效的,并且一般以治疗学上有效量施用。然而,应了解,化合物事实上施用的量通常将由医师根据有关环境来决定,包括待治疗的疾患、所选施用途径、实际施用的化合物、个别患者的年龄、体重和反应、患者症状的严重度等等。
本发明化合物的治疗剂量可以根据例如具体地治疗用途、化合物的施用方式、患者的健康和状况以及处方医师的判断变化。药物组合物中本发明化合物的比例或浓度可以视包括剂量、化学特性(例如疏水性)和施用途径的许多因素而变化。举例来说,本发明的化合物可以呈含有约0.1至约10%w/v化合物的水性生理缓冲溶液提供以供不经肠施用。一些典型的剂量范围为每日每公斤体重约1μg至约1g。在一些实施方案中,剂量范围为每日每公斤体重约0.01mg至约100mg。剂量很可能取决于例如疾病或病症的类型和进展程度、具体患者的整体健康状态、所选化合物的相对生物效力、赋形剂的配制和其施用途径的变量。可以从来源于体外或动物模型测试系统的剂量反应曲线外推有效剂量。
为了制备例如片剂的固体组合物,将主要活性成分与药物赋形剂混合来形成含有本发明化合物的均匀混合物的固体预配制组合物。当称这些预配制组合物为均质时,活性成分通常均匀地分散在组合物中,以便组合物容易再分成同等有效的单位剂型,例如片剂、丸剂和胶囊。接着这种固体预配制剂再分成含有例如约0.1mg至约1000mg本发明的活性成分的上述类型的单位剂型。
本发明的片剂或丸剂可包覆包衣或以另外方式混配,以得到提供长期作用的益处的剂型。举例来说,片剂或丸剂可以包含内部配药组分和外部配药组分,后者呈在前者上的包膜形式。两种组分可以被肠溶衣层隔开,所述肠溶衣层用于对抗在胃中崩解,并且允许内部组分完整地进入十二指肠或延迟释放。多种物质可用于此类肠溶衣层或包衣,此类物质包括大量的多元酸和多元酸与例如虫胶、鲸蜡醇和乙酸纤维素的混合物。
可以掺入本发明的化合物和组合物以供经口或通过注射施用的液体形式包括水溶液、适当调味的糖浆、水性或油性悬浮液和含食用油(例如棉籽油、芝麻油、椰子油或花生油)的调味乳液,以及酏剂和类似的药物媒介物。
用于吸入或吹入的组合物包括于药学上可接受的水性溶剂或有机溶剂或其混合物中的溶液和悬浮液,以及粉剂。液体或固体组合物可以含有如上所述的合适药学上可接受的赋形剂。在一些实施方案中,组合物通过经口或经鼻呼吸途径施用以实现局部或全身作用。组合物可以通过使用惰性气体来雾化。可以直接从喷雾装置呼吸雾化溶液,或雾化装置可以连接至面罩、帐或间歇性正压呼吸机。可以经口或经鼻从以适当方式递送制剂的装置施用溶液、悬浮液或粉剂组合物。
局部制剂可以含有一种或多种常规载体。在一些实施方案中,软膏可以含有水和一种或多种选自例如液体石蜡、聚氧乙烯烷基醚、丙二醇、白凡士林等等的疏水性载体。乳膏的载体组合物可以基于水与甘油和一种或多种其它组分(例如单硬脂酸甘油酯、PEG-单硬脂酸甘油酯和鲸蜡硬脂醇)组合。凝胶可以使用异丙醇和水,适当地与例如甘油、羟乙基纤维素等其它组分组合来配制。在一些实施方案中,局部制剂含有至少约0.1重量%、至少约0.25重量%、至少约0.5重量%、至少约1重量%、至少约2重量%或至少约5重量%的本发明化合物。局部制剂宜例如以100g包装在管内,管任选地连带有关于治疗例如牛皮癣或其它皮肤疾患的所选适应症的说明书。
化合物或组合物施用于患者的量将视所施用的物品、施用目的(例如预防或治疗)、患者状态、施用方式等等而变。在治疗应用中,组合物可以足够治愈或至少部分阻止疾病症状和其并发症的量施用于已罹患疾病的患者。有效剂量将取决于所治疗的疾病疾患以及由主治医师视例如疾病严重度、患者年龄、体重和整体状况等等的因素进行判断。
向患者施用的组合物可以呈上述药物组合物形式。这些组合物可以通过常规灭菌技术来灭菌,或者可以无菌过滤。水溶液可以包装成原样使用,或冻干,冻干制剂在施用前与无菌水性载体组合。化合物制剂的pH值通常将在3与11之间,更优选5至9且最优选7至8。应了解某些上述赋形剂、载体或稳定剂的使用将形成药物盐。
本发明化合物的治疗剂量可根据例如具体的治疗用途、化合物的施用方式、患者的健康和状况以及处方医师的判断变化。药物组合物中本发明化合物的比例或浓度可以视包括剂量、化学特性(例如疏水性)和施用途径的许多因素而变化。举例来说,本发明的化合物可以呈含有约0.1%w/v至约10%w/v化合物的水性生理缓冲溶液提供以供不经肠施用。一些典型的剂量范围为每日每公斤体重约1μg至约1g。在一些实施方案中,剂量范围为每日每公斤体重约0.01mg至约100mg。剂量很可能取决于例如疾病或病症的类型和进展程度、具体患者的整体健康状态、所选化合物的相对生物效力、赋形剂的配制和其施用途径的变量。可以从来源于体外或动物模型测试系统的剂量反应曲线外推有效剂量。
V.标记化合物和测定方法
本公开的化合物还可以用于研究正常和异常组织中的生物过程。因此,本发明的另一方面涉及本发明的标记化合物(放射性标记、荧光标记等),其不仅可用于成像技术中,并且也可以用于体外与体内测定中,用于定位和定量包括人的组织样品中的PD-1或PD-L1蛋白质,并且通过抑制标记化合物的结合来鉴定PD-L1配体。因此,本发明包括含有此类标记化合物的PD-1/PD-L1结合测定。
本发明还包括本公开的同位素取代化合物。“同位素取代”化合物为其中一个或多个原子被原子数相同但原子质量或质量数不同,例如原子质量或质量数不同于在自然界中通常发现(即天然存在)的原子质量或质量数的原子置换或取代的本发明化合物。应了解“放射性标记”化合物是掺入至少一种放射性同位素(例如放射性核素)的化合物。可以掺入本发明的化合物中的合适放射性核素包括但不限于3H(氚又写成T)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I和131I。掺入本发明的放射性标记化合物中的放射性核素将取决于放射性标记化合物的特定应用。举例来说,对于体外PD-L1蛋白质标记和竞争测定,掺入3H、14C、82Br、125I、131I、35S或的化合物一般最为有用。对于放射性成像应用,11C、18F、125I、123I、124I、131I、75Br、76Br或77Br一般最为有用。
在一些实施方案中,放射性核素选自由3H、14C、125I、35S和82Br组成的群。用于放射性同位素掺入有机化合物中的合成方法是本领域中已知的。
特定地说,本发明的标记化合物可以用于筛选测定中以鉴定和/或评估化合物。举例来说,可以通过追踪标记,监测在与PD-L1蛋白质接触时的浓度变化,来评估新合成或鉴定的标记化合物(即测试化合物)结合PD-L1蛋白质的能力。举例来说,可以评估测试化合物(标记)减少已知结合于PD-L1蛋白质的另一化合物(即标准化合物)的结合的能力。因此,测试化合物与标准化合物竞争与PD-L1蛋白质结合的能力直接与其结合亲合力相关。相反,在一些其它筛选测定中,标准化合物进行标记且测试化合物未进行标记。因此,监测进行标记的标准化合物的浓度,以评估标准化合物与测试化合物之间的竞争,并因此确定测试化合物的相对结合亲合力。
VI.药盒
本公开还包括药盒,所述药盒可用于例如治疗或预防与PD-L1活性,包括PD-L1与例如PD-1和B7-1(CD80)的其它蛋白质的相互作用相关的疾病或病症,例如癌症或感染,所述药盒包括一个或多个含有包含治疗有效量的式(I)化合物或其任一实施方案的药物组合物的容器。此类药盒还可包括多种常规药盒组件中的一种或多种,例如具有一种或多种药学上可接受的载体的容器、额外容器等,如本领域技术人员显而易知。药盒中还可以包括作为插页或作为标签的说明书,其指示组分的施用量、施用准则和/或组分混合准则。
本文中可以使用以下缩写:aq.(水溶液);br(宽峰);d(双峰);dd(双二重峰);DCM(二氯甲烷);DMF(N,N-二甲基甲酰胺);Et(乙基);EtOAc(乙酸乙酯);g(克);h(小时);HPLC(高效液相色谱法);Hz(赫兹);J(耦合常数);LCMS(液相色谱法-质谱分析法);m(多重峰);M(摩尔浓度);MS(质谱分析法);Me(甲基);MeCN(乙腈);MeOH(甲醇);mg(毫克);min.(分钟);mL(毫升);mmol(毫摩尔);nM(纳摩尔浓度);NMR(核磁共振谱法);Ph(苯基);r.t.(室温),s(单峰);t(三重峰或叔);TBS(叔丁基二甲基硅烷基);tert(叔);tt(三重三重峰);TFA(三氟乙酸);THF(四氢呋喃);μg(微克);μL(微升);μM(微摩尔浓度);wt%(重量百分比)。
将通过特定实施例更详细地描述本发明。出于说明的目的,提供下列实施例,并且不意图以任何方式限制本发明。本领域技术人员将容易识别多个非关键参数,这些参数可以变化或修改,结果基本上相同。已经根据本文所述的至少一种测定,发现所述实施例的化合物抑制PD-1/PD-L1蛋白质/蛋白质相互作用的活性。
实施例
下文提供本发明化合物的实验程序。在Waters质量引导的分级分离系统上,对所制备的一些化合物进行开放存取的制备型LCMS纯化。已在文献中详细描述用于操作这些系统的基础设备设置、方案和控制软件。参见例如Blom,“Two-Pump At Column DilutionConfiguration for Preparative LC-MS”,K.Blom,J.Combi.Chem.,2002,4,295-301;Blom等人,“Optimizing Preparative LC-MS Configurations and Methods for ParallelSynthesis Purification”,J.Combi.Chem.,2003,5,670-83;以及Blom等人,“PreparativeLC-MS Purification:Improved Compound Specific Method Optimization”,J.Combi.Chem.,2004,6,874-883。
实施例1
(R)-1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:3-氯-4-羟基-5-硝基苯甲酸甲酯
在0℃下向3-氯-4-羟基苯甲酸甲酯(Alfa Aesar,#A512389:10.0g,53.6mmol)于乙酸(20.0mL)中的溶液中逐滴加入乙酸(20.0mL)和硝酸(4.72mL,112mmol)的混合物。接着去除冰浴并且将稠混合物在室温下搅拌2小时。接着在0℃下将等体积水加入至反应悬浮液中。过滤混合物并且用冷水洗涤。获得黄色固体作为所需产物,不进行进一步纯化。LC-MSC8H7ClNO5(M+H)+的计算值:m/z=232.0;实验值232.0。
步骤2:3-氨基-5-氯-4-羟基苯甲酸甲酯
使3-氯-4-羟基-5-硝基苯甲酸甲酯(2.08g,8.98mmol)在氢气环境压力下使用钯/碳(10重量%,0.57g,0.539mmol)在乙酸乙酯(15mL)中氢化1小时。所得悬浮液经Celite垫过滤并且用EtOAc洗涤并在减压下去除溶剂,得到粗产物,其通过柱色谱法(用MeOH/DCM0%-10%洗脱)来纯化。LC-MS C8H9ClNO3(M+H)+的计算值:m/z=202.0;实验值202.0。
步骤3:2-(3-溴-2-甲基苯基)-7-氯苯并[d]噁唑-5-甲酸甲酯
