CN109996797B - 作为乳酸脱氢酶的抑制剂的1h-吡唑-1-基-噻唑及其使用方法 - Google Patents
作为乳酸脱氢酶的抑制剂的1h-吡唑-1-基-噻唑及其使用方法 Download PDFInfo
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- CN109996797B CN109996797B CN201780052447.5A CN201780052447A CN109996797B CN 109996797 B CN109996797 B CN 109996797B CN 201780052447 A CN201780052447 A CN 201780052447A CN 109996797 B CN109996797 B CN 109996797B
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- fluoro
- pyrazol
- sulfamoylbenzyl
- thiazole
- cyclopropylmethyl
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- 238000000034 method Methods 0.000 title abstract description 37
- 102000003855 L-lactate dehydrogenase Human genes 0.000 title abstract description 16
- 108700023483 L-lactate dehydrogenases Proteins 0.000 title abstract description 16
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- FEMRJHRHQBPLPI-UHFFFAOYSA-N 2-pyrazol-1-yl-1,3-thiazole Chemical class C1=CC=NN1C1=NC=CS1 FEMRJHRHQBPLPI-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 201000011510 cancer Diseases 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 6
- 230000004761 fibrosis Effects 0.000 claims abstract description 6
- -1 5- (cyclopropylmethyl) -4- (3-fluoro-4-sulfamoylbenzyl) -3- (3- ((5-methylthiophen-2-yl) ethynyl) phenyl) -1H-pyrazol-1-yl Chemical group 0.000 claims description 84
- HMVYYTRDXNKRBQ-UHFFFAOYSA-N 1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC=N1 HMVYYTRDXNKRBQ-UHFFFAOYSA-N 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
- 229910052736 halogen Chemical group 0.000 claims description 21
- 150000002367 halogens Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 150000003254 radicals Chemical class 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000002246 antineoplastic agent Substances 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000003003 spiro group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- JTDOQROGALOTHV-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3,4-difluorophenyl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1=C(C2=C(F)C=CC(C3=NN(C(CC4CC4)=C3CC3=CC=C(S(=O)(=O)N)C(F)=C3)C=3SC=C(N=3)C(=O)O)=C2)C=C(F)C(F)=C1 JTDOQROGALOTHV-UHFFFAOYSA-N 0.000 claims description 5
- KWSZFGQAKJYXKP-UHFFFAOYSA-N 2-[3-[3-(tert-butylcarbamoyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound CC(C)(C)NC(=O)C1=C(F)C=CC(=C1)C1=NN(C2=NC(=CS2)C(O)=O)C(CC2CC2)=C1CC1=CC(F)=C(C=C1)S(N)(=O)=O KWSZFGQAKJYXKP-UHFFFAOYSA-N 0.000 claims description 4
- ATTZHOSTJBBUDW-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(2-propan-2-yl-2,6-diazaspiro[3.3]heptan-6-yl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)N1CC2(C1)CN(C2)C(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F ATTZHOSTJBBUDW-UHFFFAOYSA-N 0.000 claims description 4
- DRKIXPJVJMUXDS-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(pyrrolidine-1-carbonyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)C(=O)N1CCCC1)CC1=CC(=C(C=C1)S(N)(=O)=O)F DRKIXPJVJMUXDS-UHFFFAOYSA-N 0.000 claims description 4
- LXKPHHHUCRWTQC-UHFFFAOYSA-O CC1=CC=C(S1)C#CC1=CC=CC(=C1)C1=NN(C2=NC(=CS2)B(O)O)C(CC2CC2)=C1CC1=CC(F)=C(C=C1)[SH+](N)=O Chemical compound CC1=CC=C(S1)C#CC1=CC=CC(=C1)C1=NN(C2=NC(=CS2)B(O)O)C(CC2CC2)=C1CC1=CC(F)=C(C=C1)[SH+](N)=O LXKPHHHUCRWTQC-UHFFFAOYSA-O 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 claims description 4
- UFPAYOAGLFERRT-UHFFFAOYSA-O CC1=CC=C(S1)C#CC1=CC=CC(=C1)C1=NN(C2=NC(=CS2)C(O)=O)C(CC2CC2)=C1CC1=CC=C(C(F)=C1)[SH+](N)=O Chemical compound CC1=CC=C(S1)C#CC1=CC=CC(=C1)C1=NN(C2=NC(=CS2)C(O)=O)C(CC2CC2)=C1CC1=CC=C(C(F)=C1)[SH+](N)=O UFPAYOAGLFERRT-UHFFFAOYSA-O 0.000 claims description 3
- SZORBDBPCWOMAT-UHFFFAOYSA-O CC1=CC=C(S1)C1CC1C1=CC=CC(=C1)C1=NN(C(CC2CC2)=C1CC1=CC(F)=C(C=C1)[SH+](N)=O)C1=NC(=CS1)C(O)=O Chemical compound CC1=CC=C(S1)C1CC1C1=CC=CC(=C1)C1=NN(C(CC2CC2)=C1CC1=CC(F)=C(C=C1)[SH+](N)=O)C1=NC(=CS1)C(O)=O SZORBDBPCWOMAT-UHFFFAOYSA-O 0.000 claims description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 3
- LTIVLMCQANXDBA-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(4,4-dimethylcyclohexen-1-yl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C=1CCC(CC=1)(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F LTIVLMCQANXDBA-UHFFFAOYSA-N 0.000 claims 4
- WSSIXFDCAWCQAH-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(4-methoxycyclohexen-1-yl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound COC1CCC(=CC1)C1=CC(=CC=C1F)C1=NN(C(CC2CC2)=C1CC1=CC(F)=C(C=C1)S(N)(=O)=O)C1=NC(=CS1)C(O)=O WSSIXFDCAWCQAH-UHFFFAOYSA-N 0.000 claims 4
- DCICOUMGAZARHK-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(4-methylcyclohexen-1-yl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C=1CCC(CC=1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F DCICOUMGAZARHK-UHFFFAOYSA-N 0.000 claims 4
- HLRYZGDLHKQTNR-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(6-methylcyclohexen-1-yl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C=1C(CCCC=1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F HLRYZGDLHKQTNR-UHFFFAOYSA-N 0.000 claims 4
- GYHPBZVCJVWUBH-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[4-fluoro-3-[4-(trifluoromethyl)cyclohexen-1-yl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound NS(=O)(=O)C1=C(F)C=C(CC2=C(CC3CC3)N(N=C2C2=CC=C(F)C(=C2)C2=CCC(CC2)C(F)(F)F)C2=NC(=CS2)C(O)=O)C=C1 GYHPBZVCJVWUBH-UHFFFAOYSA-N 0.000 claims 4
- JWKQPDFRLKNFHO-UHFFFAOYSA-O CC1=CC=C(S1)C2CC(C2)C3=CC=CC(=C3)C4=NN(C(=C4CC5=CC(=C(C=C5)[SH+](=O)N)F)CC6CC6)C7=NC(=CS7)C(=O)O Chemical compound CC1=CC=C(S1)C2CC(C2)C3=CC=CC(=C3)C4=NN(C(=C4CC5=CC(=C(C=C5)[SH+](=O)N)F)CC6CC6)C7=NC(=CS7)C(=O)O JWKQPDFRLKNFHO-UHFFFAOYSA-O 0.000 claims 4
- KVMWANVTJDRIDI-UHFFFAOYSA-N 2-[3-(3-acetyl-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(C)(=O)C=1C=C(C=CC=1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O KVMWANVTJDRIDI-UHFFFAOYSA-N 0.000 claims 2
- XSZHUPLCBZMQNK-UHFFFAOYSA-N 2-[3-(3-benzamido-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(C1=CC=CC=C1)(=O)NC=1C=C(C=CC=1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O XSZHUPLCBZMQNK-UHFFFAOYSA-N 0.000 claims 2
- AEYQFZKMMAJQAZ-UHFFFAOYSA-N 2-[3-(3-but-1-ynyl-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(#CCC)C=1C=C(C=CC=1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O AEYQFZKMMAJQAZ-UHFFFAOYSA-N 0.000 claims 2
- ZQHDGXQMMOIECU-UHFFFAOYSA-N 2-[3-[3-(1H-benzimidazol-2-yl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound N1C(=NC2=C1C=CC=C2)C=1C=C(C=CC=1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O ZQHDGXQMMOIECU-UHFFFAOYSA-N 0.000 claims 2
- JFHLWRXRXVAWGU-UHFFFAOYSA-N 2-[3-[3-(3-chloro-4-methoxyphenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC=1C=C(C=CC=1OC)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O JFHLWRXRXVAWGU-UHFFFAOYSA-N 0.000 claims 2
- VFRURTXMKPAJER-UHFFFAOYSA-N 2-[3-[3-(3-chloro-4-methoxyphenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC=1C=C(C=CC=1OC)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O VFRURTXMKPAJER-UHFFFAOYSA-N 0.000 claims 2
- QLVMKYZRTQCAQW-UHFFFAOYSA-N 2-[3-[3-(3-chlorophenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC=1C=C(C=CC=1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O QLVMKYZRTQCAQW-UHFFFAOYSA-N 0.000 claims 2
- VTWRHUVLDIIOKA-UHFFFAOYSA-N 2-[3-[3-(3-chlorophenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC=1C=C(C=CC=1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O VTWRHUVLDIIOKA-UHFFFAOYSA-N 0.000 claims 2
- AGLCAMWDTDFLAD-UHFFFAOYSA-N 2-[3-[3-(3-cyanophenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(#N)C=1C=C(C=CC=1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O AGLCAMWDTDFLAD-UHFFFAOYSA-N 0.000 claims 2
- BTUWCLJGHJFCFX-UHFFFAOYSA-N 2-[3-[3-(3-tert-butylphenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(C)(C)(C)C=1C=C(C=CC=1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O BTUWCLJGHJFCFX-UHFFFAOYSA-N 0.000 claims 2
- KZSIREZSBRFYSI-UHFFFAOYSA-N 2-[3-[3-(4-chloro-3-fluorophenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=C(C=C(C=C1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O)F KZSIREZSBRFYSI-UHFFFAOYSA-N 0.000 claims 2
- MZJCNMXGCRFMJW-UHFFFAOYSA-N 2-[3-[3-(4-chloro-3-fluorophenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=C(C=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O)F MZJCNMXGCRFMJW-UHFFFAOYSA-N 0.000 claims 2
- LNVSGWLJBYRGSE-UHFFFAOYSA-N 2-[3-[3-(4-chloro-3-methylphenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=C(C=C(C=C1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O)C LNVSGWLJBYRGSE-UHFFFAOYSA-N 0.000 claims 2
- FHVKJZZQLBPYJU-UHFFFAOYSA-N 2-[3-[3-(4-chloro-3-methylphenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=C(C=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O)C FHVKJZZQLBPYJU-UHFFFAOYSA-N 0.000 claims 2
