CA3051054A1 - Pyridine compounds as allosteric shp2 inhibitors - Google Patents
Pyridine compounds as allosteric shp2 inhibitors Download PDFInfo
- Publication number
- CA3051054A1 CA3051054A1 CA3051054A CA3051054A CA3051054A1 CA 3051054 A1 CA3051054 A1 CA 3051054A1 CA 3051054 A CA3051054 A CA 3051054A CA 3051054 A CA3051054 A CA 3051054A CA 3051054 A1 CA3051054 A1 CA 3051054A1
- Authority
- CA
- Canada
- Prior art keywords
- c6alkyl
- optionally substituted
- formula
- compound
- heterocycle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- 230000003281 allosteric effect Effects 0.000 title description 2
- 150000003222 pyridines Chemical class 0.000 title 1
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 75
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 75
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 58
- 201000010099 disease Diseases 0.000 claims abstract description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims description 505
- 125000000623 heterocyclic group Chemical group 0.000 claims description 490
- 125000002950 monocyclic group Chemical group 0.000 claims description 299
- 125000001072 heteroaryl group Chemical group 0.000 claims description 236
- 229910052736 halogen Inorganic materials 0.000 claims description 220
- 150000002367 halogens Chemical class 0.000 claims description 220
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 199
- 125000000217 alkyl group Chemical group 0.000 claims description 192
- 125000004429 atom Chemical group 0.000 claims description 192
- 125000003118 aryl group Chemical group 0.000 claims description 175
- 150000003839 salts Chemical class 0.000 claims description 140
- 229910052757 nitrogen Inorganic materials 0.000 claims description 135
- 125000004585 polycyclic heterocycle group Chemical group 0.000 claims description 128
- 239000000651 prodrug Substances 0.000 claims description 126
- 229940002612 prodrug Drugs 0.000 claims description 126
- -1 substituted Chemical class 0.000 claims description 126
- 239000012453 solvate Substances 0.000 claims description 124
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 108
- 125000003367 polycyclic group Chemical group 0.000 claims description 106
- 229910052717 sulfur Inorganic materials 0.000 claims description 104
- 125000005842 heteroatom Chemical group 0.000 claims description 103
- 125000003342 alkenyl group Chemical group 0.000 claims description 101
- 229910052698 phosphorus Inorganic materials 0.000 claims description 99
- 125000000304 alkynyl group Chemical group 0.000 claims description 80
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 40
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 35
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 29
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 13
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- 238000004519 manufacturing process Methods 0.000 claims description 10
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- 206010024291 Leukaemias acute myeloid Diseases 0.000 claims description 8
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- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 8
- 208000037538 Myelomonocytic Juvenile Leukemia Diseases 0.000 claims description 8
- 206010029260 Neuroblastoma Diseases 0.000 claims description 8
- 206010029748 Noonan syndrome Diseases 0.000 claims description 8
- 208000010708 Noonan syndrome with multiple lentigines Diseases 0.000 claims description 8
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- 201000001441 melanoma Diseases 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 238000011282 treatment Methods 0.000 abstract description 18
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- 150000004677 hydrates Chemical class 0.000 description 72
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- 230000002829 reductive effect Effects 0.000 description 63
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
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- 238000006243 chemical reaction Methods 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000007832 Na2SO4 Substances 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
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- 235000011152 sodium sulphate Nutrition 0.000 description 31
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- 150000001721 carbon Chemical group 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
- 239000012448 Lithium borohydride Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 238000002953 preparative HPLC Methods 0.000 description 16
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 16
- 239000002904 solvent Substances 0.000 description 15
- 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 14
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 14
- 235000019798 tripotassium phosphate Nutrition 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- 235000017550 sodium carbonate Nutrition 0.000 description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 11
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 9
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 9
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 9
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- TYIKXPOMOYDGCS-UHFFFAOYSA-N (2,3-dichlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1Cl TYIKXPOMOYDGCS-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
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
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- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Pyridine Compounds (AREA)
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| PCT/US2018/013018 WO2018136264A1 (en) | 2017-01-23 | 2018-01-09 | Pyridine compounds as allosteric shp2 inhibitors |
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2018
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- 2018-01-09 JP JP2019539779A patent/JP7240320B2/ja active Active
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- 2018-01-09 WO PCT/US2018/013018 patent/WO2018136264A1/en not_active Ceased
- 2018-01-09 BR BR112019014527-3A patent/BR112019014527A2/pt not_active Application Discontinuation
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- 2018-01-09 RU RU2019126455A patent/RU2019126455A/ru unknown
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| EP4230623A3 (en) | 2023-10-11 |
| JP7240320B2 (ja) | 2023-03-15 |
| EP3571189A1 (en) | 2019-11-27 |
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| JP2023018094A (ja) | 2023-02-07 |
| MX2019008696A (es) | 2019-09-13 |
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| WO2018136264A1 (en) | 2018-07-26 |
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| CN110431134A (zh) | 2019-11-08 |
| US20240092795A1 (en) | 2024-03-21 |
| SG11201906412SA (en) | 2019-08-27 |
| AU2018210196B2 (en) | 2022-06-02 |
| IL268031B (en) | 2022-06-01 |
| EP3571189B1 (en) | 2023-03-29 |
| US20200017517A1 (en) | 2020-01-16 |
| KR20190110588A (ko) | 2019-09-30 |
| US11673896B2 (en) | 2023-06-13 |
| AU2018210196A1 (en) | 2019-08-15 |
| RU2019126455A (ru) | 2021-02-24 |
| IL268031A (en) | 2019-09-26 |
| WO2018136264A9 (en) | 2018-10-25 |
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