CA3020287A1 - Pyrazolo[1,5-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders - Google Patents
Pyrazolo[1,5-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders Download PDFInfo
- Publication number
- CA3020287A1 CA3020287A1 CA3020287A CA3020287A CA3020287A1 CA 3020287 A1 CA3020287 A1 CA 3020287A1 CA 3020287 A CA3020287 A CA 3020287A CA 3020287 A CA3020287 A CA 3020287A CA 3020287 A1 CA3020287 A1 CA 3020287A1
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- Prior art keywords
- compound
- alkyl
- cycloalkyl
- membered
- substituted
- Prior art date
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- BCJQJAVVUTUJPF-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-2-carboxamide Chemical class N1=CC=CN2N=C(C(=O)N)C=C21 BCJQJAVVUTUJPF-UHFFFAOYSA-N 0.000 title abstract 3
- 238000011282 treatment Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 469
- 238000000034 method Methods 0.000 claims abstract description 375
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
- 208000035475 disorder Diseases 0.000 claims abstract description 36
- 208000009829 Lewy Body Disease Diseases 0.000 claims abstract description 29
- 201000002832 Lewy body dementia Diseases 0.000 claims abstract description 27
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 24
- 208000015872 Gaucher disease Diseases 0.000 claims abstract description 22
- 208000001089 Multiple system atrophy Diseases 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 158
- 150000002367 halogens Chemical class 0.000 claims description 158
- -1 -O-(C1-8 haloalkyl) Chemical group 0.000 claims description 152
- 125000000217 alkyl group Chemical group 0.000 claims description 137
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 131
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 121
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 119
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 110
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 93
- 125000001424 substituent group Chemical group 0.000 claims description 93
- 239000001257 hydrogen Substances 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 80
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 78
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 76
- 125000000623 heterocyclic group Chemical group 0.000 claims description 69
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 67
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 61
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 56
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 52
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 39
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 35
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 34
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 32
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 30
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 27
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 24
- 125000002541 furyl group Chemical group 0.000 claims description 24
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 24
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
- 125000002883 imidazolyl group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 21
- 125000002971 oxazolyl group Chemical group 0.000 claims description 21
- 125000000335 thiazolyl group Chemical group 0.000 claims description 21
- 125000001544 thienyl group Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 19
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 13
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 12
- 206010012289 Dementia Diseases 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 10
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000002757 morpholinyl group Chemical group 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 208000020925 Bipolar disease Diseases 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 206010030348 Open-Angle Glaucoma Diseases 0.000 claims description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 7
- 206010015037 epilepsy Diseases 0.000 claims description 7
- 208000024714 major depressive disease Diseases 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- 208000030761 polycystic kidney disease Diseases 0.000 claims description 7