- UGINMIXQQIABOZ-UHFFFAOYSA-N 2-[3-[3-(4-chlorophenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=CC=C(C=C1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O UGINMIXQQIABOZ-UHFFFAOYSA-N 0.000 claims 2
- UPGVPGAQOISYHW-UHFFFAOYSA-N 2-[3-[3-(4-chlorophenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=CC=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O UPGVPGAQOISYHW-UHFFFAOYSA-N 0.000 claims 2
- ZTRNNCWPBDVQFO-UHFFFAOYSA-N 2-[3-[3-(4-cyanophenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(#N)C1=CC=C(C=C1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O ZTRNNCWPBDVQFO-UHFFFAOYSA-N 0.000 claims 2
- MOBDQQTUXPNFNU-UHFFFAOYSA-N 2-[3-[3-(4-cyanophenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(#N)C1=CC=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O MOBDQQTUXPNFNU-UHFFFAOYSA-N 0.000 claims 2
- MTPXJNQHCYQXPE-UHFFFAOYSA-N 2-[3-[3-(4-cyclobutylphenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CCC1)C1=CC=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O MTPXJNQHCYQXPE-UHFFFAOYSA-N 0.000 claims 2
- TZHUTYPHUZZXHC-UHFFFAOYSA-N 2-[3-[3-(4-cyclopropyl-3-fluorophenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O)F TZHUTYPHUZZXHC-UHFFFAOYSA-N 0.000 claims 2
- KLHQZYNCWMSBAI-UHFFFAOYSA-N 2-[3-[3-(4-tert-butylphenyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=CC(=CC=C1F)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O KLHQZYNCWMSBAI-UHFFFAOYSA-N 0.000 claims 2
- ZLTHHRYZEIGEGY-UHFFFAOYSA-N 2-[3-[3-(4-tert-butylphenyl)phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O ZLTHHRYZEIGEGY-UHFFFAOYSA-N 0.000 claims 2
- ZPBZCEVOIKPIHW-UHFFFAOYSA-N 2-[3-[3-(cyclohexen-1-yl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C=1CCCCC=1)CC1=CC(=C(C=C1)S(N)(=O)=O)F ZPBZCEVOIKPIHW-UHFFFAOYSA-N 0.000 claims 2
- QBGLDVCNOMGNAC-UHFFFAOYSA-N 2-[3-[3-(tert-butylcarbamoyl)phenyl]-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C(C)(C)(C)NC(=O)C=1C=C(C=CC=1)C1=NN(C(=C1CC1=CC=C(C=C1)S(N)(=O)=O)CC1CC1)C=1SC=C(N=1)C(=O)O QBGLDVCNOMGNAC-UHFFFAOYSA-N 0.000 claims 2
- ADWCKXIAWARNSR-UHFFFAOYSA-N 2-[3-[3-[2-(5-chlorothiophen-2-yl)ethynyl]phenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound ClC1=CC=C(S1)C#CC=1C=C(C=CC=1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O ADWCKXIAWARNSR-UHFFFAOYSA-N 0.000 claims 2
- XIRSNTPLNHWWPT-UHFFFAOYSA-N 2-[5-(1-cyclopropylethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-[2-(5-methylthiophen-2-yl)ethynyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C(C)C1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=CC=C1)C#CC=1SC(=CC=1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F XIRSNTPLNHWWPT-UHFFFAOYSA-N 0.000 claims 2
- FXRDUWPHCZUIHF-UHFFFAOYSA-N 2-[5-(2-cyclopropylpropan-2-yl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-[2-(5-methylthiophen-2-yl)ethynyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C(C)(C)C1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=CC=C1)C#CC=1SC(=CC=1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F FXRDUWPHCZUIHF-UHFFFAOYSA-N 0.000 claims 2
- JBKNLRLPIZKEHA-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-(4-fluoro-3-spiro[2.5]oct-6-en-6-ylphenyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)C1=CCC2(CC2)CC1)CC1=CC(=C(C=C1)S(N)(=O)=O)F JBKNLRLPIZKEHA-UHFFFAOYSA-N 0.000 claims 2
- AQKDZULHWBNLPJ-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(2,3-dihydro-1H-inden-5-yl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)C=1C=C2CCCC2=CC=1)CC1=CC(=C(C=C1)S(N)(=O)=O)F AQKDZULHWBNLPJ-UHFFFAOYSA-N 0.000 claims 2
- KECQWABAINQEGE-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3,5-dichlorophenyl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC(=C1)Cl)Cl)CC1=CC(=C(C=C1)S(N)(=O)=O)F KECQWABAINQEGE-UHFFFAOYSA-N 0.000 claims 2
- FIRYYXPTJWEZEO-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3,5-difluorophenyl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC(=C1)F)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F FIRYYXPTJWEZEO-UHFFFAOYSA-N 0.000 claims 2
- ARICFHHVPLAWQC-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3,5-difluorophenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C=CC=1)C1=CC(=CC(=C1)F)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F ARICFHHVPLAWQC-UHFFFAOYSA-N 0.000 claims 2
- DDNUJBYWAKUOTI-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3,5-dimethoxyphenyl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC(=C1)OC)OC)CC1=CC(=C(C=C1)S(N)(=O)=O)F DDNUJBYWAKUOTI-UHFFFAOYSA-N 0.000 claims 2
- ZBDVFGUFYPPXRH-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3,5-dimethylphenyl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC(=C1)C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F ZBDVFGUFYPPXRH-UHFFFAOYSA-N 0.000 claims 2
- KZCXZNZXEVGTBZ-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3-ethyl-4-methoxyphenyl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=C(C=C1)OC)CC)CC1=CC(=C(C=C1)S(N)(=O)=O)F KZCXZNZXEVGTBZ-UHFFFAOYSA-N 0.000 claims 2
- FFIWYRXKAFUTCN-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3-ethyl-4-methoxyphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound CCC1=C(OC)C=CC(=C1)C1=CC(=CC=C1)C1=NN(C2=NC(=CS2)C(O)=O)C(CC2CC2)=C1CC1=CC(F)=C(C=C1)S(N)(=O)=O FFIWYRXKAFUTCN-UHFFFAOYSA-N 0.000 claims 2
- PJFDETIPRSZSRM-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(3-fluoro-4-methylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C=CC=1)C1=CC(=C(C=C1)C)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F PJFDETIPRSZSRM-UHFFFAOYSA-N 0.000 claims 2
- SOJQTDIBDMTZJT-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(4,4-difluorocyclohexen-1-yl)-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C=1CCC(CC=1)(F)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F SOJQTDIBDMTZJT-UHFFFAOYSA-N 0.000 claims 2
- MWFSDCSVJBEDKQ-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-(4-cyclopropylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C1=CC=C(C=C1)C1=CC(=CC=C1)C1=NN(C(=C1CC1=CC(=C(C=C1)S(N)(=O)=O)F)CC1CC1)C=1SC=C(N=1)C(=O)O MWFSDCSVJBEDKQ-UHFFFAOYSA-N 0.000 claims 2
- QAFHBOUWRGDMHW-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-[3-(dimethylamino)phenyl]-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC=C1)N(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F QAFHBOUWRGDMHW-UHFFFAOYSA-N 0.000 claims 2
- BESNLORQPDQSPM-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-[4-(dimethylamino)phenyl]-4-fluorophenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC=C(C=C1)N(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F BESNLORQPDQSPM-UHFFFAOYSA-N 0.000 claims 2
- LINSNRHGOBQTNQ-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[3-[4-(dimethylamino)phenyl]phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C=CC=1)C1=CC=C(C=C1)N(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F LINSNRHGOBQTNQ-UHFFFAOYSA-N 0.000 claims 2
- AKDOPYTZJPLCET-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(1H-imidazol-2-yl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)C=1NC=CN=1)CC1=CC(=C(C=C1)S(N)(=O)=O)F AKDOPYTZJPLCET-UHFFFAOYSA-N 0.000 claims 2
- JKGSLSHYHSJXTR-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(1H-inden-2-yl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)C=1CC2=CC=CC=C2C=1)CC1=CC(=C(C=C1)S(N)(=O)=O)F JKGSLSHYHSJXTR-UHFFFAOYSA-N 0.000 claims 2
- WISPUGCBGDEBHD-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(3-fluoro-4-methylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=C(C=C1)C)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F WISPUGCBGDEBHD-UHFFFAOYSA-N 0.000 claims 2
- GWBDMWZDPJWBLA-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(3-fluorophenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound NS(=O)(=O)c1ccc(Cc2c(CC3CC3)n(nc2-c2ccc(F)c(c2)-c2cccc(F)c2)-c2nc(cs2)C(O)=O)cc1F GWBDMWZDPJWBLA-UHFFFAOYSA-N 0.000 claims 2
- RLDGSILHRATEJR-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(3-methylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC=C1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F RLDGSILHRATEJR-UHFFFAOYSA-N 0.000 claims 2
- PHKMDVMAELVNRO-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(3-propan-2-ylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=CC=C1)C(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F PHKMDVMAELVNRO-UHFFFAOYSA-N 0.000 claims 2
- WFLKHKDJJJSAIT-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(4-fluoro-3-methylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=C(C=C1)F)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F WFLKHKDJJJSAIT-UHFFFAOYSA-N 0.000 claims 2
- KTDSTZDBDDTKRQ-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(4-methoxy-3-methylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC(=C(C=C1)OC)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F KTDSTZDBDDTKRQ-UHFFFAOYSA-N 0.000 claims 2
