SG178454A1 - Heterocyclic compounds and uses thereof - Google Patents
Heterocyclic compounds and uses thereof Download PDFInfo
- Publication number
- SG178454A1 SG178454A1 SG2012010849A SG2012010849A SG178454A1 SG 178454 A1 SG178454 A1 SG 178454A1 SG 2012010849 A SG2012010849 A SG 2012010849A SG 2012010849 A SG2012010849 A SG 2012010849A SG 178454 A1 SG178454 A1 SG 178454A1
- Authority
- SG
- Singapore
- Prior art keywords
- alkyl
- compound
- heteroaryl
- aryl
- taken together
- Prior art date
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims abstract description 58
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 3
- -1 cyano, hydroxy Chemical group 0.000 claims description 496
- 125000000217 alkyl group Chemical group 0.000 claims description 277
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 274
- 229910052757 nitrogen Inorganic materials 0.000 claims description 241
- 150000001875 compounds Chemical class 0.000 claims description 237
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 220
- 125000004122 cyclic group Chemical group 0.000 claims description 195
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 191
- 125000001072 heteroaryl group Chemical group 0.000 claims description 189
- 125000003118 aryl group Chemical group 0.000 claims description 173
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 165
- 125000005843 halogen group Chemical group 0.000 claims description 158
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 155
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 150
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 146
- 229910052739 hydrogen Inorganic materials 0.000 claims description 142
- 239000001257 hydrogen Substances 0.000 claims description 142
- 125000003342 alkenyl group Chemical group 0.000 claims description 140
- 125000000304 alkynyl group Chemical group 0.000 claims description 139
- 125000004423 acyloxy group Chemical group 0.000 claims description 137
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 137
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 137
- 125000003545 alkoxy group Chemical group 0.000 claims description 136
- 125000003368 amide group Chemical group 0.000 claims description 134
- 125000002252 acyl group Chemical group 0.000 claims description 131
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 129
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 128
- 229910019142 PO4 Inorganic materials 0.000 claims description 128
- 239000004202 carbamide Substances 0.000 claims description 128
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 128
- 239000010452 phosphate Substances 0.000 claims description 128
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 123
- 229910052721 tungsten Inorganic materials 0.000 claims description 105
- 229910052799 carbon Inorganic materials 0.000 claims description 55
- 108091007960 PI3Ks Proteins 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 39
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 210000001072 colon Anatomy 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 230000002611 ovarian Effects 0.000 claims description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 2
- 201000004624 Dermatitis Diseases 0.000 claims description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 230000036783 anaphylactic response Effects 0.000 claims description 2
- 208000003455 anaphylaxis Diseases 0.000 claims description 2
- 208000010668 atopic eczema Diseases 0.000 claims description 2
- 206010006451 bronchitis Diseases 0.000 claims description 2
- 208000024908 graft versus host disease Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000008171 proliferative glomerulonephritis Diseases 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 24
- 201000010099 disease Diseases 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 14
- 150000005829 chemical entities Chemical class 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 description 96
- 125000002950 monocyclic group Chemical group 0.000 description 69
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 63
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 61
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 61
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 60
- 102000038030 PI3Ks Human genes 0.000 description 50
- 125000001424 substituent group Chemical group 0.000 description 49
- 125000002098 pyridazinyl group Chemical group 0.000 description 38
- 125000000168 pyrrolyl group Chemical group 0.000 description 36
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 34
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 33
- 125000004076 pyridyl group Chemical group 0.000 description 33
- 125000001544 thienyl group Chemical group 0.000 description 32
- 125000004432 carbon atom Chemical group C* 0.000 description 31
- 125000002541 furyl group Chemical group 0.000 description 31
- 125000002883 imidazolyl group Chemical group 0.000 description 31
- 125000002971 oxazolyl group Chemical group 0.000 description 31
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 31
- 125000003373 pyrazinyl group Chemical group 0.000 description 31
- 125000003226 pyrazolyl group Chemical group 0.000 description 31
- 125000000714 pyrimidinyl group Chemical group 0.000 description 31
- 125000000335 thiazolyl group Chemical group 0.000 description 31
- 125000004193 piperazinyl group Chemical group 0.000 description 30
- 125000003386 piperidinyl group Chemical group 0.000 description 30
- 125000006413 ring segment Chemical group 0.000 description 29
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 26
- 125000002757 morpholinyl group Chemical group 0.000 description 24
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 23
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 23
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 23
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 22
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 22
- 125000001041 indolyl group Chemical group 0.000 description 22
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 22
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 22
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 22
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 22
- 125000004306 triazinyl group Chemical group 0.000 description 22
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 21
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 21
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 21
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 21
- 108091000080 Phosphotransferase Proteins 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 102000020233 phosphotransferase Human genes 0.000 description 20
- 150000003254 radicals Chemical group 0.000 description 20
- 125000000547 substituted alkyl group Chemical group 0.000 description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 19
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 18
- 125000004429 atom Chemical group 0.000 description 18
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 18
- 125000005981 pentynyl group Chemical group 0.000 description 18
- 125000003107 substituted aryl group Chemical group 0.000 description 18
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- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 17
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 17
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 17
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 17
- 125000005017 substituted alkenyl group Chemical group 0.000 description 17
- 125000004426 substituted alkynyl group Chemical group 0.000 description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- 125000003709 fluoroalkyl group Chemical group 0.000 description 16
- 125000005842 heteroatom Chemical group 0.000 description 16
- 230000000670 limiting effect Effects 0.000 description 15
- 125000004452 carbocyclyl group Chemical group 0.000 description 14
- 125000005884 carbocyclylalkyl group Chemical group 0.000 description 14
- 125000004093 cyano group Chemical group *C#N 0.000 description 14
- 229910052740 iodine Inorganic materials 0.000 description 14
- 125000002393 azetidinyl group Chemical group 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 150000002632 lipids Chemical class 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 230000019491 signal transduction Effects 0.000 description 12
- 238000003419 tautomerization reaction Methods 0.000 description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 12
- 125000001246 bromo group Chemical group Br* 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 125000002632 imidazolidinyl group Chemical group 0.000 description 11
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 10
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 7
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