WO2015106292A1 - Ligands de tyrosine-kinase bcr-abl capables de se dimériser dans une solution aqueuse, et procédés d'utilisation de ceux-ci - Google Patents
Ligands de tyrosine-kinase bcr-abl capables de se dimériser dans une solution aqueuse, et procédés d'utilisation de ceux-ci Download PDFInfo
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- WO2015106292A1 WO2015106292A1 PCT/US2015/011271 US2015011271W WO2015106292A1 WO 2015106292 A1 WO2015106292 A1 WO 2015106292A1 US 2015011271 W US2015011271 W US 2015011271W WO 2015106292 A1 WO2015106292 A1 WO 2015106292A1
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- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- alkyl
- amino
- ethoxy
- substituted
- Prior art date
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- 239000003446 ligand Substances 0.000 title claims abstract description 105
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 title claims abstract description 71
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 title claims abstract description 71
- 238000000034 method Methods 0.000 title claims description 44
- 239000007864 aqueous solution Substances 0.000 title description 12
- 230000000447 dimerizing effect Effects 0.000 title description 3
- 239000000178 monomer Substances 0.000 claims abstract description 267
- 239000012736 aqueous medium Substances 0.000 claims abstract description 24
- 239000000539 dimer Substances 0.000 claims abstract description 22
- 238000001727 in vivo Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 314
- -1 cycloalkenylalkyl Chemical group 0.000 claims description 262
- 125000004432 carbon atom Chemical group C* 0.000 claims description 157
- 229910052739 hydrogen Inorganic materials 0.000 claims description 120
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 120
- 125000005843 halogen group Chemical group 0.000 claims description 98
- 239000001257 hydrogen Substances 0.000 claims description 94
- 125000001072 heteroaryl group Chemical group 0.000 claims description 92
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 91
- 125000005647 linker group Chemical group 0.000 claims description 89
- 125000001424 substituent group Chemical group 0.000 claims description 84
- 229910052736 halogen Inorganic materials 0.000 claims description 79
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 71
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 68
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 66
- 235000002639 sodium chloride Nutrition 0.000 claims description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 125000001931 aliphatic group Chemical group 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000004429 atom Chemical group 0.000 claims description 44
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 40
- 125000001624 naphthyl group Chemical group 0.000 claims description 39
- 125000004043 oxo group Chemical group O=* 0.000 claims description 35
- 229910052760 oxygen Inorganic materials 0.000 claims description 35
- 229920006395 saturated elastomer Polymers 0.000 claims description 33
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 125000002883 imidazolyl group Chemical group 0.000 claims description 15
- 150000004677 hydrates Chemical class 0.000 claims description 14
- 239000002207 metabolite Substances 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
- 125000004450 alkenylene group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- ZTUUVDYQBLRAAC-UHFFFAOYSA-N bicyclo[2.2.1]hept-2-ene-5-carboxamide Chemical compound C1C2C(C(=O)N)CC1C=C2 ZTUUVDYQBLRAAC-UHFFFAOYSA-N 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000006413 ring segment Chemical group 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- GBLRQXKSCRCLBZ-YVQAASCFSA-N (1R,2S,1'R,2'S)-doxacurium Chemical compound COC1=C(OC)C(OC)=CC(C[C@H]2[N@+](CCC3=C2C(=C(OC)C(OC)=C3)OC)(C)CCCOC(=O)CCC(=O)OCCC[N@@+]2(C)[C@@H](C3=C(OC)C(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=C(OC)C=2)=C1 GBLRQXKSCRCLBZ-YVQAASCFSA-N 0.000 claims description 10
- 229910003827 NRaRb Inorganic materials 0.000 claims description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 229910052705 radium Inorganic materials 0.000 claims description 10
- 229910052701 rubidium Inorganic materials 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- GGNIKGLUPSHSBV-UHFFFAOYSA-N thiazole-5-carboxamide Chemical compound NC(=O)C1=CN=CS1 GGNIKGLUPSHSBV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 8
- 229960002411 imatinib Drugs 0.000 claims description 8
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 8
- 229910052710 silicon Inorganic materials 0.000 claims description 8
- 239000010703 silicon Substances 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 6
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 6
- VHDBSLVLZYWMMM-UHFFFAOYSA-N N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide Chemical compound NCCOCCOCCNC(C1=CC(=CC=C1)C1=NC=NC(=C1)NC1=CC=C(C=C1)OC(F)(F)F)=O VHDBSLVLZYWMMM-UHFFFAOYSA-N 0.000 claims description 6
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000005960 1,4-diazepanyl group Chemical group 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002137 L01XE24 - Ponatinib Substances 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 229910006069 SO3H Inorganic materials 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000004970 halomethyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- FHPMSPHSCATFOI-UHFFFAOYSA-N oxaborole-5-carboxamide Chemical compound O1B=CC=C1C(=O)N FHPMSPHSCATFOI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 4
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 claims description 4
- 229960001131 ponatinib Drugs 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- DCMXZGHPFREOGR-WFLWKIQJSA-N (1R,2R,4R)-N-[2-[2-[2-[2-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound O=C(NCCOCCOCCOCCOCCOCCOCCNC(=O)[C@H]1[C@H]2C=C[C@@H](C1)C2)C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F DCMXZGHPFREOGR-WFLWKIQJSA-N 0.000 claims description 3
- ALXSLSBGLWOEQN-TVZXLZGTSA-N (1R,2R,4R)-N-[2-[2-[2-[2-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC1=CC(=NC=N1)C=1C=NN(C1)CCOCCOCCOCCNC(=O)[C@H]1[C@H]2C=C[C@@H](C1)C2)(F)F ALXSLSBGLWOEQN-TVZXLZGTSA-N 0.000 claims description 3
- BDFBNEPMHOIFFT-BERHBOFZSA-N (1R,2S,4S)-N-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC1=CC(=NC=N1)C=1C=C(C(=O)NCCOCCOCCNC(=O)[C@@H]2[C@H]3C=C[C@H](C2)C3)C=CC1)(F)F BDFBNEPMHOIFFT-BERHBOFZSA-N 0.000 claims description 3
- DCMXZGHPFREOGR-KQDQWFAOSA-N (1S,2S,4S)-N-[2-[2-[2-[2-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound O=C(NCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1[C@@H]2C=C[C@H](C1)C2)C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F DCMXZGHPFREOGR-KQDQWFAOSA-N 0.000 claims description 3
- JKPQXECVKYDDLU-IRYADYCUSA-N (1S,2S,4S)-N-[2-[2-[4-[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]piperazin-1-yl]ethoxy]ethyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC1=CC(=NC=N1)C=1C=C(C(=O)N2CCN(CC2)CCOCCNC(=O)[C@@H]2[C@@H]3C=C[C@H](C2)C3)C=CC1)(F)F JKPQXECVKYDDLU-IRYADYCUSA-N 0.000 claims description 3
- FHKZFZBVHLQDEC-OZNIXHKMSA-N 2-[[6-[4-[2-[2-[2-[2-[[(1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl]piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide Chemical compound [C@H]12[C@@H](C[C@H](C=C1)C2)C(NCCOCCOCCOCCN2CCN(CC2)C2=CC(=NC(=N2)C)NC=2SC(=CN2)C(=O)NC2=C(C=CC=C2C)Cl)=O FHKZFZBVHLQDEC-OZNIXHKMSA-N 0.000 claims description 3
- 239000003840 Bafetinib Substances 0.000 claims description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 3
- 239000002145 L01XE14 - Bosutinib Substances 0.000 claims description 3
- LPMMCUHTJWBBQK-UHFFFAOYSA-N N-[2-[2-[2-[[4-[2-aminoethoxy(phenyl)boranyl]benzoyl]amino]ethoxy]ethoxy]ethyl]-3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide Chemical compound NCCOB(C1=CC=C(C(=O)NCCOCCOCCNC(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O)C=C1)C1=CC=CC=C1 LPMMCUHTJWBBQK-UHFFFAOYSA-N 0.000 claims description 3
- MJXVVZUGTDLMIK-UHFFFAOYSA-N [2-methyl-4-[2-[2-[2-[2-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]boronic acid Chemical compound CC1=C(C=CC(=C1)C(NCCOCCOCCOCCOCCOCCOCCNC(C1=CC(=CC=C1)C1=NC=NC(=C1)NC1=CC=C(C=C1)OC(F)(F)F)=O)=O)B(O)O MJXVVZUGTDLMIK-UHFFFAOYSA-N 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- ZGBAJMQHJDFTQJ-DEOSSOPVSA-N bafetinib Chemical compound C1[C@@H](N(C)C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=NC=3)C(C)=CC=2)C=C1C(F)(F)F ZGBAJMQHJDFTQJ-DEOSSOPVSA-N 0.000 claims description 3
- 229950002365 bafetinib Drugs 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 claims description 3
- 229960003736 bosutinib Drugs 0.000 claims description 3
- 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 3
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 3
- 229960001346 nilotinib Drugs 0.000 claims description 3
- XVVNLLFTOALISQ-UHFFFAOYSA-N phenyl-[4-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]borinic acid Chemical compound OB(C1=CC=C(C(=O)NCCOCCOCCNC(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O)C=C1)C1=CC=CC=C1 XVVNLLFTOALISQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- SYPMMTNYDPAXRM-XXOIVITRSA-N (1R,2S,4S,5S,6R)-5,6-dihydroxy-N-[2-[2-[2-[2-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]heptane-2-carboxamide Chemical compound O[C@H]1[C@@H]2C[C@@H]([C@H]([C@H]1O)C2)C(=O)NCCOCCOCCOCCOCCOCCOCCNC(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O SYPMMTNYDPAXRM-XXOIVITRSA-N 0.000 claims description 2
- UPPIGOBFTMWMCV-QNZNQXNQSA-N (1R,2S,4S,5S,6R)-5,6-dihydroxy-N-[2-[2-[2-[2-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]heptane-2-carboxamide Chemical compound O[C@H]1[C@@H]2C[C@@H]([C@H]([C@H]1O)C2)C(=O)NCCOCCOCCOCCN2N=CC(=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F UPPIGOBFTMWMCV-QNZNQXNQSA-N 0.000 claims description 2
- CJASKSCNNRNZRE-FKKRYKJISA-N (1R,2S,4S,5S,6R)-5,6-dihydroxy-N-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]heptane-2-carboxamide Chemical compound O[C@H]1[C@@H]2C[C@@H]([C@H]([C@H]1O)C2)C(=O)NCCOCCOCCNC(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O CJASKSCNNRNZRE-FKKRYKJISA-N 0.000 claims description 2
- NXLLJJRZGRQVPI-HIOZGICLSA-N (1R,2S,4S,5S,6R)-5,6-dihydroxy-N-[2-[2-[4-[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]piperazin-1-yl]ethoxy]ethyl]bicyclo[2.2.1]heptane-2-carboxamide Chemical compound O[C@H]1[C@@H]2C[C@@H]([C@H]([C@H]1O)C2)C(=O)NCCOCCN2CCN(CC2)C(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O NXLLJJRZGRQVPI-HIOZGICLSA-N 0.000 claims description 2
- SYPMMTNYDPAXRM-ZWRBOZOESA-N (1S,2R,4R,5R,6S)-5,6-dihydroxy-N-[2-[2-[2-[2-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]bicyclo[2.2.1]heptane-2-carboxamide Chemical compound O[C@@H]1[C@H]2C[C@H]([C@@H]([C@@H]1O)C2)C(=O)NCCOCCOCCOCCOCCOCCOCCNC(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O SYPMMTNYDPAXRM-ZWRBOZOESA-N 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- PVRLCVGNRDUXDM-UHFFFAOYSA-N 1-hydroxy-3,3-dimethyl-N-[2-[2-[2-[2-[2-[2-[2-[[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-2,1-benzoxaborole-5-carboxamide Chemical compound OB1OC(C2=C1C=CC(=C2)C(=O)NCCOCCOCCOCCOCCOCCOCCNC(C2=CC(=CC=C2)C2=NC=NC(=C2)NC2=CC=C(C=C2)OC(F)(F)F)=O)(C)C PVRLCVGNRDUXDM-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0834—Compounds having one or more O-Si linkage
- C07F7/0836—Compounds with one or more Si-OH or Si-O-metal linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- Bcr-Abl tyrosine kinase arises as a result of fusion between break point cluster (Bcr) gene at human chromosome 22 and Abelson (Abl) tyrosine kinase gene at human chromosome 9 and has been implicated as a cause of chronic myelogenous leukemia.