- JVBHCRGWZLXWFU-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(4-propan-2-ylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC=C(C=C1)C(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F JVBHCRGWZLXWFU-UHFFFAOYSA-N 0.000 claims 2
- IOBPUYATXHZELK-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-(3-propan-2-ylphenyl)phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C=CC=1)C1=CC(=CC=C1)C(C)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F IOBPUYATXHZELK-UHFFFAOYSA-N 0.000 claims 2
- JGUCYBDFJJQXKA-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-(4-methoxy-3-methylphenyl)phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound COC1=C(C)C=C(C=C1)C1=CC(=CC=C1)C1=NN(C2=NC(=CS2)C(O)=O)C(CC2CC2)=C1CC1=CC(F)=C(C=C1)S(N)(=O)=O JGUCYBDFJJQXKA-UHFFFAOYSA-N 0.000 claims 2
- YIWWBEONXCOSIN-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-(4-methylphenyl)phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C=CC=1)C1=CC=C(C=C1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F YIWWBEONXCOSIN-UHFFFAOYSA-N 0.000 claims 2
- GCRRCAUFYPHJQP-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-(4-propan-2-ylphenyl)phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound CC(C)C1=CC=C(C=C1)C1=CC(=CC=C1)C1=NN(C2=NC(=CS2)C(O)=O)C(CC2CC2)=C1CC1=CC(F)=C(C=C1)S(N)(=O)=O GCRRCAUFYPHJQP-UHFFFAOYSA-N 0.000 claims 2
- MNZKJKNWHBEJRT-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-(5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound NS(=O)(=O)C1=C(F)C=C(CC2=C(CC3CC3)N(N=C2C2=CC(=CC=C2)C2=CC3=C(CCCC3)C=C2)C2=NC(=CS2)C(O)=O)C=C1 MNZKJKNWHBEJRT-UHFFFAOYSA-N 0.000 claims 2
- NISXVMZQMROEAX-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-[2-(3-methylthiophen-2-yl)ethynyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=CC=C1)C#CC=1SC=CC=1C)CC1=CC(=C(C=C1)S(N)(=O)=O)F NISXVMZQMROEAX-UHFFFAOYSA-N 0.000 claims 2
- IISQVTDZRGLKFH-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-[4-(2,2,2-trifluoroethyl)phenyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C=CC=1)C1=CC=C(C=C1)CC(F)(F)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F IISQVTDZRGLKFH-UHFFFAOYSA-N 0.000 claims 2
- CBGIAHOSHFLDPJ-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[4-fluoro-3-(5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=C(C=C1)F)C1=CC=2CCCCC=2C=C1)CC1=CC(=C(C=C1)S(N)(=O)=O)F CBGIAHOSHFLDPJ-UHFFFAOYSA-N 0.000 claims 2
- WBJPOGLPMUBIBW-UHFFFAOYSA-N 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[4-fluoro-3-[4-(trifluoromethyl)phenyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)CC1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C=1C=C(C(=CC=1)F)C1=CC=C(C=C1)C(F)(F)F)CC1=CC(=C(C=C1)S(N)(=O)=O)F WBJPOGLPMUBIBW-UHFFFAOYSA-N 0.000 claims 2
- WOLPVXXSIOZPNT-UHFFFAOYSA-N 2-[5-(dicyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-[3-[2-(5-methylthiophen-2-yl)ethynyl]phenyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C(C1=C(C(=NN1C=1SC=C(N=1)C(=O)O)C1=CC(=CC=C1)C#CC=1SC(=CC=1)C)CC1=CC(=C(C=C1)S(N)(=O)=O)F)C1CC1 WOLPVXXSIOZPNT-UHFFFAOYSA-N 0.000 claims 2
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Abstract
本公开提供式(II)的化合物及其药用盐。变量例如n、R、R3、R10、X、Y和Z是在本文中限定的。这些化合物起到乳酸脱氢酶抑制剂的作用并且用于治疗癌症和纤维化。该化合物可以特别用于治疗其中出现从氧化磷酸化到糖酵解的代谢转化的癌症形式。本公开还提供含有该式的化合物的药物组合物和用于治疗患有其中出现从氧化磷酸化到糖酵解的代谢转化的癌症、纤维化或其它病症的患者的方法。
Description
相关申请的引证
本申请要求2016年6月29日提交的美国临时申请号62/356,065的优先权,其通过引证以其整体并入本文中。
背景技术
靶向在癌细胞代谢中涉及的酶的药剂提供了有吸引力的治疗途径,因为有可能优先针对癌症组织而非正常组织。尽管正常组织通常仅当氧气供应不足时使用糖酵解,但癌症组织严重依赖有氧糖酵解,而与氧气供应水平无关。这种性质被称为沃伯格(Warburg)效应(Vander Heidenet al.,Science,2009,324(5930):1029-1033)。在其中丙酮酸被转化成乳酸的糖酵解的最后步骤中涉及乳酸脱氢酶(LDH)。丙酮酸进入TCA(三羧酸)循环的速率降低和同时的乳酸产生的增加对肿瘤的生长和存活是至关重要的。LDH有两种不同的亚基,LDHA和LDHB,但这两种亚基都具有相同的活性位点,并催化丙酮酸到乳酸的转化。在癌症患者中,血清总乳酸脱氢酶(LDH5,LDHA亚基的四聚体;在糖酵解中涉及的主要LDH同工酶)水平经常增加,并且LDHA的基因上调。肿瘤细胞可以然后代谢乳酸作为能量来源。LDH的抑制导致线粒体呼吸的刺激作为补偿机制。LDH抑制预计降低细胞有效代谢葡萄糖的能力,并降低肿瘤细胞增殖和肿瘤生长。因此,抑制LDH活性的化合物具有开发抗癌疗法的潜力。
LDHA抑制剂先前是已知的。例如,棉酚(gossypol)是LDH的非选择性抑制剂,其阻断NADH的结合,其中LDHA和乳酸脱氢酶B(LDHB)的Ki分别为1.9和1.4μM(Doherty et al.,J.Clin.Invest.,2013,123(9):3685-3692)。Billiard et al.(Cancer and Metabolism,2013,1(19):1-17)报道了3-((3-氨甲酰基-7-(3,5-二甲基异噁唑-4-基)-6-甲氧基喹啉-4-基)氨基)苯甲酸的某些衍生物是LDH的有效抑制剂,并且对LDHA抑制的选择性比LDHB抑制多10至80倍。然而,发现所述抑制剂的体内生物利用度是差的。
鉴于上述情况,仍然需要提供新的LDH抑制剂,其具有用于治疗癌症的改进的效力、选择性和/或生物利用度。
发明内容
一种式(II)的化合物:
或其药用盐,其中:
X是氢或卤素;
Y是氢或C1-C2烷基;
Z是-CO2H、-CONH2、-CONH(CN)、-CONHSO2CH3、-CONH(OH)、-COCF3、CH(OH)CF3、-CH2OH或
-B(OH)2;
n是0、1、2或3;
R在每次出现时独立地选自卤素、羟基、C1-C4烷基、C1-C4烷氧基;
R3是-C(O)CH3、取代或未取代的苯基基团、取代或未取代的茚满基基团、取代或未取代的四氢萘基基团、取代或未取代的环己烯基基团、取代或未取代的茚基基团、取代或未取代的2,6-二氮杂螺[3.3]庚基基团、取代或未取代的咪唑基基团、取代或未取代的二氢呋喃基基团、取代或未取代的吡咯烷基基团、取代或未取代的吡啶基基团、取代或未取代的嘧啶基基团、取代或未取代的噻唑基基团、取代或未取代的螺[2.5]辛-5-烯基、取代或未取代的苯并咪唑基基团或-L-Q,其中L是亚乙炔基基团,亚乙烯基基团、亚环丙基基团或亚环丁基基团,和其中Q是氢、C1-C5烷基基团、取代或未取代的具有1至3个选自N、O和S的杂原子的五元杂环、-NR5C(O)R4、-C(O)NR5R6,其中R4是氢、C1-C5烷基或取代或未取代的苯基,R5和R6各自独立地是氢或C1-C5烷基,其中R5和R6可选地形成环,和其中R4和R5可选地形成环;和
R10是(环丙基)C0-C4烷基,环丙基可选地被甲基或环丙基取代,或者以螺取向稠合到环丙基基团上。
已经发现,由式(II)限定的化合物在抑制乳酸脱氢酶A(LDHA)和/或乳酸脱氢酶B(LDHB)活性方面是有效的,从而使该化合物在治疗癌症方面有效。还已经发现,LDHA和/或LDHB的抑制剂对于治疗纤维化(包括特发性肺纤维化)是有用的。LDH抑制剂被指出用于涉及从氧化磷酸化到糖酵解的代谢转化的病理。因此,本公开提供了治疗涉及代谢转化为糖酵解的病理的方法,包括给患有这样的公开的患者给予本公开的化合物。代谢转化为糖酵解经常发生在癌细胞中。预见到的是,式(II)化合物对于治疗癌症是期望的,因为该化合物,相对于其它脱氢酶(例如GAPDH和PHGDH),对LDHA和/或LDHB是选择性的,和/或具有对于抗癌剂理想的溶解度、渗透性和/或药代动力学分布(例如ADME)。
因此,本公开进一步提供一种治疗患者中的癌症的方法,包括向患者给予有效量的式(II)化合物或其前药或药用盐。
在另一个实施方式中,本公开提供治疗患者中的纤维化(包括特发性肺纤维化)的方法,包括向患者给予有效量的式(II)化合物或其前药或药用盐。
还提供治疗具有对抗癌剂有抗性的癌细胞的患者的方法,包括向患者给予有效量的式(II)化合物或其前药或药用盐,以及该抗癌剂,从而该化合物、其前药或药用盐使癌细胞对该抗癌剂再敏化。
本发明提供抑制细胞中乳酸脱氢酶A(LDHA)和/或乳酸脱氢酶B活性(LDHB)的方法,包括向细胞给予式(II)化合物或其前药或药用盐。
具体实施方式
本发明提供式(I)的化合物
或其药用盐或前药。如下情况符合式(I)。
Ar1是可选地取代的包含至少一个5元或6元单环杂芳基的部分,该杂环芳基含有一个、两个或三个选自氮、氧和硫的杂原子。
U是芳基、-C(O)芳基、Het或-C(O)Het,其各自是可选地取代的,其中Het是包含杂环烷基的单环或二环部分,该杂环烷基含有至少两个双键和一个、两个或三个选自氮、氧和硫的杂原子。
R1独立地选自卤素、-CO2R4、-C(O)NR5R6、-(C1-C8烃基)、-C(O)NHOH、-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单或二环杂环)、-C(O)O-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单或二环杂环)、-P(O)(OH)2、-SO2(OH)、-B(OR13)(OR14)、-C(O)NHS(O)2Me和-SO2NR5R6,除卤素之外的R1各自是取代或未取代的。
R2独立地选自羟基、卤素、-CN、-NO2、C1-C8烃基、-O(C1-C8烃基)、-(C0-C4烃基)C3-C8环烷基、-O(C0-C4烃基)C3-C8环烷基、-(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C6-C12芳基、-(C0-C4烃基)C6-C12芳基、-O(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单和二环杂环)、-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单和二环杂环)、-P(O)(OH)2、-B(OR13)(OR14)、-SO2(OH)、-C(O)NHS(O)2Me和-SO2NR5R6,除卤素之外的R1各自是取代或未取代的。
V是芳基、杂芳基或杂环烷基,其各自被-(R2)n取代,其中杂芳基或杂环烷基是5元或6元单环部分,其含有一个、两个或三个选自氮、氧和硫的杂原子。
R2独立地选自羟基、卤素、-CN、-NO2、C1-C8烃基、-O(C1-C8烃基)、-(C0-C4烃基)C3-C8环烷基、-O(C0-C4烃基)C3-C8环烷基、-(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C6-C12芳基、-(C0-C4烃基)C6-C12芳基、-O(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)、-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)、-C(O)R4、-CO2R4、-C(O)NR5R6、-NR5C(O)R4、-(CH2)qNR5(SO2)R4、-(CH2)qNR5C(O)R4、-(CH2)qNR7C(O)NR5R6、-(CH2)qNR5R6、-(CH2)qSO2NR5R6、-(CH2)qSO2R4,C1-C8烃基、-O(C1-C8烃基)、-(C0-C4烃基)C3-C8环烷基、-O(C0-C4烃基)C3-C8环烷基、-(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C6-C12芳基、-(C0-C4烃基)C6-C12芳基、-O(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)、-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)各自是取代或未取代的。
R3独立地选自羟基、卤素、-CN、-NO2、-SF5、C1-C8烃基、-O(C1-C8烃基)、-(C0-C4烃基)C3-C8环烷基、-O(C0-C4烃基)C3-C8环烷基、-(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C6-C12芳基、-(C0-C4烃基)C6-C12芳基、-O(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)、-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)、-C(O)R4、-CO2R4、-C(O)NR5R6、-NR5C(O)R4、-(CH2)qNR5(SO2)R4、-(CH2)qNR5C(O)R4、-(CH2)qNR7C(O)NR5R6、-(CH2)qNR5R6、-(CH2)qSO2NR5R6、-(CH2)qSO2R4,C1-C8烃基、-O(C1-C8烃基)、-(C0-C4烃基)C3-C8环烷基、-O(C0-C4烃基)C3-C8环烷基、-(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C3-C8环烯基、-O(C0-C4烃基)C6-C12芳基、-(C0-C4烃基)C6-C12芳基、-O(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)、-(C0-C4烃基)(具有1至4个独立地选自N、O和S的杂原子的单环和二环杂环)各自是取代或未取代的;或者当W是苯基时,则两个R3部分和它们所连接的苯基基团形成萘基基团,其可选地被至少一个额外的R3部分取代。
每个R4、R5、R6、R7、R8和R9是相同或不同的,并且各自是氢、C1-C8烷基、C2-C8烯基、C3-C6环烷基、C6-C12芳基、杂芳基或杂环烷基。
每个R13和R14是相同或不同的,并且各自是氢、C1-C8烷基、C2-C8烯基、C3-C6环烷基、C6-C12芳基,其中R13和R14可选地彼此连接以形成环。
X是键、-CR8R9-、-NR5-、-CR8NR5-、-NR5CR8-、-NR5C(O)、-O-、-SO-、-SO2-或-S-。
m、n和q是相同或不同的,并且各自是0或1-5的整数;和p是0、1或2。
条件是,当Ar1是喹啉基时,则U不是嘧啶基;且当Ar1-U是2-(1H-吲哚-1-基)噻唑基时,则在吲哚基基团上3-位的X不是键或-CH2-,或者在吲哚基基团上3-位的W不是苯基,或者在吲哚基基团上3-位的R3不是苄基;并且当Ar1-U是2-(1H-吡唑-1-基)噻唑基时,则在吡唑基基团上3-位的W不是4-三氟甲基苯基或4-硝基苯基,或者在吡唑基基团上4-位的X不是键。
本公开包括式(II)的化合物或药用盐:
其中
X是氢或卤素;
Y是氢或C1-C2烷基;
Z是-CO2H、-CONH2、-CONH(CN)、-CONHSO2CH3、-CONH(OH)、-COCF3、CH(OH)CF3、-CH2OH或-B(OH)2;
n是0、1、2或3;
R在每次出现时独立地选自卤素、羟基、C1-C4烷基、C1-C4烷氧基;
R3是-C(O)CH3、取代或未取代的苯基基团、取代或未取代的茚满基基团、取代或未取代的四氢萘基基团、取代或未取代的环己烯基基团、取代或未取代的茚基基团、取代或未取代的2,6-二氮杂螺[3.3]庚基基团、取代或未取代的咪唑基基团、取代或未取代的二氢呋喃基基团、取代或未取代的吡咯烷基基团、取代或未取代的吡啶基基团、取代或未取代的嘧啶基基团、取代或未取代的噻唑基基团、取代或未取代的螺[2.5]辛-5-烯基;取代或未取代的苯并咪唑基基团或-L-Q,其中L是亚乙炔基基团,亚乙烯基基团、亚环丙基基团或亚环丁基基团,且其中Q是氢、C1-C5烷基基团、取代或未取代的具有1至3个选自N、O和S的杂原子的五元杂环、-NR5C(O)R4、-C(O)NR5R6,其中R4是氢、C1-C5烷基或取代或未取代的苯基,R5和R6各自独立地是氢或C1-C5烷基,其中R5和R6可选地形成环,和其中R4和R5可选地形成环;
R10是(环丙基)C1-C4烷基,环丙基可选地被甲基或环丙基取代,或者以螺取向稠合到环丙基基团上,或者R10是(环丙基)C1-C4烷基,其中C1-C4烷基被环丙基取代。