- 201000000980 schizophrenia Diseases 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 7
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 6
- 201000009273 Endometriosis Diseases 0.000 claims description 6
- 125000005647 linker group Chemical group 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 241000282414 Homo sapiens Species 0.000 claims description 4
- 125000004970 halomethyl group Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 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 4
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 2
- 239000000203 mixture Substances 0.000 abstract description 143
- 150000002894 organic compounds Chemical class 0.000 abstract description 37
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 415
- 239000007787 solid Substances 0.000 description 338
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 324
- 238000004128 high performance liquid chromatography Methods 0.000 description 222
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 239000000243 solution Substances 0.000 description 101
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 description 100
- 238000005481 NMR spectroscopy Methods 0.000 description 72
- 125000003545 alkoxy group Chemical group 0.000 description 67
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- 125000003118 aryl group Chemical group 0.000 description 39
- 229910052938 sodium sulfate Inorganic materials 0.000 description 39
- 235000011152 sodium sulphate Nutrition 0.000 description 39
- 239000007832 Na2SO4 Substances 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 150000003857 carboxamides Chemical class 0.000 description 37
- 125000003636 chemical group Chemical group 0.000 description 35
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 150000002431 hydrogen Chemical class 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 150000001408 amides Chemical class 0.000 description 24
- 239000004698 Polyethylene Substances 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- 101150041968 CDC13 gene Proteins 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- OOXIEUXBOSSXJM-UHFFFAOYSA-N 2-cyclopropylpropan-2-amine Chemical compound CC(C)(N)C1CC1 OOXIEUXBOSSXJM-UHFFFAOYSA-N 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 19
- FWMSRTUYRNVOMA-UHFFFAOYSA-N CCOC(=O)C1=C2N=C(Cl)C=C(C)N2N=C1 Chemical compound CCOC(=O)C1=C2N=C(Cl)C=C(C)N2N=C1 FWMSRTUYRNVOMA-UHFFFAOYSA-N 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- IXCXVGWKYIDNOS-BYPYZUCNSA-N (1s)-1-cyclopropylethanamine Chemical compound C[C@H](N)C1CC1 IXCXVGWKYIDNOS-BYPYZUCNSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 125000001188 haloalkyl group Chemical group 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- YCAVTOUTYRMOGQ-UHFFFAOYSA-N ethyl 7-[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound C=1C=NC2=C(C(=O)OCC)C=NN2C=1C(C=1)=CC=CC=1NC(=O)C1=CC=CC(C(F)(F)F)=C1 YCAVTOUTYRMOGQ-UHFFFAOYSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- 125000003226 pyrazolyl group Chemical group 0.000 description 14
- 229910052782 aluminium Inorganic materials 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 230000008878 coupling Effects 0.000 description 13
- 238000010168 coupling process Methods 0.000 description 13
- 238000005859 coupling reaction Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- VLVCERQEOKPRTG-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-amine;hydrochloride Chemical compound Cl.CC(N)C(F)(F)F VLVCERQEOKPRTG-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 125000001715 oxadiazolyl group Chemical group 0.000 description 10
- 125000002755 pyrazolinyl group Chemical group 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 125000002636 imidazolinyl group Chemical group 0.000 description 9
- 125000005968 oxazolinyl group Chemical group 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 125000001113 thiadiazolyl group Chemical group 0.000 description 9
- 125000002769 thiazolinyl group Chemical group 0.000 description 9
- 125000005881 triazolinyl group Chemical group 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- YPXGHKWOJXQLQU-UHFFFAOYSA-N ethyl 5-amino-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1N YPXGHKWOJXQLQU-UHFFFAOYSA-N 0.000 description 8