- Bcr break point cluster
- Abl Abelson
- tyrosine kinase gene at human chromosome 9 has been implicated as a cause of chronic myelogenous leukemia.
- Several inhibitors of Bcr-Abl tyrosine kinase have been developed for the treatment of chronic myelogenous leukemia, for example imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.
- the kinase domain of Bcr-Abl tyrosine kinase contains at least two binding pockets, i.e., a myristoyl binding pocket and an ATP binding pocket, and inhibitors of Bcr-Abl tyrosine kinase generally bind to the ATP binding pocket.
- Bcr-Abl tyrosine kinase inhibitors in treating cancer (e.g., chronic myelogenous leukemia) has been limited by the emergence of resistant Bcr-Abl tyrosine kinase mutants.
- such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g., a dimer).
- Contemplated monomers may include a ligand moiety (e.g., a pharmacophore for the target biomolecule), a linker element, and a connector element that joins the ligand moiety and the linker element.
- a ligand moiety e.g., a pharmacophore for the target biomolecule
- linker element e.g., a pharmacophore for the target biomolecule
- a connector element that joins the ligand moiety and the linker element.
- contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules
- a first monomer capable of forming a biologically useful multimer capable of modulating a Bcr-Abl tyrosine kinase having a first binding site when in contact with a second monomer in an aqueous media is provided.
- Such a first monomer may be represented by the formula:
- X 1 is a first ligand moiety capable of modulating the first binding site on said Bcr-Abl tyrosine kinase
- Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
- Z 1 is a first linker capable of binding to the second monomer; and the second monomer is represented by the formula:
- X 2 -Y 2 -Z 2 (Formula II) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein X 2 is a second ligand moiety capable of modulating a second binding site on said Bcr-Abl tyrosine kinase;
- Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ; and Z 2 is a second linker capable of binding to the first monomer through Z 1 .
- a therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer and a second monomer is provided.
- a first monomer may be represented by:
- X 1 is a first ligand moiety capable of modulating a first Bcr-Abl tyrosine kinase binding site
- Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
- Z 1 is a first linker capable of binding to Z 2 to form the multimer
- X 2 is a second ligand moiety capable of modulating a second Bcr-Abl tyrosine kinase binding site
- Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ; and Z 2 is a boronic acid or oxaborale moiety capable of binding with the Z 1 moiety of Formula I to form the multimer; and
- a first monomer is provided, wherein the first monomer is represented by the formula X 3 -Y 3 -Z 3 (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
- X 3 is a first ligand moiety capable of modulating a Bcr-Abl tyrosine kinase binding site; Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3 ; and Z 3 is a linker capable of forming a therapeutic multimer with another monomer or other monomers of Formula III, wherein Z 3 is the same for the first monomer and other monomers of the multimer.
- a method of treating a disease associated with a Bcr-Abl tyrosine kinase in a patient in need thereof can include administering to said patient a first monomer represented by: X 1 -Y 1 -Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 1 is a first ligand moiety capable of modulating a first Bcr-Abl tyrosine kinase binding site; and administering to said patient a second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), wherein X 2 is a second ligand moiety capable of modulating a second Bcr-Abl tyrosine kinase binding site, wherein upon administration, said first monomer and said second monomer forms a multimer in vivo that binds to the first and the second Bcr- Abl
- FIG. 1 shows a screenshot of a protein X-ray crystal structure in which the structures of imatinib and dasatinib are overlaid, according to an embodiment.
- FIG. 2 shows a non-limiting set of pharmacophores (i.e., ligands) with preferred attachment points for connecting the pharmacophores to connecting moieties indicated by arrows, according to an embodiment.
- pharmacophores i.e., ligands
- such monomers may be capable of binding to another monomer in an aqueous media (e.g., in vivo) to form a multimer, (e.g., a dimer).
- Contemplated monomers may include a ligand moiety (e.g., a pharmacophore moiety), a linker element, and a connector element that joins the ligand moiety and the linker element.
- a ligand moiety e.g., a pharmacophore moiety
- linker element e.g., a pharmacophore moiety
- a connector element that joins the ligand moiety and the linker element.
- contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g.
- contemplated monomers may be separate or separatable in a solid or in an aqueous media under one set of conditions, and when placed in an aqueous media having one or more biomolecules (e.g., under a different set of conditions) can 1) form a multimer with another monomer through the linker on each monomer; and either: 2a) bind to the biomolecule in two or more locations (e.g., protein binding sites) through each ligand moiety of the respective monomer or 2b) bind to two or more biomolecules through each ligand moiety of the respective monomer.
- locations e.g., protein binding sites
- disclosed monomers may interact with another appropriate monomer (i.e., a monomeric pair) in an aqueous media (e.g., in vivo) to form a multimer (e.g., a dimer) that can bind to two separate target biomolecule binding sites (e.g., protein binding sites).
- a multimer e.g., a dimer
- the two separate target binding sites can be proximal binding sites on the same target, for example, the myristoyl binding pocket and ATP binding pocket of Bcr-Abl tyrosine kinase.
- the ligand moiety of a contemplated monomer may be a pharmacophore or a ligand moiety that is, e.g., capable of binding to and/or modulating a biomolecule, such as, for example, a protein, e.g, a specific protein binding site, a component of a biological cell, such as a ribosome (composed of proteins and nucleic acids) or an enzyme active site (e.g., a protease, such as tryptase).
- the linker element comprises a functional group capable of forming a chemical bond with another linker element.
- the linker moiety may also serve as a signaling entity or“reporter,” and in some instances the assembly of two or more linkers can produce a fluorescent entity or fluorophore with properties distinct from the individual linker moiety.
- a plurality of monomers, each comprising a linker element may react to form a multimer connected by the linker elements.
- the multimer may be formed in vivo.
- the multimer may have enhanced properties relative to the monomers that form the multimer. For example, in certain embodiments, the multimer may bind to a target with greater affinity than any of the monomers that form the multimer. Also described are methods of making the compositions and methods of administering the compositions.
- the first ligand moiety and the second ligand moiety may each be capable of binding to a binding site of Bcr-Abl tyrosine kinase.
- X 1 , X 2 , X 3 and X 4 of Formulae I, II, III or IV may each be capable of binding to a binding site of a Bcr-Abl tyrosine kinase.
- a ligand moiety may be capable of binding to the myristoyl binding pocket of Bcr-Abl tyrosine kinase or the ATP binding pocket of Bcr-Abl tyrosine kinase.
- the first ligand moiety may be capable of binding to the myristoyl binding pocket of Bcr-Abl tyrosine kinase and the second ligand moiety may be capable of binding to the ATP binding pocket of Bcr-Abl tyrosine kinase.
- a plurality of monomers may assemble to form a multimer.
- the multimer may be used for a variety of purposes. For example, in some instances, the multimer may be used to perturb a biological system. As described in more detail below, in some embodiments, the multimer may bind to or modulate a target biomolecule, such as a protein (e.g., Bcr-Abl tyrosine kinase). In certain embodiments, a contemplated multimer may be used as a pharmaceutical.
- a multimer may form in vivo upon administration of suitable monomers to a subject.
- the multimer may be capable of interacting with a relatively large target site as compared to the individual monomers that form the multimer.
- a target may comprise, in some embodiments, two protein binding sites separated by a distance such that a multimer, but not a monomer, may be capable of binding to both binding sites essentially simultaneously.
- contemplated multimers may bind to a target with greater affinity as compared to a monomer binding affinity alone.
- a contemplated multimer may advantageously exhibit enhanced properties relative to the monomers that form the multimer.
- a multimer may have improved binding properties as compared to the monomers alone.
- a multimer may have improved signaling properties.
- the fluorescent properties of a multimer may be different as compared to a monomer.
- the fluorescent brightness of a multimer at a particular wavelength may be significantly different (e.g., greater) than the fluorescent brightness at the same wavelength of the monomers that form the multimer.
- a difference in signaling properties between the multimer and the monomers that form the multimer may be used to detect formation of the multimer.
- detection of the formation of the multimer may be used to screen monomers, as discussed in more detail below.
- the multimers may be used for imaging or as diagnostic agents.
- a multimer may be a homomultimer (i.e., a multimer formed from two or more essentially identical monomers) or may be a heteromultimer (i.e., a multimer formed from two or more substantially different monomers).
- a contemplated multimer may comprise 2 to about 10 monomers, for example, a multimer may be a dimer, a trimer, a tetramer, or a pentamer.
- a monomer may comprise a ligand moiety, a linker element, and a connector element that associates the ligand moiety with the linker element.
- the linker element of a first monomer may combine with the linker element of a second monomer.
- the linker element may comprise a functional group that can react with a functional group of another linker element to form a bond linking the monomers.
- the linker element of a first monomer may be substantially the same as the linker element of a second monomer.
- the linker element of a first monomer may be substantially different than the linker element of a second monomer.
- the ligand moiety may be a pharmacophore.
- the ligand moiety (e.g., a pharmacophore) may bind to a target molecule with a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.
- a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.
- the IC 50 of the first monomer against a first target binding site and the IC 50 of the second monomer against a second target binding site may be greater than the apparent IC 50 of a combination of the monomers against the first target binding site and the second target binding site.
- the concentration of the first monomer may be held constant while the concentration of the second monomer is varied.
- the combination of monomers may be any suitable ratio.