在式(II)中,X可以是氟、-氯、烷基或环烷基,并且可以在邻位或间位(相对于连接苯基的点)。本公开包括式(II)化合物和盐,其中X是氟并且在相对于连接苯基的点的间位。
可以取代R3的基团包括卤素、CHO、C1-C6烷基、C1-C6烷氧基、环丙基、环丁基、单和二(C1-C烷基胺)C0-C2烷基、C1-C2卤代烷基和C1-C2卤代烷氧基。
在式(II)中,R3可以是取代的苯基基团,被氟、氯、C1-C5烷基基团、-CF3、-CHF2、CH3O-、CH3CO-、-CN、-N(CH3)2或它们的组合取代。
在式(II)中,R3可以是-L-Q,并且Q是呋喃基、苯硫基、噁唑基、噻唑基或2,3-二氢呋喃基基团,R3各自可以是未取代的或被一个或多个取代基取代的,取代基在每次出现时独立地选自卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、二氟甲基、环丙基和环丁基。
在式(II)中,R3可以是被C1-C5烷基基团、-CF3或CH3O-取代的1-环己烯基团。
在式(II)中,R3可以是螺[2.5]辛-5-烯基基团。
在式(II)中,R3是顺式-亚乙烯基基团或反式-亚乙烯基基团。
在式(II)中,R3可以是被氟、氯、C1-C5烷基、-CHF2、-CF3或它们的组合取代的五元杂环。
在式(II)中,R3可以是下式的2,6-二氮杂螺[3.3]庚基基团
在式(II)中,R10可以是(环丙基)CH2-。
在式(II)中,R3可以是-L-Q,其中L是乙炔基基团且Q是五元杂芳基基团,其是未取代的或被一个或多个取代基取代的,取代基独立地选自卤素、C1-C5烷基、C1-C5烷氧基、-CHF2、-CF3、环丙基和环丁基。
在式(II)中,Q可以是五元杂芳基基团,其选自噻吩基、噻唑基、噁唑基和呋喃基,其各自是未取代的或被一个或多个取代基取代的,取代基独立地选自卤素、C1-C5烷基、C1-C5烷氧基、-CHF2、-CF3、环丙基和环丁基。
在式(II)中,R10可以是(环丙基)CH2-或(环丙基)CH2CH2-。
在式(II)中,Y可以是氢。
在式(II)中,Z可以是-COOH、-CH2OH或-CONH2。
式(II)化合物的变量的任何上述定义可以被组合,只要形成稳定的化合物,并且所有这样的组合都在本公开范围内。
本公开包括式(II)化合物和药用盐,其中
n是0;X是在间位的氟;Y是氢;Z是-COOH、-CH2OH或-CONH2;
R3是-L-Q,其中L是乙炔基基团且Q是五元杂芳基基团,其选自噻吩基、噻唑基、噁唑基和呋喃基,其各自是未取代的或被一个或多个取代基取代的,取代基独立地选自卤素、C1-C5烷基、C1-C5烷氧基、-CHF2、-CF3、环丙基和环丁基;并且
R10是(环丙基)C0-C4烷基。
式(II)可以包括下文中表7的如下化合物或它们的药用盐:
式(I)的化合物(包括式(Ia)的化合物)和式(II)化合物如下在表7中阐述为代表性实例。在本公开中还包括列举的化合物的前药和药用盐。
术语
在描述本发明的上下文中(尤其在如下权利要求书的上下文中)使用术语“一个”和“一种”和“该”和“至少一种”和类似指示词被解释为覆盖单数和复数二者,除非本文另有说明或与上下文明显矛盾。在列举的一个或多个项目之前使用术语“至少一种”(例如至少一种A和B)解释为指选自所列举的项目中的一个项目(A或B)或两个或更多个所列举项目的任何组合(A和B),除非在本文另有说明或与上下文明显矛盾。术语“包含”、“具有”、“包括”和“含有”解释为开放式术语(即,意思是“包括但不限于”),除非另外说明。本文中引述数值范围仅旨在用作单独提及落入该范围内的每个单独数值的速记方法,除非在本文中另有说明,并且每个单独值都被并入到本说明书中,就像它在本文中被单独引述一样。本文中描述的所有方法可以以任何合适的顺序实施,除非在本文中另有说明或与上下文明显矛盾。使用本文中提供的任何的和所有的实例或指示实例的语言(例如,“例如”)仅仅是为了更好地示例性说明本发明,而不对本发明的范围赋予限制,除非另外要求保护。说明书中的任何语言都不应被解释为表示任何未要求保护的要素对于本发明的实践是必不可以少的。
如本文中使用的术语“取代的”是在指定的原子或基团上的任一个或多个氢被选自所指出基团的基团替代,条件是不超出所指定的原子的正常价态。当取代基是氧代(即,=O)时,则在原子上的2个氢被替代。当氧代基团取代杂芳族部分时,所形成的分子有时可以采取互变异构形式。例如在2或4位被氧代基取代的吡啶基基团有时可以写作吡啶或羟基吡啶。只有取代基和/或变量的组合导致稳定的化合物或有用的合成中间体,这样的组合才是允许的。稳定的化合物或稳定的结构意味着化合物足够稳定,能够从反应混合物中分离出来并随后配制成有效的治疗剂。除非另外明确说明,取代基被命名为核心结构。例如,要理解的是,氨基烷基指连接该取代基到核心结构的点在烷基部分中,和烷基氨基指连接点是到氨基基团的氮的键。
可以在“取代的”或“可选地取代的”位置上存在的合适基团包括但不限于卤素(氟、氯、溴和碘);氰基;-OH;-CH2F,-CHF2,-CF3,硝基;具有1至约8个碳原子或1至约6个碳原子的直链、支链或环状烷基基团(包括环烷基和(环烷基)烷基基团);烯基和炔基基团,包括具有一个或多个不饱和键和2至约8个或2至约6个碳原子的基团;具有一个或多个氧键连和1至约8个或1至约6个碳原子的烷氧基基团;芳氧基,如苯氧基;烷硫基基团,包括具有一个或多个硫醚键连和1至约8个碳原子或1至约6个碳原子的那些,具有2至约8个碳原子的烷酰基基团。例如,可以在“取代的”或“可选地取代的”位置上存在的合适基团包括羟基、卤素、-CH2F、-CHF2、-CF3、氰基、烷基基团和烷氧基基团。两个谐烷基取代基(即,连接于相同碳原子的两个取代基)可以可选地形成环。这样的取代基团的非限制性实例是螺[2.5]辛基和螺[2.5]辛烯基基团。
在任何如上实施方式中,术语“烷基”意指含有例如约1至约8个碳原子,例如约1至约6个碳原子的直链或支链烷基取代基。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、正己基和类似基团。这个定义也应用于作为基团的一部分出现的任何“烷基”,例如在C3-C6环烷基烷基、羟基烷基、卤代烷基(例如单卤代烷基、二卤代烷基和三卤代烷基)、氰基烷基、氨基烷基、烷基氨基、二烷基氨基、芳基烷基等中。烷基可以是取代或未取代的,如本文中描述的。甚至在其中烷基是亚烷基链(例如,-(CH2)n-)的情况下,烷基基团也可以是取代或未取代的。取代的亚烷基链的实例包括-CF2-环丙基。
在任何如上实施方式中,术语“羟基”指基团-OH。
在任何如上实施方式中,术语“烷氧基”包括连接于二价氧的直链或支链烷基基团。烷基基团与本文中描述的相同。
在任何上述实施方式中,术语“卤”指选自氟、氯、溴和碘的卤素。
在本文中描述的任何实施方式中,本发明的化合物还可以作为前药提供,其是药物衍生物或药物前体化合物,其通常是非活性的或者是不完全活性的,直到其在体内通过正常代谢过程,如酯或酰胺形式的药物的水解而转化成活性药物。可以选择和使用前药替代母体药物,因为,例如,以其前药形式,与母体药物相比,其是更小毒性的,和/或可以具有更好的吸收、分布、代谢和排泄(ADME)特性,和类似特性。前药还可以用于改进药物如何与不是其预定目标的细胞或过程选择性地相互作用。例如,这种方法可以特别例如用于预防或减少不良反应,尤其是在癌症治疗中,该癌症治疗可能尤其倾向于具有严重的意外和不希望的副作用。
术语“前药”指化合物的衍生物,该衍生物当给予温血动物(例如人)时被转化为化合物(药物)。例如,本发明的衍生化合物的酶和/或化学水解裂解以如下方式发生:已证实的药物形式被释放,并且分离出的一个或多个部分保持无毒或被代谢,从而产生无毒代谢物。例如,羧酸基团可以被酯化,例如被甲基基团或乙基基团酯化,以产生酯。当向受试者给予酯时,酯被酶或非酶、还原、氧化或水解裂解以显露出阴离子基团。阴离子基团可以被如下部分(例如酰氧基甲基酯)酯化,部分被裂解以显露出中间体化合物,该中间体化合物随后分解以产生活性化合物。
前药可以在分离和纯化式(I)化合物(包括式(Ia)化合物)的过程中原位制备,或者通过将纯化的化合物与合适的衍生剂分开反应来制备。例如,羟基基团可以通过在催化剂存在下用羧酸处理而转化成酯。可裂解的醇前药部分的实例包括取代或未取代的、支链或非支链的烷基酯部分,例如乙基酯,烯基酯,二烷基氨基烷基酯,例如二甲氨基乙基酯,酰氨基烷基酯,酰氧基烷基酯(例如新戊酰氧基甲基酯),芳基酯,例如苯基酯,芳基烷基酯,例如苄基酯,其可选地例如被甲基、卤素或甲氧基取代基取代,芳基和芳基烷基酯,酰胺,烷基酰胺,二烷基酰胺和羟基酰胺。
在了解了本文公开内容的情况下,还将理解的是,本发明的化合物可以是前药的形式,并且这样的前药可以使用本领域普通技术人员公知的试剂和合成转化来制备。特定前药的有效性可以使用本领域普通技术人员公知的一种或多种分析方法(例如药代动力学、生物测定、体内功效研究和类似方法)测定。
更具体地,可以使用常规化学过程制备式(I)化合物(包括式(Ia)化合物)的前药。例如在式(I)化合物上的羟基取代基可以被以下取代:-CO-烷基、-CO2烷基、-CONH-烷基、-CO-烯基、-CO2-烯基、-CONH-烯基、-CO-芳基、-CO2-芳基、-CONH-芳基、-CO-杂环、-CO2-杂环、-CONH-杂环或-PO3H2。羟基的具体改性基团包括例如乙酰基、丙酰基、异丁酰基、新戊酰基、棕榈酰基、苯甲酰基、4-甲基苯甲酰基、二甲基氨甲酰基、二甲基氨基甲基羰基、磺基、丙氨酰基和富马酰基基团。
氨基基团可以被以下取代:-CO-烷基、-CO2-烷基、-CO-烯基、-CO2-烯基、-CO2-芳基、-CO-芳基、-CO-杂环、-CO2-杂环或-PO3H2。烷基、烯基、芳基和杂环部分可选地被以下取代:卤素、烷基、羟基、烷氧基、羧基、氨基、氨基酸残基、-PO3H2、-SO3H、-OPO3H2和-OSO3H。氨基的具体改性基团包括例如叔丁基、二十二烷酰基、新戊酰基甲氧基、丙氨酰基、己基氨甲酰基、戊基氨甲酰基、3-甲基硫代-1-(乙酰氨基)丙基羰基、1-磺基-1-(3-乙氧基-4-羟基苯基)甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基羰基、四氢呋喃基和吡咯烷基甲基。
羧基的适当改性基团包括例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊酰氧基甲基、羧甲基、二甲氨基甲基、1-(乙酰氧基)乙基、1-(乙氧基羰基氧基)乙基、1-(异丙氧基羰基氧基)乙基、1-(环己氧基羰基氧基)乙基、羧甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基、苄基、苯基、邻甲苯基、吗啉代乙基、N,N-二乙基氨甲酰基甲基和苯二甲酰基。
在任何上述实施方式中,短语“盐”或“药用盐”旨在包括通过常规化学方法由含有碱或酸部分的母体化合物合成的无毒盐。通常,这样的盐可以通过使游离酸或碱形式的这些化合物与化学计量量的适当碱或酸在水中或有机溶剂中或在两者的混合物中进行反应来制备。例如,可以使用无机酸(例如盐酸、硫酸、磷酸或氢溴酸)、有机酸(例如草酸、丙二酸、柠檬酸、富马酸、乳酸、苹果酸、琥珀酸、酒石酸、乙酸、三氟乙酸、葡糖酸、抗坏血酸、甲基磺酸或苄基磺酸)、无机碱(例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁或氢氧化铵)、有机碱(例如甲胺、二乙胺、三乙胺、三乙醇胺、乙二胺、三(羟甲基)甲胺、胍、胆碱或辛可以宁)或氨基酸(例如赖氨酸、精氨酸或丙氨酸)。通常,如醚、乙酸乙酯、乙醇、异丙醇或乙腈的非水介质是典型的。合适的盐的列举见于Remington’s Pharmaceutical Sciences,18thed.,Mack Publishing Company,Easton,PA,1990,第1445页,和Journal ofPharmaceutical Science,66,2-19(1977)。例如,它们可以是碱金属(例如钠或钾)的盐,碱土金属(例如钙)的盐,或铵盐。
本文中描述的方法包括以药物组合物的形式给予式(I)化合物或其前药或药用盐。特别地,药物组合物将包含至少一种式(I)化合物或其前药或药用盐和药用载体。本文中描述的药用赋形剂,例如媒介物、佐剂、载体或稀释剂,对于本领域技术人员是公知的,并且对于公众是容易获得的。典型地,药用载体是在使用条件下对活性化合物是化学惰性的载体和没有有害副作用或毒性的载体。
药物组合物可以作为口服、舌下、透皮、皮下、局部、通过上皮层或粘膜皮肤层吸收、静脉内、鼻内、动脉内、肌内、瘤内、瘤周、腹膜间、鞘内、直肠、阴道或气溶胶制剂给予。在一些方面,将药物组合物口服或静脉内给予。
根据任何实施方式,式(I)的化合物或其前药或药用盐可以口服给予需要其的受试者。适于口服给予的制剂可以由以下组成:(a)液体溶液,如溶解在如水、盐水或橙汁的稀释剂中的有效量的化合物,并且包括添加剂,如环糊精(例如α-、β-或γ-环糊精、羟丙基环糊精)或聚乙二醇(例如PEG400);(b)胶囊、小袋、片剂、含片和锭剂,其各自含有作为固体或颗粒的预定量的活性成分;(c)粉末;(d)在适当液体中的悬浮液;和(e)合适的乳液和凝胶。液体制剂可以包括稀释剂,如水和醇,例如乙醇、苯甲醇和聚乙烯醇,添加或不添加药用表面活性剂、悬浮剂或乳化剂。胶囊形式可以是普通的硬壳或软壳明胶类型,含有例如表面活性剂、润滑剂和惰性填料,如乳糖、蔗糖、磷酸钙和玉米淀粉。片剂形式可以包括以下一种或多种:乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、海藻酸、微晶纤维素、阿拉伯树胶、明胶、瓜尔胶、胶态二氧化硅、交联羧甲基纤维素钠、滑石、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸和其它赋形剂、着色剂、稀释剂、缓冲剂、崩解剂、润湿剂、防腐剂、调味剂和药理学相容的载体。含片形式可以包含香料中的活性成分,香料通常是蔗糖和阿拉伯树胶或西黄蓍胶,以及包含在惰性基体中的活性成分的软锭剂,惰性基体例如明胶和甘油,或者蔗糖和阿拉伯树胶,乳液,凝胶和类似物,其除了活性成分之外,还包含本领域已知的这样的载体。
适合于肠胃外给予的制剂包括水性和非水性的等渗无菌注射液,其可以含有抗氧化剂、缓冲剂、抑菌剂和,使得制剂与预期接受者的血液等渗的溶质,以及水性和非水性无菌悬浮液,其可以包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂。式(I)的化合物或其盐可以在药物载体中的生理可接受的稀释剂中给予,药物载体例如无菌液体或液体混合物,其包括水,盐水,葡萄糖水溶液和相关的糖溶液,醇,例如乙醇、异丙醇或十六烷醇,二醇,例如丙二醇或聚乙二醇,甘油缩酮,例如2,2-二甲基-1,3-二氧戊环-4-甲醇,醚,例如聚(乙二醇)400,油,脂肪酸,脂肪酸酯或甘油酯,或乙酰化的脂肪酸甘油酯,添加或不添加药用表面活性剂,例如皂或洗涤剂,悬浮剂,例如果胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂和其它药物佐剂。
可以在肠胃外制剂中使用的油包括石油、动物油、植物油或合成油。油的具体实例包括花生油、豆油、芝麻油、棉籽油、玉米油、橄榄油、凡士林油和矿物油。用于在肠胃外制剂中使用的适当脂肪酸包括油酸、硬脂酸和异硬脂酸。油酸乙酯和肉豆蔻酸异丙酯是合适的脂肪酸酯的实例。用于在肠胃外制剂中使用的合适的皂类包括脂肪酸碱金属、铵和三乙醇胺盐,且合适的洗涤剂包括(a)阳离子洗涤剂,如二甲基二烷基卤化铵和烷基吡啶鎓卤化物,(b)阴离子洗涤剂,如烷基、芳基和烯烃磺酸盐,烷基、烯烃、醚和单甘油酯硫酸盐,和磺基琥珀酸盐,(c)非离子洗涤剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺和聚氧乙烯-聚丙烯共聚物,(d)两性洗涤剂,例如烷基-β-氨基丙酸盐,和2-烷基咪唑啉季铵盐,和(3)它们的混合物。
肠胃外制剂在溶液中典型地含有约0.5至约25重量%的抑制剂。在这样的制剂中可以使用合适的防腐剂和缓冲剂。为了最小化或消除在注射位点处的刺激,这样的组合物可以含有一种或多种具有约12至约17的亲水亲脂平衡(HLB)的非离子型表面活性剂。在这样的制剂中的表面活性剂的量的范围为约5至约15重量%。合适的表面活性剂包括聚乙二醇山梨醇脂肪酸酯,例如山梨醇单油酸酯和环氧乙烷与疏水碱的高分子量加合物,其是通过环氧丙烷与丙二醇的缩合形成的。肠胃外制剂可以存在于单位剂量或多剂量密封容器中,例如安瓿和小瓶中,并且可以储存在冷冻干燥的(冻干的)条件下,其只需要在使用前即刻添加注射用无菌液体载体,例如水。临时注射溶液和悬浮液可以由之前描述的种类的无菌粉末、颗粒和片剂制备。
抑制剂可以制成可注射制剂。对于可注射组合物的有效药物载体的要求是本领域普通技术人员公知的。参见Pharmaceutics and Pharmacy Practice,J.B.LippincottCo.,Philadelphia,Pa.,Banker and Chalmers,eds.,第238-250页(1982),和ASHPHandbook on Injectable Drugs,Toissel,4th ed.,第622-630页(1986)。
局部施用的组合物通常为液体(例如漱口液)、霜剂、糊剂、洗液和凝胶的形式。局部给予包括对口腔粘膜的施用,口腔粘膜包括口腔、口腔上皮、腭、牙龈和鼻粘膜。在一些实施方式中,组合物含有至少一种活性组分和合适的媒介物或载体。其还可以含有其它组分,如抗刺激剂。载体可以是液体、固体或半固体。在实施方式中,组合物是水溶液,如漱口液。可选地,组合物可以是用于各种组分的悬浮液、乳液、凝胶、洗液或霜剂媒介物。在一个实施方式中,主要的媒介物是水或生物相容性溶剂,其基本上是中性的或者已经使其是基本中性的。液体媒介物可以包括其它材料,例如缓冲剂、醇、甘油和矿物油,其具有本领域已知的各种乳化剂或分散剂以获得希望的pH、稠度和粘度。可能的是,组合物可以被制备为固体,例如粉末或颗粒。固体可以在使用前直接施用或溶解在水或生物相容的溶剂中以形成溶液,该溶液基本上是中性的或已经使其是基本中性的,并且其然后可以施用到目标部位。在本发明的实施方式中,用于局部施用于皮肤的媒介物可以包括水,缓冲溶液,各种醇,二醇,例如甘油,脂质材料,例如脂肪酸,矿物油,磷酸甘油酯,胶原蛋白,明胶和基于有机硅的材料。
式(I)的化合物或其前药或药用盐,可以单独或与其它合适组分组合地制成气溶胶制剂,以经由吸入给予。这些气溶胶制剂可以放入加压的可接受的推进剂中,如二氯二氟甲烷、丙烷、氮气等。它们还可以被配制为用于非加压制剂的药物,例如在喷雾器或雾化器中。
根据本发明,给予哺乳动物(特别是人和其它哺乳动物)的剂量应当足以实现希望的响应。本领域技术人员将认识到,剂量将取决于多种因素,包括哺乳动物的年龄、病症或疾病状态、疾病倾向、一个或多个遗传缺陷以及体重。剂量的大小还将由以下确定:给予的途径、时间和频率,以及可能伴随给予特定抑制剂的任何不良副作用和期望作用的存在、性质和程度。本领域技术人员将理解,各种病症或疾病状态可能需要涉及多次给予的长期治疗。
本发明的方法包括给予有效量的式(I)化合物或其前药或药用盐。“有效量”指足以在个体中显示出有意义的益处的量,例如促进以下方面中的至少一种:肿瘤细胞毒性(例如抑制生长、抑制癌细胞存活、减少增殖、减小肿瘤(例如实体瘤)的大小和/或质量),或治疗、治愈、预防、延迟发作、停止或改善与特定癌症相关的一个或多个其它相关医学病症。在患者中观察到的有意义的益处可以是任何合适的程度(10、20、30、40、50、60、70、80、90%或更多)。在一些方面,在给予式(I)化合物(包括式(Ia)化合物)或其前药或药学上可以接受的盐之后,癌症的一种或多种症状被预防、减轻、停止或消除,从而至少在某种程度上有效治疗癌症。