将3-氨基-5-氯-4-羟基苯甲酸甲酯(1.04g,5.16mmol)、3-溴-2-甲基苯甲醛(AstaTech,#52940:0.98g,4.92mmol)于EtOH(25ml)中的混合物置于小瓶中并在室温下搅拌1小时。接着浓缩混合物。使残余物再溶于二氯甲烷(25mL)中并加入二氯二氰基醌(1.12g,4.92mmol)。将混合物在室温下搅拌30分钟。将反应物用二氯甲烷稀释并且用Na2S2O3水溶液和NaHCO3水溶液洗涤。有机相经MgSO4干燥,过滤并且浓缩滤液。粗残余物未经进一步纯化直接使用。LC-MS C16H12BrClNO3(M+H)+的计算值:m/z=380.0;实验值379.9。
步骤4:(2-(3-溴-2-甲基苯基)-7-氯苯并[d]噁唑-5-基)甲醇
在-78℃下向2-(3-溴-2-甲基苯基)-7-氯苯并[d]噁唑-5-甲酸甲酯(395.0mg,1.04mmol)于DCM(10.0ml)中的溶液中逐滴加入二异丁基氢化铝的DCM溶液(1.0M,2.08ml,2.08mmol)。使混合物缓慢升温至0℃。接着将混合物用EtOAc和DCM淬灭,接着用罗氏盐(Rochell′s salt)水溶液淬灭。将混合物在室温下用力搅拌1小时。分离有机相并且经MgSO4干燥,接着经短Celite垫过滤以去除固体。浓缩滤液并且通过柱色谱法(用0-5%MeOH/DCM洗脱)来纯化。LC-MS C15H12BrClNO2(M+H)+的计算值:m/z=352.0;实验值352.0。
步骤5:(7-氯-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-5-基)甲醇
将(2-(3-溴-2-甲基苯基)-7-氯苯并[d]噁唑-5-基)甲醇(113mg,0.322mmol)、双(频哪醇根基)二硼(98mg,0.386mmol)、二氯[1,1′-双(二苯基膦基)二茂铁]钯(II)二氯甲烷加合物(26.3mg,0.032mmol)和无水乙酸钾(79mg,0.804mmol)于1,4-二噁烷(3.5mL)中的混合物用氮气净化并在110℃下搅拌2小时。将粗物质用DCM稀释,并且接着经Celite过滤。浓缩滤液。残余物通过快速色谱法(用0-40%EtOAc/己烷洗脱)来纯化。LC-MS C21H24BClNO4(M+H)+的计算值:m/z=400.2;实验值400.2。
步骤6:5-(羟基甲基)-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-7-甲腈
在室温下将经过搅拌的(7-氯-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-5-基)甲醇(1.08g,2.63mmol)、氰化锌(0.253g,2.11mmol)和甲烷磺酸根基(2-二叔丁基膦基-2′,4′,6′-三异丙基-1,1′-联苯)(2′-氨基-1,1′-联苯-2-基)钯(II)(0.171g,0.211mmol)于THF(5.27ml)和水(5.27ml)中的混合物脱气并且用N2回填三次。将其在90℃下加热过夜。将反应混合物在热的时用THF稀释。使其冷却至室温并过滤以去除不溶固体。滤液真空浓缩。接着加入乙腈。将所得浆状物过滤并且用乙腈洗涤。收集固体并且未经进一步纯化直接用于下一步。LC-MS C22H24BN2O4(M+H)+的计算值:m/z=391.2;实验值:391.2。
步骤7:5-甲酰基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-7-甲腈
向5-(羟基甲基)-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-7-甲腈(1.51g,3.68mmol)于DCM(16.4mL)和DMF(2.0ml)中的溶液中加入戴斯-马丁高碘烷(Dess-Martin periodinane)(2.49g,5.70mmol)。将混合物在室温下搅拌3小时。将粗混合物用饱和Na2S2O3和饱和NaHCO3淬灭。将混合物用DCM萃取三次。合并有机相,干燥并过滤。浓缩滤液。将乙醚加入至残余物中以形成浆状物,进行过滤,得到所需醛。LCMS C22H22BN2O4(M+H)+的计算值:m/z=389.2;实验值389.2。
步骤8:7-溴-N-(3-氯-2-甲基苯基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
向7-溴-2-甲基吡啶并[3,2-d]嘧啶-4-醇(Combi-Blocks,目录号ST-6117:175mg,0.729mmol)、苄基三乙基氯化铵(332mg,1.46mmol)和N,N-二乙基苯胺(174μl,1.09mmol)于乙腈(3.6ml)中的混合物加入磷酰氯(408μl,4.37mmol)。将混合物在90℃下搅拌2小时。接着使反应冷却至室温。在减压下去除挥发物。残余物直接使用。
向含以上残余物的2-丙醇(3.6ml)加入3-氯-2-甲基苯胺(113mg,0.800mmol)和甲烷磺酸(47.2μl,0.727mmol)。将混合物在80℃下搅拌2小时。接着使反应冷却至室温。混合物通过NaHCO3水溶液小心淬灭,用DCM萃取。合并的DCM溶液经MgSO4干燥并且过滤。浓缩滤液。残余物通过快速色谱法(0-70%EtOAc/己烷)来纯化。LC-MS C15H13BrClN4(M+H)+的计算值:m/z=363.0;实验值363.0。
步骤9:N-(3-氯-2-甲基苯基)-2-甲基-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺
将7-溴-N-(3-氯-2-甲基苯基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺(250mg,0.687mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼杂环戊烷(159mg,1.03mmol)、四(三苯基膦)钯(0)(79mg,0.069mmol)和磷酸钾(365mg,1.72mmol)于叔丁醇(3.4ml)和水(3.4ml)中的混合物用N2净化并密封。将所得混合物在100℃下搅拌3小时。使反应混合物冷却,接着用乙酸乙酯萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并在减压下浓缩。粗残余物未经进一步纯化直接用于下一步。LC-MS C17H16ClN4(M+H)+的计算值:m/z=311.2;实验值311.2。
步骤10:4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-甲醛
向小瓶馈入N-(3-氯-2-甲基苯基)-2-甲基-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺(214mg,0.689mmol)、THF(5.5ml)、搅拌棒和水(1.4ml)。向此溶液加入高碘酸钠(736mg,3.44mmol),接着加入四氧化锇(水中4%w/w,270μl,0.034mmol)。在室温下搅拌1小时后将反应用饱和硫代硫酸钠水溶液淬灭。接着将混合物用DCM萃取,并且合并的有机层用水、盐水洗涤,经MgSO4干燥,过滤,并且真空浓缩。粗残余物未经进一步纯化直接用于下一步。LC-MS C16H14ClN4O(M+H)+的计算值:m/z=313.1;实验值313.1。
步骤11:(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇
将4-((3-氯-2-甲基苯基)氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-甲醛(215mg,0.687mmol)和(R)-吡咯烷-3-醇(71.9mg,0.825mmol)于DCM(4.6ml)中的混合物在室温下搅拌30分钟。接着加入三乙酰氧基硼氢化钠(219mg,1.03mmol)。将混合物在室温下进一步搅拌1小时。将反应用NH4OH水溶液淬灭,通过DCM萃取。将有机相合并,并且经MgSO4干燥。在过滤后,将DCM溶液浓缩并且残余物通过快速色谱法(0-12%MeOH/DCM)来纯化,得到所需产物。LC-MS C20H23ClN5O(M+H)+的计算值:m/z=384.2;实验值384.2。
步骤12:(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
将(R)-1-((4-((3-氯-2-甲基苯基)氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇(229mg,0.597mmol)、5-甲酰基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-7-甲腈(步骤7:255mg,0.657mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(47.0mg,0.060mmol)和磷酸钾(317mg,1.493mmol)于水(1.0ml)和1,4-二噁烷(5.0ml)中的混合物用N2净化并接着密封。将反应在100℃下搅拌2小时。使反应冷却至室温。将反应混合物用DCM和H2O稀释。分离各层。将水层用DCM萃取三次。有机层经MgSO4干燥,过滤并且浓缩,得到粗残余物,其未经进一步纯化直接用于下一步。LC-MS C36H32N7O3(M+H)+的计算值:m/z=610.3;实验值610.4。
步骤13:(R)-1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
将(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈(16mg,0.026mmol)和哌啶-4-甲酸叔丁酯(9.7mg,0.052mmol)于DCM(500μL)中的混合物在室温下搅拌2小时。接着加入三乙酰氧基硼氢化钠(16.7mg,0.079mmol)。将混合物在室温下进一步搅拌1小时。将反应用三氟乙酸(404μL,5.25mmol)处理并在室温下搅拌30分钟。在蒸发挥发物后,残余物在MeOH中稀释,接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到所需TFA盐。LC-MS C42H43N8O4(M+H)+的计算值:m/z=723.3;实验值723.3。1H NMR(500MHz,DMSO)δ9.08(s,1H),8.38(d,J=9.5Hz,2H),8.19(d,J=7.1Hz,1H),8.10(s,1H),7.65-7.55(m,2H),7.48(d,J=6.8Hz,1H),7.42(t,J=7.7Hz,1H),7.18(d,J=7.5Hz,1H),4.72(s,2H),4.59-4.41(m,3H),3.76-3.20(m,6H),3.09-2.90(m,2H),2.56(s,3H),2.49(s,3H),2.48(s,1H),2.39-2.25(m,1H),2.14-2.02(m,2H),1.96(s,3H),1.96-1.86(m,1H),1.80-1.68(m,2H)。
实施例2