- the ratio of the first monomer to the second monomer may be between 10:1 to 1:10, in some embodiments between 5:1 and 1:5, and in some embodiments between 2:1 and 1:2. In some cases, the ratio of the first monomer to the second monomer may be essentially 1:1.
- the ratio of the smaller of the IC 50 of the first monomer and the second monomer to the apparent IC 50 of the multimer may be at least 3.0. In other instances, the ratio of the smaller IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 10.0. In some embodiments, the ratio of the smaller IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 30.0. When the concentration of the first monomer is held constant, the ratio of the apparent IC 50 of the multimer to the IC 50 of the second monomer may be, in some embodiments, at least 3.0, at least 10.0, or at least 30.0.
- the apparent IC 50 resulting from an essentially equimolar combination of monomers against the first target binding site and the second target binding site may be, in some embodiments, at least about 3 to 10 fold lower, at least about 10 to 30 fold lower, at least about 30 fold lower, or at least about 40 to 50 fold lower than the lowest of the IC 50 of the second monomer against the second target binding site or the IC 50 of the first monomer against the first target binding site.
- the affinity of the multimer for the target biomolecule(s) are less than 1 ⁇ M, in some embodiments, less than 1 nM, in some embodiments, less than 1 pM, in some embodiments, less than 1 fM, and in some
- Affinities of individual heterodimerizing monomers for the target biomolecule can be assessed through the testing of the respective monomers in appropriate assays for the target activity or biology because they do not typically self-associate.
- the testing of homodimerizing monomers may not, in some embodiments, afford an affinity for the monomeric or dimeric state, but rather the observed effect (e.g. IC 50 ) is a result of the monomer-dimer dynamics and equilibrium, with the apparent binding affinity (or IC 50 ) being, e.g., a weighted measure of the monomer and dimeric inhibitory effects upon the target.
- the pH of the aqueous fluid in which the multimer forms may be between pH 1 and 9, in some embodiments, between pH 1 and 3, in some embodiments, between pH 3 and 5, in some embodiments, between pH 5 and 7, and in some embodiments, between pH 7 and 9.
- the multimer may be stable in an aqueous solution having a pH between pH 1 and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9.
- the aqueous solution may have a physiologically acceptable pH.
- the ligand moiety may be capable of binding to a target and at least partially disrupting a biomolecule-biomolecule interaction (e.g., a protein-protein interaction). In some embodiments, the ligand moiety may be capable of binding to a target and at least partially disrupting an intramolecular protein interaction. In some embodiments, the ligand moiety may be capable of at least partially stabilizing a biomolecule-biomolecule interaction. In certain embodiments, the ligand moiety may be capable of at least partially inhibiting a conformational change in a biomolecule target.
- a biomolecule-biomolecule interaction e.g., a protein-protein interaction
- the ligand moiety may be capable of binding to a target and at least partially disrupting an intramolecular protein interaction.
- the ligand moiety may be capable of at least partially stabilizing a biomolecule-biomolecule interaction. In certain embodiments, the ligand moiety may be capable of at least partially inhibiting a conformational change in a biomolecule target.
- the linker element may be capable of generating a signal.
- the linker element may be capable of fluorescing.
- the linker element may have greater fluorescence when the monomer to which it is attached is part of a multimer as compared to when the monomer to which it is attached is not part of a multimer.
- the fluorescent brightness of a linker element may increase by at least 2-fold, in some embodiments, by at least 5-fold, in some embodiments, by at least 10-fold, in some embodiments, by at least 50-fold, in some embodiments, by at least 100-fold, in some embodiments, by at least 1000-fold, and in some embodiments, by at least 10000-fold.
- a linker element in a multimer may have a peak fluorescence that is red-shifted relative to the peak fluorescence of the linker element in a monomer. In other embodiments, a linker element may have a peak fluorescence that is blue-shifted relative to the peak fluorescence of a linker element in a monomer.
- a first monomer may be capable of forming a biologically useful multimer capable of modulating a Bcr-Abl tyrosine kinase binding site when in contact with a second monomer in an aqueous media.
- a first monomer may be represented by the formula:
- X 1 is a first ligand moiety capable of binding to or modulating a first binding site on said Bcr-Abl tyrosine kinase; Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
- Z 1 is a first linker capable of binding to the second monomer; and a second monomer may be represented by the formula:
- X 2 is a second ligand moiety capable of binding to a second binding site on said Bcr-Abl tyrosine kinase
- Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ; and Z 2 is a second linker capable of binding to the first monomer through Z 1 .
- first and second monomer capable of forming a multimer when in contact in an aqueous solution each has a different linker, e.g., Z 1 and Z 2 are different, the monomers may be referred to as‘hetero’ monomers.
- first and second monomer capable of forming a multimer when in contact in an aqueous solution each has the same linker, e.g., Z 1 and Z 2 are the same, the monomers may be referred to as‘homo’ monomers.
- X 1 and X 2 are different.
- a monomer may be represented by the formula:
- X 3 is a ligand moiety capable of binding to a binding site of Bcr-Abl tyrosine kinase
- Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3 ;
- Z 3 is a linker capable of binding to one or more Z 3 moieties from other X 3 -Y 3 -Z 3 monomers to form a biologically useful multimer.
- a first monomer is capable of forming a biologically useful multimer when in contact with a second monomer in an aqueous media, wherein the first monomer is represented by the formula:
- X 1 is a first ligand moiety capable of binding to a first binding site of Bcr-Abl tyrosine kinase
- Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1 ;
- Z 1 is a first linker capable of binding to the second monomer (e.g., in-vivo); and the second monomer is represented by the formula:
- X 4 is a second ligand moiety capable of binding to a second binding site of Bcr- Abl tyrosine kinase, wherein the first binding site is e.g., within about 10, 20, 30, 40, 50, 60, 70, 80 or more ⁇ , e.g. within about 50 ⁇ of the second binding site;
- Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 4 ; and Z 4 is a second linker capable of binding to the first monomer through Z 1 .
- a first monomer may be capable of forming a biologically useful multimer when in contact with one, two, three or more monomers (e.g. a first silyl monomer and a second silyl monomer).
- a first and second monomer may be represented by the formula:
- X 3 -Y 3 -Z 3 (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 3 is a first ligand moiety capable of binding to and modulating a first binding site of Bcr-Abl tyrosine kinase; Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3 ; Z 3 is linker capable of forming a therapeutic multimer (e.g., dimer) with another monomer or other monomers of Formula III, wherein Z 3 is the same for the first and second monomer, as noted below.
- X 3 is a first ligand moiety capable of binding to and modulating a first binding site of Bcr-Abl tyrosine kinase
- Y 3 is absent or is a connector moiety covalently bound to X 3 and Z 3
- Z 3 is linker capable of forming a therapeutic multimer (e.g., dimer)
- the monomers when a first and second monomer capable of forming a multimer (e.g., dimer) when in contact in an aqueous solution and each monomer have the same linker, e.g., Z 3 , the monomers may be referred to as‘homo’ monomers.
- the second binding site may be within 30 ⁇ of the first binding site.
- the maximum distance between the first ligand moiety (e.g., first binding site) and the second ligand moiety (e.g., second binding site) in the biologically useful multimer is less than about 25 ⁇ , in some embodiments less than 20 ⁇ , and in some embodiments less than 15 ⁇ .
- the connector moiety may have a length of less than about 15 ⁇ . In certain other embodiments, the connector moiety may have a length of less than about 10 ⁇ . In still other embodiments, the connector moiety may have a length of less than about 5 ⁇ . [0037] In some embodiments, a monomer may be selected from the group consisting of:
- linker moieties Z 1 , Z 2 , Z 3 and Z 4 of Formulas I, II, III and IV may, in some embodiments, be the same or different.
- linker moieties are independently contemplated herein.
- the first monomer is represented by the formula
- X 1 -Y 1 -Z 1 wherein Z 1 is a first linker that, for example, may form a dimer with a second monomer, e.g., X 2 -Y 2 -Z 2 or X 4 -Y 4 -Z 4 , wherein, for example, Z 1 may be a diol and Z 2 or Z 4 may independently be a boronic acid or oxaborole moiety.
- Z 1 is a first linker selected from the group consisting of
- a 1 is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
- a 2 independently for each occurrence, is (a) absent; or (b) selected from the group consisting of–N–, acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, provided that at least one of A 1 and A 2 is present; or
- a 1 and A 2 together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;
- a 3 is selected from the group consisting of -NHR’, -SH, or -OH; W is CR’ or N;
- R’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -NO 2 , -SH, or -OH;
- n 1-6;
- R 1 is (a) absent; or (b) selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -NO 2 , -SH, or -OH;
- Q 1 is (a) absent; or (b) selected from the group consisting of substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic; or
- R 1 and Q 1 together with the atoms to which they are attached form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;
- BB independently for each occurrence, is a 4-8 membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one or more groups represented by R 2 , wherein the two substituents comprising -OH have a 1,2 or 1,3 configuration;
- each R 2 is independently selected from hydrogen, halogen, oxo, sulfonate, -NO 2 , -CN, - OH, -NH 2 , -SH, -COOH, -CONHR’, -CONH-SO 2 -R’, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R 2 together with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 membered cycloalkyl or heterocyclic bicyclic ring system;
- a 1 independently for each occurrence, is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
- R’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -NO 2 , -SH, or -OH; c) ;
- BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety;
- a 3 independently for each occurrence, is selected from the group consisting of–NHR’ or–OH;
- R 3 and R 4 are independently selected from the group consisting of H, C 1-4 alkyl, phenyl, or R 3 and R 4 taken together from a 3-6 membered ring;
- R 5 and R 6 are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C 1-4 alkoxy; halogen; -OH; -CN; - COOH; -CONHR’; or R 5 and R 6 taken together form phenyl or a 4-6 membered heterocycle; and
- R’ is selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroar l, -NH 2 , -NO 2 , -SH, or -OH;
- a 1 is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
- a 3 independently for each occurrence, is selected from the group consisting of–NHR’ or–OH;
- AR is a fused phenyl or 4-7 membered aromatic or partially aromatic heterocyclic ring, wherein AR is optionally substituted by oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; -S- C 1-4 alkyl; halogen; -OH; -CN; -COOH; -CONHR’;
- R 5 and R 6 are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; -OH; -CN; - COOH; CONHR’; and R’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or na hth l, substituted or unsubstituted heteroaryl, -NH 2 , -NO 2 , -SH, or–OH;
- Q 1 is selected from the group consisting of C 1-4 alkyl, alkylene, or a bond; C 1- 6 cycloalkyl; a 5-6 membered heterocyclic ring; or phenyl;
- Q 2 independently for each occurrence, is selected from the group consisting of H, C 1- 4 alkyl, alkylene, or a bond; C 1-6 cycloalkyl; a 5-6 membered heterocyclic ring; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted phenyl or naphthyl; or substituted or unsubstituted heteroaryl;
- a 3 independently for each occurrence, is selected from the group consisting of–NH 2 or -OH;
- a 4 independently for each occurrence, is selected from the group consisting of -NH- NH 2 ; -NHOH, -NH-OR’’, or–OH;
- R’’ is selected from the group consisting of H or C 1-4 alkyl
- a 5 is selected from the group consisting of–OH, -NH 2 , -SH, -NHR’’’;
- R’’’ is selected from -NH 2 ; -OH; phenoxy; heteroaryloxy; and C 1-4 alkoxy;
- R 5 and R 6 are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; -OH; -CN; - COOH; -CONHR’; or R 5 and R 6 taken together may form a 5-6 membered ring;
- R’ is selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH 2 , -SH, or–OH.