有效量可以取决于在个体中期望的生物效应、待治疗的病症和/或式(I)化合物(包括式(Ia)化合物)或其前药或药学上可以接受的盐以及个体的具体特征而变化。在这方面,根据待治疗的癌症的类型,可以将任何合适剂量的式(I)化合物或其前药或药用盐给予患者(例如人)。在确定“有效量”的过程中考虑的各种一般考虑因素对本领域技术人员来说是已知的,并且例如描述在如下文献中:Gilman et al.,eds.,Goodman And Gilman’s:ThePharmacological Bases of Therapeutics,8th ed.,Pergamon Press,1990;和Remington’s Pharmaceutical Sciences,17th ed.,Mack Publishing Co.,Easton,Pa.,1990,其各自通过引证并入本文中。式(I)的化合物(包括式(Ia)化合物)或其前药或其药用盐的剂量理想地包含约0.1mg每公斤(kg)哺乳动物的体重(mg/kg)至约400mg/kg(例如约0.75mg/kg,约5mg/kg,约30mg/kg,约75mg/kg,约100mg/kg,约200mg/kg或约300mg/kg)。在另一个实施方式中,式(I)化合物(包括式(Ia)化合物)的剂量包括约0.5mg/kg至约300mg/kg(例如约0.75mg/kg,约5mg/kg,约50mg/kg,约100mg/kg或约200mg/kg),约10mg/kg至约200mg/kg(例如,约25mg/kg,约75mg/kg或约150mg/kg),或约50mg/kg至约100mg/kg(例如,约60mg/kg,约70mg/kg或约90mg/kg)。
在一个方面,式(I)的化合物抑制LDHA和/或LDHB。在一个实施方式中,相对于其它脱氢酶(例如,GAPDH和PHGDH),式(I)的化合物对于LDHA和/或LDHB是选择性的。例如,与一种或多种其它脱氢酶相比,化合物对于LDHA和/或LDHB的选择性可以是至少2倍(例如至少5倍,至少10倍,至少20倍,至少50倍或至少100倍)。
尽管升高水平的LDHA是许多类型癌症的标志,大多数癌症是糖酵解和/或缺氧的,但LDHB在一些癌症(例如肺腺癌、前列腺癌)中可以是过表达的。参见,例如,McCleland etal.,Clin Cancer Res,2013;19(4):773-784和Leiblich et al.,Oncogene,2006;25(20):2953-2960。因此,在本发明的一些方面中,预想提供一种化合物,其可以选择性地抑制LDHB或抑制LDHA和LDHA二者。在一个实施方式中,式(I)的化合物可以有效抑制LDHB。在这样的实施方式中,化合物对于LDHA可以具有或不具有选择性,使得与LDHB相比,抑制对于LDHA是选择性更大的,或者LDHA的抑制约等于LDHB的抑制,或者相对于LDHA,抑制对于LDHB的选择性更大。
LDHA和/或LDHB的抑制已经在本领域中被描述为癌症的可行治疗。参见例如Billiard et al.(Cancer and Metabolism,2013,1(19):1-17)。因此,某些本发明的式(I)的化合物(其包括式(Ia)化合物)或其前药或药用盐可以给予需要其的患者以治疗癌症。虽然不希望受任何特定理论的束缚,但据信LDH的抑制刺激线粒体呼吸并降低细胞增殖和致肿瘤潜在性。抗癌活性可以通过任何合适的方法测量,包括本文中描述的测定。一般来说,活性将作为乳酸产量的函数,量化糖酵解的%ECAR(细胞外酸化率)和/或作为线粒体呼吸的量度的%OCR(耗氧速率)来测量。
癌症的类型没有特别限制,但是在某些方面,癌症的特征为相对于相同类型的正常组织是缺氧的和/或高度糖酵解的。如本文中使用的“缺氧”细胞涉及一种或多种暂时或永久暴露于低于在组织中被认为是正常或健康的细胞中的典型pO2的氧分压(pO2)的细胞。缺氧细胞可以包括,例如,具有减少的或没有脉管系统入口的细胞,例如在实体瘤中。
可以用本发明方法治疗的癌症的实例包括头颈部、眼、皮肤、嘴、喉、食道、胸部、骨骼、肺、结肠、乙状结肠、直肠、胃、前列腺、乳房、卵巢、肾脏、肝脏、胰腺、大脑、肠、心脏或肾上腺的癌症。更具体地,癌症包括实体瘤、肉瘤、癌、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏肿瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管源性癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、卡波西肉瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、血源性肿瘤、急性淋巴母细胞白血病、急性淋巴母细胞B细胞白血病、急性淋巴母细胞T细胞白血病、急性骨髓母细胞白血病、急性早幼粒细胞白血病、急性单核细胞白血病、急性红白血病、急性巨核细胞白血病、急性骨髓单核细胞白血病、急性非淋巴细胞性白血病、急性未分化白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、毛细胞白血病或多发性骨髓瘤。参见,例如,Harrison’s Principles of InternalMedicine,Eugene Braunwald et al.eds.,491-762页(15th ed.,2001)。在一些方面,癌症是实体瘤。根据一个实施方式,癌症选自白血病、黑色素瘤、肝癌、胰腺癌、肺癌、结肠癌、脑癌、卵巢癌、乳腺癌、前列腺癌和肾癌。在另一个实施方式中,癌症是肝癌、胰腺癌、非小细胞肺癌、乳腺癌或肾癌。
本发明提供一种治疗具有对抗癌剂有抗性的癌细胞的患者的方法,包括向患者给予有效量的式(I)的化合物(包括式(Ia)化合物)或其前药或药用盐和抗癌剂,由此化合物、其前药或药用盐使癌细胞对抗癌剂再敏化。癌细胞与本文中描述的相同。根据一个实施方式,癌细胞选自白血病、黑色素瘤、肝癌、胰腺癌、肺癌、结肠癌、脑癌、卵巢癌、乳腺癌、前列腺癌和肾癌。在另一个实施方式中,癌细胞是肝癌、胰腺癌、非小细胞肺癌、乳腺癌或肾癌。
在该方法的某些实施方式中,式(I)的化合物(包括式(Ia)化合物)或其前药或药用盐,可以与抗癌剂(例如化疗剂)和/或放射疗法共同给予。在一个方面,方法包括给予一定量的化合物、前药或盐,其有效地使癌细胞对一种或多种治疗方案(例如化疗或放疗)敏感。术语“共同给予的”或“共同给予”是指同时或顺序给予。可以将一种化合物在给予另一种化合物之前、同时或之后给予。
可以给予一种或多于一种,例如两种、三种或更多种抗癌剂。关于这一点,本发明涉及一种药物组合物,其包含药用载体和如下物质的组合:式(I)化合物(包括式(Ia)化合物)或其前药或药用盐和至少一种抗癌剂(例如化疗剂)。
抗癌剂的实例包括铂化合物(例如顺铂、卡铂、奥沙利铂)、烷基化剂(例如环磷酰胺、异环磷酰胺、苯丁酸氮芥、氮芥、噻替派、美法仑、白消安、甲基苄肼、链脲佐菌素、替莫唑胺、达卡巴嗪、苯达莫司汀)、抗肿瘤抗生素(例如柔红霉素、阿霉素、伊达比星、表阿霉素、米托蒽醌、博莱霉素、丝裂霉素C、普卡霉素、放线菌素)、紫杉烷类(例如,紫杉醇和多西紫杉醇)、抗代谢物(例如,5-氟尿嘧啶、阿糖胞苷、培美曲塞、硫鸟嘌呤、氟尿苷、卡培他滨和甲氨蝶呤)、核苷类似物(例如,氟达拉滨、氯法拉滨、克拉屈滨、喷司他丁、奈拉滨)、拓扑异构酶抑制剂(例如,拓扑替康和伊立替康)、低甲基化剂(例如,阿扎胞苷和地西他滨)、蛋白酶体抑制剂(例如硼替佐米)、表鬼臼毒素(例如,依托泊苷和替尼泊苷)、DNA合成抑制剂(例如,羟基脲)、长春花生物碱(例如,长春新碱、长春地辛、长春瑞滨和长春碱)、酪氨酸激酶抑制剂(例如,伊马替尼、达沙替尼、尼洛替尼、索拉非尼、舒尼替尼)、单克隆抗体(例如,利妥昔单抗、西妥昔单抗、帕内图单抗、托西莫单抗、曲妥珠单抗、阿仑单抗、吉妥珠单抗奥佐米星、贝伐单抗)、亚硝基脲(例如,卡莫司汀、福莫司汀和洛莫司汀)、酶(例如,L-天冬酰胺酶)、生物制剂(例如,干扰素和白细胞介素)、六甲基三聚氰胺、米托坦、血管生成抑制剂(例如,沙利度胺、来那度胺)、类固醇(例如,泼尼松、地塞米松和泼尼松龙)、激素制剂(例如,他莫昔芬、雷洛昔芬、亮脯利特、比卡鲁胺、格拉司琼、氟他胺)、芳香化酶抑制剂(例如,来曲唑和阿那曲唑)、三氧化二砷、维甲酸、非选择性环氧合酶抑制剂(例如,非甾体抗炎剂、水杨酸盐、阿司匹林、吡罗昔康、布洛芬、吲哚美辛、萘普生、双氯芬酸、托美汀、酮洛芬、萘丁美酮、奥沙普秦)、选择性环氧合酶-2(COX-2)抑制剂或它们的任何组合。
为了本发明的目的,术语“患者”典型地涉及哺乳动物。例如,受试者可以是患有需要化疗和/或放疗的疾病的任何患者。哺乳动物包括但不限于啮齿目,例如小鼠,和兔形目,例如兔子。在一些方面,哺乳动物来自食肉目,包括猫科动物(猫)和犬科动物(狗),偶蹄目,包括牛科动物(牛)和猪科动物(猪),或者属于奇蹄目,包括马科动物(马)。在一些方面,哺乳动物属于灵长目、猿目或猴目(猴),或属于类人猿目(人和猿)。在本发明的实施方式中,患者是人。
本发明进一步涉及抑制细胞中乳酸脱氢酶A(LDHA)和/或乳酸脱氢酶B(LDHB)活性的方法,该方法包括向细胞给予式(I)化合物(包括式(Ia)化合物)或其前药或药用盐,由此LDHA和/或LDHB的活性被抑制。LDHA和LDHB活性可以通过本领域中已知的用于测量酶抑制性的任何方法进行测量,包括通过本文中描述的测定进行测量。典型地,LDHA和LDHB活性的抑制将通过相对于对照样品,乳酸积累的减少和/或丙酮酸的增加来证明。
提供如下实施例用于进一步示例性说明,并且它们不应以任何方式被解释为是限制性的。
实施例
实施例1
该实施例描述了用于表征在本发明的一个实施方式中的式(I)的化合物的人LDHA初级生化测定。
将测试化合物放置在Greiner Bio-One(Monroe,NC)1536孔黑色固体底部测定板中。作为测定缓冲液,使用200毫摩尔(mM)Tris HCl,pH 7.4,100微摩尔(μM)EDTA和0.01%TWEEN-20TM,最终浓度。在测定缓冲液中,LDHA试剂是2纳摩尔(nM)人LDHA(Meridian LifeScience,Inc.,Memphis,TN),最终浓度。在测定缓冲液中,底物试剂是0.06mM NADH和0.2mM丙酮酸钠,最终浓度。在测定缓冲液中,刃天青/黄递酶偶联剂是0.037mM刃天青和0.133毫克/毫升(mg/mL)黄递酶,最终浓度。步骤的顺序,试剂的数量和类型,以及每个步骤所需的时间阐述在表1中。通过荧光发射测量LDHA活性的抑制。
表1
实施例2
该实施例描述了用于表征在本发明的一个实施方式中的式(I)化合物的人LDHB对筛选(counterscreen)生化测定。
将测试化合物放置在Greiner Bio-One(Monroe,NC)1536孔黑色固体底部测定板中。作为测定缓冲液,使用200mM Tris HCl,pH 7.4,100μMEDTA和0.01%TWEEN-20TM,最终浓度。在测定缓冲液中,LDHB试剂是2nM人LDHB(Meridian Life Science,Inc.,Memphis,TN),最终浓度。在测定缓冲液中,底物试剂是0.13mM NADH和0.16mM丙酮酸钠,最终浓度。在测定缓冲液中,刃天青/黄递酶偶联剂是0.037mM刃天青和0.133mg/mL黄递酶,最终浓度。步骤的顺序,试剂的数量和类型,以及每个步骤所需的时间阐述在表2中。通过荧光发射测量LDHB活性的抑制。
表2
实施例3
该实施例描述了用于表征在本发明的一个实施方式中的式(I)的化合物的人PHGDH对筛选生化测定。
将测试化合物放置在Greiner Bio-One(Monroe,NC)1536孔黑色固体底部测定板中。作为测定缓冲液,使用50mM TEA,pH 8.0,10mM MgCl2,0.05%BSA,和0.01%TWEEN-20TM,最终浓度。在测定缓冲液中,底物试剂是10μM EDTA,0.625mM谷氨酸,500nM人PSAT1,500nM人PSPH,0.05mM 3-磷酸甘油酸,0.1mM刃天青,和0.1mg/mL黄递酶,最终浓度。在测定缓冲液中,PHGDH试剂是0.15mM NAD+和10nM人PHGDH,最终浓度。步骤的顺序,试剂的数量和类型,以及每个步骤所需的时间阐述在表3中。通过荧光发射测量PHGDH活性的抑制。
表3
实施例4
该实施例描述了用于表征在本发明的一个实施方式中的式(I)的化合物的人GAPDH对筛选生化测定。
将测试化合物放置在Greiner Bio-One(Monroe,NC)1536孔黑色固体底部测定板中。作为测定缓冲液,使用105mM Tris HCl,pH 7.4,10μM EDTA,1.27mM KH2PO4,0.875mMMgCl2,0.0875%BSA,0.01mM DTT,和0.01%TWEEN-20TM,最终浓度。在测定缓冲液中,底物试剂是0.48mM甘油醛-3-磷酸,0.06mM刃天青,和0.21mg/mL黄递酶,最终浓度。在测定缓冲液中,GAPDH试剂是0.007mM NAD+和2.5nM人GAPDH,最终浓度。步骤的顺序,试剂的数量和类型,以及每个步骤所需的时间阐述在表4中。通过荧光发射测量GAPDH活性的抑制。
表4
实施例5
该实施例描述了用于表征在本发明的一个实施方式中的式(I)的化合物的通过质谱(MS)的细胞基代谢物测定。
步骤的顺序,试剂的数量和类型,以及每个步骤所需的时间阐述在表5中。
表5
实施例6
该实施例描述了用于表征在本发明的一个实施方式中的式(I)的化合物的通过比色/荧光检测的细胞基代谢物测定。
细胞基HT乳酸测定是一种小型化的Biovision乳酸比色/荧光测定试剂盒(货号K607-100)。该测定是以1536板形式进行的约3.5小时的测定。应该对每个细胞系进行细胞数量优化,以获得其中乳酸产量大约等于90%的标准曲线范围的的最佳数量。采用以下细胞系进行每孔细胞数量的优化:MiaPaCa2-500个细胞/孔,SNU398-500个细胞/孔,和P493-500个细胞/孔。步骤的顺序,试剂的数量和类型,以及每个步骤所需的时间阐述在表6中。
表6
实施例7-33描述了制备本发明要求保护的化合物的一般方法。
实施例7
步骤1:2-(3-(3-取代-4-取代苯基)-5-(环丙基甲基)-4-(3-取代-4-氨磺酰基苄
基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯的一般合成
方法A-在密封的微波小瓶中将二噁烷(2mL)和水(0.5mL)添加到2-(3-(3-溴-4-取代苯基)-5-(环丙基甲基)-4-(3-取代-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(0.2mmol,1当量)、磷酸钾(0.4mmol,2当量)、S-PHOS(5摩尔%)、SPhos Palladacycle G3(2.5mol%)和适当的硼酸/酯或三氟硼酸钾的混合物中。将反应混合物用氩气鼓泡几分钟,然后在预热的加热块中在100℃下搅拌1-6小时。当通过LCMS检测到反应完成时,将反应混合物冷却并与金属清除剂一起搅拌1小时。然后将反应混合物用乙酸乙酯稀释并过滤通过寅式盐(celite)垫。将滤液浓缩并在二氧化硅上使用梯度洗脱(在己烷中20-40%乙酸乙酯)直接纯化。
方法B-将2-(3-(3-溴-4-取代苯基)-5-(取代)-4-(3/4-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(1mmol)、三(叔丁基鏻)四氟硼酸盐(10mol%)、氯化烯丙基钯二聚物(5mol%)和DABCO(2mmol,2当量)在二噁烷中(0.5摩尔浓度)的混合物用氩气鼓泡5分钟。添加适当的炔烃(1.5mmol,1.5当量),并将反应混合物在室温下搅拌过夜。在反应完成后,添加二氧化硅结合的钯清除剂,并将浆液在室温下搅拌1小时,随后用乙酸乙酯稀释和过滤通过寅式盐垫。将滤液浓缩并将残余物在二氧化硅上使用梯度洗脱(在己烷中20-40%乙酸乙酯)直接纯化,产生在下一步采用的希望的化合物。
步骤2:2-(3-(3-取代-4-取代苯基)-5-(环丙基甲基)-4-(3-取代-4-氨磺酰基苄
基)-1H-吡唑-1-基)噻唑-4-甲酸
将LiOH在水中的1.5摩尔溶液添加到2-(3-(3-取代-4-取代苯基)-5-(环丙基甲基)-4-(3-取代-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(1当量)在THF/MeOH(3mL/1.5mL)中的溶液中,并在室温下搅拌0.5-1小时。在反应完成后,将溶剂在减压下蒸发,并将残余物溶解在DMSO中。最后,在制备HPLC上纯化标题化合物。
实施例8
该实施例描述了在本发明的一个实施方式中的2-(5-(烷基)-3-苯基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸和2-(3-(烷基)-5-苯基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸的合成。参见方案1。
方案1
步骤1:1-苯基-3-烷基-1,3-二酮的合成
向搅拌中的1-(1H-苯并[d][1,2,3]三唑-1-基)-2-烷基酮(200mmol)和乙醚溴化镁(magnesium bromide diethyl etherate)(413mmol)在CH2Cl2中的溶液中添加1-苯基乙酮衍生物(165mmol)。在数分钟内滴加二异丙基乙基胺(500mmol),并将反应混合物在室温下搅拌2小时。当通过LCMS检测到完成时,将反应用1.0M HCl缓慢猝灭并用1.0M HCl和盐水洗涤。将残余物在Na2SO4是干燥,过滤和在减压下浓缩。将残余物在二氧化硅上用梯度洗脱(在己烷中0-30%乙酸乙酯,在20CV上)直接纯化。在下一个步骤中使用所形成的油,而不用进一步的纯化或表征。
步骤2:4-(2-苯甲酰基-3-氧代)-3-烷基-苯磺酰胺的合成
将1-苯基-3-烷基-1,3-二酮(150mmol)和碳酸铯(Cs2CO3,226mmol)溶解在DMSO(50ml)中。将反应混合物在室温下搅拌10分钟,此时添加碘化钾(KI,150mmol)和4-(溴甲基)-苯磺酰胺(165mmol)。将形成的混合物在室温下搅拌1小时。当通过LCMS检测到完成时,将反应混合物用远过量的乙酸乙酯稀释并过滤通过寅式盐。将滤液用1M HCl、饱和NH4Cl水溶液和盐水洗涤,在Na2SO4上干燥、过滤和在减压下浓缩。将残余物在二氧化硅上使用梯度洗脱(在己烷中20-40%乙酸乙酯,在16CV上)直接纯化。
步骤3:2-(5-(烷基)-3-苯基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸
乙酯
方法A-将4-(2-苯甲酰基-3-氧代)-3-烷基-苯磺酰胺(6.7mmol)、2-肼基噻唑-4-甲酸乙酯,2HBr(7.3mmol)和对甲苯磺酸(pTsOH,20mmol)在二噁烷中的溶液在密封的容器中在微波中在160℃下加热15分钟。当通过LCMS检测到完成时,将反应混合物用乙酸乙酯稀释并过滤通过寅式盐。将溶剂在减压下移除,并将粗产物在二氧化硅上用梯度洗脱(在己烷中0-100%乙酸乙酯,在15CV上)直接纯化。
方法B-将4-(2-(苯甲酰基)-3-氧代-3-烷基-苯磺酰胺(113mmol)、对甲苯磺酸(pTsOH,57mmol)和吡咯烷(57mmol)在乙醇中溶液在100℃下搅拌1小时,之后添加2-肼基噻唑-4-甲酸乙酯,2HBr(136mmol)。将形成的反应混合物回流过夜。当通过LCMS检测到完成时,将溶剂在减压下移除,并将残余物在没有后处理的情况下在二氧化硅上使用梯度洗脱(在己烷中20-40%乙酸乙酯,在20CV上)直接纯化。将区域异构体的混合物作为单一的峰收集。在移除溶剂后,经由反相制备柱使用梯度洗脱(用0.1%TFA改性的水中的用0.1%TFA改性的50-100%乙腈,在25CV上)分离区域异构体。收集第二洗脱峰并浓缩,和将形成的固体与NaHCO3的澄清溶液一起搅拌。通过过滤收集沉淀物,用水洗涤并随后干燥,首先在空气下干燥过夜,然后通过高真空在P2O5下干燥,形成无色粉末。
步骤4:2-(5-(烷基)-3-苯基)-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸
的合成
向2-(5-(烷基)-3-苯基)-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(0.07mmol)在THF/MeOH中的溶液中添加1.5M LiOH(0.27mmol)。将反应混合物在室温下搅拌1小时。当通过LCMS检测到完成时,通过加压气流移除溶剂。将残余物溶解到DMSO中,并经由制备反相使用梯度洗脱(用0.1%TFA改性的水中的0.1%TFA改性的的4-100%乙腈)直接纯化。将产物级分直接冷冻并冻干过夜,产生类白色粉末。
实施例9
该实施例描述了在本发明的一个实施方式中的2-溴噻唑-4-甲酸叔丁酯1的制备。参见方案2。
方案2