(R)-1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)-3-甲基吡咯烷-3-醇
本化合物是使用与针对实施例1步骤11所述类似的程序,用(R)-3-甲基吡咯烷-3-醇代替(R)-吡咯烷-3-醇制备。LC-MS C21H25ClN5O(M+H)+的计算值:m/z=398.2;实验值398.2。
步骤2:(R)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例1步骤12所述类似的程序,用(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)-3-甲基吡咯烷-3-醇(步骤1)代替(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇制备。LC-MS C37H34N7O3(M+H)+的计算值:m/z=624.3;实验值624.3。
步骤3:(R)-1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例1步骤13所述类似的程序,用(R)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(步骤2)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C43H45N8O4(M+H)+的计算值:m/z=737.4;实验值737.4。
实施例3
(S)-1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:(S)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)-3-甲基吡咯烷-3-醇
本化合物是使用与针对实施例1步骤11所述类似的程序,用(S)-3-甲基吡咯烷-3-醇代替(R)-吡咯烷-3-醇制备。LC-MS C21H25ClN5O(M+H)+的计算值:m/z=398.2;实验值398.2。
步骤2:(S)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例1步骤12所述类似的程序,用(S)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)-3-甲基吡咯烷-3-醇(步骤1)代替(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇制备。LC-MSC37H34N7O3(M+H)+的计算值:m/z=624.3;实验值624.3。
步骤3:(S)-1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例1步骤13所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(步骤2)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C43H45N8O4(M+H)+的计算值:m/z=737.4;实验值737.4。
实施例4
(S)-1-((7-氰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:(S)-2-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基氨基)丙-1-醇
本化合物是使用与针对实施例1步骤11所述类似的程序,用(S)-2-氨基丙-1-醇代替(R)-吡咯烷-3-醇制备。LC-MS C19H23ClN5O(M+H)+的计算值:m/z=372.2;实验值372.2。
步骤2:(S)-5-甲酰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例1步骤12所述类似的程序,用(S)-2-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基氨基)丙-1-醇(步骤1)代替(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇制备。LC-MS C35H32N7O3(M+H)+的计算值:m/z=598.3;实验值598.3。
步骤3:(S)-1-((7-氰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例1步骤13所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(步骤2)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H43N8O4(M+H)+的计算值:m/z=711.3;实验值711.3。
实施例5
(S)-1-((7-氰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:(S)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基氨基)丙-2-醇
本化合物是使用与针对实施例1步骤11所述类似的程序,用(S)-1-氨基丙-2-醇代替(R)-吡咯烷-3-醇制备。LC-MS C19H23ClN5O(M+H)+的计算值:m/z=372.2;实验值372.2。
步骤2:(S)-5-甲酰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例1步骤12所述类似的程序,用(S)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基氨基)丙-2-醇(步骤1)代替(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇制备。LC-MS C35H32N7O3(M+H)+的计算值:m/z=598.3;实验值598.3。
步骤3:(S)-1-((7-氰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例1步骤13所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(步骤2)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H43N8O4(M+H)+的计算值:m/z=711.3;实验值711.3。
实施例6
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
将(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈(实施例1步骤12:16mg,0.026mmol)、(R)-吡咯烷-3-甲酸(6.0mg,0.052mmol)和三乙胺(7.3μL,0.052mmol)于DCM(500μL)中的混合物在室温下搅拌2小时。接着加入三乙酰氧基硼氢化钠(16.69mg,0.079mmol)。将混合物在室温下进一步搅拌1小时。将反应混合物在MeOH中稀释,接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC41H41N8O4(M+H)+的计算值:m/z=709.3;实验值709.3。
实施例7
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(R)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例2步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC42H43N8O4(M+H)+的计算值:m/z=723.3;实验值723.3。
实施例8
(R)-1-((7-氰基-2-(3′-(7-(((S)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例3步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC42H43N8O4(M+H)+的计算值:m/z=723.3;实验值723.3。
实施例9
(R)-1-((7-氰基-2-(3′-(7-(((S)-1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例4步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C40H41N8O4(M+H)+的计算值:m/z=697.3;实验值697.3。
实施例10
(R)-1-((7-氰基-2-(3′-(7-(((S)-2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例5步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C40H41N8O4(M+H)+的计算值:m/z=697.3;实验值697.3。
实施例11
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
将(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈(实施例1步骤12:16mg,0.026mmol)、(R)-3-甲基吡咯烷-3-甲酸(6.8mg,0.052mmol)和三乙胺(7.3μL,0.052mmol)于DCM(500μL)中的混合物在室温下搅拌2小时。接着加入三乙酰氧基硼氢化钠(16.7mg,0.079mmol)。将混合物在室温下进一步搅拌1小时。将反应混合物在MeOH中稀释,接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC42H43N8O4(M+H)+的计算值:m/z=723.3;实验值723.3。1H NMR(600MHz,DMSO)δ9.87(s,1H),8.77(d,J=1.7Hz,1H),8.15(d,J=7.3Hz,1H),8.10(s,1H),7.95(s,1H),7.90-7.81(m,2H),7.55(t,J=7.7Hz,1H),7.44(d,J=6.9Hz,1H),7.36(t,J=7.8Hz,1H),7.06(d,J=7.3Hz,1H),4.21(dt,J=6.3,3.6Hz,1H),3.87-3.80(m,1H),3.79-3.72(m,2H),3.72-3.66(m,1H),2.92(d,J=9.1Hz,1H),2.71(dd,J=9.6,6.1Hz,1H),2.65(q,J=8.0Hz,1H),2.62-2.54(m,2H),2.48-2.46(m,6H),2.46-2.43(m,1H),2.38(dd,J=9.6,3.5Hz,1H),2.33-2.26(m,2H),2.05-1.99(m,1H),1.98(s,3H),1.60-1.50(m,2H),1.24(s,3H)。
实施例12