- a 1 may be selected from the group consisting of C 1 - C 3 alkylene optionally substituted with one, two, or three halogens, or–C(O)-.
- Z 1 may be , wherein R 2 , independently for each occurrence, is selected from H, C 1-4 alkyl, or two R 1 moieties taken together form a 5- or 6-membered cycloalkyl or heterocyclic ring, wherein R 3 is H, or
- Z 1 may be . In some cases, Z 1 may be
- Z 1 may be .
- Z 1 may be a monosaccharide or a disaccharide.
- Z 1 may be selected from the group consisting of , H
- X is selected from O, S, CH, NR’, or when X is NR’, N may be covalently bonded to Y of Formula I;
- R’ is selected from the group consisting of H, C 1-4 alkyl
- R 5 , R 6 , and R 7 are independently selected from the group consisting of H, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; -OH; -CN; - COOH; -CONHR’; or a mono- or bicyclic heterocyclic optionally substituted with amino, halo, hydroxyl, oxo, or cyano; and
- AA is a 5-6 membered heterocyclic ring optionally substituted by C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 1-4 alkoxy; halogen; -OH; -CN; -COOH; - CONHR’, or -S- C 1-4 alkyl.
- Z 1 may be .
- Z 1 may be .
- X may be nitrogen.
- Z 1 may be [0047]
- Z 1 may be For example, in some cases, the
- Z 1 may be In other instances, Z 1 may be In some embodiments, Z 1
- Z 1 may be .
- Z 1 may be .
- Z 1 may be [0049]
- Z 1 may be 5 .
- Z 1 may be .
- Z 1 may be .
- Z 1 may be .
- Z 1 may be . In other embodiments, Z 1
- the second monomer may be X 2 -Y 2 -Z 2 (Formula II), wherein Z 2 is a boronic acid or oxaborale moiety, and wherein X 2 is a second ligand capable of binding to a second target biomolecule segment (e.g. a segment of a fusion protein or a binding site of tandem binding sites), and Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 .
- X 1 and X 2 may be different.
- the second monomer may be X 4 -Y 4 -Z 4 (Formula IV), wherein Z 4 is a boronic acid or oxaborale moiety, and wherein X 4 is a second ligand moiety capable of binding to a protein binding site, wherein the protein binding site is within e.g., about 50 ⁇ of the binding site (e.g. a segment of a fusion protein or a second binding site of tandem binding sites), and Y 4 is absent or is a connector moiety covalently bound to X 4 and Z 4 .
- X 1 may be capable of binding to a first binding site
- X 4 may be capble of binding to a second binding site, wherein the second binding site is within, e.g., about 50 ⁇ of the first binding site.
- X 1 and X 4 may be different.
- the linker of the second monomer for example, Z 2 or Z 4
- , may be selected from the group consisting of: , or
- R 8 is selected from the group consisting of H, halogen, oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C 2-4 alkenyl, C 1-4 alkoxy; -S- C 1-4 alkyl; -CN; - COOH; or–CONHR’;
- a 1 is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;
- AA independently for each occurrence, is phenyl, naphthyl, or a 5-7 membered heterocyclic or heteroaryl ring having one, two, or three heteroatoms, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halogen, C 1- 4 alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C 2-4 alkenyl, C 1-4 alkoxy; -S- C 1-4 alkyl; -CN; -COOH;–CONHR’; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and R’ is H or C 1-4 alkyl.
- R 8 and the substituent comprising boronic acid may be ortho to each other, and R 8 may be–CH 2 NH 2 .
- monomer may be selected from the group consisting of: ,
- the linker of the second monomer may be selected from
- the linker of the second monomer may be selected from the group consisting of: ; wherein
- R 8 is selected from the group consisting of H, halogen, oxo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo or thio; C 2-4 alkenyl, C 1-4 alkoxy; -S- C 1-4 alkyl; -CN; - COOH; or–CONHR’;
- AA independently for each occurrence, is a 5-7 membered heterocyclic ring having one, two, or three heteroatoms, or phenyl, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halo, C 1-4 alkyl optionally substituted by hydroxyl, amino, halo, or thio; C 2-4 alkenyl, C 1-4 alkoxy; -S- C 1-4 alkyl; -CN; -COOH;–
- R’ is H or C 1-4 alkyl.
- a monomer may be represented by the formula:
- a 3 is–OH, -SH, or -NHR’
- R 3 is selected from the group consisting of H, halo, C 1-4 alkyl, C 3-6 cycloalkyl, and heterocycle, wherein C 1-4 alkyl, C 3-6 cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; and
- R 4 is selected from the group consisting of H, halo, C 1-4 alkyl, C 3-6 cycloalkyl, and heterocycle, wherein C 1-4 alkyl, C 3-6 cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; or
- R 3 and R 4 can be taken together with the atoms to which they are attached to form a substituted or unsubstituted phenyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated heterocycle;
- R’ is H or C 1-4 alkyl
- R’ is C 1-4 alkyl optionally substituted with hydroxyl; -NH 2 ; -OH; and C 1-4 alkoxy;
- R 3 is selected from the group consisting of H, halo, C 1-4 alkyl, C 3-6 cycloalkyl and heterocycle, wherein C 1-4 alkyl, C 3-6 cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl;
- R 4 is selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl and heterocycle, wherein C 1-4 alkyl, C 3-6 cycloalkyl, or heterocycle may be optionally substituted by one, two or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; or R 3 and R 4 can be taken together with the atoms to which they are attached to form a substituted or unsubstituted phenyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated heterocycle; and
- Z 3 is a linker moiety capable of binding to one or more X 3 -Y 3 -Z 3 monomers to form a biologically useful multimer.
- silyl monomers are contemplated that are capable of forming a biologically useful multimer when in contact with one, two, three or more second silyl monomers in an aqueous media.
- the silyl monomers can be represented by Formula III above, (e.g., X 3 -Y 3 -Z 3 ), but wherein Z 3 is independently selected from the group consisting of: ; wherein
- R W is absent or selected from the group consisting of -C 1-4 alkyl-, -O-C 1-4 alkyl-, -N(R a )-, -N(R a )-C 1-4 alkyl-, -O-, -C(O)C 1-4 alkyl-, -C(O)-O-C 1-4 alkyl-, -C 2-6 alkenyl-, -C 2-6 alkynyl-, -C 3- 6 cycloalkyl-, -phenyl- and -heterocycle-; wherein C 1-4 alkyl, R a , R b , C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, phenyl and heteroaryl may be optionally substituted by one, two, three or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, -C(O)C 1-4 alkyl
- W 1 independently for each occurrence, is (a) absent; or (b) selected from the group consisting of -C 1-4 alkyl-, -O-C 1-4 alkyl-, -C(O)-C 1-4 alkyl-, -N(R a )-C 1-4 alkyl-, -C(O)-O-C 1-4 alkyl-, -C 2-6 alkenyl-, -C 2-6 alkynyl-, -C 3-6 cycloalkyl-, -phenyl- or -heteroaryl-; wherein C 1-4 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, R’, phenyl and heteroaryl are optionally substituted independently, for each occurrence, with one, two, three or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, -C(O)C 1-6 alkyl,
- R’ is independently selected, for each occurrence, from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted
- Q 1 is independently selected, for each occurrence, from the group consisting of -NHR’, -SH, -OH, -O-C 1 - 6 alkyl, -S-C 1-6 alkyl, phenoxy, -S-phenyl, heteroaryl, -O-heteroaryl, -S- heteroaryl, halogen and -O-C 1 - 6 alkyl-NR a R b ;
- R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-4 alkyl; wherein C 1-4 alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl; or
- R a and R b together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl;
- R 1 and R 2 are selected independently, for each occurrence, from the group consisting of -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, -C 1-6 alkyl-NR a R b , phenyl and heteroaryl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, R a , R b , phenyl and heteroaryl, independently selected, for each occurrence, may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkyl, and phenyl; or
- R 1 and R 2 together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl;
- BB independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one, two, three or more groups represented by R BB ; wherein R 1 , independently for each occurrence, may be optionally bonded to BB; each R BB is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, -CONHR’, substituted or unsubstituted aliphatic, and substituted or unsubstituted heteroaliphatic; or two R BB together with the atoms to which they are attached form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system; and
- Q 2A is absent or selected from the group consisting of–NH-, -S-, -O-, -O-C 1 - 6 alkyl-, - C 1 - 6 alkyl-O-, -N(R’)-C 1 - 6 alkyl-, -C 1 -6alkyl-N(R’)-, -S-C 1 - 6 alkyl-, -C 1 - 6 alkyl-S- and -O-C 1 - 6 alkyl-NR a -; or Q 2A and R 1 , together with the silicon to which they are attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C 1-6 alkyl;
- W 1 and W 1A are (a) absent; or (b) selected from the group consisting of -O-, -C 1-4 alkyl-, -O-C 1-4 alkyl-, -N(R a )-C 1-4 alkyl-, -C(O)C 1-4 alkyl-, -C(O)-O- C 1-4 alkyl-, -C 2-6 alkenyl-, -C 2-6 alkynyl-, -C 3-6 cycloalkyl-, -phenyl- and -heteroaryl-; wherein C 1- 4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, R’, phenyl and heteroaryl may be optionally substituted independently, for each occurrence, with one, two, three or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, -C(
- R’ is independently selected, for each occurrence, from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted
- Q 1 and Q 1A are independently selected, for each occurrence, from the group consisting of -NHR’, -SH, -OH, -O-C 1 - 6 alkyl, -S-C 1-6 alkyl, phenoxy, -S-phenyl, heteroaryl, -O-heteroaryl, -S-heteroaryl, halogen and -O-C 1 - 6 alkyl-NR a R b ;
- R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-4 alkyl; wherein C 1-4 alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl; or
- R a and R b together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl;
- R 1 and R 2 are selected independently, for each occurrence, from the group consisting of -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, -C 1-6 alkyl-NR a R b , phenyl and heteroaryl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, R a , R b , phenyl and heteroaryl, independently selected, for each occurrence, may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkyl, and phenyl; or
- R 1 and R 2 together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl;
- W 2A is selected from the group consisting of N and CR W2A .