将2,2,2-三氯乙酰亚氨酸叔丁酯(tert-butyl 2,2,2-trichloroacetimidate)(17.20ml,96mmol,2当量)添加到搅拌中的2-溴噻唑-4-甲酸(10g,48.1mmol,1当量)在二氯甲烷(DCM)(100mL)和四氢呋喃(THF)(50mL)中的悬浮液中,随后滴加BF3·OEt2(0.938ml,7.40mmol,10mol%)。将混合物在室温下搅拌16小时,浓缩,用饱和碳酸氢盐溶液缓慢猝灭,和用乙酸乙酯萃取。将有机层用饱和碳酸氢盐和盐水洗涤,然后干燥,和将粗产物用在12CV上在己烷中5-30%的乙酸乙酯洗脱的Biotage(Charlotte,NC)快速系统中纯化。将产物级分浓缩以提供作为白色固体的2-溴噻唑-4-甲酸叔丁酯1(10.4g,82%)。
实施例10
该实施例描述了在本发明的一个实施方式中的2-肼基噻唑-4-甲酸叔丁酯2的制备。参见方案2。
将来自实施例1的2-溴噻唑-4-甲酸叔丁酯1(10.96g,41.5mmol,1当量)和水合肼(13ml,415mmol,10当量)在EtOH(80mL)中的溶液回流2小时。在反应完成后,将溶剂移除并添加冰水。通过过滤收集形成的沉淀物,用冷水洗涤和在空气下干燥。粗产物(2-肼基噻唑-4-甲酸叔丁酯2)的纯度足以用于后续反应。
实施例11
该实施例描述了在本发明的一个实施方式中的2-肼基噻唑-4-甲酸乙酯3的制备。参见方案2。
将溴代丙酮酸乙酯(15.71ml,113mmol)添加到2-乙酰基肼硫代酰胺(2-acetylhydrazinecarbothioamide)(15g,113mmol)在乙醇(200mL)中的悬浮液中,并在室温下搅拌30分钟直到溶液变澄清,然后回流1.5小时。然后将溶液浓缩并与20mL MeOH和300mL醚一起搅拌。通过过滤收集黄色沉淀物,用醚洗涤,并干燥以获得作为HBr盐的黄色固体(2-肼基噻唑-4-甲酸乙酯3)。
实施例12
该实施例描述了在本发明的一个实施方式中的取代的苯甲酰乙腈4的合成的一般过程。参见方案3。
方案3
将乙腈(ACN)(5.33ml,102mmol,2当量)滴加到在-78℃下的1摩尔浓度的二异丙基氨基锂(LDA)(102ml,102mmol,2当量)在THF(40ml)中的冷却溶液中。将反应混合物搅拌30分钟,和然后在15分钟内滴加酰氯(51.0mmol,1当量)在20mL THF中的溶液。使反应在4小时内达到室温,然后用1M(摩尔浓度)HCl猝灭。将产物用乙酸乙酯萃取。随后将有机层用水和盐水洗涤,并在MgSO4上干燥。将粗产物在用在12CV上的在己烷中5-75%乙酸乙酯洗脱的Biotage(Charlotte,NC)快速系统上纯化,以获得作为黄色固体的取代的苯甲酰基乙腈4。
实施例13
该实施例描述了在本发明的一个实施方式中的4-(2-氰基-3-氧代-3-芳基丙基)苯磺酰胺5的合成的一般过程。参见方案3。
将2,6-二甲基-1,4-二氢-吡啶-3,5-二甲酸二乙酯(Hantzsch酯)(12.21g,48.2mmol,1.4当量)和L-脯氨酸(0.793g,6.89mmol,20mol%)添加到3-氧代-3-苯基-丙腈4(34.4mmol,1当量)和4-甲酰基苯磺酰胺(7.02g,37.9mmol,1.1当量)在乙醇(150mL)中的溶液中。将混合物在60℃下搅拌30分钟。然后将混合物冷却,与硅胶一起混合,浓缩和在Biotage(Charlotte,NC)快速系统上在6CV上用己烷中20-100%的乙酸乙酯和然后在8CV上用100%乙酸乙酯纯化,以获得作为白色固体的4-(2-氰基-3-氧代-3-芳基丙基)苯磺酰胺5。
实施例14
该实施例描述了在本发明的一个实施方式中的2-(5-氨基-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸酯6的合成的一般过程。参见方案3。
将2-肼基噻唑-4-甲酸乙酯氢溴酸盐(3,1.5g,5.59mmol,1当量)、4-(2-氰基-3-氧代-3-芳基丙基)苯磺酰胺(5.59mmol,1当量)和对甲苯磺酸(2.128g,11.19mmol,2当量)在乙醇(15mL)中的混合物在微波中加热15分钟。通过过滤收集形成的沉淀物,并将其用冷乙醇洗涤以获得作为黄色固体的纯产物(2-(5-氨基-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯6)。
实施例15
该实施例描述了在本发明的一个实施方式中的2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7的合成的一般过程。参见方案3。
将对甲苯磺酸(5.37g,28.2mmol,3.5当量)添加到(2-(5-氨基-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯6(8.07mmol,1当量)在ACN(100mL)中的悬浮液中,并搅拌10分钟。在此期间,溶液变澄清,然后在室温下在10-15分钟的时间段内滴加NaNO2(1.113g,16.13mmol,2当量)和KI(4.02g,24.20mmol,3当量)在10mL水中的预混合的溶液。使反应混合物在室温下搅拌过夜。在反应完成后,在减压下移除过量的溶剂,并将粗产物用乙酸乙酯萃取。用饱和硫代硫酸钠溶液、水和盐水洗涤有机层。将粗产物在Biotage(Charlotte,NC)快速系统上使用在20柱体积上在二氯甲烷中1-15%的丙酮或己烷中1-100%的乙酸乙酯洗脱的高效柱纯化以获得纯产物。
实施例16
该实施例描述了在本发明的一个实施方式中的2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7的三氟甲基化的一般过程。
方案4
将2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7(0.4g,0.673mmol)和1,10-菲咯啉(三氟甲基)铜(I)8(0.316g,1.009mmol,1.5当量)的混合物用氩气脱气,然后添加DMF(2mL)并在55℃下搅拌1小时。将反应混合物用乙酸乙酯稀释并用1摩尔浓度HCl、水和盐水洗涤。将有机层用MgSO4干燥、浓缩并且在用12CV上的己烷中20-100%的乙酸乙酯洗脱的Biotage(Charlotte,NC)快速系统上纯化以获得作为白色固体的2-(5-三氟甲基-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯9。
实施例17
该实施例描述了在本发明的一个实施方式中的2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7的Suzuki偶联的一般过程。参见方案4。
在密封的微波小瓶中,将2摩尔浓度的Na2CO3(0.17mL,0.336mmol,2当量)添加到2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7(0.168mmol,1当量)、SILIACATTM DPP-Pd(0.1g)、硼酸(0.336mmol,2当量)在二甲醚(DME)(2mL)中的混合物中,然后在微波中在130℃下加热30分钟。将反应混合物通过吹送加压气流浓缩。将残余物溶解在DMF(2mL)中,并与二氧化硅结合的DMT一起搅拌,随后过滤通过硫醇树脂筒以移除任何浸出的钯。最后,将化合物在制备HPLC上纯化以获得纯耦联产物10。
实施例18
该实施例描述了在本发明的一个实施方式中的2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(7)的Sonogashira偶联的一般过程。参见方案4。
在氮气氛下向2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7(0.202mmol,1当量)、双(三苯基膦)氯化钯(II)(0.014g,0.020mmol,10mol%)和CuI(3.84mg,0.020mmol,10mol%)在THF(1mL)中的混合物中添加三乙胺(TEA)(0.169ml,1.211mmol,6当量),随后添加炔烃(0.404mmol,2当量)。将小瓶密封并在80℃下搅拌4小时。在反应完成后,将产物用乙酸乙酯萃取,并将有机层用1摩尔HCl和盐水洗涤。将粗产物在用20-100%乙酸乙酯洗脱的Biotage(Charlotte,NC)快速系统上或者在制备HPLC中纯化以获得纯偶联产物10。
实施例19
该实施例描述了在本发明的一个实施方式中的2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7的氰化的一般过程。参见方案4。
将2-(5-碘-3-芳基-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯7(0.168mmol,1当量)和CuCN(0.023g,0.252mmol,1.5当量)在二甲亚砜(DMSO)(0.5ml)中的混合物在160℃下在微波中加热0.5小时。将产物用乙酸乙酯萃取。将有机层用饱和碳酸氢盐溶液、水和盐水洗涤。将粗产物在用15CV上的己烷中30-100%的乙酸乙酯洗脱的Biotage(Charlotte,NC)快速系统上纯化以获得纯产物10。
实施例20
该实施例描述了在本发明的一个实施方式中的乙基和甲基酯10的水解的一般过程。参见方案4。
将LiOH在水中的1.5摩尔浓度的溶液添加到2-(3-芳基-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯10(0.252mmol,1当量)在THF/MeOH(3mL/1.5mL)中的溶液中,并在室温下搅拌0.5-1小时。在反应完成后,将溶剂在减压下蒸发,并将残余物溶解在DMSO中。最后,在制备HPLC上纯化化合物11。
实施例21
该实施例描述了在本发明的一个实施方式中的2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(2-(5-甲基噻吩-2-基)环丙基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸130的合成。参见方案5。
方案5
步骤1:(E)-4,4,5,5-四甲基-2-(2-(5-甲基噻吩-2-基)乙烯基)-1,3,2-二氧杂环
戊硼烷的合成
在氮气鼓泡下向在DCM中的2-乙炔基-5-甲基噻吩(1.5g,12.28mmol)、4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(3.56ml,24.55mmol)中添加双(环戊二烯基)锆(IV)盐酸盐(0.317g,1.228mmol)和TEA(0.171ml,1.228mmol),然后将小瓶封盖并在60℃下搅拌2小时。将反应混合物用DCM稀释,用水和盐水洗涤。将粗产物在用20CV上的己烷中0-40%的乙酸乙酯洗脱的快速系统上在80g硅胶柱上纯化。黄色固体(2.9g,产率为94%)。
步骤2:4,4,5,5-四甲基-2-((1R,2R)-2-(5-甲基噻吩-2-基)环丙基)-1,3,2-二氧
杂-环戊硼烷
当在冰浴中冷却时,向二碘甲烷(3.22ml,40.0mmol)在DCM(40mL)中的溶液中添加二乙基锌(19.99ml,19.99mmol)(己烷中的1摩尔浓度溶液)。在该温度下将反应搅拌2小时,然后在0℃下添加(E)-,4,5,5-四甲基-2-(2-(5-甲基噻吩-2-基)乙烯基)-1,3,2-二氧杂环戊硼烷(2g,7.99mmol)在DCM(20mL)中的溶液,并然后将反应在室温(RT)下搅拌另外3天。将反应混合物用水/HCl猝灭并用DCM萃取。用水和盐水洗涤有机层。将粗产物在用25CV上的己烷中0-100%的乙酸乙酯洗脱的快速系统上在120g硅胶柱上纯化。黄色油(1.56g,产率73%)。
步骤3-4:2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(2-(5-甲基噻
吩-2-基)环丙基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸,TFA
将在二噁烷/水中的2-(3-(3-溴苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(0.1g,0.161mmol)、4,4,5,5-四甲基-2-((1R,2R)-2-(5-甲基噻吩-2-基)环丙基)-1,3,2-二氧杂环戊硼烷(0.064g,0.242mmol)、磷酸钾(0.069g,0.323mmol)和二氯[1,1'-双(二叔丁基膦)二茂铁]钯(II)(6.45mg,0.016mmol)用氩气鼓泡,然后封盖,并在110℃下搅拌6小时。将反应用乙酸乙酯稀释,并过滤通过寅式盐,然后与Pd清除剂一起搅拌,再次过滤以获得粗固体,将其在用20CV上的己烷中20-40%的乙酸乙酯洗脱的快速系统上在12g硅胶柱上纯化。
将产物2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(2-(5-甲基噻吩-2-基)环丙基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(0.11g,0.163mmol)在THF/MeOH中用水中的1.5摩尔浓度LiOH(5当量)水解。用1摩尔浓度HCl酸化并用乙酸乙酯萃取。在蒸发溶剂后,将粗材料溶解在DMSO中,并在制备HPLC上纯化。
实施例22
该实施例描述了在本发明的一个实施方式中的顺式-2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(3-(5-甲基噻吩-2-基)环丁基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸132和反式-2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(3-(5-甲基噻吩-2-基)环丁基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸133的合成。参见方案6。
方案6
步骤1-2:新戊酸3-(5-甲基噻吩-2-基)环丁酯的合成
当在冰/丙酮浴中冷却时,向醚中的新戊酸3-氧代环丁酯(5g,29.4mmol)中滴加(5-甲基噻吩-2-基)溴化镁(64.6ml,32.3mmol),然后在室温下搅拌过夜。将反应用氯化铵猝灭并用乙酸乙酯萃取。用盐水洗涤有机层。将粗产物在用16CV上的己烷中0-30%的乙酸乙酯洗脱的快速系统上在220g金硅胶柱上纯化。黄色油(3.8g,产率为48%)。
当冷却至0℃时,向DCM(50mL)中的上述新戊酸3-羟基-3-(5-甲基噻吩-2-基)环丁酯(3.3g,12.30mmol,1当量)和三乙基硅烷(2.357ml,14.76mmol,1.2当量)中添加三氟乙酸(1.895ml,24.59mmol,2当量)。将反应在室温下搅拌2小时,然后用碳酸氢盐溶液猝灭。将有机层进一步用碳酸氢盐和盐水洗涤,用硫酸镁干燥并浓缩以得到油,其在下一步骤中原样使用。
步骤3:3-(5-甲基噻吩-2-基)环丁-1-醇的合成
将来自步骤2的粗黄色油溶解在THF-MeOH中,并用在水中的1.5摩尔浓度LiOH(5当量)处理以水解酯。在室温下搅拌4小时后,将反应混合物浓缩并用乙酸乙酯萃取两次。将粗产物在用25CV上的己烷中0-50%的乙酸乙酯洗脱的快速系统上在120g金硅胶柱上纯化。黄色油(1.1g,产率为53%)。
步骤4:2-(3-碘环丁基)-5-甲基噻吩
当在冰浴中冷却时,向在DCM中的3-(5-甲基噻吩-2-基)环丁醇(0.5g,2.97mmol,1当量)、三苯基膦(1.013g,3.86mmol,1.3当量)和咪唑(0.303g,4.46mmol,1.5当量)中添加碘(0.905g,3.57mmol,1.2当量)。将反应混合物回流过夜。移除过量的DCM,并将残余物悬浮在醚中,并过滤通过寅式盐。将滤液浓缩并在用超过15CV上的己烷洗脱的快速系统上在40g金硅胶柱上纯化。黄色油(0.38g,产率为46%)。
步骤5:顺式和反式2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(3-(5-
甲基噻吩-2-基)环丁基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸的合成
将在微波小瓶中的锌(得自Strem的纳米锌粉,货号30-1500)(0.132g,2.018mmol)用氩气脱气,然后在氩气下用喷灯加热。当冷却时,添加0.5mL的干燥THF,然后添加1,2-二溴乙烷(0.017ml,0.202mmol),并用喷灯加热直到其鼓泡,冷却并重复该过程两次。将混合物再次冷却到室温,并添加TMS-Cl(0.026ml,0.202mmol),然后用喷灯加热直到其鼓泡,冷却并重复该过程两次。将反应冷却到室温,并添加2-(3-碘环丁基)-5-甲基噻吩(0.224g,0.807mmol),用热抢温和地温热,并在室温下剧烈搅拌0.5小时。
在另一个小瓶中,在氩气下将2-(3-(3-溴苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(0.125g,0.202mmol)、CPhos(4.40mg,10.09μmol)和CPhos Pd G3(sigma货号763004)(4.07mg,5.04μmol)置入0.5mL THF中。将第一溶液用注射器抽出(在针和注射器之间使用过滤器以移除固体颗粒)并在室温下添加到起始材料和催化剂的THF悬浮液中,然后在65℃下搅拌1小时。将反应混合物用1摩尔浓度的HCl猝灭,然后用乙酸乙酯萃取。将有机层用水和盐水洗涤,并然后在用20CV上的己烷洗脱的快速系统上在12g硅胶柱上纯化。
将2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(3-(5-甲基噻吩-2-基)环丁基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(0.12g,0.174mmol)在THF/MeOH中用在水中的1.5摩尔浓度的LiOH水解。将反应混合物用1摩尔浓度的HCl酸化并用乙酸乙酯萃取。将在蒸发乙酸乙酯后获得的粗材料置于DMSO中,并在制备HPLC上纯化以分离异构体。在最后的梯度洗脱液中有2个峰非常接近。第一个峰被认为是顺式异构体132,和第二个峰被认为是反式异构体133。
实施例23
在本发明的一个实施方式中的(2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-基)硼酸135的合成。参见方案7。
方案7
步骤1:2-(4-氯噻唑-2-基)肼-1,1,2-三甲酸三叔丁酯的合成
将在叔丁醇(100ml)中的2,4-二氯噻唑(9g,58.4mmol)、肼-1,1,2-三甲酸三叔丁酯(24.28g,73.0mmol)、Cs2CO3(28.6g,88mmol)和[tBuXPhosPd(烯丙基)]OTf(http://jmcct.com/products-services/product_p582.html货号Pd-174)(1.691g,2.92mmol)用氩气鼓泡5分钟,然后在80℃下搅拌过夜。将反应与silia-DMT一起搅拌以移除任何残留的钯,然后用乙酸乙酯稀释,并过滤通过寅式盐垫。将滤液浓缩以得到深色残余物,将其在用25柱体积上的己烷中0-30%的乙酸乙酯洗脱的快速系统上在220g金硅胶柱上纯化。黄色固体(9.3g,产率为36%)。
步骤2:2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)噻唑-2-基)肼-1,
1,2-三甲酸三叔丁酯的合成
将2-(4-氯噻唑-2-基)肼-1,1,2-三甲酸三叔丁酯(0.73g,1.622mmol)、双(频哪醇合)二硼(0.824g,3.24mmol)、XPhosPd(巴豆基)Cl(http://jmcct.com/products-services/product_p578.html)(货号Pd-170)(0.055g,0.081mmol)和乙酸钾(0.478g,4.87mmol)在二噁烷(体积:5ml)中的混合物用氩气鼓泡,然后在110℃下搅拌6小时。将反应与silia-DMT一起搅拌以移除任何残留的钯,然后用乙酸乙酯稀释,并过滤通过寅式盐垫。将滤液浓缩并在用25CV柱体积上的己烷中5-40%的乙酸乙酯洗脱的快速系统上在40g金硅胶柱上纯化。黄色固体(0.73g,产率为83%)。