- HNYVPKNVKSTVJO-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound C1=CC=NC2=C(C(=O)O)C=NN21 HNYVPKNVKSTVJO-UHFFFAOYSA-N 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229940124530 sulfonamide Drugs 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 239000011593 sulfur Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- VUGCBIWQHSRQBZ-UHFFFAOYSA-N 2-methylbut-3-yn-2-amine Chemical compound CC(C)(N)C#C VUGCBIWQHSRQBZ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 150000001733 carboxylic acid esters Chemical class 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- 125000004043 oxo group Chemical group O=* 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- TZAYQOISLSBMIP-UHFFFAOYSA-N (2-cyano-4-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C=C1C#N TZAYQOISLSBMIP-UHFFFAOYSA-N 0.000 description 5
- XDBHWPLGGBLUHH-UHFFFAOYSA-N (3-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C#N)=C1 XDBHWPLGGBLUHH-UHFFFAOYSA-N 0.000 description 5
- NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 description 5
- ADJBXDCXYMCCAD-UHFFFAOYSA-N (4-fluoro-2-methoxyphenyl)boronic acid Chemical compound COC1=CC(F)=CC=C1B(O)O ADJBXDCXYMCCAD-UHFFFAOYSA-N 0.000 description 5
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
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- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
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- 229940001482 sodium sulfite Drugs 0.000 description 1
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- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 150000008053 sultones Chemical class 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 125000006173 tetrahydropyranylmethyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001166 thiolanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- YOWGRWHKDCHINP-UHFFFAOYSA-N tributyl(1,3-oxazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CO1 YOWGRWHKDCHINP-UHFFFAOYSA-N 0.000 description 1
- WUOFQGMXQCSPPV-UHFFFAOYSA-N tributyl(1,3-thiazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CS1 WUOFQGMXQCSPPV-UHFFFAOYSA-N 0.000 description 1
- SANWDQJIWZEKOD-UHFFFAOYSA-N tributyl(furan-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CO1 SANWDQJIWZEKOD-UHFFFAOYSA-N 0.000 description 1
- ISUMXRDJZLNDIM-UHFFFAOYSA-N tributyl-(4-chloropyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC(Cl)=CC=N1 ISUMXRDJZLNDIM-UHFFFAOYSA-N 0.000 description 1
- MHSMAFNXVWZVOC-UHFFFAOYSA-N tributyl-(5-chloropyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=C(Cl)C=N1 MHSMAFNXVWZVOC-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P35/00—Antineoplastic agents
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Landscapes
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662318929P | 2016-04-06 | 2016-04-06 | |
| US62/318,929 | 2016-04-06 | ||
| PCT/US2017/026280 WO2017176960A1 (en) | 2016-04-06 | 2017-04-06 | Pyrazolo[1,5-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders |
Publications (1)
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|---|---|
| CA3020287A1 true CA3020287A1 (en) | 2017-10-12 |
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|---|---|
| US (4) | US11192892B2 (OSRAM) |
| EP (1) | EP3440080A4 (OSRAM) |
| JP (1) | JP7038063B2 (OSRAM) |
| KR (2) | KR20180133461A (OSRAM) |
| CN (1) | CN109311887B (OSRAM) |
| AU (1) | AU2017246455B2 (OSRAM) |
| BR (1) | BR112018070586A8 (OSRAM) |
| CA (1) | CA3020287A1 (OSRAM) |
| IL (1) | IL262177B (OSRAM) |
| MX (1) | MX2018012211A (OSRAM) |
| SG (1) | SG11201808830YA (OSRAM) |
| WO (1) | WO2017176960A1 (OSRAM) |
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| ES2958391T3 (es) | 2014-11-06 | 2024-02-08 | Bial R&D Invest S A | Imidazo[1,5-a]pirimidinas sustituidas y su uso en el tratamiento de trastornos médicos |
| DK3215511T3 (da) | 2014-11-06 | 2024-05-13 | Bial R&D Invest S A | Substituerede pyrazolo(1,5-a)pyrimidiner og deres anvendelse i behandlingen af medicinske lidelser |
| CA2966581A1 (en) | 2014-11-06 | 2016-05-12 | Lysosomal Therapeutics Inc. | Substituted pyrrolo[1,2-a]pyrimidines and their use in the treatment of medical disorders |