- R W2A is selected from the group consisting of hydrogen, C 1-4 alkyl, -O-C 1-4 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl and heteroaryl; wherein C 1-4 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, phenyl and heteroaryl may be optionally substituted independently, for each occurrence, with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl and cyano;
- BB independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety; wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety may be optionally substituted with one, two, three or more groups represented by R BB ; wherein R 1 , independently for each occurrence, may be optionally bonded to BB;
- each R BB is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, -CONHR’, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic; or two R BB together with the atoms to which they are attached may form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system.
- a monomer may be capable of reacting with one or more other monomers to form a multimer.
- a first monomer may react with a second monomer to form a dimer.
- a first monomer may react with a second monomer and a third monomer to form a trimer.
- a first monomer may react with a second monomer, a third monomer, and a fourth monomer to form a tetramer.
- each of the monomers that form a multimer may be essentially the same.
- each of the monomers that form a multimer may be substantially different.
- at least some of the monomers that form a multimer may be essentially the same or may be substantially different.
- the linker element of a first monomer and the linker element of a second monomer may be substantially different.
- a connector element of a first monomer and a connector element of a second monomer may be substantially different.
- the ligand moiety (e.g., a pharmacophore) of a first monomer and the ligand moiety (e.g., a pharmacophore) of the second monomer may be substantially different.
- formation of a multimer from a plurality of monomers may be irreversible. In some embodiments, formation of a multimer from a plurality of monomers may be reversible.
- the multimer may have an oligomer or dimer dissociation constant between 10 mM and 1 nM, in some embodiments between 1 mM and 100 nM, in some embodiments between 1 mM and 1 PM, and in some embodiments between 500 PM and 1 PM.
- the multimer may have a dissociation constant of less than 10 mM, in some embodiments less than 1 mM, in some embodiments less than 500 PM, in some embodiments less than 100 PM, in some embodiments less than 50 PM, in some embodiments less than 1 PM, in some embodiments less than 100 nM, and in some embodiments less than 1 nM.
- dissociation constant of less than 10 mM, in some embodiments less than 1 mM, in some embodiments less than 500 PM, in some embodiments less than 100 PM, in some embodiments less than 50 PM, in some embodiments less than 1 PM, in some embodiments less than 100 nM, and in some embodiments less than 1 nM.
- ligand moieties X 1 , X 2 , X 3 and X 4 of Formulas I, II, III and IV may, in some embodiments, be different.
- ligand moieties are independently contemplated herein.
- the ligand moiety may be a pharmacophore.
- pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects. In some embodiments, identification of a
- pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule.
- pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high- throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.
- monomers that include a pharmacophore may bind to the myristoyl binding pocket of Bcr-Abl tyrosine kinase or to the ATP binding pocket of Bcr-Abl tyrosine kinase.
- Such monomers may form a multimer, as disclosed herein, that may be capable of binding to the myristoyl binding pocket and the ATP binding pocket of Bcr-Abl tyrosine kinase.
- a ligand e.g., a pharmacophore
- an attachment point on a pharmacophore may be chosen so as to preserve at least some ability of the pharmacophore to bind to a binding site.
- preferred attachment points may be identified using X-ray crystallography. The following description of a non-limiting exemplary method illustrates how a preferred attachment point may be identified. For example, as shown in FIG.
- a small molecule 110 (dark gray) labeled “STI2” in the PDB file [also known as Imatinib or Gleevec or STI-571] may be identified.
- the Imatinib pyridyl ring (indicated by black circle 120) contains a nitrogen atom in the 3 position, which constitutes an adenine ring mimetic.
- the corresponding adenine ring mimetic in the new pharmacophore 140 should be aligned to this element.
- the final conformation and orientation of the newly aligned pharmacophore 140 in the site may be determined using a variety of approaches known to computational chemists, but can be done as simply as performing an energy minimization using a molecular mechanics forcefield.
- the alphanumeric identifiers in FIG. 1 correspond to amino acid residues in the 3K5V structure, where the letter of the identifier is the one-letter amino acid symbol and the number of the identifier is the position of the amino acid residue in the primary sequence of the protein.
- Attachment points such as the one labeled 150 on the aligned pharmacophore permit access to solvent exposed amino acid residues on the outer lip of the ATP-binding pocket such as T338 and L389 in the 3K5V structure and are considered preferred attachment points for linkers. It should be apparent to those skilled in the art that overlays of the imatinib pharmacophore with other alternate pharmacophores can be used to identify potential attachment points.
- FIG. 2 provides a non-limiting set of pharmacophores (i.e., ligands) showing preferred attachment points (indicated by circled arrows) for connecting the pharmacophore to a linker.
- pharmacophores i.e., ligands
- preferred attachment points indicated by circled arrows
- X 1 is a first ligand moiety capable of binding to a first binding site (e.g., the myristoyl binding pocket) of Bcr-Abl tyrosine kinase.
- X 2 is a second ligand moiety capable of binding to a second binding site (e.g., the ATP binding pocket) of Bcr-Abl tyrosine kinase, or to another binding site, e.g., near or adjacent to the first binding site.
- the disclosed ligand moieties, X 1 , X 2 , X 3 and X 4 of Formulas I, II, III and IV may be or include binding site ligands as described herein. It will be appreciated that the ligands disclosed herein can be attached at any open site to a–Y-Z moiety (e.g., -Y 1 -Z 1 , -Y 2 -Z 2 , -Y 3 -Z 3 , and -Y 4 -Z 4 ) as described herein. Such embodiments described below include specific references to each attachment site.
- Exemplary binding site ligands include Bcr-Abl tyrosine kinase ATP binding site li ands re resented b the formula: , wherein:
- T 1 and T 2 are each hydrogen, or together form ⁇ O or ⁇ S;
- R 1 is:
- R 6 is alkyl, alkenyl, alkynyl, cycloalkyl
- cycloalkylalkyl cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with U 1 , U 2 and one or more groups U 3 ;
- R 2 is:
- R 3 is:
- (1) are each independently hydrogen or R 6 ;
- (1) are each independently hydrogen or R 6 ;
- R 7 and R 8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with U 1 , U 2 and U 3 ; or
- any two of R 9 , R 10 , and R 11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with U 1 , U 2 and U 3 ;
- R 13 is:
- R 14 is:
- R 15 is:
- U 1 , U 2 and U 3 are each independently:
- U 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of U 1 , U 2 and U 3 ;
- any two of U 1 , U 2 , and U 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
- any two of U 1 , U 2 , and U 3 may together be—O—(CH 2 ) r —O—, where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
- U 4 and U 5 are each independently:
- (1) are each independently hydrogen or U 6 ;
- U 7 and U 8 , or U 6 and U 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with U 1 , U 2 and U 3 ; or
- U 7 or U 8 together with U 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with U 1 , U 2 and U 3 ;
- U 11 and U 12 are each independently:
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- a Bcr-Abl tyrosine kinase ATP binding site ligand may be represented by imatinib, nilotinib, bosutinib, ponatinib, DCC-2036, GNF5, or bafetinib.
- Exemplary Bcr-Abl tyrosine kinase myristoyl binding site ligands include those represented by the formula:
- L is selected from the group consisting of a bond, -O- and -NR 5 -, wherein R 5 is hydrogen or C 1-4 alkyl;
- R 1 is selected from the group consisting of -U 3 NR 6 R 7 , -U 3 OR 7 and -U 3 R 7 , wherein U 3 is a bond or C 1-4 alkylene, R 6 is hydrogen or C 1-4 alkyl and R 7 is selected from the group consisting of C 6-10 aryl and C 5-6 heteroaryl; wherein any aryl or heteroaryl is optionally substituted with 1 to 3 radicals independently selected from the group consisting of halo, amino, C 1-4 alkyl, halo- substituted C 1-4 alkyl, C 1-4 alkoxy and halo-substituted C 1-4 alkoxy;
- R 2 is selected from the group consisting ofhydrogen, halo, amino, C 1-4 alkyl, halo- substituted C 1-4 alkyl, C 1-4 alkoxy and halo-substituted C 1-4 alkoxy;
- R 3 is selected from the group consisting of C 3-8 heterocycloalkyl-C 0-4 alkyl, C 5- 10 heteroaryl-C 0-4 alkyl and C 6-10 aryl-C 0-4 alkyl; wherein any alkyl group is optionally substituted with 1 to 3 radicals selected from the group consisting of hydroxy, halo and amino; and any aryl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 3 radicals independently selected from the group consisting of halo, nitro, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy- C 1-6 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, phenyl, C 3-8 heterocycloalkyl, - U 3 C(O)NR 8 R 8 , -U 3 C(O)NR 8 R 9 , -U 3 C(O)R 9 , -U 3 S(O)NR
- R 10 is C 5-6 heteroaryl and R 11 is hydroxy-C 1-4 alkyl
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula: ,
- R 1 is pyrazolyl; wherein said pyrazolyl is unsubstituted or substituted with 1 to 2 R 6 groups;
- R 2 is pyrrolidinyl; wherein said pyrrolidinyl is substituted with one R 7 group;
- R 3 is selected from hydrogen and halo
- R 4 is selected from -SF 5 and -Y 2 -CF 2 -Y 3 ;
- R 6 at each occurrence is independently selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
- R 7 is selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl- amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyl)oxy, carboxy, methoxy-carbonyl, phosphonooxy, cyano, and amino-carbonyl;
- Y is selected from CH and N;
- Y 1 is selected from CH and N;
- Y 2 is selected from CF 2 , O and S(O) 0-2 ;
- Y 3 is selected from hydrogen, chloro, fluoro, methyl, difluoromethyl, and
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula: ,
- Y at each occurrence is independently selected from N and CH;
- Y 1 is selected from N and CR 5 ; wherein R 5 is selected from hydrogen, methoxy and imidazolyl; wherein said imidazolyl is unsubstituted or substituted with methyl;
- R 1 is selected from pyrazolyl, thiazolyl, pyrrolyl, imidazolyl, isoxazolyl, furanyl and thienyl; wherein said thiazolyl, pyrrolyl, imidazolyl, isoxazolyl, furanyl, or thienyl of R 1 is unsubstituted or substituted with 1 to 3 R 6 groups;
- R 2 is selected from pyrrolidinyl, piperidinyl, azetidinyl, morpholino, piperazinyl, 2-oxa- 6-azaspiro[3.4]-octanyl, 3-azabicyclo[3.1.0]hexan-3-yl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl, hexahydropyrrolo[3,4-c]pyrrolyl, 6-oxo-2,7-diazaspiro[4.4]-nonanyl, 1H-pyrrolo[3,4- c]pyridinyl, 1,4-oxazepan-4-yl, 2-oxooxazolidinyl, 1,4-diazepanyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, 3,8-dioxa-10-azabicyclo[4.3.1]decanyl, -OR
- R 3 is selected from hydrogen and halo
- R 4 is selected from -SF 5 and -Y 2 -CF 2 -Y 3 ;
- R 5a is selected from hydrogen and C 1-4 alkyl
- R 5b is selected from C 1-4 alkyl and tetrahydro-2H-pyran-4-yl; wherein said alkyl of R 5b is unsubstituted or substituted with 1 to 3 groups independently selected from hydroxy and dimethyl-amino;
- R 6 at each occurrence is independently selected from hydrogen, hydroxy, methyl, hydroxy, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl, cyclopropyl and dimethyl-amino-carbonyl;
- R 7 at each occurrence is independently selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyl)oxy, carboxy, methoxy- carbonyl, phosphonooxy, cyano, and amino-carbonyl; or two R 7 groups combine with the atom to which they are attached to form a ring selected from cyclopropyl, azetidin-3-yl and 3- azabicyclo[3.1.0]hexan-3
- Y 2 is selected from CF 2 , O and S(O) 0-2 ;
- Y 3 is selected from hydrogen, halo, methyl, difluoromethyl and trifluoromethyl; or pharmaceutically acceptable salts thereof.