步骤3:(2-肼基噻唑-4-基)硼酸,2HCl
向在二噁烷(15mL)中的2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)噻唑-2-基)肼-1,1,2-三甲酸三叔丁酯(4.43g,8.18mmol)中添加在二噁烷中的4摩尔浓度的HCl(100mL),然后在室温下搅拌4小时。将反应混合物浓缩,并将残余物悬浮在200mL乙醚中以得到白色沉淀物,将该白色沉淀物通过过滤收集,并在P2O5干燥剂下在高真空下干燥以获得白色固体。(1.25g,产率为66%)。
步骤4:(2-(3-(3-溴苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡
唑-1-基)噻唑-4-基)硼酸和(2-(5-(3-溴苯基)-3-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄
基)-1H-吡唑-1-基)噻唑-4-基)硼酸的合成
向在乙醇中的4-(2-(3-溴苯甲酰基)-4-环丙基-3-氧代丁基)-2-氟苯磺酰胺(2.455g,5.24mmol)中添加吡咯烷(0.217ml,2.62mmol)和对甲苯磺酸(0.499g,2.62mmol),然后回流6小时。将反应混合物冷却,并添加(2-肼基噻唑-4-基)硼酸(1.25g,7.86mmol),在70℃下搅拌过夜。在2小时后,LCMS显示作为区域异构体的具有相同质量的2种产物,将它们在使用用水(0.1%TFA)中40-100%的乙腈(0.1%TFA)洗脱的120g金C188柱的反相快速系统中分离。
步骤5:(2-(3-(3-溴苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡
唑-1-基)噻唑-4-基)硼酸或(2-(3-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-5-(3-((5-
甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-基)硼酸的合成
将在DMF(1mL)中的(2-(3-(3-溴苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-基)硼酸或(2-(5-(3-溴苯基)-3-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-基)硼酸(0.1g,0.169mmol)、2-乙炔基-5-甲基噻吩(0.026g,0.211mmol)、[P(tBu)3]Pd(巴豆基)Cl(http://jmcct.com/products-services/product_p429.html)(货号Pd-162)(1.688mg,4.23μmol)和DABCO(0.038g,0.338mmol)在室温下搅拌4小时。在反应完成后,将反应混合物与钯清除剂(silia-DMT)一起搅拌1小时,然后过滤通过注射器,并在制备HPLC上纯化,以获得(2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)-苯基)-1H-吡唑-1-基)噻唑-4-基)硼酸135或(2-(3-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-5-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-基)硼酸。
实施例24
该实施例描述了在本发明的一个实施方式中的2-(3-(3-叔丁基氨甲酰基-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸147的合成。参见方案8。
方案8
步骤1:2-(3-(3-(叔丁基氨甲酰基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨
磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯的合成
向2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(100.0mg,0.156mmol)、PdCl2(1.38mg,0.0078mmol)和PPh3(4.0mg,0.0156mmol)在DMSO(1.8mL)中的混合物中相继添加CsF(26.0mg,0.171mmol)和水(0.2mL)。使反应混合物在室温下搅拌5分钟,并添加异氰酸叔丁酯(26.4μL,0.234mmol)。将反应混合物在微波反应器中在150℃下辐照25分钟。将反应混合物倒至水中,并用乙酸乙酯萃取(3×15mL)。将有机层用盐水(1×20mL)洗涤并用无水硫酸镁干燥。将合并的有机层在旋转蒸发器中浓缩,并将粗产物(43.0mg)在下一个步骤中使用。
步骤2:2-(3-(3-(叔丁基氨甲酰基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨
磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸的合成。
将得自步骤1的2-(3-3-(叔丁基氨基甲酰基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(43.0mg,0.065mmol)溶解在二噁烷和MeOH(1.0mL/0.5mL)的混合物中,并添加1.0mL的NaOH的1N水溶液。将反应混合物在室温下搅拌2小时。将反应混合物通过添加1.0M盐酸水溶液中和,用乙酸乙酯(15mL)稀释,用水(10mL)洗涤,并用无水硫酸镁干燥。将有机层用旋转蒸发器浓缩,并将残余物溶解在DMSO中,并通过HPLC纯化(Phenomenex Gemini C18,40%至100%CH3CN的H2O/CH3CN梯度4分钟,0.1%TFA)以给出标题化合物147(11.0mg,26%)。2-(3-(3-(叔丁基氨甲酰基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸:1H-NMR(MeOD)δ:8.21(s,1H),7.79-7.69(m,3H),7.19(dd,J=8.6,10.0Hz,1H),7.11-7.05(m,2H),4.21(s,2H),3.28(d,J=6.8Hz,2H),1.44(s,9H),1.18-1.10(m,1H),0.43-0.39(m,2H),0.28-0.24(m,2H);MS(ES)630.1[M+H]+,LCMS RT=1.048分钟。
实施例25
在本发明的一个实施方式中的2-(5-(环丙基甲基)-3-(4-氟-3-(6-异丙基-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸158的合成。参见方案9。
方案9
将2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(50mg,0.078mmol,1当量)、2-异丙基-2,6-二氮杂螺[3.3]庚烷(12mg,0.086mmol,1.1当量)和甲苯(2.5mL)在氩气下添加到小瓶中。添加Pd2(dba)3(3.5mg,0.004mmol,0.05当量)、R-BINAP(7.3mg,0.012mmol,0.15当量)、Cs2CO3(77mg,0.235mmol,3.0当量)和2滴Et3N,并将反应混合物伴随搅拌下加热至110℃ 16小时。在冷却到室温后,将沉淀物通过过滤移除,并用EtOAc和MeOH洗涤。将滤液在真空中浓缩,然后再溶解在MeOH中,并用LiOH的1M水溶液(2mL)处理,并在室温下搅拌2小时。将反应用2M HCl猝灭,和然后用CH2Cl2萃取(×3)。将合并的有机相在真空中浓缩,并将得到的有机残余物通过HPLC纯化以提供6.0mg(11.4%)的期望的化合物158。1H NMR(MeOD)δ:8.19(s,1H),7.79(t,J=8.1Hz,1H),7.10(s,1H),7.08(d,J=4.8Hz,1H),7.00(d,J=8.9Hz,2H),6.28(d,J=8.5Hz,1H),4.35(d,J=11.7Hz,2H),4.28(d,J=11.6Hz,2H),3.70(s,2H),3.45(p,J=6.5,12.8Hz,1H),3.28(d,J=6.9Hz,2H),2.66(s,2H),1.24(d,J=6.48Hz,6H),1.17-1.12(m,1H),0.34-0.32(m,2H),0.22-0.21(m,2H);MS(ES)m/z 669.0[M+H]+;LCMS RT=0.970分钟。
实施例26
在本发明的一个实施方式中的2-(5-(环丙基甲基)-3-(4-氟-3-((5-甲基噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酰胺162的合成。参见方案10。
方案10
向火烧的干燥的圆底烧瓶中加入2-(5-(环丙基甲基)-3-(4-氟-3-((5-甲基噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(20mg,0.032mmol)。添加DMF(750mL),并将该溶液冷却到0℃。添加HATU(13.2mg,0.035mmol)和DIPEA(8.4uL,0.048mmol)并将反应混合物在0℃下搅拌30分钟。添加氨(10μL,1,4-二噁烷中0.5M),并将反应混合物在室温下搅拌15分钟。将反应混合物通过HPLC纯化(PhenomenexGemini C18,50%至95%CH3CN的H2O/CH3CN梯度5分钟,0.1%TFA)以给出标题化合物162(11mg,36%)。1H-NMR(d6-DMSO)δ8.12(s,1H),7.72-7.44(m,5H),7.62(s,2H),7.24(d,1H,J=4Hz),7.16(d,1H,J=12Hz),7.06(d,1H,J=8Hz),6.83(d,1H,J=2Hz),4.18(s,2H),3.16(m,2H),2.5(s,3H),1.08(m,1H),0.34(m,2H),0.17(m,2H);MS(ES)m/z 632.2[M+H]+;LCMSRT=0.77分钟。
实施例27
该实施例描述了根据以下一般方案的在本发明的一个实施方式中的2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',4',6-三氟-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸136的合成。参见方案11。
方案11
步骤1:2-(5-(环丙基甲基)-3-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼
烷-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯的合成。
向2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(500.0mg,0.78mmol)、双(频哪醇合)二硼(400mg,1.56mmol)和PdCl2(dppf)(58.0mg,0.078mmol)的混合物中添加KOAc(300mg,3.13mmol)与DME(8.0mL)。将反应混合物在微波反应器中在150℃下辐照20分钟。将反应混合物冷却到室温,用EtOAc稀释,并过滤通过硅胶塞。然后用EtOAc洗涤塞。将粗产物吸收到寅式盐上,并在硅胶柱上用0-50%己烷:EtOAc纯化以提供2-(5-(环丙基甲基)-3-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(399mg,74%):1H NMR(MeOD)δ8.19(s,1H),7.82-7.80(m,1H),7.77-7.72(m,2H),7.08-7.04(m,3H),4.38(q,7.27,14.29Hz,2H),4.16(s,2H),3.25(d,J=6.78Hz,2H),1.40(t,7.27Hz,3H),1.32(s,12H),1.14-1.12(m,1H),0.42-0.38(m,2H),0.29-0.25(m,2H);MS(ES)m/z 685.0[M+H]+;LCMS RT=1.217分钟。
步骤2:2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',4',6-三氟-[1,
1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸的合成。
将2-(5-(环丙基甲基)-3-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(50mg,0.075mmol,1.0当量)、4-溴-1-氯-2-甲基苯(45mg,0.22mmol,3.0当量)、PdCl2(dppf)(5.3mg,0.0073mmol,0.1当量)、THF(2.0mL)和1M Cs2CO3水溶液(0.9mL,0.9mmol,12.0当量)在小瓶中合并,并然后在微波反应器中在120℃下加热45分钟。在冷却到室温后,将反应混合物用H2O稀释,然后用EtOAc萃取(×3)。将合并的有机层用NaCl饱和水溶液洗涤,在Na2SO4上干燥,然后过滤并在真空中浓缩。将有机残余物在二氧化硅上通过快速层析纯化(在己烷中0-100%EtOAc的梯度)。将纯化的乙酯溶解在MeOH(3.0mL)中并用LiOH的1M水溶液(2mL)处理。将反应在室温下搅拌16小时,然后用1M HCl猝灭,并用EtOAc萃取(×3)。将合并的有机层在真空中浓缩,并然后将形成的有机残余物通过HPLC纯化以得到2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',4',6-三氟-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(11.1mg,23%):1H NMR(MeOD)δ:8.19(s,1H),7.75(t,J=7.9Hz,1H),7.65-7.61(m,1H),7.54(dd,J–2.19,7.37Hz,1H),7.34(bs,1H),7.22(dd,J=8.63,10.59Hz,1H),7.18(d,=9.55Hz,1H),7.10(bs,1H),7.08(d,J=4.03Hz,1H),4.19(s,2H),3.27(d,J=6.85Hz,2H),2.41(s,3H),1.16-1.10(m,1H),0.42-0.37(m,2H),0.26-0.23(m,2H);MS(ES)m/z 665.0[M+H]+,LCMS RT=1.307分钟。
实施例28
该实施例描述了在本发明的一个实施方式中的2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',4',6-三氟-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸136的合成。参见方案12。
方案12
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',4',6-三氟-[1,1'-联
苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸的合成。
向2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(50.0mg,0.078mmol)、双(三叔丁基膦)钯(8.0mg,0.016mmol)和(3,4-二氟苯基)硼酸(24.7mg,0.16mmol)在THF(4.0mL)中的混合物中添加碳酸铯的1.0M溶液(2.0mL)。将反应混合物在微波反应器中在120℃下辐照30分钟。将反应混合物冷却到室温。然后向该反应混合物中添加1.0M LiOH(水溶液)(3.0mL)并使其在室温下搅拌16小时。此时将反应用HCl水溶液酸化,并用乙酸乙酯萃取(3×15mL)。将有机层用无水硫酸镁干燥。将有机层使用旋转蒸发器浓缩,并将残余物溶解在DMSO中,和通过HPLC(PhenomenexGemini C18,40%至100%CH3CN的H2O/CH3CN梯度4分钟,0.1%TFA)纯化以给出标题化合物(10.0mg,24%)。1H NMR(MeOD)δ8.19(s,1H),7.75(t,8.01Hz,1H),7.65-7.61(m,1H),7.54(dd,J=2.11,7.59Hz,1H),7.42-7.37(m,1H),7.35-7.30(m,1H),7.23(dd,J=8.43,10.54Hz,1H),7.12-7.06(m,3H),4.18(s,2H),3.27(d,J=6.89Hz,2H),1.18-1.08(m,1H),0.42-0.38(m,1H),0.27-0.23(m,1H);MS(ES)m/z 642.9[M+H]+;LCMS RT=1.256分钟。
实施例29
该实施例描述了在本发明的一个实施方式中的2-(3-(3-乙酰基-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸140的合成。方案13。
方案13
2-(3-(3-乙酰基-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡
唑-1-基)噻唑-4-甲酸140的合成
向干燥的微波小瓶中加入2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(150mg,0.235mmol)、1,4-二噁烷(5mL)、Pd(PPh3)4(5.5mg,0.0047mmol)和三丁基(1-乙氧基乙烯基)锡烷(238μL,0.705mmol)。将小瓶封盖并在微波反应器中在120℃下加热30分钟。将反应混合物冷却并通过旋转蒸发器浓缩。将残余物通过快速层析(Combi-flash Rf,己烷:乙酸乙酯,0-50%梯度)纯化以给出2-(3-(3-乙酰基-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(100mg,71%)。将该酯(100mg,0.166mmol)溶解在THF/MeOH(1mL:1mL)中并添加LiOH(5M,500μL)。将反应混合物在室温下搅拌过夜。将反应混合物通过添加盐酸(1.2M)中和,用乙酸乙酯(15mL)稀释,用水(10mL)洗涤,并用无水硫酸镁干燥。将有机层使用旋转蒸发器浓缩,溶解在DMSO和MeOH的混合物中,并通过HPLC(Phenomenex Gemini C18,40%至100%CH3CN的H2O/CH3CN梯度4分钟,0.1%TFA)纯化以给出标题化合物140(40mg,42%)。MS(ES)m/z 573.0[M+H]+;LCMS RT=1.07分钟。
实施例31
该实施例描述了在本发明的一个实施方式中的2-(5-(环丙基甲基)-3-(4-氟-3-(吡咯烷-1-羰基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸154的合成。参见方案14。
方案14
2-(5-(环丙基甲基)-3-(4-氟-3-(吡咯烷-1-羰基)苯基)-4-(3-氟-4-氨磺酰基苄
基)-1H-吡唑-1-基)噻唑-4-甲酸的合成。
步骤1.
向2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(100.0mg,0.156mmol)在CH3CN(1.0mL)和甲苯(1.0mL)中的溶液中添加Mo(CO)6(61.7mg,0.234mmol)、Pd(OAc)2(3.5mg,0.0156mmol)、T-BINAP(10.5mg,0.0156mmol)、Cs2CO3(76.2mg,0.234mmol)和吡咯烷(20.0μL,0.234mmol)。将反应混合物在90℃下加热16小时。将反应混合物倒入水中,并用乙酸乙酯萃取(3×15mL)。将有机层用盐水(1×20mL)洗涤并用无水硫酸镁干燥。将合并的有机层在旋转蒸发器中浓缩,并将粗产物(31.0mg)用于下一个步骤。
步骤2.