| JP7046827B2 (ja) * | 2016-04-06 | 2022-04-04 | リソソーマル・セラピューティクス・インコーポレイテッド | イミダゾ［１，５－ａ］ピリミジニルカルボキサミド化合物および医学的障害の処置におけるその使用 |
| WO2017176960A1 (en) | 2016-04-06 | 2017-10-12 | Lysosomal Therapeutics Inc. | Pyrazolo[1,5-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders |
| WO2017176962A1 (en) | 2016-04-06 | 2017-10-12 | Lysosomal Therapeutics, Inc. | Pyrrolo[1,2-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders |
| US11345698B2 (en) | 2016-05-05 | 2022-05-31 | Bial—R&D Investments, S.A. | Substituted imidazo[1,2-a]pyridines, substituted imidazo[1,2-a]pyrazines, related compounds, and their use in the treatment of medical disorders |
| BR112018072552A8 (pt) | 2016-05-05 | 2023-03-14 | Lysosomal Therapeutics Inc | Compostos de imidazo [1,2-b]piridazinas e imidazo [1,5-b] piridazinas substituídas, composição farmacêutica que os compreende e seu uso no tratamento de distúrbios médicos |
| CN110698484B (zh) * | 2019-06-05 | 2021-11-05 | 陕西理工大学 | 含吡唑并[1,5-a]嘧啶的衍生物、药用组合物及应用 |
| CN115108972A (zh) * | 2022-08-29 | 2022-09-27 | 北京迪泰医药科技有限公司 | 一种2-甲基-3-氟-5-溴吡啶的合成方法 |
| WO2025014639A2 (en) * | 2023-07-07 | 2025-01-16 | The Johns Hopkins University | Neutral sphingomyelinase inhibitors |
| WO2025146216A1 (zh) * | 2024-01-05 | 2025-07-10 | 成都赜灵生物医药科技有限公司 | 六并五氮杂环酰胺类化合物及其用途 |
| CN118184599A (zh) * | 2024-02-29 | 2024-06-14 | 重庆药友制药有限责任公司 | 一种阿莫奈韦中间体的制备方法 |
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| US4838925A (en) | 1986-04-25 | 1989-06-13 | E. I. Du Pont De Nemours And Company | Heterocyclic acyl sulfonamides |
| JP3763997B2 (ja) | 1999-05-13 | 2006-04-05 | 富士写真フイルム株式会社 | 感熱記録材料 |
| JP4331823B2 (ja) | 1999-05-21 | 2009-09-16 | 富士フイルム株式会社 | ピロロ［１，２−ａ］−１，３，５−トリアジン−４−オン系化合物 |
| AU2930501A (en) | 2000-01-07 | 2001-07-24 | Transform Pharmaceuticals, Inc. | High-throughput formation, identification, and analysis of diverse solid-forms |
| TWI243164B (en) | 2001-02-13 | 2005-11-11 | Aventis Pharma Gmbh | Acylated indanyl amines and their use as pharmaceuticals |
| JP4070966B2 (ja) | 2001-06-28 | 2008-04-02 | 株式会社カネボウ化粧品 | 新規ガラクトシルセラミド類縁体及び用途 |
| DE60206952T2 (de) | 2001-10-22 | 2006-06-22 | Pfizer Inc. | Imidazopyridinverbindungen als 5-ht4-rezeptormodulatoren |
| CN1281606C (zh) | 2002-03-01 | 2006-10-25 | 安斯泰来制药有限公司 | 含氮杂环化合物 |
| JP2006502180A (ja) | 2002-09-20 | 2006-01-19 | ファイザー株式会社 | ５−ｈｔ４レセプターモジュレーターとしてのｎ−置換されたピペリジニル−イミダゾピリジン化合物 |
| DOP2003000703A (es) | 2002-09-20 | 2004-03-31 | Pfizer | Compuestos de imidazopiradina como agonistas del receptor 5-ht4 |
| WO2004052315A2 (en) | 2002-12-11 | 2004-06-24 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| JP2004277337A (ja) | 2003-03-14 | 2004-10-07 | Sumitomo Pharmaceut Co Ltd | ピラゾロ［１，５−ａ］ピリミジン誘導体 |
| MXPA05011270A (es) | 2003-04-21 | 2006-01-24 | Pfizer | Compuestos de imidazopiridina que tienen actividad agonista del receptor 5-ht4 y actividad antagonista del receptor 5-ht3. |
| AU2004289327A1 (en) | 2003-11-12 | 2005-05-26 | Amicus Therapeutics Inc. | Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat Gaucher disease |
| GB0329214D0 (en) | 2003-12-17 | 2004-01-21 | Glaxo Group Ltd | Novel compounds |
| GB0400812D0 (en) | 2004-01-14 | 2004-02-18 | Celltech R&D Ltd | Novel compounds |
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| US20200017507A1 (en) | 2020-01-16 |
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| SG11201808830YA (en) | 2018-11-29 |
| CN109311887A (zh) | 2019-02-05 |
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| US10934298B2 (en) | 2021-03-02 |
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| US9840510B1 (en) | 2017-12-12 |
| KR20180133461A (ko) | 2018-12-14 |
| CN109311887B (zh) | 2022-09-13 |
| EP3440080A1 (en) | 2019-02-13 |
| KR20230104752A (ko) | 2023-07-10 |
| JP7038063B2 (ja) | 2022-03-17 |
| BR112018070586A8 (pt) | 2023-03-14 |
| US20190330213A1 (en) | 2019-10-31 |
| IL262177B (en) | 2022-06-01 |
| AU2017246455A1 (en) | 2018-10-25 |
| US12116369B2 (en) | 2024-10-15 |
| US11192892B2 (en) | 2021-12-07 |
| US20230098494A1 (en) | 2023-03-30 |
| JP2019510790A (ja) | 2019-04-18 |
| US20170349598A1 (en) | 2017-12-07 |
| WO2017176960A1 (en) | 2017-10-12 |
| BR112018070586A2 (pt) | 2019-02-05 |
| AU2017246455B2 (en) | 2021-09-30 |
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