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(R)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例2步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC43H45N8O4(M+H)+的计算值:m/z=737.4;实验值737.4。
实施例13
(R)-1-((7-氰基-2-(3′-(7-(((S)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例3步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC43H45N8O4(M+H)+的计算值:m/z=737.4;实验值737.4。
实施例14
(R)-1-((7-氰基-2-(3′-(7-(((S)-1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例4步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H43N8O4(M+H)+的计算值:m/z=711.3;实验值711.3。
实施例15
(R)-1-((7-氰基-2-(3′-(7-(((S)-2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(S)-5-甲酰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例5步骤2)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H43N8O4(M+H)+的计算值:m/z=711.3;实验值711.3。
实施例16
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:7-溴-2-(二氟甲基)-4H-吡啶并[3,2-d][1,3]噁嗪-4-酮
将3-氨基-5-溴代吡啶甲酸(PharmBlock目录号PB0554:645mg,2.97mmol)和2,2-二氟乙酸酐(4.14g,23.8mmol)的混合物在60℃下搅拌3小时。在冷却至室温后,挥发物通过旋转蒸发仪和高真空泵去除。残余物直接用于下一步。LC-MS C8H4BrF2N2O2(M+H)+的计算值:m/z=276.9;实验值277.0。
步骤2:7-溴-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-醇
将厚壁玻璃管中7-溴-2-(二氟甲基)-4H-吡啶并[3,2-d][1,3]噁嗪-4-酮(801mg,2.89mmol)和氢氧化铵水溶液(8.0ml,28%)的混合物密封并在85℃下搅拌2小时。在冷却至室温后,接着蒸发溶液并且将残余物用CH3CN和甲苯再稀释。悬浮液再次蒸发并且残余物未经进一步纯化即用于下一步。LC-MS C8H5BrF2N3O(M+H)+的计算值:m/z=276.0;实验值276.0。
步骤3:7-溴-N-(3-氯-2-甲基苯基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-胺
向7-溴-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-醇(来自步骤2的粗产物:750mg,2.72mmol)、苄基三乙基氯化铵(1238mg,5.43mmol)和N,N-二乙基苯胺(648μl,4.08mmol)于乙腈(13.6ml)中的混合物加入磷酰氯(1.52ml,16.3mmol)。将混合物在75℃下搅拌2小时。接着使反应冷却至室温。在减压下去除挥发物。
向3-氯-2-甲基苯胺(409mg,2.89mmol)和7-溴-4-氯-2-(二氟甲基)吡啶并[3,2-d]嘧啶(以上残余物)于2-丙醇(14.4ml)中的溶液中加入甲烷磺酸(188μl,2.89mmol)。将混合物在80℃下搅拌2小时。接着使反应冷却至室温。混合物通过NaHCO3水溶液小心淬灭。将沉淀过滤,用水洗涤并且通过空气干燥。固体直接用于下一步。LC-MS C15H11BrClF2N4(M+H)+的计算值:m/z=399.0;实验值399.0。
步骤4:N-(3-氯-2-甲基苯基)-2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺
将7-溴-N-(3-氯-2-甲基苯基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-胺(841mg,2.10mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼杂环戊烷(537μl,3.16mmol)、四(三苯基膦)钯(0)(243mg,0.21mmol)和磷酸钾(1117mg,5.26mmol)于叔丁醇(7.0ml)和水(7.0ml)中的混合物用N2净化并接着在100℃下搅拌3小时。使反应冷却至室温。将反应混合物用水稀释并且用DCM萃取。有机层经MgSO4干燥,过滤并且浓缩,得到粗残余物,其通过快速色谱法(0-30%EtOAc/DCM)来纯化。LC-MS C17H14ClF2N4(M+H)+的计算值:m/z=347.1;实验值347.1。
步骤5:4-(3-氯-2-甲基苯基氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-甲醛
向小瓶馈入N-(3-氯-2-甲基苯基)-2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺(195mg,0.562mmol)、THF(4.5ml)、搅拌棒和水(1.1ml)。向此溶液加入高碘酸钠(601mg,2.81mmol),接着四氧化锇(水中4%w/w,221μl,0.028mmol)。在室温下搅拌1小时后,将反应用饱和硫代硫酸钠水溶液淬灭。接着将混合物用DCM萃取,并且将合并的有机层用水、盐水洗涤,经MgSO4干燥,过滤,并且真空浓缩。粗残余物未经进一步纯化直接用于下一步。LC-MS C16H12ClF2N4O(M+H)+的计算值:m/z=349.1;实验值349.1。
步骤6:(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇
将4-((3-氯-2-甲基苯基)氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-甲醛(101mg,0.290mmol)和(R)-吡咯烷-3-醇(30.3mg,0.348mmol)于DCM(1931μl)中的混合物在室温下搅拌30分钟。接着加入三乙酰氧基硼氢化钠(92mg,0.434mmol)。将混合物在室温下进一步搅拌1小时。将反应用NH4OH水溶液淬灭并且通过DCM萃取。将有机相合并且经MgSO4干燥。在过滤后,DCM溶液浓缩成残余物,其通过快速色谱法(0-12%MeOH/DCM)来纯化。LC-MSC20H21ClF2N5O(M+H)+的计算值:m/z=420.1;实验值420.2。
步骤7:(R)-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈
将(R)-1-((4-((3-氯-2-甲基苯基)氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇(34.4mg,0.082mmol)、5-甲酰基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-7-甲腈(实施例1步骤7:35mg,0.090mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(6.5mg,8.2μmol)和磷酸钾(43.5mg,0.205mmol)于水(140μl)和1,4-二噁烷(690μl)中的混合物用N2净化并接着密封。将反应在100℃下搅拌2小时。使反应冷却至室温。将反应混合物用DCM和H2O稀释。分离各层。将水层用DCM萃取三次。有机层经MgSO4干燥,过滤并且浓缩,得到粗残余物,其未经进一步纯化直接用于下一步。LC-MS C36H30F2N7O3(M+H)+的计算值:m/z=646.2;实验值646.3。
步骤8:(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
将(R)-2-(3′-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(9.5mg,0.015mmol)和哌啶-4-甲酸叔丁酯(5.45mg,0.029mmol)的混合物在室温下搅拌2小时。接着加入三乙酰氧基硼氢化钠(9.36mg,0.044mmol)。将混合物在室温下搅拌1小时。接着向混合物加入三氟乙酸(300μL)并搅拌30分钟。蒸发挥发物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC42H41F2N8O4(M+H)+的计算值:m/z=759.3;实验值759.6。1H NMR(500MHz,DMSO)δ10.63(s,1H),9.13(s,1H),8.52(d,J=2.0Hz,1H),8.39(d,J=1.6Hz,1H),8.19(dd,J=7.9,1.5Hz,1H),8.11(d,J=2.1Hz,1H),7.64(dd,J=8.1,1.3Hz,1H),7.59(t,J=7.7Hz,1H),7.49(dd,J=7.5,1.5Hz,1H),7.41(t,J=7.8Hz,1H),7.16(dd,J=7.6,1.3Hz,1H),6.74(t,J=54.5Hz,1H),4.85-4.65(m,2H),4.58-4.40(m,3H),3.74-3.00(m,8H),2.78-2.54(m,1H),2.50(s,3H),2.32-1.91(m,5H),1.95(s,3H),1.79-1.67(m,1H)。
实施例17
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(R)-2-(3′-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(实施例16步骤7)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H39F2N8O4(M+H)+的计算值:m/z=745.3;实验值745.3。
实施例18
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(R)-2-(3′-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(实施例16步骤7)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C42H41F2N8O4(M+H)+的计算值:m/z=759.3;实验值759.6。
实施例19