将2-(5-(环丙基甲基)-3-(4-氟-3-(2-吡咯烷-1-羰基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(31.0mg,0.047mmol)溶解在二噁烷/MeOH(1.0mL/0.5mL)中,并添加NaOH(1.0mL,1M水溶液)。将反应混合物在室温下搅拌2小时。将反应混合物通过添加盐酸(1.0M水溶液)中和,用乙酸乙酯(15mL)稀释,用水(10mL)洗涤,并用无水硫酸镁干燥。将有机层使用旋转蒸发器浓缩,溶解在DMSO中,并通过HPLC(PhenomenexGemini C18,40%至100%CH3CN的H2O/CH3CN梯度4分钟,0.1%TFA)纯化以给出标题化合物154(10.0mg,24%):1H NMR(MeOD)δ8.22(s,1H),7.75-7.71(m,2H),7.54(dd,J=2.2,6.4Hz,1H),7.24(t,J=8.8Hz,1H),7.07(t,J=7.4Hz,2H),4.20(s,2H),3.59(t,J=7.1Hz,2H),3.30(d,J=6.9Hz,2H),3.19(t,J=2H),2.03-1.91(m,4H),0.95-0.86(m,1H),0.45-0.40(m,2H),0.29-0.25(m,2H);MS(ES)m/z 628.0[M+H]+;LCMS RT=0.968分钟。
实施例32
该实施例描述了在本发明的一个实施方式中的2-(5-(环丙基甲基)-3-(4-氟-3-(2-氧代吡咯烷-1-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸202的合成。参见方案15。
方案15
2-(5-(环丙基甲基)-3-(4-氟-3-(2-氧代吡咯烷-1-基)苯基)-4-(3-氟-4-氨磺酰
基苄基)-1H-吡唑-1-基)噻唑-4-甲酸的合成。
步骤1:
向2-(3-(3-溴-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(100.0mg,0.156mmol)、Pd2(dba)3(7.1mg,0.0078mmol)和Xantphos(13.5mg,0.0234mmol)在1,4-二噁烷(2.5mL)中的混合物中添加Cs2CO3(71.1mg,0.218mmol)。将反应混合物在室温下搅拌5分钟,并添加苯甲酰胺(24.5mg,0.202mmol)。将反应混合物在微波反应器中在160℃下加热20分钟。将反应混合物过滤经过寅式盐,用CH2Cl2洗涤,并真空浓缩。将粗产物(50.0mg)用于下一个步骤。
步骤2:
将2-(5-(环丙基甲基)-3-(4-氟-3-(2-氧代吡咯烷-1-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸乙酯(50.0mg)溶解在二噁烷/MeOH(1.0mL/0.5mL)中,并添加NaOH(1.0mL,1M水溶液)。将反应混合物在室温下搅拌2小时。将反应混合物通过添加盐酸(1.0M水溶液)中和,用乙酸乙酯(15mL)稀释,用水(10mL)洗涤,并用无水硫酸镁干燥。将有机层使用旋转蒸发器浓缩,溶解在DMSO中,并通过HPLC(Phenomenex Gemini C18,40%至100%CH3CN的H2O/CH3CN梯度4分钟,0.1%TFA)纯化以给出标题化合物202(11.0mg,11%):MS(ES)m/z614.0[M+H]+;LCMS RT=1.005分钟。
实施例33
方案16
步骤1:2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)-N-取代的噻唑-4-甲酰胺的合成。参见方案16。
将2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(0.1g,0.158mmol)和CDI(0.051g,0.316mmol)在ACN中的混合物在60℃下搅拌0.5小时,然后添加适当的胺(2当量)和DBU(0.048ml,0.316mmol),再次在60℃下搅拌12小时。过滤反应混合物并使用加压气流移除溶剂。将粗材料溶解在DMSO中,并在制备HPLC上纯化。
实施例34
该实施例描述了作为实施方式的举例的式(I)化合物的通过在实施例1中阐述的试验所测量的生化LDHA抑制活性。参见表7。指定化合物和基于IC50的活性水平如下:+++<100nM;++100nM-1000nM;+>1000nM-57000nM;和->57000nM。
表7
实施例35
该实施例描述了通过在实施例6中阐述的试验测量的,在本发明的一个实施方式中的示例性的式(I)化合物的乳酸产生的细胞抑制。参见表8。表8中的乳酸活性由0至3个加号代表,如下:+++<1μM;++1-10μM;+10-57μM;和->57μM。
表8
Claims (11)
1.一种式(II)的化合物或其药用盐:
其中
X是氢或卤素;
Y是氢或C1-C2烷基;
Z是-CO2H、-CONH2、-CONH(CN)、-CONHSO2CH3、-CONH(OH)、-COCF3、CH(OH)CF3、-CH2OH或-B(OH)2;
n是0、1、2或3;
R在每次出现时独立地选自卤素、羟基、C1-C4烷基、C1-C4烷氧基;
R10是(环丙基)C1-C4烷基,所述环丙基可选地被甲基或环丙基取代,或者以螺取向稠合到环丙基基团上,或者R10是(环丙基)C1-C4烷基,其中所述C1-C4烷基被环丙基取代。
2.根据权利要求1所述的化合物或盐,其中,X是氟。
3.根据权利要求1或2所述的化合物或盐,其中,R10是(环丙基)CH2-或(环丙基)CH2CH2-。
4.根据权利要求1至3中任一项所述的化合物或盐,其中,Y是氢。
5.根据权利要求1至4中任一项所述的化合物或盐,其中,Z是-COOH、-CH2OH或-CONH2。
6.根据权利要求1所述的化合物或其药用盐,其中,所述化合物是
2-(5-(环丙基甲基)-3-(6-氟-4'-甲基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(101);
2-(5-(环丙基甲基)-3-(6-氟-4'-(三氟甲基)-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(102);
2-(5-(环丙基甲基)-3-(6-氟-2'-甲基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(103);
2-(5-(环丙基甲基)-3-(6-氟-4'-甲氧基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(104);
2-(5-(环丙基甲基)-3-(6-氟-4',4'-二甲基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(106);或
2-(5-(环丙基甲基)-3-(4-氟-3-(6-异丙基-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(158)。
7.一种化合物或其药用盐,其中,所述化合物是
2-(5-(环丙基甲基)-3-(6-氟-4'-甲基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(101);
2-(5-(环丙基甲基)-3-(6-氟-4'-(三氟甲基)-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(102);
2-(5-(环丙基甲基)-3-(6-氟-2'-甲基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(103);
2-(5-(环丙基甲基)-3-(6-氟-4'-甲氧基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(104);
2-(5-(环丙基甲基)-3-(4-氟-3-(1H-茚-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(105);
2-(5-(环丙基甲基)-3-(6-氟-4',4'-二甲基-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(106);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(4',4',6-三氟-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(107);
2-(5-(环丙基甲基)-3-(4-氟-3-(螺[2.5]辛-5-烯-6-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(108);
2-(3-(3-(丁-1-炔-1-基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(109);
2-(3-(3-((5-(叔丁基)噻吩-2-基)乙炔基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(110);
2-(5-(环丙基甲基)-3-(4-氟-3-((2-甲基噻唑-5-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(111);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(112);
2-(5-(2-环丙基乙基)-3-(4-氟-3-((5-甲基噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(113);
2-(5-(环丙基甲基)-3-(4-氟-3-((5-甲基噻唑-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(114);
2-(5-(2-环丙基乙基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(115);
2-(5-(1-环丙基乙基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(116);
2-(5-(环丙基甲基)-3-(3-((5-环丙基噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(117);
2-(3-(3-((5-氯噻吩-2-基)乙炔基)苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(118);
(E)-2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(2-(5-甲基噻吩-2-基)乙烯基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(119);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((3-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(120);
2-(5-(环丙基甲基)-3-(3-((5-(二氟甲基)噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(121);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噁唑-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(122);
2-(4-(3-氟-4-氨磺酰基苄基)-5-((1-甲基环丙基)甲基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(123);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-(三氟甲基)噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(124);
2-(5-(环丙基甲基)-3-(3-((3,5-二甲基噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(125);
2-(5-(二环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(126);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-异丙基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(127);
2-(5-(2-环丙基丙烷-2-基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(128);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基呋喃-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(129);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(2-(5-甲基噻吩-2-基)环丙基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(130);
2-(4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-5-(螺[2.2]戊烷-1-基)-1H-吡唑-1-基)噻唑-4-甲酸(131);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((顺式)-3-(5-甲基噻吩-2-基)环丁基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(132);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(3-(5-甲基噻吩-2-基)环丁基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(133);
2-(5-([1,1'-联(环丙烷)]-2-基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(134);
(2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-基)硼酸(135);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',4',6-三氟-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(136);
2-(5-(环丙基甲基)-3-(3',6-二氟-4'-甲基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(137);
2-(5-(环丙基甲基)-3-(6-氟-4'-(三氟甲基)-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(138);
2-(3-(4'-氯-6-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(139);
2-(3-(3-乙酰基-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(140);
2-(5-(环丙基甲基)-3-(6-氟-3'-甲基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(141);
2-(5-(环丙基甲基)-3-(6-氟-4'-异丙基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(142);
2-(5-(环丙基甲基)-3-(4-氟-3-(5,6,7,8-四氢萘-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(143);
2-(3-(4'-氯-3',6-二氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(144);
2-(5-(环丙基甲基)-3-(3-(吡咯烷-1-羰基)苯基)-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(145);
2-(5-(环丙基甲基)-3-(6-氟-2',3',4',5'-四氢-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(146);
2-(3-(3-(叔丁基氨甲酰基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(147);
2-(5-(环丙基甲基)-3-(3-(4,5-二氢呋喃-2-基)-4-氟苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(148);
2-(3-(3'-氯-6-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(149);
2-(5-(环丙基甲基)-3-(6-氟-4'-甲氧基-3'-甲基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(150);
2-(5-(环丙基甲基)-3-(6-氟-3',5'-二甲基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(151);
2-(3-(3-苯甲酰氨基-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(152);
2-(5-(环丙基甲基)-3-(6-氟-3',5'-二甲氧基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(153);
2-(5-(环丙基甲基)-3-(4-氟-3-(2-氧代吡咯烷-1-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(154);
2-(5-(环丙基甲基)-3-(3-(2,3-二氢-1H-茚-5-基)-4-氟苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(155);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3',5',6-三氟-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(156);
2-(5-(环丙基甲基)-3-(3',5'-二氯-6-氟-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(157);
2-(5-(环丙基甲基)-3-(4-氟-3-(6-异丙基-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(158);
2-(5-(环丙基甲基)-3-(4-氟-3-(1H-咪唑-2-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(159);
2-(3-(3-(1H-苯并[d]咪唑-2-基)-4-氟苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(160);
2-(5-(环丙基甲基)-3-(4-氟-3-(2-甲基-1H-咪唑-5-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(161);
2-(5-(环丙基甲基)-3-(4-氟-3-((5-甲基噻吩-2-基)乙炔基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酰胺(162);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酰胺(163);
2-(3-(4'-氯-3'-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(164);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(4'-甲氧基-3'-甲基-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(165);
2-(3-(4'-氯-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(166);
2-(5-(环丙基甲基)-3-(3'-氟-4'-甲基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(167);
2-(3-(4'-(叔丁基)-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(168);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(4'-异丙基-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(169);
2-(3-(4'-氯-3'-甲基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(170);
2-(3-(4'-环丙基-3'-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(171);
2-(3-(3'-氯-4'-甲氧基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(172);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3'-异丙基-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(173);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-(5,6,7,8-四氢萘-2-基)苯基)-1H-吡唑-1-基)噻唑-4-甲酸(174);
2-(3-(3'-氯-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(175);
2-(3-(4'-氰基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(176);
2-(5-(环丙基甲基)-3-(3',5'-二氟-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(177);
2-(5-(环丙基甲基)-3-(4'-(二甲基氨基)-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(178);
N-氰基-2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)噻唑-4-甲酰胺(179);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-1-基)-N-(甲基磺酰基)噻唑-4-甲酰胺(180);
4-((5-(环丙基甲基)-1-(4-(羟基甲基)噻唑-2-基)-3-(3-((5-甲基噻吩-2-基)乙炔基)苯基)-1H-吡唑-4-基)甲基)-2-氟苯磺酰胺(181);
2-(5-(环丙基甲基)-3-(3'-乙基-4'-甲氧基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(182);
2-(3-(4'-环丙基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(183);
2-(3-(4'-环丁基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(184);
2-(3-(4'-氯-6-氟-3'-甲基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(185);
2-(5-(环丙基甲基)-3-(3'-乙基-6-氟-4'-甲氧基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(186);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(4'-(2,2,2-三氟乙基)-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(187);
2-(3-(3-(叔丁基氨甲酰基)苯基)-5-(环丙基甲基)-4-(4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(188);
2-(3-(3-(1H-苯并[d]咪唑-2-基)苯基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(189);
2-(5-(环丙基甲基)-3-(4'-(二甲基氨基)-6-氟-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(190);
2-(3-(3'-氯-6-氟-4'-甲氧基-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(191);
2-(3-(3'-(叔丁基)-6-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(192);
2-(3-(4'-(叔丁基)-6-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(193);
2-(5-(环丙基甲基)-3-(3'-(二甲基氨基)-6-氟-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(194);
2-(5-(环丙基甲基)-3-(4',6-二氟-3'-甲基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(195);
2-(5-(环丙基甲基)-3-(3',6-二氟-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(196);
2-(5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-3-(4'-甲基-[1,1'-联苯]-3-基)-1H-吡唑-1-基)噻唑-4-甲酸(198);
2-(5-(环丙基甲基)-3-(6-氟-3'-异丙基-[1,1'-联苯]-3-基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(199);
2-(3-(3'-氰基-6-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(200);
2-(3-(4'-氰基-6-氟-[1,1'-联苯]-3-基)-5-(环丙基甲基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(201);或
2-(5-(环丙基甲基)-3-(4-氟-3-(2-氧代吡咯烷-1-基)苯基)-4-(3-氟-4-氨磺酰基苄基)-1H-吡唑-1-基)噻唑-4-甲酸(202)。
8.一种药物组合物,包含权利要求1至7中任一项所述的化合物或药用盐和药用载体。
9.权利要求1至7中任一项所述的化合物或其药用盐在制备用于治疗患者中的纤维化或癌症的药剂中的用途。
10.根据权利要求9所述的用途,其中,所述纤维化是特发性肺纤维化。
11.权利要求1至7中任一项所述的化合物或其药用盐在制备用于治疗具有对抗癌剂有抗性的癌细胞的患者中的癌症的药剂中的用途,所述治疗包括向所述患者给予有效量的所述化合物或其药用盐和所述抗癌剂,由此所述化合物或其药用盐使所述癌细胞对所述抗癌剂再敏化。
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US20220331360A1 (en) | 2019-08-07 | 2022-10-20 | The United States Of America,As Represented By The Secretary,Department Of Health And Human Services | T cells having enhanced anti-tumor activity |
US11752138B2 (en) | 2020-05-18 | 2023-09-12 | Vanderbilt University | Treating primary or idiopathic hyperoxaluria with small molecule inhibitors of lactate dehydrogenase |
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ITPI20090140A1 (it) | 2009-11-09 | 2011-05-10 | Univ Pisa | Composto inibitore dell'enzima lattato deidrogenasi (ldh) e composizione farmaceutica che comprende tale composto |
EP2635279A4 (en) | 2010-11-05 | 2014-10-29 | Glaxosmithkline Ip No 2 Ltd | CHEMICAL COMPOUNDS |
ITPI20110143A1 (it) | 2011-12-20 | 2013-06-21 | Univ Pisa | Agenti terapeutici in grado di ridurre la produzione cellulare di acido lattico e composizioni farmaceutiche che comprendono tali composti |
WO2013096151A1 (en) * | 2011-12-22 | 2013-06-27 | Glaxosmithkline Llc | Chemical compounds |
US9750761B2 (en) * | 2014-05-21 | 2017-09-05 | University Of Rochester | LDH inhibitors as treatment for fibrosis and fibrotic-related disorders |
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WO2013096153A1 (en) * | 2011-12-22 | 2013-06-27 | Glaxosmithkline Llc | Chemical compounds |
WO2015054283A1 (en) * | 2013-10-08 | 2015-04-16 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2015140133A1 (en) * | 2014-03-17 | 2015-09-24 | F. Hoffmann-La Roche Ag | Piperidine-dione derivatives |
WO2016109559A2 (en) * | 2014-12-29 | 2016-07-07 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Small molecule inhibitors of lactate dehydrogenase and methods of use thereof |
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AU2017290233A1 (en) | 2019-01-24 |
EP3478677B1 (en) | 2021-09-01 |
JP2019523237A (ja) | 2019-08-22 |
EP3478677A1 (en) | 2019-05-08 |
US10954228B2 (en) | 2021-03-23 |
US20190276448A1 (en) | 2019-09-12 |
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