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
- X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalk
- Y is -NH-, -O-, -S-, or -NR-;
- R is C 1-6 alkyl
- R 1 , R 2 , R 3 , and R 4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkyls
- alkynylsulfonamido of 2-6 carbon atoms hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, aminoalkyl of 1-4 carbon atoms, N- alkylaminoalkyl of 2-7 carbon atoms, N,N-dialkylaminoalkyl of 3-14 carbon atoms, phenylamino, benzylamino, ,
- R 5 is alkyl of 1-6 carbon atoms, alkyl optionally substituted with one or more halogen atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, nitro, cyano, or alkyl of 1-6 carbon atoms groups;
- R 6 is hydrogen, alkyl of 1-6 carbon atoms, or alkenyl of 2-6 carbon atoms
- R 7 is chloro or bromo
- R 8 is hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, N- alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms, N- cycloalkylaminoalkyl of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl-piperidino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxy
- n is an integer from 1-4, q is an integer from 1-3, and p is an integer from 0-3;
- any two of the substituents R 1 , R 2 , R 3 , or R 4 that are located on contiguous carbon atoms can together be the divalent radical -O-C(R 8 ) 2 -O-;
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the f rm l
- Ring T is a 5-membered heteroaryl ring containing 1-2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R t groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1-4 R e groups;
- Ring A is a 5- or 6-membered aryl or heteroaryl ring
- Ring B is a 5- or 6-membered aryl or heteroaryl ring
- R 1 , R 2 , and R 3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
- R 2 and R 3 taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatorns selected from N, O and S(O) r -;
- each occurrence of R 4 is independently selected from alkyl, haloalkyl, trifluoromethyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
- n 0,1 , 2, 3 or 4;
- n 2 or 3;
- p 0, 1, 2, 3, 4 or 5;
- r 0, 1 or 2;
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula: ,
- R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl
- R 2 represents phenyl substituted by one or two substituents selected from the group consisting of C 1-6 alkyl, trifluoro-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl- amino-C 1-6 alkyl, (C 1-6 alkyl) 2 N-C 1-6 alkyl, N-cyclohexyl-N-C 1-6 alkylamino-C 1-6 alkyl, C 1- 6 alkoxy-C(O)-piperidino-C 1-6 alkyl, N-C 1-6 alkyl-piperazino-C 1-6 alkyl, C 1-6 alkoxy-C(O)-C 1- 6 alkyl, hydroxy, C 1-6 alkoxy, trifluoro-C 1-6 alkoxy, 1H-imidazolyl-C 1-6 alkoxy, C 1-6 alkyl-C(O)-, benzoyloxy, carboxy, carbamoyl, C
- R 3 represents hydrogen, C 1-6 alkyl, or halo
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the f rm l
- R 1 is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-C 1-6 alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1H-indolyl or 1H- imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or C 1-6 alkyl- substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,
- R 2 and R 3 are each independently of the other hydrogen or C 1-6 alkyl, one or two of the radicals R 4 , R 5 , R 6 , R 7 and R 8 are each nitro, fluoro-substituted C 1-6 alkoxy or a radical represented by:
- R 9 is hydrogen or C 1-6 alkyl
- X is oxo, thio, imino, N-C 1-6 alkyl-imino, hydroximino or O-C 1-6 alkyl-hydroximino
- Y is oxygen or the group NH
- n 0 or 1
- R 10 is phenyl that is unsubstituted or substituted by halogen, cyano, C 1-6 alkoxy, carboxy, C 1-6 alkyl, or by 4-methyl-piperazinylmethyl; C 5-7 alkyl; thienyl; 2-naphthyl;
- R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, C 1- 6 alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or C 1-6 alkyl-C(O)-, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy;
- a Bcr-Abl tyrosine kinase ligand may be represented by: , or a pharmaceutically acceptable salt thereof.
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula: , wherein:
- E 1 is phenyl substituted with 1, 2, or 3 groups independently selected from fluoro and methyl;
- A is selected from the group consisting of imidazolyl and pyrazolyl, wherein A is substituted at any suitable position with a 10-membered bicyclic heteroaryl ring optionally substituted with 1, 2, or 3 R 1 groups;
- R 1 is independently selected from the group consisting of C 1-6 alkyl, branched C 3-7 alkyl, C 3-8 carbocyclyl, halogen, fluoroC 1-6 alkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R 2 ) 2 NC(O)-, -N(R 2 )C(O)R’, (R 2 ) 2 NSO 2 -, - N(R 2 )SO 2 R 2 , -(CH 2 ) q N(R 2 ) 2 , -O(CH 2 ) q N(R 2 ) 2 , -O(CH 2 ) q O-C 1-6 alkyl, -N(R 2 )(CH 2 ) q O-C 1-6 alkyl, -N(R 2 )(CH 2 ) q O-C 1-6 alkyl, -N(R 2 )(CH 2
- R 2 is H, C 1-6 alkyl, branched C 3-7 alkyl, C 3-8 carbocyclyl, or phenyl;
- t is 1, 2, or 3;
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- Exemplary Bcr-Abl tyrosine kinase ligands include those represented by the formula:
- Ring A is selected from the group consisting of phenylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, and triazinylene;
- Ring B is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and 1,2-dihydropyridazinyl, each optionally substituted with 1, 2, or 3 groups independently selected from C 1-6 alkyl, halo, and amino;
- R 1 is -(CH 2 ) n -R 5 , wherein R 5 is a saturated, nitrogen-containing heterocyclic group substituted by oxo, a saturated, nitrogen-containing heterocyclic group, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, C 1-6 alkoxy, C 1-6 alkyl, alkyoxycarbonyl, halo, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl,
- R 2 is selected from C 1-6 alkyl, halogen, haloalkyl, trifluoromethyl, hydroxyalkyl, C 1- 6 alkoxy, alkoxyalkyl, alkoxycarbonyl, acyl, amino, monoalkylamino, dialkylamino, nitro, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, and cyano;
- R 3 is selected from hydrogen, C 1-6 alkoxy, and halo
- R 4 is selected from hydrogen, C 1-6 alkyl, and halo
- n 1, 2, 3, or 4;
- a Bcr-Abl tyrosine kinase ligand may be represented by:
- connector moieties Y 1 , Y 2 , Y 3 , and Y 4 of Formulas I, II, III and IV may, in some embodiments, be the same or different.
- connector moieties are independently contemplated herein.
- a monomer may comprise a connector that joins the ligand moiety with the linker element.
- such connectors do not have significant binding or other affinity to an intended target.
- a connector may contribute to the affinity of a ligand moiety to a target.
- a connector element may be used to connect the linker element to the ligand moiety.
- a connector element may be used to adjust spacing between the linker element and the ligand moiety.
- the connector element may be used to adjust the orientation of the linker element and the ligand moiety.
- the spacing and/or orientation the linker element relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target.
- connectors with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a multimer to its target biomolecule.
- connectors with restricted degrees of freedom are preferred to promote cellular permeability of the monomer.
- the connector element may be used for modular assembly of monomers.
- a connector element may comprise a functional group formed from reaction of a first and second molecule.
- a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a linker element.
- the connector element may comprise a spacer having a first functional group that forms a bond with a ligand moiety and a second functional group that forms a bond with a linker element.
- Contemplated connecters may be any acceptable (e.g. pharmaceutically and/or chemically acceptable) bivalent linker that, for example, does not interfere with
- linkers may be substituted or unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, acyl, sulfone, phosphate, ester, carbamate, or amide.
- Contemplated connectors may include polymeric connectors, such a polyethylene glycol (e.g., , where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and X is C; O; S(O) q , where q is 0, 1, or 2; NH; N- alkyl; or -C(O)-) or other pharmaceutically acceptable polymers.
- polymeric connectors such as a polyethylene glycol (e.g., where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and X is C; O; S(O) q , where q is 0, 1, or 2; NH; N- alkyl; or -C(O)-) or other pharmaceutically acceptable polymers.
- a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 11 atoms in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.
- a connector may have the following structure: , where:
- n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
- R 1 and R 2 are, independently for each occurrence, selected from the group consisting of H, C 1-6 alkyl, C 1-6 heteroalkyl, phenyl, or heteroaryl, wherein alkyl, heteroalkyl, phenyl, and heteroaryl are optionally substituted with–OH, -NH 2 ,–SH, -COOH, -C(O)NH 2 , halo, phenyl, and heteroaryl; or
- a connector may comprise a phenyl, naphthyl, or mono or bicyclic heteroaryl ring, each optionally substituted.
- a connector may com rise one or more of the following aryl structures:
- a connector may compise a triazole ring having the following structure: , where R 1 and R 2 are the remainder of the connector.
- a monomer comprising a triazole-containing connector may have the following general structure:
- Such triazole-joined compounds may be formed, e.g., as a result of a“click” type reaction (i.e., an azide-alkyne cycloaddition).
- a first segment of a connector having a terminal alkyne and a second segment of a connector having a terminal azide may be joined by a“click” reaction to form a single connector joined by a triazole, as shown above.
- the first connector and the second connector each are less than or equal to 20 atoms in length, or in some embodiments each are less than or equal to 12 atoms in length.
- a connecter moiety may maximally span from about 5 ⁇ to about 50 ⁇ , in some embodiments about 5 ⁇ to about 25 ⁇ , in some embodiments about 20 ⁇ to about 50 ⁇ , in some embodiments about 20 ⁇ to about 30 ⁇ , and in some embodiments about 6 ⁇ to about 15 ⁇ in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.
- a connecter moiety may maximally span from about 1 ⁇ to about 20 ⁇ , in some embodiments about 1 ⁇ to about 10 ⁇ , in some embodiments about 1 ⁇ to about 5 ⁇ , and in some embodiments about 5 ⁇ to about 15 ⁇ in length.
- a connector moiety may maximally span about 1 ⁇ , about 3 ⁇ , about 5 ⁇ , about 7 ⁇ , about 9 ⁇ , about 11 ⁇ , about 13 ⁇ , about 15 ⁇ , about 17 ⁇ , or about 19 ⁇ .
- a connector may be selected from the group consisting of:
- R 13 is selected from the group consisting of H and C 1-6 alkyl
- s is an integer from 0-10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and t is an integer from 0-10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
- heterocyclyl may be a 5-7 membered heterocyclic ring comprising 1 or 2 nitrogen atoms.