(R)-1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例16所述类似的程序(步骤1-7),在步骤1中用三氟乙酸酐代替2,2-二氟乙酸酐制备。LC-MS C36H29F3N7O3(M+H)+的计算值:m/z=664.2;实验值664.2。
步骤2:(R)-1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例1步骤13所述类似的程序,用(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(步骤1)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C42H40F3N8O4(M+H)+的计算值:m/z=777.3;实验值777.3。
实施例20
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例19步骤1)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H38F3N8O4(M+H)+的计算值:m/z=763.3;实验值763.3。
实施例21
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(实施例19步骤1)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C42H40F3N8O4(M+H)+的计算值:m/z=777.3;实验值777.3。
实施例22
(S)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(S)-吡咯烷-3-甲酸代替(R)-吡咯烷-3-甲酸和(R)-2-(3′-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(实施例16步骤7)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H39F2N8O4(M+H)+的计算值:m/z=745.3;实验值745.3。
实施例23
(S)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(S)-3-甲基吡咯烷-3-甲酸代替(R)-吡咯烷-3-甲酸和(R)-2-(3′-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(实施例16步骤7)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C42H41F2N8O4(M+H)+的计算值:m/z=759.3;实验值759.3。
实施例24
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-4-甲基哌啶-4-甲酸
本化合物是使用与针对实施例16所述类似的程序,在步骤8中用4-甲基哌啶-4-甲酸叔丁酯代替哌啶-4-甲酸叔丁酯制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC43H43F2N8O4(M+H)+的计算值:m/z=773.3;实验值773.3。
实施例25
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-N,N-二甲基哌啶-4-甲酰胺
向(R)-1-((7-氰基-2-(3′-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸(实施例16:7.0mg,9.22μmol)、二甲胺(2.0M甲醇溶液,0.014ml)和N,N-二异丙基乙胺(5μl,0.028mmol)于DMF(0.3ml)中的溶液中加入HATU(7.0mg,0.018mmol)。在室温下搅拌2小时后,将反应混合物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C44H46F2N9O3(M+H)+的计算值:m/z=786.4;实验值786.4。
实施例26
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-N-甲基哌啶-4-甲酰胺
本化合物是使用与针对实施例25所述类似的程序,用甲胺溶液代替二甲胺溶液制备。将反应混合物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C43H44F2N9O3(M+H)+的计算值:m/z=772.4;实验值772.3。
实施例27
(R)-3-(1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酰胺基)丙酸
本化合物是使用与针对实施例25所述类似的程序,用3-氨基丙酸叔丁酯代替二甲胺溶液制备。在形成酰胺键后,将反应混合物用三氟乙酸(0.5mL)处理并在室温下搅拌1小时。接着将反应混合物浓缩,再溶于MeOH中且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C45H46F2N9O5(M+H)+的计算值:m/z=830.4;实验值830.3。
实施例28
(R)-1-((7-氰基-2-(3′-(2-环丙基-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
步骤1:(R)-2-(3′-(2-环丙基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例16所述类似的程序(步骤1-7),在步骤1中用环丙烷甲酸酐代替2,2-二氟乙酸酐制备。LC-MS C38H34N7O3(M+H)+的计算值:m/z=636.3;实验值636.4。
步骤2:(R)-1-((7-氰基-2-(3′-(2-环丙基-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(R)-2-(3′-(2-环丙基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(步骤1)代替(R)-5-甲酰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C43H43N8O4(M+H)+的计算值:m/z=735.3;实验值735.3。
实施例29
(R)-1-((2-(3′-(2-氨基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-7-氰基苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:N-(7-溴-4-氧代基-3,4-二氢吡啶并[3,2-d]嘧啶-2-基)乙酰胺
将3-氨基-5-溴代吡啶甲酰胺(1.88g,8.70mmol)和氨基甲酰氯盐酸盐(1.30g,11.31mmol)于环丁砜(5.44ml)和二甲基砜(5.44ml)中的混合物在密封小瓶中在165℃下搅拌5小时。在冷却至室温后,将反应用水小心稀释以形成悬浮液。沉淀通过过滤收集并且用水洗涤。固体在空气中干燥且未进行进一步纯化直接使用。将以上固体(685mg,2.84mmol)和乙酸酐(13.4ml)的混合物在115℃下搅拌8小时。在冷却至室温后,将混合物用DCM稀释并且用水洗涤。有机层经MgSO4干燥,过滤并且浓缩,得到粗物质,其直接用于下一步。LC-MSC9H8BrN4O2(M+H)+的计算值:m/z=283.0;实验值283.0。
步骤2:7-溴-N4-(3-氯-2-甲基苯基)吡啶并[3,2-d]嘧啶-2,4-二胺
向N-(7-溴-4-氧代基-3,4-二氢吡啶并[3,2-d]嘧啶-2-基)乙酰胺(201mg,0.710mmol)、苄基三乙基氯化铵(323mg,1.420mmol)和N,N-二乙基苯胺(169μl,1.065mmol)于乙腈(3.5ml)中的混合物加入POCl3(397μl,4.26mmol)。将混合物在75℃下搅拌2小时。接着使反应冷却至室温。在减压下去除挥发物。
向3-氯-2-甲基苯胺(100mg,0.710mmol)和N-(7-溴-4-氯吡啶并[3,2-d]嘧啶-2-基)乙酰胺(以上残余物)于2-丙醇(3549μl)中的溶液中加入甲烷磺酸(46.1μl,0.710mmol)。将混合物在80℃下搅拌2小时。接着使反应冷却至室温。混合物通过NaHCO3水溶液小心淬灭。将沉淀过滤,用水洗涤并且通过空气干燥。固体直接用于下一步。LC-MSC14H12BrClN5(M+H)+的计算值:m/z=364.0;实验值364.0。
步骤3:(R)-1-((2-氨基-4-(3-氯-2-甲基苯基氨基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇
本化合物是使用与针对实施例16所述类似的程序(步骤4-6),在步骤4中用7-溴-N4-(3-氯-2-甲基苯基)吡啶并[3,2-d]嘧啶-2,4-二胺代替7-溴-N-(3-氯-2-甲基苯基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-胺制备。LC-MS C19H22ClN6O(M+H)+的计算值:m/z=385.2;实验值385.2。
步骤4:1-((7-氰基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸叔丁酯
将5-甲酰基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-7-甲腈(实施例1步骤7:684mg,1.76mmol)和哌啶-4-甲酸叔丁酯(392mg,2.11mmol)于DCM(7.0ml)中的混合物在室温下搅拌2小时。接着加入三乙酰氧基硼氢化钠(560mg,2.64mmol)。将混合物在室温下进一步搅拌1小时。将反应用NH4OH水溶液淬灭并通过DCM萃取。将有机相合并,并且经MgSO4干燥。在过滤后,DCM溶液浓缩成残余物,其通过快速色谱法(0-20%EtOAc/己烷)来纯化。LC-MS C32H41BN3O5(M+H)+的计算值:m/z=558.3;实验值558.3。
步骤5:(R)-1-((2-(3′-(2-氨基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-7-氰基苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
将(R)-1-((2-氨基-4-((3-氯-2-甲基苯基)氨基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇(33.9mg,0.088mmol)、1-((7-氰基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸叔丁酯(54mg,0.097mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(6.9mg,8.8μmol)和磷酸钾(46.7mg,0.22mmol)于水(150μl)和1,4-二噁烷(750μl)中的混合物用N2净化并接着在100℃下搅拌3小时。使反应冷却至室温。将反应混合物用DCM和H2O稀释。分离各层。将水层用DCM萃取三次。将有机层合并,经MgSO4干燥,过滤并且浓缩,得到粗残余物。残余物溶于DCM(1mL)中并且用三氟乙酸(1.0mL)处理。在室温下搅拌30分钟后,蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C41H42N9O4(M+H)+的计算值:m/z=724.3;实验值724.4。
实施例30
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-基)甲基)-3-甲基吡咯烷-3-醇
本化合物是使用与针对实施例16步骤6所述类似的程序,用(R)-3-甲基吡咯烷-3-醇代替(R)-吡咯烷-3-醇制备。LC-MS C21H23ClF2N5O(M+H)+的计算值:m/z=434.2;实验值434.2。
步骤2:(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例29所述类似的程序,在步骤5中用(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-基)甲基)-3-甲基吡咯烷-3-醇(步骤1)代替(R)-1-((2-氨基-4-(3-氯-2-甲基苯基氨基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C43H43F2N8O4(M+H)+的计算值:m/z=773.3;实验值773.3。
实施例31
(S)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例30所述类似的程序,用(S)-3-甲基吡咯烷-3-醇代替(R)-3-甲基吡咯烷-3-醇制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC43H43F2N8O4(M+H)+的计算值:m/z=773.3;实验值773.3。
实施例32
(R)-1-((7-氰基-2-(3′-(2-(羟基甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
步骤1:7-溴-2-(羟基甲基)吡啶并[3,2-d]嘧啶-4(3H)-酮
在0℃下向3-氨基-5-溴代吡啶甲酰胺(142mg,0.657mmol)于THF中的溶液中加入乙酸2-氯-2-氧代基乙酯(90mg,0.66mmol)。将混合物在室温下搅拌直至LCMS显示反应结束。接着将水缓慢加入至混合物中。将沉淀过滤并收集,用少量水和CH3CN洗涤。在空气干燥后,直接使用固体。
将厚玻璃管中以上固体和氢氧化铵(水溶液,28%,1.7ml,12.04mmol)的混合物在85℃下搅拌2小时。在冷却至室温后,将溶液蒸发并且将残余物用CH3CN和甲苯再稀释。悬浮液再次蒸发并且残余物未经进一步纯化即用于下一步。LC-MS C8H7BrN3O2(M+H)+的计算值:m/z=256.0;实验值256.1。
步骤2:7-溴-2-((叔丁基二甲基硅烷基氧基)甲基)吡啶并[3,2-d]嘧啶-4(3H)-酮
向7-溴-2-(羟基甲基)吡啶并[3,2-d]嘧啶-4(3H)-酮(185mg,0.722mmol)和咪唑(73.8mg,1.084mmol)于DMF(4817μl)中的溶液中加入叔丁基二甲基氯硅烷(120mg,0.795mmol)。将混合物在室温下搅拌2小时。接着将混合物浓缩并且残余物通过快速色谱法(0-20%EtOAc/己烷)来纯化,得到所需产物。LC-MS C14H21BrN3O2Si(M+H)+的计算值:m/z=370.1;实验值370.1。
步骤3:7-溴-2-((叔丁基二甲基硅烷基氧基)甲基)-N-(3-氯-2-甲基苯基)吡啶并[3,2-d]嘧啶-4-胺
在0℃下向7-溴-2-((叔丁基二甲基硅烷基氧基)甲基)吡啶并[3,2-d]嘧啶-4(3H)-酮(201mg,0.54mmol)和DIEA(190μl,1.09mmol)于DCM(2.2ml)中的混合物加入甲烷磺酰氯(85μl,1.09mmol)。将混合物在室温下搅拌3小时。接着将3-氯-2-甲基苯胺(100mg,0.71mmol)加入至混合物中并且将对应混合物在室温下进一步搅拌过夜。将混合物用DCM稀释并且接着用水洗涤。DCM溶液经MgSO4干燥并过滤。滤液浓缩。残余物通过快速色谱法(0-40%EtOAc/己烷)来纯化。LC-MS C21H27BrClN4OSi(M+H)+的计算值:m/z=493.1;实验值493.1。
步骤4:(R)-1-((2-(3′-(2-((叔丁基二甲基硅烷基氧基)甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-7-氰基苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
本化合物是使用与针对实施例1所述类似的程序(步骤9-13),用7-溴-2-((叔丁基二甲基硅烷基氧基)甲基)-N-(3-氯-2-甲基苯基)吡啶并[3,2-d]嘧啶-4-胺(步骤3)代替7-溴-N-(3-氯-2-甲基苯基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺制备。结束后,反应溶液直接用于下一步。LC-MS C48H57N8O5Si(M+H)+的计算值:m/z=853.4;实验值853.4。
步骤5:(R)-1-((7-氰基-2-(3′-(2-(羟基甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸
在室温下向以上反应溶液(步骤4)加入三乙胺三氢氟酸盐(411μl,60当量)。将混合物在此温度下进一步搅拌1小时。接着将反应混合物浓缩并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MSC42H43N8O5(M+H)+的计算值:m/z=739.3;实验值739.5。
实施例33
(R)-1-((7-氰基-2-(3′-(3-(((R)-3-羟基吡咯烷-1-基)甲基)-6-甲基-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
步骤1:5-溴-N-叔丁基-3-(2-氧代基丙基)吡啶甲酰胺
在-40℃下在N2氛围下向二异丙基胺(3.42ml,24.0mmol)于THF(10mL)中的溶液中加入丁基锂(2.5M己烷,12.79ml,32.0mmol)。将混合物在此温度下搅拌5分钟。接着加入5-溴-N-(叔丁基)-3-甲基吡啶甲酰胺(2.71g,10.0mmol)于THF(2mL)中的溶液。将反应在-40℃下搅拌30分钟,接着升温至-10℃。接着在-40℃下在搅拌下将以上混合物加入至含乙酸乙酯(1.17ml,12.0mmol)的THF(6mL)中。在加入后,将反应进一步搅拌并缓慢升温至-10℃。接着反应通过加入NH4Cl水溶液淬灭。接着将混合物用DCM萃取三次。将有机相合并且经MgSO4干燥并过滤。浓缩滤液并且残余物通过快速色谱法,使用EtOAc/己烷(0-25%)来纯化,得到所需产物。LC-MS C13H18BrN2O2(M+H)+的计算值:m/z=313.1;实验值313.1。
步骤2:3-溴-6-甲基-1,7-萘啶-8-醇
将5-溴-N-(叔丁基)-3-(2-氧代基丙基)吡啶甲酰胺(716mg,2.29mmol)和乙酸铵(1762mg,22.86mmol)于乙酸(1.8ml)中的混合物加热至108℃并在此温度下搅拌12小时。使反应冷却至室温。加入水,形成沉淀。过滤悬浮液并收集固体以直接使用。LC-MS C9H8BrN2O(M+H)+的计算值:m/z=239.0;实验值239.1。
步骤3:(R)-1-((8-(3-氯-2-甲基苯基氨基)-6-甲基-1,7-萘啶-3-基)甲基)吡咯烷-3-醇
本化合物是使用与针对实施例16所述类似的程序(步骤3-6),用3-溴-6-甲基-1,7-萘啶-8-醇(步骤2)代替7-溴-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-醇制备。LC-MSC21H24ClN4O(M+H)+的计算值:m/z=383.2;实验值383.3。
步骤4:(R)-5-甲酰基-2-(3′-(3-((3-羟基吡咯烷-1-基)甲基)-6-甲基-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例1步骤12所述类似的程序,用(R)-1-((8-(3-氯-2-甲基苯基氨基)-6-甲基-1,7-萘啶-3-基)甲基)吡咯烷-3-醇(步骤3)代替(R)-1-((4-(3-氯-2-甲基苯基氨基)-2-甲基吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇制备。LC-MSC37H33N6O3(M+H)+的计算值:m/z=609.3;实验值609.4。
步骤5:(R)-1-((7-氰基-2-(3′-(3-(((R)-3-羟基吡咯烷-1-基)甲基)-6-甲基-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸
本化合物是使用与针对实施例6所述类似的程序,用(R)-5-甲酰基-2-(3′-(3-((3-羟基吡咯烷-1-基)甲基)-6-甲基-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-7-甲腈(步骤4)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C42H42N7O4(M+H)+的计算值:m/z=708.3;实验值708.3。
实施例34
(R)-1-((7-氰基-2-(3′-(6-(二氟甲基)-3-(((R)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
步骤1:(R)-2-(3′-(6-(二氟甲基)-3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈
本化合物是使用与针对实施例33所述类似的程序(步骤1-4),用2,2-二氟乙酸甲酯代替乙酸乙酯制备。LC-MS C37H31F2N6O3(M+H)+的计算值:m/z=645.2;实验值645.2。
步骤2:(R)-1-((7-氰基-2-(3′-(6-(二氟甲基)-3-(((R)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸
本化合物是使用与针对实施例11所述类似的程序,用(R)-2-(3′-(6-(二氟甲基)-3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)-5-甲酰基苯并[d]噁唑-7-甲腈(步骤1)代替(R)-5-甲酰基-2-(3′-((7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2′-二甲基-[1,1′-联苯]-3-基)苯并[d]噁唑-7-甲腈制备。蒸发反应混合物并且将残余物用MeOH稀释并且接着通过制备型HPLC(pH=2,乙腈/水+TFA)来纯化,得到呈TFA盐形式的所需产物。LC-MS C43H42F2N7O4(M+H)+的计算值:m/z=758.3;实验值758.3。