- R 13 may be H. In certain other embodiments, R 13 may be C 1-6 alkyl. For example, in some embodiments, R 13 may be methyl.
- a connector may be selected from the group consisting of:
- u is an integer from 2-15 (i.e., 2, 3, 4, 5, 6,
- a connector may be selected from the group consisting of:
- R 13 is selected from the group consisting of H and C 1-6 alkyl; and s is an integer from 1-15.
- heterocyclyl may be a 5-7 membered heterocyclic ring comprising 1 or 2 nitrogen atoms.
- R 13 may be H. In certain other embodiments, R 13 may be C 1-6 alkyl. For example, in some embodiments, R 13 may be methyl.
- a connector may be selected from the group consisting of:
- a connector may be selected from the group consisting of:
- the synthetic route in Scheme Xa illustrates a general method for preparing ligand-connector derivatives. The method involves attaching the desired substituents to a carboxylic acid of the ligand.
- the desired connector can be installed by reacting the ligand 1 with the appropriate nucleophile 2 to provide 3 (ligand-connector derivative).
- Scheme Xa provides for a connector Y (e.g. Y 1 , Y 2 , Y 3 or Y 4 ).
- the desired connector attached at the carbonyl substituent can be installed by reacting carboxylic acid 1 with common coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and
- the connector may be selected from the group consisting of:
- n 1, 2, 3, 4 or 5.
- attachment point on the ligand e.g., the carboxylic acid of 1 in Scheme Xa
- the linker as represented by:
- the connector-linker moiety (i.e., Y-Z) may be formed from direct attachment of the connector-linker to the ligand (as shown in Scheme Xa’), or the connector-linker moiety may be formed from the further functionalization of any functional group in the connector with the linker (e.g., a boronic acid linker). It should be clear from the linker section described above that a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker.
- the connector-linker moiet may be: where R 1 is H or–C 1-4 alkyl.
- the connector-linker (i.e., Y-Z) moiety may be formed from direct attachment of Y-Z to the carbonyl, or the Y-Z moiety may be formed from the further functionalization of any free amino group seen in the–NH-R examples (i.e., Y examples) of Table A above to include the linker moiety (Z).
- Examples of–NH-R-Z groups (e.g., Y-Z groups) having a boronic acid, diol or silanol linker (Z) can be found in Tables A’, A’’, and A’’’, seen below.
- a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker.
- a first monomer that has a silanol linker may be capable of forming a multimer with a second monomer that has the same or different silanol linker.
- the synthetic route in Scheme Xb illustrates another general method for preparing ligand-connector derivatives.
- the method involves attaching the desired substituents to an–OH group (e.g., a phenol group) of the ligand.
- an–OH group e.g., a phenol group
- the connector (Y) may be selected from the group consisting of:
- n 1, 2, 3, 4 or 5.
- Any free amino group seen in the connector examples of Table B above may be functionalized further to include additional functional groups, e.g., a benzoyl group.
- the connector-linker moiety (i.e., Y-Z) may be formed from direct attachment of the connector-linker to the ligand (as shown in Scheme Xb’), or the connector-linker moiety may be formed from the further functionalization of any functional group in the connector with the linker (e.g., a boronic acid linker).
- a boronic acid linker Examples of Y-Z groups having a boronic acid linker (Z) can be found in Table B’, seen below. It should be clear from the linker section described above that a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker.
- the synthetic route in Scheme Xc illustrates another general method for preparing ligand-connector derivatives.
- the method involves attaching the desired substituents to an aryl halide or heteroaryl halide using, e.g., a cross-coupling reaction or nucleophilic aromatic substitution reaction.
- the connector (Y) may be selected from the group consisting of: , where n may be 0, 1, 2, 3,4 or 5.
- the connector may generally be represented for example, by: where n may be 0, 1, 2, 3, 4, 5, or 6.
- the connector may be: .
- the ligand may be further elaborated to incorporate not only a connector moiety, but also a linker, as e.g., represented by:
- the synthetic route in Scheme Xd illustrates a general method for preparing ligand-connector derivatives.
- the method involves attaching the desired carbonyl substituents to the free amine to form an amide, urea, or carbamate.
- the carbonyl group can be installed by reacting amine 12 (see Scheme Xd) with carboxylic acid 13 to provide 14 (ligand-connector derivative).
- SCHEME Xd
- -C(O)-Connector i.e., -Y
- -Y may be selected from the group consistin of:
- a first monomer and a second monomer may form a dimer in aqueous solution.
- the first monomer may form a biologically useful dimer with a second monomer in vivo.
- molecular self- assembly may be directed through noncovalent interactions, e.g., hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions, electrostatic, and/or electromagnetic interactions.
- pi-pi and pi-cation interactions can be used to drive multimerization.
- van der Waals and electromagnetic forces are other interactions that can help to drive multimerization.
- acid/base pairs and donor-acceptor pairs e.g., amide and/or sulfonamide pairs, can be employed to help direct self- assembly.
- use of hydrophobic interactions can be used for multimerization targeting a membrane-bound protein.
- metal coordination might be used when the target itself incorporates the metal, but could also be used in other scenarios.
- a therapeutic multimer compound may be formed from the multimerization in an aqueous media of a first monomer X 1 -Y 1 -Z 1 with a second monomer X 2 - Y 2 -Z 2 .
- Z 1 is a first linker capable of binding to the second monomer
- Z 2 is a second linker capable of binding to the first monomer through Z 1 .
- Z 2 is a nucleophile moiety capable of binding with the Z 1 moiety of Formula I to form the multimer.
- the first monomer forms a biologically useful dimer with a second monomer in vivo.
- a therapeutic multimer compound may be formed from the multimerization in an aqueous media of a first monomer X 1 -Y 1 -Z 1 with a second monomer X 4 -Y 4 -Z 4 .
- Z 1 is a first linker capable of binding to the second monomer
- Z 4 is a second linker capable of binding to the first monomer through Z 1 .
- the multimerization may be substantially irreversible in an aqueous media.
- the multimer may be fluorescent.
- the extent, probability and rate of the reverse reaction will depend heavily upon a range of conditions including temperature, concentration, solvent, catalysis, and binding to the target biomolecule.
- the term“irreversible” typically refers to the low probability of the reverse reaction occurring to a significant extent in an aqueous media within the timeframe of associated biological, pharmacologic and metabolic events, e.g., turn-over or degradation of the target biomolecule, signal transduction responses, drug metabolism and clearance, etc.
- the affinity of the“irreversible” multimeric assembly for the target biomolecule is at least an order of magnitude higher than that of its monomers, it is likely to persist on the target for a prolonged period and exhibit a very slow off-rate. Additionally, the binding of the“irreversible” multimeric assembly for the target biomolecule is at least an order of magnitude higher than that of its monomers, it is likely to persist on the target for a prolonged period and exhibit a very slow off-rate. Additionally, the binding of the
- “irreversible” multimeric assembly by the target biomolecule may also significantly slow the dissociative reversal of the linker reaction to regenerate monomers. Also, the irreversible extrusion of a small molecule from the multimer linkage, may ensure the linker reaction cannot be revered in an aqueous or biological milieu. Thus, in general the half-life for the
- “irreversible” multimeric assembly is considered e.g., comparable to, or longer than the half- life for, the associated biological processes, with the potential to provide a relatively long duration of pharmacologic action.
- X 1 and X 2 may be different. In some cases, X 1 and X 4 may be different.
- contemplated monomers and multimers may be administered to a patient in need thereof.
- a method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof is provided.
- the method comprises administering to the patient thereof an amount of the first monomer and an amount of a second monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo.
- a first monomer and a second monomer may be administered substantially sequentially. In other embodiments, the first monomer and the second monomer are administered substantially simultaneously. In some embodiments the monomers may be administered, sequentially or simultaneously, by different routes of administration or the same route of administration. In still further embodiments, a first monomer and a second monomer may be administered after forming a multimer.
- a method of modulating two or more target biomolecule binding sites is provided, e.g., two binding sites of Bcr-Abl tyrosine kinase.
- a first ligand moiety e.g., bound to a first monomer
- a second ligand moiety e.g., bound to a second monomer
- a second binding site e.g., the ATP binding pocket of Bcr-Abl tyrosine kinase.
- a multimer comprising the first and second ligand moieties may form prior to binding the first and second binding sites. In other embodiments, a multimer may form after one and/or two of the monomers bind the first and second binding sites.
- a multimer contemplated herein may be used to inhibit or facilitate protein-protein interactions. For example, in some cases, a contemplated multimer may be capable of activating or inactivating a signaling pathway. Without wishing to be bound by any theory, a multimer may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the multimer does not bind the target protein.
- monomers may be chosen such that a multimer formed from the monomers binds to at least two regions of a target molecule.
- a contemplated multimer may be capable of binding to a first protein binding site and a second protein binding site, wherein the second protein binding site is, e.g. between about 5 ⁇ and about 30 ⁇ of the first protein binding site, or in some embodiments within about 40 ⁇ of the first protein binding site.
- the compounds contemplated herein may be used in a method for treating diseases or conditions for which a Bcr-Abl tyrosine kinase inhibitor is indicated, for example, a compound may be used for treating treating cancer, such as chronic myelogenous leukemia.
- a method of treating a disease associated with a Bcr-Abl tyrosine kinase in a patient in need thereof is provided herein.
- a compound in the manufacture of a medicament for the treatment of diseases or conditions for which a Bcr-Abl tyrosine kinase inhibitor inhibitor is indicated is indicated.
- a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer such as chronic myelogenous leukemia.
- cancers e.g., cancers such as including hematological, epithelial including lung, breast and colon carcinomas, mesenchymal, hepatic, renal and neurological tumors
- contemplated herein is a method of treating squamous cell carcinoma, midline carcinoma or leukemia such as acute myeloid leukemia in a patient in need thereof comprising administering two or more disclosed monomers such that the monomers form a multimer (e.g. dimer) in-vivo.
- a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da. In certain embodiments, a ligand moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.
- the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.
- compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
- a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
- Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
- Treatment can be continued for as long or as short a period as desired.
- the compositions may be administered on a regimen of, for example, one to four or more times per day.
- a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
- a treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
- the present disclosure provides pharmaceutical compositions comprising monomers, dimers, and/or multimers as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
- These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
- disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
- Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
- the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
- the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
- the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid
- a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
- preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof.
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- solid dosage forms for oral administration capsules, tablets, pills, dragees, powders, granules and the like
- the subject composition is mixed with one or more
- pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4)
- disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.
- solution retarding agents such as paraffin
- absorption accelerators such as quaternary ammonium compounds
- wetting agents such as, for example, acetyl alcohol and glycerol monostearate
- absorbents such as kaolin and bentonite clay
- lubricants such a talc,
- compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
- inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
- Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
- suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
- Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- compositions and compounds may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
- a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
- Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
- an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
- the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
- compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
- polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate and cyclodextrins.
- Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants
- enteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising monomers, dimers, and/or multimers, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided.
- Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
- the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
- the pH of the duodenum is about 5.5
- the pH of the jejunum is about 6.5
- the pH of the distal ileum is about 7.5.
- enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
- Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins
- kits are provided containing one or more compositions each including the same or different monomers.
- Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition.
- kits could advantageously be packaged and sold in single or multiple kit units.
- An example of such a kit is a so-called blister pack.
- Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed.
- the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
- the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
- the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
- a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
- a memory aid is a calendar printed on the card, e.g., as follows“First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . .” etc.
- A“daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
- a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
- the memory aid should reflect this.
- compositions that include a second active agent, or administering a second active agent.
- the compounds, as described herein may be substituted with any number of substituents or functional moieties.
- substituents contained in formulas refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
- the substituent when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- the term“substituted” is contemplated to include all permissible substituents of organic and inorganic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
- heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
- substituents include acyl; aliphatic; heteroaliphatic; phenyl; naphthyl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy;
- the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds.
- stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
- acyl refers to a moiety that includes a carbonyl group.
- an acyl group may have a general formula selected from - C(O)R x ; -CO 2 (R x ); -C(O)N(R x ) 2 ; -OC(O)R x ; -OCO 2 R x ; and -OC(O)N(R x ) 2 ; wherein each occurrence of R x independently includes, but is not limited to, hydrogen, aliphatic,
- heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted.
- aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic
- hydrocarbons which are optionally substituted with one or more functional groups.
- “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
- the term“heteroaliphatic,” as used herein, refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
- Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
- the terms“aryl,”“aromatic,”“heteroaryl,” and“heteroaromatic” as used herein refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
- Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
- aryl or aromatic refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
- heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
- Heteroaryl moieties may be selected from: pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
- aryl, aromatic, heteroaryl, and heteroaromatic groups described herein can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with a group selected from: C 1-6 alkyl; phenyl; heteroaryl; benzyl; heteroarylalkyl; C 1-6 alkoxy; C 1-6 cycloalkoxy; C 1- 6 heterocyclylalkoxy; C 1-6 heterocyclyloxy; heterocyclyloxyalkyl; C 2-6 alkenyloxy; C 2- 6 alkynyloxy; phenoxy; heteroalkoxy; heteroaryloxy; C 1-6 alkylthio; phenylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF
- heterocyclic refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
- heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and
- alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C 2-6 alkenyl, and C 3- 4 alkenyl, respectively.
- alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
- alkenyloxy refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O).
- exemplary alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C 3-6 alkenyloxy.
- Exemplary“alkenyloxy” groups include, but are not limited to allyloxy, butenyloxy, etc.
- alkoxy refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-).
- exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as C 1-6 alkoxy, and C 2 - C 6 alkoxy, respectively.
- exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
- alkoxycarbonyl refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-).
- exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C 1-6 alkoxycarbonyl.
- Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
- alkynyloxy refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)).
- exemplary alkynyloxy groups include, but are not limited to, propynyloxy.
- alkyl refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1-4 alkyl, and C 1-3 alkyl, respectively.
- Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
- alkylene refers to a bivalent saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as -C 1-6 alkylene-, -C 1-4 alkylene-, and -C 1-3 alkylene-, respectively, where the alkylene has two open valences.
- Exemplary alkyl groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, 2-methyl-1-propylene, 2- methyl-2-propylene, 2-methyl-1-butylene, 3-methyl-1-butylene, 3-methyl-2-butylene, 2,2- dimethyl-1-propylene, 2-methyl-1-pentylene, 3-methyl-1-pentylene, 4-methyl-1-pentylene, 2- methyl-2-pentylene, 3-methyl-2-pentylene, 4-methyl-2-pentylene, 2,2-dimethyl-1-butylene, 3,3-dimethyl-1-butylene, 2-ethyl-1-butylene, butylene, isobutylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, etc.
- alkylcarbonyl refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-).
- exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as C 1- 6 alkylcarbonyl groups.
- Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
- alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C 2-6 alkynyl, and C 3-6 alkynyl, respectively.
- exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
- carbonyl refers to the radical -C(O)-.
- cycloalkoxy refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).
- cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C 3-6 cycloalkyl or C 4-6 cycloalkyl and derived from a cycloalkane.
- exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
- halo or“halogen” as used herein refer to F, Cl, Br, or I.
- heterocyclylalkoxy refers to a heterocyclyl- alkyl-O- group.
- heterocyclyloxyalkyl refers to a heterocyclyl-O-alkyl- group.
- heterocyclyloxy refers to a heterocyclyl-O- group.
- heteroaryloxy refers to a heteroaryl-O- group.
- connector refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed linker and a
- Contemplated connectors are generally hydrolytically stable.
- Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
- “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate.
- preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
- pharmaceutically acceptable carrier or“pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
- compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
- composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
- “Individual,”“patient,” or“subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
- the compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
- the mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired.
- “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
- the term“therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
- the compounds are administered in therapeutically effective amounts to treat a disease.
- a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.
- salts of acidic or basic groups that may be present in compounds used in the present compositions.
- Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
- the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-
- Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
- Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
- Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
- the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
- the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers.
- the enantiomers and diastereomers may be designated by the symbols“(+),”“(-).”“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
- Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds.
- the arrangement of substituents around a carbocyclic ring can also be designated as“cis” or “trans.”
- the term“cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring.
- Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”
- stereoisomers when used herein consists of all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure. Mixtures of enantiomers or diastereomers may be designated“( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
- Individual enantiomers and diastereomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
- Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
- Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
- Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
- the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
- the compound is amorphous.
- the compound is a polymorph.
- the compound is in a crystalline form.
- isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 10 B, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- a compound may have one or more H atom replaced with deuterium.
- isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
- the transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver).
- Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
- a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1-8 )alkyl, (C 2-12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
- di-N,N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl such as ⁇ -dimethylaminoethyl
- carbamoyl-(C 1 -C 2 )alkyl N,N-di(C 1 -C 2 )alkylcarbamoy
- a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1- 6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl (C 1- 6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkanoyl, ⁇ - amino(C 1-4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each D- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -C 6 )alkyl) 2 or glyco
- a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyakyl derivative, an
- oxodioxolenyl (oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine.
- a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine.
- a starting material or intermediate used in the synthesis of a contemplated compound may have an enantiomeric excess greater than 0, e.g., greater than about 95%, greater than about 98%, greater than about 99%, or essentially 100%.
- a starting material or intermediate may be essentially stereoisomerically pure.
- partial or complete loss of chiral integrity may occur during the synthesis of the contemplated compound thereby reducing or eliminating the enantiomeric excess.
- a stereoisomerically pure starting material or intermediate is used in a synthesis of a contemplated compound
- partial or complete loss of chiral integrity results in a stereoisomeric mixture.
- a stereoisomeric mixture may be partially or essentially completely resolved by subjecting the stereoisomeric mixture to a chiral purification technique (e.g., chiral HPLC purification).
- Reagents were either purchased commercially or prepared according to previously described methods.
- reaction mixture was partitioned between DCM (25 mL) and H 2 O (10 mL) and separated.
- the aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 40 mg, 15 % yield of the title compound as an off white solid.
- reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 33 mg, 13 % yield of the title compound as an off white solid.
- Linker-2 was obtained from a commercial source (Lotus).
- reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 15 mL) and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to afford 25 mg, 10 % yield of the title compound as an off white solid.
- Linker-3 was obtained from a commercial source (Lotus).
- reaction mixture was partitioned with H 2 O (20 mL) and extracted with DCM (3 X 30 mL) and separated. The combined organic layers were washed with H 2 O (20mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 550 mg, 44.4% yield, of the title compound as an off white solid.
- reaction mixture was partitioned with H 2 O (20 mL) and extracted with DCM (3 X 40 mL) and separated. The combined organic layers were washed with H 2 O (30 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 700 mg, 51% yield of the title compound as light brown oil.
- reaction mixture was partitioned with H 2 O (10 mL) and extracted with DCM (3 X 10 mL) and separated. The combined organic layers were washed with H 2 O (10 mL), saturated NaHCO 3 (10 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 20 mg, 6% yield of the title compound as an off white solid.
- reaction mixture was partitioned with H 2 O (10 mL) and extracted with DCM (3 X 10 mL) and separated. The combined organic layers were washed with H 2 O (10 mL), saturated NaHCO 3 (10 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC using formic acid method to give 18 mg, 13% yield of the title compound as an off white solid.
- reaction mixture was diluted with water (5 mL) and extracted with DCM (2 X 10 mL) and the combined organic layer were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to give 15 mg, 18% yield of the title compound as a white solid.
- reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in a crude compound which was purified by chromatography on silica gel, eluting with 1-3% methanol in DCM to give 1.2 g, 26% yield of the title compound as pale yellow oil.
- Example 52 (4-((2-(2-(2-(2-(2-(4-(3-((3-Cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6- methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)ethoxy)ethoxy)ethyl)carbamoyl)- 2-methylphenyl)boronic acid [Example 52]:
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Abstract
L'invention concerne des monomères capables de former un multimère biologiquement actif lorsqu'ils entrent en contact avec un, deux, trois ou plusieurs autres monomères dans un milieu aqueux. Selon un aspect, de tels monomères sont capables de se lier à un autre monomère dans un milieu aqueux, ( par exemple, in
vivo) pour former un multimère (par exemple, un dimère). Les monomères selon l'invention peuvent comprendre une fraction de ligand, un élément lieur, et un élément connecteur qui relie la fraction de ligand et l'élément lieur. Dans un milieu aqueux, ces monomères peuvent se lier ensemble par l'intermédiaire de chaque élément lieur et sont, donc, capables de moduler une ou plusieurs biomolécules sensiblement simultanément, par exemple, de moduler au moins deux sites de liaison sur une tyrosine kinase Bcr-Abl.
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PCT/US2015/011271 WO2015106292A1 (fr) | 2014-01-13 | 2015-01-13 | Ligands de tyrosine-kinase bcr-abl capables de se dimériser dans une solution aqueuse, et procédés d'utilisation de ceux-ci |
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CN111303195B (zh) * | 2020-04-07 | 2022-09-27 | 中国医学科学院放射医学研究所 | 一类含硼小分子化合物、其制备方法及应用 |
CN111303195A (zh) * | 2020-04-07 | 2020-06-19 | 中国医学科学院放射医学研究所 | 一类含硼小分子化合物、其制备方法及应用 |
WO2023067550A1 (fr) * | 2021-10-20 | 2023-04-27 | Yousef Najajreh | Composés inhibiteurs allostériques pour surmonter la résistance d'un cancer |
WO2023114759A3 (fr) * | 2021-12-13 | 2023-07-27 | The Regents Of The University Of California | Inhibiteurs d'abl et leurs utilisations |
US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
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