实施例A.均相时间分辨荧光(HTRF)PD-1/PD-L1结合测定
测定是在最终体积为20μL的标准的黑色384孔聚苯乙烯板中进行。抑制剂首先在DMSO中连续稀释,接着加入至板孔,接着加入其它反应组分。测定中DMSO的最终浓度为1%。测定是在具有0.05%Tween-20和0.1%BSA的PBS缓冲液(pH 7.4)中在25℃下进行。在C端具有His标签的重组人PD-L1蛋白质(19-238)是从AcroBiosystems(PD1-H5229)购得。在C端具有Fc标签的重组人PD-1蛋白质(25-167)也是从AcroBiosystems(PD1-H5257)购得。将PD-L1和PD-1蛋白质在测定缓冲液中稀释并将10μL加入至板孔中。将平板离心并且将蛋白质与抑制剂一起孵育40分钟。在孵育后,加入10μL补充有对Fc具有特异性的经铕穴状化合物标记的抗人IgG(PerkinElmer-AD0212)和结合于-别藻蓝蛋白(APC,PerkinElmer-AD0059H)的抗His抗体的HTRF检测缓冲液。在离心之后,将平板在25℃下孵育60分钟,接着在PHERAstar FS板式读数器(665nm/620nm比率)上读数。测定中的最终浓度为:3nM PD1,10nM PD-L1,1nM铕抗人IgG和20nM抗His-别藻蓝蛋白。通过使用GraphPad Prism 5.0软件,拟合对照活性百分比相对于抑制剂浓度log的曲线,来确定IC50。
实施例B.含有Src同源区2结构域的磷酸酶(SHP)测定
将U2OS/PD-L1细胞(DiscoveRx公司)维持于加入了10%FBS、0.25μg/ml嘌呤霉素的McCoy’s 5A培养基中。在去除培养基之后,细胞培养基被替换成测定培养基(具有1%FBS的RPMI1640培养基)。接着将U2OS/PD-L1细胞于20μL测定培养基中以每孔5000个细胞加入至384孔黑色透明底测定板(组织培养板,Greiner Bio-One)中。通过在DMSO中连续稀释来制备测试化合物并且通过ECHO液体处理机(Labcyte)将125nL化合物首先转移至384REMP板孔(Thermofisher),接着加入27.5μL测定培养基。将测定培养基中5μL/孔化合物转移至具有0.05%DMSO的细胞板,最终测定中为0.25μM。将Jurkat-PD-1-SHP细胞(DiscoveRx公司)在补充有10%FBS、250μg/ml潮霉素B、500μg/ml G418的RPMI1640培养基中培养。在用测定培养基替换培养基之后,将20μL中5,000个Jurkat-PD-1-SHP细胞分配至每个孔。将测定板在37℃、5%CO2下孵育2小时,接着加入2.5μL PathHunter试剂1(DiscoveRx公司)至每个孔中。将测定板在黑暗中以350rpm震荡1分钟,接着加入10μLPathHunter试剂2(DiscoveRx公司)。在室温下孵育1小时之后,用TopCount读数器(PerkinElmer)记录化学发光信号。具有DMSO的孔用作阳性对照并且不含细胞的孔用作阴性对照。通过使用GraphPad Prism 6.0软件,拟合对照活性百分比相对于化合物浓度log的曲线,来确定IC50。
实施例C.活化T细胞核因子(NFAT)测定
将PD-L1 aAPC/CHO-K1细胞(Promega)维持于加入了10%FBS、200μg/ml潮霉素B、250μg/ml遗传霉素(G418)的F-12培养基中。将Jurkat-PD-1-NFAT效应细胞(Promega)在补充有10%FBS、100μg/ml潮霉素B、500μg/ml G418的RPMI 1640培养基中培养。PD-L1aAPC/CHO-K1细胞的培养基首先替换为测定培养基(具有1%FBS的RPMI1640培养基)。接着将PD-L1 aAPC/CHO-K1细胞于10μL测定培养基中以每孔8000个细胞加入至白色384孔白色透明底测定板(组织培养板,Greiner Bio-One)中。通过在DMSO中连续稀释来制备测试化合物并且通过PlateMate Plus(Thermofisher)将DMSO中0.8μL测试化合物首先转移至384REMP板孔(Thermofisher)中,接着加入50μL平板培养基。将测定培养基中5μL化合物转移至具有0.4%DMSO的细胞中,最终测定中为2μM。在去除培养基之后,将5μL测定培养基中10,000个Jurkat-PD-1-NFAT效应细胞分配至每个孔中。将测定板在37℃、5%CO2下孵育24小时。在测定板平衡至室温15分钟后,加入20μL/孔Bio-GloTM试剂(Promega)。在室温下孵育8分钟之后,在Pherastar微量板式读数器(BMG Labtech)上读取荧光。基于相对于每个测定板内DMSO孔归一化的发光比率计算诱导倍数(FOI)。基于每种化合物的最高FOI与每个测定板内对照化合物的最大FOI的比率,报导最大诱导百分比。具有DMSO的孔用作阴性对照并且含具有最高FOI的对照化合物的孔用作阳性对照。通过使用GraphPad Prism 6.0软件,拟合对照活性百分比相对于化合物浓度log的曲线,来确定EC50。
实施例D.PD-L1全血内化分析
为了测定人类全血中的PD-L1内化,将正常人血(Biological Specialty公司,Colmar.PA)于96孔“2ml测定阻断液”(Corning,Corning NY)中在37℃下在一系列浓度的测试化合物和1ng/ml人类干扰素γ(R&D Systems公司Minn.MN)存在或不存在下孵育18-20小时。接着在黑暗中在室温下将血液与PD-L1(MIH1,eBioscience;或BD Biosciences SanJose,CA)、CD14(Life Technologies,Carlsbad,CA)一起染色30分钟。将全血/红细胞在37℃下在黑暗中溶解/固定(溶解缓冲液,BD Biosciences)5分钟并接着在1600RPM下离心5分钟。使细胞再悬浮于染色缓冲液(BD Bioscience,San Jose,CA)中并转移至96孔圆底板(Corning)中。基于CD14+(BD Biosciences)对细胞进行门控,并且通过平均荧光强度(MFI)(BD LSRFortessaTM X-20)测定PD-L1表达。通过使用GraphPad Prism 7.0软件,拟合化合物抑制百分比相对于化合物浓度log的曲线,来确定IC50。
实施例E.在大鼠、猴和犬中的体内药物动力学
对于体内药物动力学实验,经静脉内或经由口腔管饲法将测试化合物施用于雄性史泊格多利大鼠(Sprague Dawley rat)、雄性米格鲁犬(beagle dog)或雌性和雄性食蟹猕猴(Cynomolgus monkey)。对于IV给药,使用10%二甲基乙酰胺(DMAC)于酸化盐水中的制剂以0.5至1mg/kg给与测试化合物,大鼠是经由IV推注,并且犬和猴分别为5分钟或10分钟IV输注。对于经口给与,使用含0.5%甲基纤维素的柠檬酸盐缓冲液(pH 3.5)中5%DMAC以1.0至3.0mg/kg给与测试化合物。在给药前和给药后多个时间点直至24小时,收集血液样品。使用EDTA作为抗凝剂,收集所有血液样品,并且进行离心,获得血浆样品。通过LC-MS法测定测试化合物的血浆浓度。通过标准非房室法,使用WinNonlin软件程序(7.0版,Pharsight公司),使用所测量的血浆浓度计算PK参数。
在大鼠和猴中,进行至多六种测试化合物的盒式给药,以获得初步PK参数。
实施例F.结果
在HTRF PD-1/PD-L1结合测定(实施例A)、SHP测定(实施例B)、NFAT测定(实施例C)和全血内化测定(实施例D)每一个中评定如实施例1-34中所例示的本公开的化合物。展示每个分析中观察到的数值范围的截止值。针对所测试化合物获得的结果显示于表1中。
表1
除本文所述内容以外,本领域的技术人员从以上描述将显而易见本发明的多种修改。同样意图此类修改在随附权利要求书的范围内。本申请中引用的每篇参考文献,包括不限于所有专利、专利申请和公布,均以引用的方式整体并入本文中。
Claims (41)
1.一种式(I’)化合物,
或其药学上可接受的盐或立体异构体,其中:
环A为氮杂环丁烷基、吡咯烷基或哌啶基;
X1为CH或N;
R1为甲基或卤基;
R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、OH、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基或4至6元杂环烷基-C1-2烷基-,其中所述4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各具有一或两个选自O和N的杂原子作为环原子,并且其中R2的所述C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代;
R3选自(R)-3-羟基-3-甲基吡咯烷-1-基、(S)-3-羟基-3-甲基吡咯烷-1-基、(R)-3-羟基吡咯烷-1-基、(S)-3-羟基吡咯烷-1-基、(R)-2-羟基-2-甲基-乙基氨基、(S)-2-羟基-2-甲基-乙基氨基、(R)-2-羟基-1-甲基-乙基氨基和(S)-2-羟基-1-甲基-乙基氨基;并且
R4为H或C1-3烷基;并且
R5为C(O)OH、C(O)N(CH3)2、C(O)NH(CH3)或C(O)NH(CH2)2C(O)OH。
2.一种式(I)化合物,
或其药学上可接受的盐或立体异构体,其中:
环A为氮杂环丁烷基、吡咯烷基或哌啶基;
X1为CH或N;
R1为甲基或卤基;
R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、OH、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基或4至6元杂环烷基-C1-2烷基-,其中所述4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各具有一或两个选自O和N的杂原子作为环原子,并且其中R2的所述C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、-NH-C1-4烷基、-N(C1-4烷基)2、4至6元杂环烷基和4至6元杂环烷基-C1-2烷基-各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代;
R3选自(R)-3-羟基-3-甲基吡咯烷-1-基、(S)-3-羟基-3-甲基吡咯烷-1-基、(R)-3-羟基吡咯烷-1-基、(S)-3-羟基吡咯烷-1-基、(R)-2-羟基-2-甲基-乙基氨基、(S)-2-羟基-2-甲基-乙基氨基、(R)-2-羟基-1-甲基-乙基氨基和(S)-2-羟基-1-甲基-乙基氨基;并且
R4为H或C1-3烷基。
3.如权利要求1或2所述的化合物,或其药学上可接受的盐或立体异构体,其中环A为吡咯烷基。
4.如权利要求1或2所述的化合物,或其药学上可接受的盐或立体异构体,其中环A为哌啶基。
8.如权利要求1-7中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中X1为N。
9.如权利要求1-7中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中X1为CH。
10.如权利要求1-9中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R1为CH3或Cl。
11.如权利要求1-9中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R1为CH3。
12.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为C1-4烷基、C1-4烷氧基、C1-4卤基烷基、C1-4卤基烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、OH、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基或哌啶-1-基甲基,其中R2的所述C1-4烷基、C1-4烷氧基、C3-6环烷基、C3-6环烷基-C1-2烷基-、-NH-C1-4烷基、-N(C1-4烷基)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基和哌啶-1-基甲基各任选地经1个或2个独立地选自卤基、CN和OH的取代基取代。
13.如权利要求12所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为甲基、乙基、异丙基、甲氧基、乙氧基、CF3、CHF2、CFH2、OCF3、OCHF2、OCH2F、环丙基、环丁基、环己基、环丙基甲基、环丁基甲基、环己基甲基、OH、NH2、NHCH3、N(CH3)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基或哌啶-1-基甲基,其中R2的所述甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环己基、环丙基甲基、环丁基甲基、环己基甲基、NHCH3、N(CH3)2、1-氮杂环丁烷基、氮杂环丁烷-1-基甲基、1-吡咯烷基、吡咯烷-1-基甲基、1-哌啶基和哌啶-1-基甲基各任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。
14.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为C1-4烷基或C1-4卤基烷基,所述每个基团任选地经1个或2个独立地选自F、Cl、Br、CN和OH的取代基取代。
15.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为C1-4烷基或C1-4卤基烷基。
16.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为CH3、CF3、CHF2、CH(CH3)2、NH2、环丙基或CH2OH。
17.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为CH3、CF3、CHF2或CH(CH3)2。
18.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为CH3。
19.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为CF3或CHF2。
20.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为CH(CH3)2。
21.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为NH2。
22.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为环丙基。
23.如权利要求1-11中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R2为CH2OH。
24.如权利要求1-23中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R3为(R)-3-羟基-3-甲基吡咯烷-1-基或(S)-3-羟基-3-甲基吡咯烷-1-基。
25.如权利要求1-23中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R3为(R)-3-羟基吡咯烷-1-基或(S)-3-羟基吡咯烷-1-基。
26.如权利要求1-23中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R3为(R)-2-羟基-2-甲基-乙基氨基或(S)-2-羟基-2-甲基-乙基氨基。
27.如权利要求1-23中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R3为(R)-2-羟基-1-甲基-乙基氨基或(S)-2-羟基-1-甲基-乙基氨基。
28.如权利要求1-27中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R4为H或CH3。
29.如权利要求1-27中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R4为H。
30.如权利要求1-27中任一项所述的化合物,或其药学上可接受的盐或立体异构体,其中R4为CH3。
35.如权利要求1所述的化合物,其中所述化合物选自:
(R)-1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(S)-1-((7-氰基-2-(3′-(7-((3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(S)-1-((7-氰基-2-(3′-(7-((1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(S)-1-((7-氰基-2-(3′-(7-((2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((S)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((S)-1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((S)-2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((S)-3-羟基-3-甲基吡咯烷-1-基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((S)-1-羟基丙烷-2-基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((S)-2-羟基丙基氨基)甲基)-2-甲基吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(7-((3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;和
(R)-1-((7-氰基-2-(3′-(7-(((R)-3-羟基吡咯烷-1-基)甲基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸,
或其药学上可接受的盐或立体异构体。
36.如权利要求1所述的化合物,其中所述化合物选自:
(S)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(S)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-4-甲基哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-N,N-二甲基哌啶-4-甲酰胺;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-N-甲基哌啶-4-甲酰胺;
(R)-3-(1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酰胺基)丙酸;
(R)-1-((7-氰基-2-(3′-(2-环丙基-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;
(R)-1-((2-(3′-(2-氨基-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)-7-氰基苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(S)-1-((7-氰基-2-(3′-(2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(2-(羟基甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)哌啶-4-甲酸;
(R)-1-((7-氰基-2-(3′-(3-(((R)-3-羟基吡咯烷-1-基)甲基)-6-甲基-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)吡咯烷-3-甲酸;和
(R)-1-((7-氰基-2-(3′-(6-(二氟甲基)-3-(((R)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基氨基)-2,2′-二甲基联苯-3-基)苯并[d]噁唑-5-基)甲基)-3-甲基吡咯烷-3-甲酸,
或其药学上可接受的盐或立体异构体。
37.一种药物组合物,所述药物组合物包含如权利要求1-36中任一项所述的化合物或其药学上可接受的盐或立体异构体和药学上可接受的赋形剂或载体。
38.一种抑制PD-1/PD-L1相互作用的方法,所述方法包括向患者施用如权利要求1-36中任一项所述的化合物或其药学上可接受的盐或立体异构体。
39.一种治疗与PD-1/PD-L1相互作用的抑制相关的疾病或病症的方法,所述方法包括向有需要的患者施用治疗有效量的如权利要求1-36中任一项所述的化合物或其药学上可接受的盐或立体异构体。
40.如权利要求39所述的方法,其中所述疾病或病症为感染性疾病、炎症、自身免疫性疾病、癌症或神经变性病症。
41.一种增强、刺激和/或增加患者中的免疫反应的方法,所述方法包括向有需要的患者施用治疗有效量的如权利要求1-36中任一项所述的化合物或其药学上可接受的盐或立体异构体。
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